**3. Materials and methods**

#### **3.1. Patient cohort**

We analyzed 89 patients, who received a URD HSCT between 1996 and 2013. The median age of the 89 patients was 43 years (14–65). The transplanted patients had different hematological malignancies: 33 acute myeloid leukemia (AML), 19 acute limphoblastic leukemia (ALL), 9 myelodysplastic syndromes (MDS), 6 non-Hodgkin lymphoma (NHL), 6 multiple myeloma (MM), 5 Hodgkin lymphoma (HL), 4 chronic myeloid leukemia (CML), 3 chronic lymphocytic leukemia (CLL), 1 aplastic anemia syndrome (AAS), 1 Fanconi syndrome, 1 ematodermic neoplasia and 1 biphenotypic acute leukemia (BAL). The HSC source was: bone marrow no. 19, peripheral blood no. 70. Complete high-resolution, allele-level HLA-A, B, C, DRB1 and DQB1 typing of the 89 pairs of recipients and donors was previously performed: 32 pairs were 10/10 matched, 33 pairs were 9/10 and 24 were ≤8/10. Patient and transplant characteristics are summarized in **Tables 2** and **3**.

**3.2. KIR genotyping**

**Table 3.** Transplants characteristics.

**Graft type**

**Conditioning**

Bone marrow 19 Peripheral blood progenitor cells 70

Busilvex-ciclofosfamide 15 Busilvex-fludarabine 15 Fludarabine-melphalan 4 Thiotepa + others 7 Ciclofosfamide + others 14 Endoxan 4 Unknown 32 TBI 6 ATG 12

**Donor/recipient HLA-allele matching at A, B, C, DRB1 and DQB1**

10/10 32 9/10 33 ≤8/10 24

The donors' DNA that has already been typed for HLA has been preserved in our biobank; about 80% of the samples is still available. The DNA was extracted from buffy coat or whole

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Typing of KIR genes was performed with PCR-SSO Luminex, the same method already used in our laboratory to type the HLA genes. The kit used for KIR genes typing was the SSO KIR Genotyping Test (One Lambda Inc., Canoga Park, CA) and the method was performed in accordance with the manufacturer's instructions. Luminex technology is based on the ability to soundly measure multiple analytes simultaneously in a single reaction and this is done through the use of plastic microbeads (microspheres), which are color-coded with two fluorescent dyes so as to emit two different wave lengths in red and infrared. In this way a set of over 100 different microspheres can be created. The microspheres represent the solid support of oligonucleotide probes which can bind amplified DNA that is labeled with a fluorescent labeled reporter. Subsequently, the microbeads are acquired by the Luminex machine through a precision sheath fluid system, based on classical flow cytometry, which aligns them in single file, where they pass through two lasers: the red laser excites the colors inside the microbeads to identify which microbead is currently being read, while the green laser excites the color on the microbead surface, that is, the labeled reporter tag. Finally, the color signals are detected by an advanced optical system, and the signals are processed into data for each reaction [16].

blood by the automatic extractor Maxwell 16 (Promega) or by the salting out method.


**Table 2.** Patient characteristics.


**Table 3.** Transplants characteristics.

#### **3.2. KIR genotyping**

The objectives of this study are the following:

148 Stem Cells in Clinical Practice and Tissue Engineering

(GvL), relapse and disease-free survival (DFS).

**Median age (range) 43 (14–65)**

AML 33 ALL 19 MDS 9 NHL 6 MM 6 LH 5 CML 4 CLL 3 AAS 1 Fanconi syndrome 1 Ematodermic neoplasia 1 BAL 1

better and best.

**3.1. Patient cohort**

Diagnosis

**Table 2.** Patient characteristics.

**3. Materials and methods**

1. Typing of the donors' KIR genes of the transplants performed.

2. Donors classification in accordance with the KIR B Content Score in three categories: neutral,

3. Correlation of the donor KIR B status with the clinical outcome of the transplants considering overall survival, the degrees of graft versus host disease (GvHD) graft versus leukemia

We analyzed 89 patients, who received a URD HSCT between 1996 and 2013. The median age of the 89 patients was 43 years (14–65). The transplanted patients had different hematological malignancies: 33 acute myeloid leukemia (AML), 19 acute limphoblastic leukemia (ALL), 9 myelodysplastic syndromes (MDS), 6 non-Hodgkin lymphoma (NHL), 6 multiple myeloma (MM), 5 Hodgkin lymphoma (HL), 4 chronic myeloid leukemia (CML), 3 chronic lymphocytic leukemia (CLL), 1 aplastic anemia syndrome (AAS), 1 Fanconi syndrome, 1 ematodermic neoplasia and 1 biphenotypic acute leukemia (BAL). The HSC source was: bone marrow no. 19, peripheral blood no. 70. Complete high-resolution, allele-level HLA-A, B, C, DRB1 and DQB1 typing of the 89 pairs of recipients and donors was previously performed: 32 pairs were 10/10 matched, 33 pairs were 9/10 and 24 were ≤8/10. Patient and transplant characteristics are summarized in **Tables 2** and **3**.

> The donors' DNA that has already been typed for HLA has been preserved in our biobank; about 80% of the samples is still available. The DNA was extracted from buffy coat or whole blood by the automatic extractor Maxwell 16 (Promega) or by the salting out method.

> Typing of KIR genes was performed with PCR-SSO Luminex, the same method already used in our laboratory to type the HLA genes. The kit used for KIR genes typing was the SSO KIR Genotyping Test (One Lambda Inc., Canoga Park, CA) and the method was performed in accordance with the manufacturer's instructions. Luminex technology is based on the ability to soundly measure multiple analytes simultaneously in a single reaction and this is done through the use of plastic microbeads (microspheres), which are color-coded with two fluorescent dyes so as to emit two different wave lengths in red and infrared. In this way a set of over 100 different microspheres can be created. The microspheres represent the solid support of oligonucleotide probes which can bind amplified DNA that is labeled with a fluorescent labeled reporter. Subsequently, the microbeads are acquired by the Luminex machine through a precision sheath fluid system, based on classical flow cytometry, which aligns them in single file, where they pass through two lasers: the red laser excites the colors inside the microbeads to identify which microbead is currently being read, while the green laser excites the color on the microbead surface, that is, the labeled reporter tag. Finally, the color signals are detected by an advanced optical system, and the signals are processed into data for each reaction [16].

The PCR using specific primers for the KIR genes is first conducted with a specific amplification program via the GeneAmp PCR System 9700 (Applied Biosystems, Forster City, CA). The amplification products are tested by electrophoresis on 2% agarose gel and then observed and photographed under a UV transilluminator. The PCR product is biotinylated, which allows it to be detected by strepavidin-conjugated with PE (SAPE). Subsequently, the PCR products are denatured facilitating rehybridization to complementary DNA probes bound to the microbeads with a specific sequence (SSO) to recognize the polymorphic sites within KIR genes. The amplified products which have undergone a hybridization reaction are labeled with streptavidin conjugated with R-Phycoerythrin and then acquired with the flow cytometry system LABScanTM 100 (Luminex), which measures the fluorescence intensity of phycoerythrin on each microsphere. The data are then analyzed with the software HLA Fusion.

**4.2. Clinical outcome analysis**

*4.2.1. Overall survival, relapse and disease-free survival*

The overall survival rate was analyzed generating the Kaplan-Meyer curves, using the

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We observed no significant difference in the overall survival rate of those patients transplanted from A/A donor and those from B/x donor, while we found a better overall survival rate in the AML recipients, HLA mismatched with the donor, when the donor KIR B content status is best/better (37 vs. 18% at three years log-rank test P = 0.028) (**Figure 2**), whereas there

GraphPad6 Demo software; the data were compared using the log-rank test 95%CI.

is no beneficial effect in recipients with other hematological malignancies (**Figure 3**).

**Figure 2.** Overall survival rate of AML recipients of HLA mismatched MUD transplants.

**Figure 3.** Overall survival rate of recipients with other hematologic malignancies of HLA mismatched MUD transplants.

### **4. Results**

#### **4.1. Donor classification**

We typed KIR genes of the 89 selected donors of the transplanted patients and we classified them on the basis of the KIR haplotypes possessed. KIR gene frequency among the donor population was similar to that of published data [17, 18]: no. 30 (33.7%) donors were A/A and no. 59 (66.3 %) were B/x.

Then we classified them using the donor KIR B Content Score Calculator at http://www.ebi. ac.uk/ipd/kir/: no. 63 (70.8%) donors were neutral, no. 18 (20.2%) better and no. 8 (9%) best. In our analysis we combined the better and best groups to form the KIR better/best donor group (with two or more B motifs). The classification of the donors in accordance with the KIR B content score is summarized in **Table 4**.


**Table 4.** Donor classification in accordance with the KIR B content score.

#### **4.2. Clinical outcome analysis**

The PCR using specific primers for the KIR genes is first conducted with a specific amplification program via the GeneAmp PCR System 9700 (Applied Biosystems, Forster City, CA). The amplification products are tested by electrophoresis on 2% agarose gel and then observed and photographed under a UV transilluminator. The PCR product is biotinylated, which allows it to be detected by strepavidin-conjugated with PE (SAPE). Subsequently, the PCR products are denatured facilitating rehybridization to complementary DNA probes bound to the microbeads with a specific sequence (SSO) to recognize the polymorphic sites within KIR genes. The amplified products which have undergone a hybridization reaction are labeled with streptavidin conjugated with R-Phycoerythrin and then acquired with the flow cytometry system LABScanTM 100 (Luminex), which measures the fluorescence intensity of phycoerythrin on each microsphere. The data are then analyzed with the software

We typed KIR genes of the 89 selected donors of the transplanted patients and we classified them on the basis of the KIR haplotypes possessed. KIR gene frequency among the donor population was similar to that of published data [17, 18]: no. 30 (33.7%) donors were A/A and

Then we classified them using the donor KIR B Content Score Calculator at http://www.ebi. ac.uk/ipd/kir/: no. 63 (70.8%) donors were neutral, no. 18 (20.2%) better and no. 8 (9%) best. In our analysis we combined the better and best groups to form the KIR better/best donor group (with two or more B motifs). The classification of the donors in accordance with the KIR B

> **ALL recipients n = 19**

**Tot (19) Neutral (14)**

Donor KIR B status

Donor KIR B status

**Best/ better (5)**

**Other hematological malignancies n = 37**

**Tot (37) Neutral (28)**

Donor KIR B status

Donor KIR B status

**Best/better (9)**

HLA Fusion.

**4. Results**

**Donor/ recipient HLAallele matching at A, B, C, DRB1 and DQB1**

**Total n = 89**

**Total (89)**

Donor KIR B status

**Neutral (63)**

**4.1. Donor classification**

150 Stem Cells in Clinical Practice and Tissue Engineering

no. 59 (66.3 %) were B/x.

content score is summarized in **Table 4**.

Donor KIR B status

**Best/ better (26)**

**AML recipients n = 33**

**Tot (33) Neutral (21)**

**Table 4.** Donor classification in accordance with the KIR B content score.

Donor KIR B status

Donor KIR B status

**Best/ better (12)**

10/10 32 24 8 10 9 1 7 4 3 15 11 4 9/10 33 22 11 14 7 7 8 7 1 11 8 3 ≤8/10 24 17 7 9 5 4 4 3 1 11 9 2

#### *4.2.1. Overall survival, relapse and disease-free survival*

The overall survival rate was analyzed generating the Kaplan-Meyer curves, using the GraphPad6 Demo software; the data were compared using the log-rank test 95%CI.

We observed no significant difference in the overall survival rate of those patients transplanted from A/A donor and those from B/x donor, while we found a better overall survival rate in the AML recipients, HLA mismatched with the donor, when the donor KIR B content status is best/better (37 vs. 18% at three years log-rank test P = 0.028) (**Figure 2**), whereas there is no beneficial effect in recipients with other hematological malignancies (**Figure 3**).

**Figure 2.** Overall survival rate of AML recipients of HLA mismatched MUD transplants.

**Figure 3.** Overall survival rate of recipients with other hematologic malignancies of HLA mismatched MUD transplants.

Moreover, we observed that AML recipients, whose donor KIR B status was best/better, had a lower incidence of relapse than patients whose donor KIR B status was neutral (36 vs. 58%) (**Figures 4** and **5**) and a better disease-free survival rate (58 vs. 38% at three years P = 0.1) (**Figure 6**).

We have not been able to make a comparison of the 10/10 HLA matched AML recipients

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**Figure 6.** Disease-free survival rate of AML recipients of HLA mismatched MUD transplants.

The incidence of aGvHD in AML patients was: 55.17% (no. 16/29) of no aGvHD, 41.38% (no. 12/29) of aGvHD grade I and II, 3.45% (no. 1/29) of aGvHD grade III and IV (**Figure 7**).

because only one donor was best/better.

**Figure 7.** The incidence of aGvHD in AML patients.

*4.2.2. aGvHD*

**Figure 4.** Incidence of relapse in AML recipients of best/better MUD.

**Figure 5.** Incidence of relapse in AML recipients of neutral MUD.

**Figure 6.** Disease-free survival rate of AML recipients of HLA mismatched MUD transplants.

We have not been able to make a comparison of the 10/10 HLA matched AML recipients because only one donor was best/better.

#### *4.2.2. aGvHD*

Moreover, we observed that AML recipients, whose donor KIR B status was best/better, had a lower incidence of relapse than patients whose donor KIR B status was neutral (36 vs. 58%) (**Figures 4** and **5**) and a better disease-free survival rate (58 vs. 38% at three years P = 0.1)

(**Figure 6**).

152 Stem Cells in Clinical Practice and Tissue Engineering

**Figure 4.** Incidence of relapse in AML recipients of best/better MUD.

**Figure 5.** Incidence of relapse in AML recipients of neutral MUD.

The incidence of aGvHD in AML patients was: 55.17% (no. 16/29) of no aGvHD, 41.38% (no. 12/29) of aGvHD grade I and II, 3.45% (no. 1/29) of aGvHD grade III and IV (**Figure 7**).

**Figure 7.** The incidence of aGvHD in AML patients.

We observed that AML recipients, whose donor KIR B status was best/better, had more incidence of aGvHD grade I and II than patients whose donor KIR B status was neutral: 70 vs. 26% (**Figures 8** and **9**).

**5. Discussion**

(51.6 vs. 38% at three years P = 0.04).

with KIR Cen B/B).

In recent years, various studies have shown that the beneficial GvL effect promoted by alloreactive NK cells derived from the donor can improve the outcome of the HSCT from haploidentical, unrelated and HLA identical sibling donors. In particular Cooley et al. [12] have demonstrated that AML patients who received HSC transplants from unrelated Group B KIR haplotypes donors, had a better outcome after transplant because the haplotypes of Group B have a larger number of activating receptors, and this translates into better antileukemic activity. In a subsequent study [13], they found that some particular KIRs had a stronger effect and they defined three categories of donors: neutral (none or one KIR B motifs), better (two or more B motifs without KIR Cen B/B) and best (two or more B motifs

**Figure 10.** Patients with aGvHD grade I and II had a significantly better overall survival rate than patients with noGvHD

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In our study we analyzed the impact of the donor KIR B status on the outcome of the unrelated HSC transplants performed in our center. We observed no significant difference in overall survival of those patients transplanted from A/A donor and those from B/x donor, probably because we do not have a large enough cohort of transplanted patients, and we were not able to make a meaningful comparison; on the other hand, despite this small cohort of patients, we have been able to observe the powerful effect of the best/better donor KIR B status in the AML recipients HLA mismatched with the donor. They had a significantly better overall survival rate if the donor KIR B content status was best/better and they also had a higher incidence of

Even though our cohort was small, our results confirmed that the presence of more activator KIR genes in donors can improve the outcome of UDHSC HLA mismatched transplants in AML recipients whereas there is no benefit in recipients with other hematologic malignancies. Our next target is to increase the number of cases by adding the other transplants performed

aGvHD grade I and II, and had a lower rate of relapse due to GvL effects.

and to study the effect of GvL in relapse in the same patients.

**Figure 9.** Incidence of aGvHD in AML recipients of best/better MUD.

Actually, as regards patients who have aGvHD grade I and II, this results in a beneficial effect on the overall survival rate. In fact, we observed that patients with aGvHD grade I and II had a significantly better overall survival rate than patients with noGvHD (51.6 vs. 38% at three years P = 0.04) (**Figure 10**). This agrees with those studies [4] showing that patients with aGvHD I and II have a better overall survival rate and a lower rate of relapse due to a GvL effect.

**Figure 10.** Patients with aGvHD grade I and II had a significantly better overall survival rate than patients with noGvHD (51.6 vs. 38% at three years P = 0.04).

### **5. Discussion**

We observed that AML recipients, whose donor KIR B status was best/better, had more incidence of aGvHD grade I and II than patients whose donor KIR B status was neutral: 70 vs. 26%

Actually, as regards patients who have aGvHD grade I and II, this results in a beneficial effect on the overall survival rate. In fact, we observed that patients with aGvHD grade I and II had a significantly better overall survival rate than patients with noGvHD (51.6 vs. 38% at three years P = 0.04) (**Figure 10**). This agrees with those studies [4] showing that patients with aGvHD I and

II have a better overall survival rate and a lower rate of relapse due to a GvL effect.

(**Figures 8** and **9**).

154 Stem Cells in Clinical Practice and Tissue Engineering

**Figure 8.** Incidence of aGvHD in AML recipients of neutral MUD.

**Figure 9.** Incidence of aGvHD in AML recipients of best/better MUD.

In recent years, various studies have shown that the beneficial GvL effect promoted by alloreactive NK cells derived from the donor can improve the outcome of the HSCT from haploidentical, unrelated and HLA identical sibling donors. In particular Cooley et al. [12] have demonstrated that AML patients who received HSC transplants from unrelated Group B KIR haplotypes donors, had a better outcome after transplant because the haplotypes of Group B have a larger number of activating receptors, and this translates into better antileukemic activity. In a subsequent study [13], they found that some particular KIRs had a stronger effect and they defined three categories of donors: neutral (none or one KIR B motifs), better (two or more B motifs without KIR Cen B/B) and best (two or more B motifs with KIR Cen B/B).

In our study we analyzed the impact of the donor KIR B status on the outcome of the unrelated HSC transplants performed in our center. We observed no significant difference in overall survival of those patients transplanted from A/A donor and those from B/x donor, probably because we do not have a large enough cohort of transplanted patients, and we were not able to make a meaningful comparison; on the other hand, despite this small cohort of patients, we have been able to observe the powerful effect of the best/better donor KIR B status in the AML recipients HLA mismatched with the donor. They had a significantly better overall survival rate if the donor KIR B content status was best/better and they also had a higher incidence of aGvHD grade I and II, and had a lower rate of relapse due to GvL effects.

Even though our cohort was small, our results confirmed that the presence of more activator KIR genes in donors can improve the outcome of UDHSC HLA mismatched transplants in AML recipients whereas there is no benefit in recipients with other hematologic malignancies. Our next target is to increase the number of cases by adding the other transplants performed and to study the effect of GvL in relapse in the same patients.

In any case, our results confirm that NK cells derived from donors with two or more KIR B motifs have an improved ability to kill residual leukemic blasts in AML recipients of UDHSCT. As a consequence of this, the KIR genotype of the donor is another important criterion to be taken into account for the choice of the best possible donor in unrelated, sibling and haploidentical HSC transplant settings, together with all the other important factors, such as HLA matching, CMV status, blood group, age and gender. Future studies should be aimed at finding the right alloreactive subsets among donor NK cell repertoires, opening up the possibility for successful NK cell–based immunotherapy. Antileukemic NK cells, either allogeneic or unlicensed autologous NK cells, emerge as a feasible therapy option and might improve the clinical outcome in myeloid leukemia.

[4] Petersen SL. Alloreactivity as therapeutic principle in the treatment of hematologic malignancies. Studies of clinical and immunologic aspects of allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. Danish Medical Bulletin.

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1935-47

### **Author details**

Francesco Ingrassia1, 2\*, Valentina Cappuzzo1 , Rosalba Bavetta<sup>1</sup> , Serena Mistretta<sup>1</sup> , Maria Igea Vega1 , Paola Bruna Affaticati<sup>1</sup> , Maria Blando1 , Floriana Bruno<sup>1</sup> , Emanuela Collura1 , Giovanna Regina1 , Valentina Randazzo<sup>3</sup> , Alessandro Indovina4 , Felicia Farina2 and Raimondo Marcenò1

\*Address all correspondence to: francescoingrassia9@gmail.com

1 Tissue Typing and Transplant Immunology Laboratory, Transfusion Medicine, Cervello Hospital, Ospedali Riuniti Villa Sofia Cervello, Palermo, Italy


### **References**


[4] Petersen SL. Alloreactivity as therapeutic principle in the treatment of hematologic malignancies. Studies of clinical and immunologic aspects of allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. Danish Medical Bulletin. 2007;**54**(2):112

In any case, our results confirm that NK cells derived from donors with two or more KIR B motifs have an improved ability to kill residual leukemic blasts in AML recipients of UDHSCT. As a consequence of this, the KIR genotype of the donor is another important criterion to be taken into account for the choice of the best possible donor in unrelated, sibling and haploidentical HSC transplant settings, together with all the other important factors, such as HLA matching, CMV status, blood group, age and gender. Future studies should be aimed at finding the right alloreactive subsets among donor NK cell repertoires, opening up the possibility for successful NK cell–based immunotherapy. Antileukemic NK cells, either allogeneic or unlicensed autologous NK cells, emerge as a feasible therapy option and might improve the

, Rosalba Bavetta<sup>1</sup>

, Maria Blando1

, Valentina Randazzo<sup>3</sup>

1 Tissue Typing and Transplant Immunology Laboratory, Transfusion Medicine, Cervello

[1] Lee SJ, Klein J, Haagenson M, Baxter-Lowe LA, Confer DL, Eapen M, Fernandez-Vina M, Flomenberg N, Horowitz M, Hurley CK, Noreen H, Oudshoorn M, Petersdorf E, Setterholm M, Spellman S, Weisdorf D, Williams TM, Anasetti C. High-resolution donorrecipient HLA matching contributes to the success of unrelated donor marrow trans-

[2] Marsh SGE, Albert ED, Bodmer WF, Bontrop RE, Dupont B, Erlich HA, Fernández-Vina M, Geraghty DE, Holdsworth R, Hurley CK, Lau M, Lee KW, Mach B, Mayr WR, Maiers M, Müller CR, Parham P, Petersdorf EW, Sasazuki T, Strominger JL, Svejgaard A, Terasaki PI, Tiercy JM, Trowsdale J. Nomenclature for factors of the HLA system. Tissue

[3] Robinson J, Mistry K, McWilliam H, Lopez R, Parham P, Marsh SGE. The IMGT/HLA

2 Biomedicine and Neuroscience Department, University of Palermo, Palermo, Italy

, Serena Mistretta<sup>1</sup>

, Alessandro Indovina4

,

, Floriana Bruno<sup>1</sup>

,

,

clinical outcome in myeloid leukemia.

156 Stem Cells in Clinical Practice and Tissue Engineering

Francesco Ingrassia1, 2\*, Valentina Cappuzzo1

, Paola Bruna Affaticati<sup>1</sup>

, Giovanna Regina1

\*Address all correspondence to: francescoingrassia9@gmail.com

Hospital, Ospedali Riuniti Villa Sofia Cervello, Palermo, Italy

3 Haematology Laboratory, Cervello Hospital, Palermo, Italy

4 Haemopoietic Transplant Unit, Cervello Hospital, Palermo, Italy

plantation. Blood. 2007;**110**(13):4576-83. Epub 2007 Sep 4

database. Nucleic Acids Research. 2011;**39**(Suppl 1):D1171-6

and Raimondo Marcenò1

**Author details**

Maria Igea Vega1

Felicia Farina2

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Antigens. 2010;**75**:291-455

Emanuela Collura1


[16] Heinemann FM. HLA genotyping and antibody characterization using the Luminex™ multiplex technology. Transfusion Medicine and Hemotherapy. 2009;**36**:273-8

**Chapter 8**

**Provisional chapter**

**Hematopoietic Stem Cell Transplantation for Acute**

**Hematopoietic Stem Cell Transplantation for Acute** 

Eshrak Alshibani, Zeyad AlShaibani and

Eshrak Alshibani, Zeyad AlShaibani and

http://dx.doi.org/10.5772/intechopen.73562

efficacious in clinical practice.

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Khalid Ahmed Al-Anazi

**Abstract**

**1. Introduction**

Khalid Ahmed Al-Anazi

**Lymphoblastic Leukemia in the Era of Novel Therapies**

Recently, the outcomes of patients with acute lymphoblastic leukemia have improved significantly due to the progresses achieved in diagnostics and various therapeutic interventions. In particular, the availability of several novel agents and targeted therapies as well as the provision of safer modalities of stem cell transplants have yielded higher responses and improved survival rates. The role of hematopoietic stem cell transplantation is reviewed in children and adults with acute lymphoblastic leukemia in the era of novel agents and targeted therapies. Various modalities of stem cell therapies in different types of acute lymphoblastic leukemia as well as closely related issues such as graft versus tumor effect, minimal residual disease, and conditioning therapies are discussed thoroughly. In addition, various modalities of novel therapies have been discussed to be

**Keywords:** acute lymphoblastic leukemia, hematopoietic stem cell transplantation,

Acute lymphoblastic leukemia (ALL) is a clonal expansion or malignant transformation and proliferation of lymphoid progenitor cells in the bone marrow, blood, and extramedullary sites [1, 2]. It is a highly heterogeneous disease comprising several entities that have distinct clinical manifestations, therapeutic strategies as well as prognostic implications [2]. ALL can occur at any age, but 80% cases occur in children [1, 3]. The incidence of ALL follows a bimodal distribution with the first peak occurring in children 2–5 years of age, while the second peak

reduced intensity conditioning, monoclonal antibodies, immunotherapies

**Lymphoblastic Leukemia in the Era of Novel Therapies**

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

DOI: 10.5772/intechopen.73562


#### **Hematopoietic Stem Cell Transplantation for Acute Lymphoblastic Leukemia in the Era of Novel Therapies Hematopoietic Stem Cell Transplantation for Acute Lymphoblastic Leukemia in the Era of Novel Therapies**

DOI: 10.5772/intechopen.73562

Eshrak Alshibani, Zeyad AlShaibani and Khalid Ahmed Al-Anazi Eshrak Alshibani, Zeyad AlShaibani and Khalid Ahmed Al-Anazi

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.73562

#### **Abstract**

[16] Heinemann FM. HLA genotyping and antibody characterization using the Luminex™ multiplex technology. Transfusion Medicine and Hemotherapy. 2009;**36**:273-8

[17] Witt CS, Dewing C, Sayer DC, Uhrberg M, Parham P, Christiansen FT. Population frequencies and putative haplotypes of the killer cell immunoglobulin-like receptor

[18] Cook MA, Milligan DW, Fegan CD, et al. The impact of donor KIR and patient HLA-C genotypes on outcome following HLA-identical sibling hematopoietic stem cell trans-

sequences and evidence for recombination. Transplantation. 1999;**68**:1784-9

plantation for myeloid leukemia. Blood. 2004;**103**:1521-6

158 Stem Cells in Clinical Practice and Tissue Engineering

Recently, the outcomes of patients with acute lymphoblastic leukemia have improved significantly due to the progresses achieved in diagnostics and various therapeutic interventions. In particular, the availability of several novel agents and targeted therapies as well as the provision of safer modalities of stem cell transplants have yielded higher responses and improved survival rates. The role of hematopoietic stem cell transplantation is reviewed in children and adults with acute lymphoblastic leukemia in the era of novel agents and targeted therapies. Various modalities of stem cell therapies in different types of acute lymphoblastic leukemia as well as closely related issues such as graft versus tumor effect, minimal residual disease, and conditioning therapies are discussed thoroughly. In addition, various modalities of novel therapies have been discussed to be efficacious in clinical practice.

**Keywords:** acute lymphoblastic leukemia, hematopoietic stem cell transplantation, reduced intensity conditioning, monoclonal antibodies, immunotherapies

#### **1. Introduction**

Acute lymphoblastic leukemia (ALL) is a clonal expansion or malignant transformation and proliferation of lymphoid progenitor cells in the bone marrow, blood, and extramedullary sites [1, 2]. It is a highly heterogeneous disease comprising several entities that have distinct clinical manifestations, therapeutic strategies as well as prognostic implications [2]. ALL can occur at any age, but 80% cases occur in children [1, 3]. The incidence of ALL follows a bimodal distribution with the first peak occurring in children 2–5 years of age, while the second peak

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

is encountered around the age of 50 years [1, 3]. While most children with ALL are potentially curable, the prognosis in infants, adults, and elderly individuals remains poor [3].

relapse; and (5) graft versus leukemia (GVL) effect plays a major role in curing patients with ALL subjected to allogeneic HSCT [13–17]. However, there is considerable evidence for the existence of GVL effect after HSCT in patients with ALL: (1) relapse rates are lower in recipients of allogeneic HSCT compared with recipients of autologous grafts, (2) relapse rates are lower in patients who develop acute or chronic GVHD following allografts, and (3) the use of interferon immediately post-allogeneic HSCT may reduce relapse rate through stimulation of an immunological response [15, 18]. Unfortunately, the efficacy of GVL effect in the context of donor lymphocyte infusion (DLI) of ALL in the post-allogeneic HSCT setting is quite unimpressive as response rates to DLI in ALL patients receiving allografts have been

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GVL effect in ALL is influenced by the extent of leukemia burden [15]. Minimal residual disease (MRD) studies after HSCT have found a strong correlation between the presence of MRD and relapse of leukemia [16]. Frequent MRD monitoring post-allogeneic HSCT may predict ALL relapse early enough, thus allowing the implementation of various approaches such as: (1) reduction of immunosuppressive therapy, (2) DLI, and (3) adoptive T-cell therapy, but

The development of GVHD following allogeneic HSCT in patients with B-cell ALL is associated with a lower probability of leukemia relapse due to a non-specific inhibition of B-lymphocytosis [19]. Also, the improved survival in recipients of allogeneic HSCT who develop acute or chronic GVHD is attributed to the beneficial GVL effect of GVHD [14]. Chronic GVHD, particularly limited form, is associated with a significant GVL effect [13]. However, the correlation between GVHD and GVL is mainly seen in non-T cell-depleted allografts [14]. The influence of chronic GVHD on the risk of relapse has been found to be

Studies have shown that in ALL patients subjected to allogeneic HSCT, relapse rates are higher in: (1) patients receiving dual or effective GVHD prophylaxis as the intensity of the GVHD prophylactic regimen inversely correlates with the incidence of acute GVHD and (2) recipients of matched sibling donor (MSD) allografts compared with those receiving matched unrelated donor (MUD) grafts as MSD allogeneic HSCT is associated with reduced likelihood of GVHD and reduced treatment-related mortality (TRM), while MUD allografts are associated with higher incidence of GVHD and lower relapse rates due to the pronounced GVL

In ALL patients receiving allogeneic HSCT, GVL effects are associated with detectable Wilms tumor-1-specific T lymphocyte (WT1) [18]. These results support the immunogenicity of WT1 after HSCT for ALL and highlight the potential for WT1 vaccines to boost GVL effect after HSCT for ALL [18]. The lower relapse rates encountered in ALL patients receiving HSCT may

Several studies have shown the prognostic relevance of detection of MRD in patients with ALL [21–23]. MRD identified prior to allogeneic HSCT is the strongest predictor of post-HSCT

indicate that viral antigens play a role in the induction of anti-leukemic effect [14].

such approaches may be ineffective in the presence of high disease burden [15, 16].

prominent in patients with chromosomal translocations or normal cytogenetics [13].

reported to range from 0 to 18% [15, 18].

effect of GVHD [14, 17, 20].

**2.2. MRD in ALL**

Worldwide, different induction chemotherapeutic regimens are utilized in the treatment of patients with ALL [4–7]. Examples are—(1) USA and Canada: CCG series in children and CALGB in adults, modified DFCI 91-01 and 95-01, in addition to hyper-fractionated hyper-CVAD (cyclophosphamide, vincristine, cytarabine, dexamethasone, methotrexate, and doxorubicin); (2) UK: ALL-97, revised ALL-99 for children and UKALL XII for adults; (3) France: FRALLE-93 in children, LALA-94 in adults and GRAALL-2003; (4) Germany: pediatric DCOG-ALL or Berlin-Frankfurt-Munster [standard or augmented regimen]; (5) Italy: AIEPO [pediatric] and GIMEMA [adults]; (6) Holland and Belgium: HOVON-70; (7) Spain: PETHEMA ALL-96; (8) Sweden and Finland: pediatric NOPHO-92 and adult Nordic protocols; and (9) Mexico: LALIN (pediatric) and LALA (adult) [4–7]. Sometimes, different chemotherapeutic regimens are used in the same geographic location or even in the same country [4–7]. Additionally, these treatment regimens undergo modifications or even total replacement once new literature data or results of large studies become available [4–8]. Despite the development of several induction regimens, there is no single best regimen for induction therapy in ALL [4–8]. The main constituents of these chemotherapeutic regimens are almost similar with different dosing and treatment schedules and they include: daunorubicin, doxorubicin, or idarubicin; prednisolone or dexamethasone; vincristine; L-asparaginase; cyclophosphamide; 6-mercaptopurine; and intrathecal (IT) as well as intravenous (IV) methotrexate [4–8].

Recently, the more intensified pediatric ALL induction regimens have been used in adolescents and young adults (AYAs), 15–40 years of age, having ALL, and their use has been associated with superior response rates [4, 6, 9]. Several studies have shown that AYAs treated with adult chemotherapeutic regimens have poorer outcome compared with patients belonging to the same age group treated with pediatric-inspired regimens [4, 6, 9]. Additionally, certain cancer centers, such as Dana-Farber Cancer Center, USA, are currently treating patients between the ages of 1 and 50 years with the same regimens of chemotherapy [5]. The recent incorporation of novel and targeted therapies, such as tyrosine kinase inhibitors (TKIs), nelarabine and rituximab, into the induction therapy of ALL has further improved the response rates and the outcomes in general [4, 5, 10–12].

### **2. HSCT in ALL patients**

#### **2.1. GVL effect in ALL**

Several studies have shown that (1) in adults with ALL receiving cytotoxic chemotherapy, the high incidence of relapse is the main cause of treatment failure, hence post-remission therapy particularly the efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) is a critical issue; (2) the rates of relapse of ALL following HSCT are higher than those encountered in other hematologic malignancies; (3) relapse of ALL post-allogeneic HSCT is a major cause of treatment failure as it is associated with an extremely poor prognosis; (4) graft versus host disease (GVHD) encountered in the post-HSCT period has a protective effect against disease relapse; and (5) graft versus leukemia (GVL) effect plays a major role in curing patients with ALL subjected to allogeneic HSCT [13–17]. However, there is considerable evidence for the existence of GVL effect after HSCT in patients with ALL: (1) relapse rates are lower in recipients of allogeneic HSCT compared with recipients of autologous grafts, (2) relapse rates are lower in patients who develop acute or chronic GVHD following allografts, and (3) the use of interferon immediately post-allogeneic HSCT may reduce relapse rate through stimulation of an immunological response [15, 18]. Unfortunately, the efficacy of GVL effect in the context of donor lymphocyte infusion (DLI) of ALL in the post-allogeneic HSCT setting is quite unimpressive as response rates to DLI in ALL patients receiving allografts have been reported to range from 0 to 18% [15, 18].

GVL effect in ALL is influenced by the extent of leukemia burden [15]. Minimal residual disease (MRD) studies after HSCT have found a strong correlation between the presence of MRD and relapse of leukemia [16]. Frequent MRD monitoring post-allogeneic HSCT may predict ALL relapse early enough, thus allowing the implementation of various approaches such as: (1) reduction of immunosuppressive therapy, (2) DLI, and (3) adoptive T-cell therapy, but such approaches may be ineffective in the presence of high disease burden [15, 16].

The development of GVHD following allogeneic HSCT in patients with B-cell ALL is associated with a lower probability of leukemia relapse due to a non-specific inhibition of B-lymphocytosis [19]. Also, the improved survival in recipients of allogeneic HSCT who develop acute or chronic GVHD is attributed to the beneficial GVL effect of GVHD [14]. Chronic GVHD, particularly limited form, is associated with a significant GVL effect [13]. However, the correlation between GVHD and GVL is mainly seen in non-T cell-depleted allografts [14]. The influence of chronic GVHD on the risk of relapse has been found to be prominent in patients with chromosomal translocations or normal cytogenetics [13].

Studies have shown that in ALL patients subjected to allogeneic HSCT, relapse rates are higher in: (1) patients receiving dual or effective GVHD prophylaxis as the intensity of the GVHD prophylactic regimen inversely correlates with the incidence of acute GVHD and (2) recipients of matched sibling donor (MSD) allografts compared with those receiving matched unrelated donor (MUD) grafts as MSD allogeneic HSCT is associated with reduced likelihood of GVHD and reduced treatment-related mortality (TRM), while MUD allografts are associated with higher incidence of GVHD and lower relapse rates due to the pronounced GVL effect of GVHD [14, 17, 20].

In ALL patients receiving allogeneic HSCT, GVL effects are associated with detectable Wilms tumor-1-specific T lymphocyte (WT1) [18]. These results support the immunogenicity of WT1 after HSCT for ALL and highlight the potential for WT1 vaccines to boost GVL effect after HSCT for ALL [18]. The lower relapse rates encountered in ALL patients receiving HSCT may indicate that viral antigens play a role in the induction of anti-leukemic effect [14].

#### **2.2. MRD in ALL**

is encountered around the age of 50 years [1, 3]. While most children with ALL are potentially

Worldwide, different induction chemotherapeutic regimens are utilized in the treatment of patients with ALL [4–7]. Examples are—(1) USA and Canada: CCG series in children and CALGB in adults, modified DFCI 91-01 and 95-01, in addition to hyper-fractionated hyper-CVAD (cyclophosphamide, vincristine, cytarabine, dexamethasone, methotrexate, and doxorubicin); (2) UK: ALL-97, revised ALL-99 for children and UKALL XII for adults; (3) France: FRALLE-93 in children, LALA-94 in adults and GRAALL-2003; (4) Germany: pediatric DCOG-ALL or Berlin-Frankfurt-Munster [standard or augmented regimen]; (5) Italy: AIEPO [pediatric] and GIMEMA [adults]; (6) Holland and Belgium: HOVON-70; (7) Spain: PETHEMA ALL-96; (8) Sweden and Finland: pediatric NOPHO-92 and adult Nordic protocols; and (9) Mexico: LALIN (pediatric) and LALA (adult) [4–7]. Sometimes, different chemotherapeutic regimens are used in the same geographic location or even in the same country [4–7]. Additionally, these treatment regimens undergo modifications or even total replacement once new literature data or results of large studies become available [4–8]. Despite the development of several induction regimens, there is no single best regimen for induction therapy in ALL [4–8]. The main constituents of these chemotherapeutic regimens are almost similar with different dosing and treatment schedules and they include: daunorubicin, doxorubicin, or idarubicin; prednisolone or dexamethasone; vincristine; L-asparaginase; cyclophosphamide;

curable, the prognosis in infants, adults, and elderly individuals remains poor [3].

6-mercaptopurine; and intrathecal (IT) as well as intravenous (IV) methotrexate [4–8].

rates and the outcomes in general [4, 5, 10–12].

**2. HSCT in ALL patients**

160 Stem Cells in Clinical Practice and Tissue Engineering

**2.1. GVL effect in ALL**

Recently, the more intensified pediatric ALL induction regimens have been used in adolescents and young adults (AYAs), 15–40 years of age, having ALL, and their use has been associated with superior response rates [4, 6, 9]. Several studies have shown that AYAs treated with adult chemotherapeutic regimens have poorer outcome compared with patients belonging to the same age group treated with pediatric-inspired regimens [4, 6, 9]. Additionally, certain cancer centers, such as Dana-Farber Cancer Center, USA, are currently treating patients between the ages of 1 and 50 years with the same regimens of chemotherapy [5]. The recent incorporation of novel and targeted therapies, such as tyrosine kinase inhibitors (TKIs), nelarabine and rituximab, into the induction therapy of ALL has further improved the response

Several studies have shown that (1) in adults with ALL receiving cytotoxic chemotherapy, the high incidence of relapse is the main cause of treatment failure, hence post-remission therapy particularly the efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) is a critical issue; (2) the rates of relapse of ALL following HSCT are higher than those encountered in other hematologic malignancies; (3) relapse of ALL post-allogeneic HSCT is a major cause of treatment failure as it is associated with an extremely poor prognosis; (4) graft versus host disease (GVHD) encountered in the post-HSCT period has a protective effect against disease

Several studies have shown the prognostic relevance of detection of MRD in patients with ALL [21–23]. MRD identified prior to allogeneic HSCT is the strongest predictor of post-HSCT relapse in ALL patients [23]. Thus, elimination of pre-HSCT MRD in patients with ALL by novel therapeutic approaches or drug combinations may decrease the risk of post-HSCT relapse and improve overall survival (OS) [23].

ALL who lack poor prognostic factors will benefit from autologous HSCT. Also, HR patients with ALL who are likely to benefit from autologous HSCT include: (1) rapid responders who achieve CR after the first induction therapy and (2) those with negative pre-HSCT MRD [25, 26, 28, 29]. In ALL patients, autologous HSCT should be performed after completion of consolidation chemotherapy as an alternative to maintenance chemotherapy [25]. Autologous HSCT combined with post-transplantation maintenance therapy could be a valid therapeutic option in adult patients with ALL [26, 30]. Adoptive immunotherapy and maintenance therapy after autologous HSCT reduce relapse rate and improve outcome in patients with ALL [30, 32]. Post-autologous HSCT maintenance therapy can be in the form of: (1) 6-mercaptopurine, methotrexate, vincristine, and prednisolone or (2) TKIs in patients with Philadelphia chromosome-positive (Ph+) ALL [27, 30]. Novel therapies, such as blinatumomab, may reduce the burden of MRD before stem cell collection prior to autologous HSCT, thus making the combination of novel therapies and autologous HSCT a real alternative to allogeneic HSCT and prolonged maintenance therapy for ALL patients [27]. Improved DFS and low relapse rates can be achieved after autologous HSCT in adults with ALL who (1) rapidly respond to the first induction chemotherapy and (2) achieve MRD prior to autologous HSCT [26, 28]. Long-term outcome of allogeneic HSCT is superior to autologous HSCT or maintenance chemotherapy [27–29]. Several studies have failed to demonstrate the superiority of autologous HSCT over chemotherapy in adult patients with ALL [27–29]. Before the era of novel therapies and haploidentical HSCT, the prognosis of patients with ALL who relapse post-autologous HSCT was

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reported to be dismal due to the few available therapeutic options [29].

for transplant-eligible patients with ALL has not been defined yet [38].

Allogeneic HSCT cures hematologic malignancies through two major mechanisms: (1) pretransplantation conditioning therapy that kills leukemic cells directly and (2) graft versus tumor (GVT) effect [33]. Over the past 25–30 years, the outcome of HSCT has been steadily improving due to improvements in: (1) conditioning therapies, (2) GVHD prophylaxis and therapy, (3) supportive care facilities, (4) new antifungal agents, (5) better diagnostic tools, (6) incorporation of novel and targeted therapies such as TKIs into conventional therapeutic regimens, and (7) donor selection by improvement of human leukocyte antigen (HLA) typing methods and the increased use of MUDs [13, 34, 35]. Also, the use of flow cytometry and PCR for evaluation of MRD and monitoring of early relapse has improved the outcome of HSCT further [34]. Pre-transplantation detection of MRD by flow cytometry or PCR has been associ-

For the past 40 years, the standard myeloablative conditioning (MAC) regimen for ALL is composed of total body irradiation (TBI) 1200 cGy and IV cyclophosphamide 120 mg/Kg body weight [36, 37]. In patients with ALL, relapse is common after HSCT [37]. Attempts to decrease the risk of relapse following HSCT include: (1) modulation of the conditioning regimen by increasing TBI dose to >1200 cGy or adding a second chemotherapeutic agents such as etoposide and (2) decreasing the intensity of the conditioning regimen by relying on immune modulation, GVL effect, for disease control [36]. However, the optimal conditioning therapy

**2.4. Allogeneic HSCT conditioning therapies**

ated with lower OS and relapse-free survival [34].

MRD evaluation or monitoring in ALL patients can be performed by: (1) flow cytometry, (2) real-time quantitative polymerase chain reaction (RT-Q-PCR), and (3) next-generation sequencing (NGS) [21, 22]. Currently, analysis of MRD is mostly performed by PCR analysis of immunoglobulin (IG) and T-cell receptor (TCR) gene rearrangements, and this method has sensitivity of 10−4 in patients with ALL [21, 24]. However, despite the broad clinical usefulness of MRD evaluation, false-positive MRD results can be obtained due to massive B-lymphocyte regeneration after HSCT [24].

NGS enables precise and sensitive detection of multiple antigen receptor rearrangements, thus providing more specific readout compared to RT-Q-PCR, and this will reflect positively on the treatment interventions in ALL patients undergoing HSCT [24]. MRD determines the outcome of autologous HSCT in patients with HR-ALL [25]. In patients with ALL planned for autologous HSCT, MRD evaluation by PCR or NGS may play a role in the direction of therapy as it can predict long-term relapse-free survival [26, 27]. For example, patients with SR-ALL who do not have HR features at diagnosis and who have pre-transplantation negative MRD can be offered autologous HSCT combined with maintenance therapy [26].

#### **2.3. Autologous HSCT in ALL**

Complete remission (CR) can be achieved in approximately 80% of adults with ALL, but relapse occurs frequently leading to poor long-term disease-free survival that ranges between 25 and 40% [28, 29]. The post-remission therapies for patients with ALL generally include: (1) consolidation followed by maintenance chemotherapy, (2) allogeneic HSCT for high-risk (HR) patients, and (3) autologous HSCT for standard-risk (SR) patients or HR patients who do not have an HLA identical sibling donor [26, 29]. Therefore, after achieving first CR, intensive therapies, such as allogeneic HSCT and autologous HSCT, are generally offered to patients who are eligible for HSCT [28].

Autologous HSCT was first introduced as a treatment for ALL patients nearly 60 years ago [29]. However, autologous HSCT has been underutilized in ALL patients [29, 30]. Autologous HSCT performed in patients with ALL in CR1 has produced leukemia-free survival ranging between 45 and 65% [29]. Strategies to enhance autologous GVL effect after HSCT may enhance long-term survival in ALL patients subjected to autologous HSCT [31].

In patients with ALL, factors identifying patients who are at high risk of relapse include: (1) age more than 35 years, (2) T-cell type of ALL, (3) elevated white blood cell (WBC) count at presentation, (4) elevated serum lactic dehydrogenase (LDH) level at diagnosis, (5) extramedullary disease (EMD) prior to HSCT, (6) specific cytogenetic abnormalities, (7) blast cell proportion ≥5% on day 15 of induction therapy, and (8) having MRD at various stages during therapy [26, 27]. These factors indicate poor prognosis and decreased OS as well as disease-free survival (DFS) [26, 27]. Factors such as the risk features at the time of diagnosis and MRD following induction therapy greatly affect the outcome of autologous HSCT in ALL patients [29]. SR patients with ALL who lack poor prognostic factors will benefit from autologous HSCT. Also, HR patients with ALL who are likely to benefit from autologous HSCT include: (1) rapid responders who achieve CR after the first induction therapy and (2) those with negative pre-HSCT MRD [25, 26, 28, 29]. In ALL patients, autologous HSCT should be performed after completion of consolidation chemotherapy as an alternative to maintenance chemotherapy [25]. Autologous HSCT combined with post-transplantation maintenance therapy could be a valid therapeutic option in adult patients with ALL [26, 30]. Adoptive immunotherapy and maintenance therapy after autologous HSCT reduce relapse rate and improve outcome in patients with ALL [30, 32]. Post-autologous HSCT maintenance therapy can be in the form of: (1) 6-mercaptopurine, methotrexate, vincristine, and prednisolone or (2) TKIs in patients with Philadelphia chromosome-positive (Ph+) ALL [27, 30]. Novel therapies, such as blinatumomab, may reduce the burden of MRD before stem cell collection prior to autologous HSCT, thus making the combination of novel therapies and autologous HSCT a real alternative to allogeneic HSCT and prolonged maintenance therapy for ALL patients [27]. Improved DFS and low relapse rates can be achieved after autologous HSCT in adults with ALL who (1) rapidly respond to the first induction chemotherapy and (2) achieve MRD prior to autologous HSCT [26, 28]. Long-term outcome of allogeneic HSCT is superior to autologous HSCT or maintenance chemotherapy [27–29]. Several studies have failed to demonstrate the superiority of autologous HSCT over chemotherapy in adult patients with ALL [27–29]. Before the era of novel therapies and haploidentical HSCT, the prognosis of patients with ALL who relapse post-autologous HSCT was reported to be dismal due to the few available therapeutic options [29].

#### **2.4. Allogeneic HSCT conditioning therapies**

relapse in ALL patients [23]. Thus, elimination of pre-HSCT MRD in patients with ALL by novel therapeutic approaches or drug combinations may decrease the risk of post-HSCT

MRD evaluation or monitoring in ALL patients can be performed by: (1) flow cytometry, (2) real-time quantitative polymerase chain reaction (RT-Q-PCR), and (3) next-generation sequencing (NGS) [21, 22]. Currently, analysis of MRD is mostly performed by PCR analysis of immunoglobulin (IG) and T-cell receptor (TCR) gene rearrangements, and this method has sensitivity of 10−4 in patients with ALL [21, 24]. However, despite the broad clinical usefulness of MRD evaluation, false-positive MRD results can be obtained due to massive B-lymphocyte

NGS enables precise and sensitive detection of multiple antigen receptor rearrangements, thus providing more specific readout compared to RT-Q-PCR, and this will reflect positively on the treatment interventions in ALL patients undergoing HSCT [24]. MRD determines the outcome of autologous HSCT in patients with HR-ALL [25]. In patients with ALL planned for autologous HSCT, MRD evaluation by PCR or NGS may play a role in the direction of therapy as it can predict long-term relapse-free survival [26, 27]. For example, patients with SR-ALL who do not have HR features at diagnosis and who have pre-transplantation negative MRD

Complete remission (CR) can be achieved in approximately 80% of adults with ALL, but relapse occurs frequently leading to poor long-term disease-free survival that ranges between 25 and 40% [28, 29]. The post-remission therapies for patients with ALL generally include: (1) consolidation followed by maintenance chemotherapy, (2) allogeneic HSCT for high-risk (HR) patients, and (3) autologous HSCT for standard-risk (SR) patients or HR patients who do not have an HLA identical sibling donor [26, 29]. Therefore, after achieving first CR, intensive therapies, such as allogeneic HSCT and autologous HSCT, are generally offered to patients

Autologous HSCT was first introduced as a treatment for ALL patients nearly 60 years ago [29]. However, autologous HSCT has been underutilized in ALL patients [29, 30]. Autologous HSCT performed in patients with ALL in CR1 has produced leukemia-free survival ranging between 45 and 65% [29]. Strategies to enhance autologous GVL effect after HSCT may

In patients with ALL, factors identifying patients who are at high risk of relapse include: (1) age more than 35 years, (2) T-cell type of ALL, (3) elevated white blood cell (WBC) count at presentation, (4) elevated serum lactic dehydrogenase (LDH) level at diagnosis, (5) extramedullary disease (EMD) prior to HSCT, (6) specific cytogenetic abnormalities, (7) blast cell proportion ≥5% on day 15 of induction therapy, and (8) having MRD at various stages during therapy [26, 27]. These factors indicate poor prognosis and decreased OS as well as disease-free survival (DFS) [26, 27]. Factors such as the risk features at the time of diagnosis and MRD following induction therapy greatly affect the outcome of autologous HSCT in ALL patients [29]. SR patients with

enhance long-term survival in ALL patients subjected to autologous HSCT [31].

can be offered autologous HSCT combined with maintenance therapy [26].

relapse and improve overall survival (OS) [23].

162 Stem Cells in Clinical Practice and Tissue Engineering

regeneration after HSCT [24].

**2.3. Autologous HSCT in ALL**

who are eligible for HSCT [28].

Allogeneic HSCT cures hematologic malignancies through two major mechanisms: (1) pretransplantation conditioning therapy that kills leukemic cells directly and (2) graft versus tumor (GVT) effect [33]. Over the past 25–30 years, the outcome of HSCT has been steadily improving due to improvements in: (1) conditioning therapies, (2) GVHD prophylaxis and therapy, (3) supportive care facilities, (4) new antifungal agents, (5) better diagnostic tools, (6) incorporation of novel and targeted therapies such as TKIs into conventional therapeutic regimens, and (7) donor selection by improvement of human leukocyte antigen (HLA) typing methods and the increased use of MUDs [13, 34, 35]. Also, the use of flow cytometry and PCR for evaluation of MRD and monitoring of early relapse has improved the outcome of HSCT further [34]. Pre-transplantation detection of MRD by flow cytometry or PCR has been associated with lower OS and relapse-free survival [34].

For the past 40 years, the standard myeloablative conditioning (MAC) regimen for ALL is composed of total body irradiation (TBI) 1200 cGy and IV cyclophosphamide 120 mg/Kg body weight [36, 37]. In patients with ALL, relapse is common after HSCT [37]. Attempts to decrease the risk of relapse following HSCT include: (1) modulation of the conditioning regimen by increasing TBI dose to >1200 cGy or adding a second chemotherapeutic agents such as etoposide and (2) decreasing the intensity of the conditioning regimen by relying on immune modulation, GVL effect, for disease control [36]. However, the optimal conditioning therapy for transplant-eligible patients with ALL has not been defined yet [38].

The MAC regimens for ALL consist of: TBI (1200–1400 cGy) in addition to one or more chemotherapeutic agents [36]. In children with ALL, the MAC therapies include: (1) TBI 1000– 1200 cGy + cyclophosphamide, (2) TBI 1000–1200 cGy + cyclophosphamide + etoposide, (3) TBI 1320–1400 cGy + cyclophosphamide, and (4) TBI 1320–1400 cGy + cyclophosphamide + etoposide [36]. Studies have shown that (1) etoposide + fractionated TBI and cyclophosphamide + fractionated TBI are equally effective, (2) effectiveness of chemotherapy alone, such as IV busulfan + melphalan, conditioning therapy in patients with HR ALL, (3) there is an advantage of substituting etoposide for cyclophosphamide or increasing the TBI dose to ≥13 Gy when cyclophosphamide is used, and (4) treosulfan, etoposide, and cyclophosphamide conditioning regimen has favorable toxicity profile with lower NRM [33, 35, 39, 40].

(5) presence of comorbid medical conditions [44, 48]. Compared with MAC regimens, RIC regimens have been associated with acceptable rates of donor engraftment and lower rates of TRM [48]. In children with ALL, the use of RIC regimens has achieved long-term DFS, but it has been associated with high rates of TRM, acute and chronic GVHD, myelosuppression, and disease relapse [44, 48]. In adult patients with HR-ALL receiving umbilical cord blood transplantation (UCBT): (1) MAC regimens have been associated with DFS comparable to that reported with other stem cell sources and (2) the results of RIC regimens are encouraging [49]. New therapeutic strategies for adults with ALL are increasingly utilized with better outcomes and they include: (1) various TKIs for Ph+ ALL, (2) pediatric inspired chemotherapeutic regimens for Philadelphia chromosome-negative (Ph−) ALL, and (3) HLA-haploidentical HSCT [44]. However, the optimal therapeutic modality should be selected after taking the following factors into consideration: age of the patient, Philadelphia chromosome positivity, donor availability, disease risk stratification, and efficacy as well as safety of the therapeutic

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Cytogenetic abnormalities occur in 60–85% of patients with ALL. However, numerical chromosomal abnormalities, alone or in association with structural changes, occur in 50% of ALL patients [2, 50, 51]. The most common chromosomal abnormalities that are encountered in patients with ALL are listed in **Table 1** [2, 50, 51]. In patients with ALL, certain HR features predict poor long-term outcome even in patients receiving intensive chemotherapy. These HR features are shown in **Table 2** [2, 3, 50, 52–55]. Patients having HR features, including HR cytogenetic abnormalities and genetic mutations, are less likely to respond well to chemotherapy and are more likely to relapse. Hence, this category of patients may require not only more intensified chemotherapeutic regimens but also novel therapies as well as HSCT in order to have optimal control of their leukemia [2, 3, 50, 52–55]. The main indications of allogeneic HSCT in children and adults with ALL are shown in **Table 3** [7, 23, 51–54, 56–65]. In adults with ALL, post-remission therapies include: consolidation chemotherapy followed by maintenance therapy, autologous HSCT, and allogeneic HSCT [66, 67]. There is controversy regarding the role of frontline allogeneic HSCT for patients with ALL in CR1 [68]. However, three meta-analyses showed potential benefit of allogeneic HSCT in CR1 [67–69]. These three meta-analyses included 41 studies and they came to the following conclusions: (1) myeloablative MSD allografts had absolute survival benefit of 10–15% at 5 years compared to chemotherapy alone or chemotherapy followed by autologous HSCT, (2) MSD allografts improve survival in patients younger than 35 years and are the optimal post-remission therapy in ALL patients ≥15 years old, (3) no beneficial effect of autologous HSCT in comparison to chemotherapy, and (4) MSD allografts offer superior OS as well as DFS and significantly reduce the risk of relapse but carry increased risk of NRM [67–69]. For patients with relapsed and refractory ALL, allogeneic HSCT is the only potentially curative therapeutic modality [68]. Three major studies that included 1419 patients with relapsed ALL in adults showed that the prognosis of relapsed ALL in adults was very poor and that the 5-year OS of adults with

relapsed ALL not subjected to allogeneic HSCT ranged between 0.0 and 10% [70–72].

measure [44].

**2.5. Allogeneic HSCT in ALL**

In comparison to TBI-containing conditioning regimens, fludarabine and pharmacokinetictargeted busulfan conditioning therapy appears to be safer and equally effective in controlling ALL [41]. Fludarabine + amsacrine + cytarabine (FLAMSA) + anti-thymocyte globulin (ATG) + fractionated TBI conditioning regimen followed by allogeneic HSCT is feasible and effective in patients with HR or relapsed ALL, thus presenting a potential alternative to the classical TBI and cyclophosphamide MAC therapy [37]. Studies have shown that (1) combination of busulfan and clofarabine provides an effective control while maintaining a favorable safety profile and has produced OS and NRM rates comparable to those achieved with traditional TBI-based conditioning regimens and (2) busulfan + fludarabine + ATG + TBI conditioning therapy has achieved excellent outcomes in all patients with ALL except older patients with comorbidities [38, 42, 43].

The incorporation of etoposide into the intensified conditioning regimens has been associated with improved disease control but at the expense of higher rates of toxicity and TRM [37]. Medium-dose etoposide, cyclophosphamide, and TBI conditioning therapy is suitable for adults with HR-ALL in CR1 and SR-ALL in CR2, below the age of 50 years, as it has been shown to be associated with: lower relapse rate, no increase in toxicity, and better OS [44, 45]. In children and adolescents with ALL, the addition of etoposide to TBI + cyclophosphamide conditioning regimen should be avoided due to increased risk of mortality. Also, TBI dose >1300 cGy should be avoided due to increased risk of second malignancy [36]. In children with ALL in CR1 and CR2, the incorporation of alemtuzumab, anti-CD52 monoclonal antibody, into the MAC therapy in MUD allografts has produced durable engraftment with low rates of GVHD and comparable rates of DFS to recipients of MSD transplants [46]. Thiotepa-based conditioning regimen for allogeneic HSCT in patients with ALL is feasible and effective, and it has produced main outcomes comparable to those achieved by other conditioning therapies [47]. In children with ALL transplanted in second CR, the 3-year DFS using MAC followed by allogeneic HSCT has been reported to range between 30% and 70% [48].

Reduced intensity conditioning (RIC) regimens have been used extensively in adults with hematologic malignancies including ALL [48]. In MAC regimens, relapse protection is provided by dose-intensive chemotherapy ± TBI, while in RIC regimens, relapse protection is provided by GVL effect [44, 48]. The indications for RIC-allogeneic HSCT include: (1) old age, (2) poor performance status, (3) active infection, (4) significant organ dysfunction, and (5) presence of comorbid medical conditions [44, 48]. Compared with MAC regimens, RIC regimens have been associated with acceptable rates of donor engraftment and lower rates of TRM [48]. In children with ALL, the use of RIC regimens has achieved long-term DFS, but it has been associated with high rates of TRM, acute and chronic GVHD, myelosuppression, and disease relapse [44, 48]. In adult patients with HR-ALL receiving umbilical cord blood transplantation (UCBT): (1) MAC regimens have been associated with DFS comparable to that reported with other stem cell sources and (2) the results of RIC regimens are encouraging [49]. New therapeutic strategies for adults with ALL are increasingly utilized with better outcomes and they include: (1) various TKIs for Ph+ ALL, (2) pediatric inspired chemotherapeutic regimens for Philadelphia chromosome-negative (Ph−) ALL, and (3) HLA-haploidentical HSCT [44]. However, the optimal therapeutic modality should be selected after taking the following factors into consideration: age of the patient, Philadelphia chromosome positivity, donor availability, disease risk stratification, and efficacy as well as safety of the therapeutic measure [44].

#### **2.5. Allogeneic HSCT in ALL**

The MAC regimens for ALL consist of: TBI (1200–1400 cGy) in addition to one or more chemotherapeutic agents [36]. In children with ALL, the MAC therapies include: (1) TBI 1000– 1200 cGy + cyclophosphamide, (2) TBI 1000–1200 cGy + cyclophosphamide + etoposide, (3) TBI 1320–1400 cGy + cyclophosphamide, and (4) TBI 1320–1400 cGy + cyclophosphamide + etoposide [36]. Studies have shown that (1) etoposide + fractionated TBI and cyclophosphamide + fractionated TBI are equally effective, (2) effectiveness of chemotherapy alone, such as IV busulfan + melphalan, conditioning therapy in patients with HR ALL, (3) there is an advantage of substituting etoposide for cyclophosphamide or increasing the TBI dose to ≥13 Gy when cyclophosphamide is used, and (4) treosulfan, etoposide, and cyclophosphamide con-

In comparison to TBI-containing conditioning regimens, fludarabine and pharmacokinetictargeted busulfan conditioning therapy appears to be safer and equally effective in controlling ALL [41]. Fludarabine + amsacrine + cytarabine (FLAMSA) + anti-thymocyte globulin (ATG) + fractionated TBI conditioning regimen followed by allogeneic HSCT is feasible and effective in patients with HR or relapsed ALL, thus presenting a potential alternative to the classical TBI and cyclophosphamide MAC therapy [37]. Studies have shown that (1) combination of busulfan and clofarabine provides an effective control while maintaining a favorable safety profile and has produced OS and NRM rates comparable to those achieved with traditional TBI-based conditioning regimens and (2) busulfan + fludarabine + ATG + TBI conditioning therapy has achieved excellent outcomes in all patients with ALL except older patients

The incorporation of etoposide into the intensified conditioning regimens has been associated with improved disease control but at the expense of higher rates of toxicity and TRM [37]. Medium-dose etoposide, cyclophosphamide, and TBI conditioning therapy is suitable for adults with HR-ALL in CR1 and SR-ALL in CR2, below the age of 50 years, as it has been shown to be associated with: lower relapse rate, no increase in toxicity, and better OS [44, 45]. In children and adolescents with ALL, the addition of etoposide to TBI + cyclophosphamide conditioning regimen should be avoided due to increased risk of mortality. Also, TBI dose >1300 cGy should be avoided due to increased risk of second malignancy [36]. In children with ALL in CR1 and CR2, the incorporation of alemtuzumab, anti-CD52 monoclonal antibody, into the MAC therapy in MUD allografts has produced durable engraftment with low rates of GVHD and comparable rates of DFS to recipients of MSD transplants [46]. Thiotepa-based conditioning regimen for allogeneic HSCT in patients with ALL is feasible and effective, and it has produced main outcomes comparable to those achieved by other conditioning therapies [47]. In children with ALL transplanted in second CR, the 3-year DFS using MAC followed by allogeneic HSCT has been reported to range

Reduced intensity conditioning (RIC) regimens have been used extensively in adults with hematologic malignancies including ALL [48]. In MAC regimens, relapse protection is provided by dose-intensive chemotherapy ± TBI, while in RIC regimens, relapse protection is provided by GVL effect [44, 48]. The indications for RIC-allogeneic HSCT include: (1) old age, (2) poor performance status, (3) active infection, (4) significant organ dysfunction, and

ditioning regimen has favorable toxicity profile with lower NRM [33, 35, 39, 40].

with comorbidities [38, 42, 43].

164 Stem Cells in Clinical Practice and Tissue Engineering

between 30% and 70% [48].

Cytogenetic abnormalities occur in 60–85% of patients with ALL. However, numerical chromosomal abnormalities, alone or in association with structural changes, occur in 50% of ALL patients [2, 50, 51]. The most common chromosomal abnormalities that are encountered in patients with ALL are listed in **Table 1** [2, 50, 51]. In patients with ALL, certain HR features predict poor long-term outcome even in patients receiving intensive chemotherapy. These HR features are shown in **Table 2** [2, 3, 50, 52–55]. Patients having HR features, including HR cytogenetic abnormalities and genetic mutations, are less likely to respond well to chemotherapy and are more likely to relapse. Hence, this category of patients may require not only more intensified chemotherapeutic regimens but also novel therapies as well as HSCT in order to have optimal control of their leukemia [2, 3, 50, 52–55]. The main indications of allogeneic HSCT in children and adults with ALL are shown in **Table 3** [7, 23, 51–54, 56–65].

In adults with ALL, post-remission therapies include: consolidation chemotherapy followed by maintenance therapy, autologous HSCT, and allogeneic HSCT [66, 67]. There is controversy regarding the role of frontline allogeneic HSCT for patients with ALL in CR1 [68]. However, three meta-analyses showed potential benefit of allogeneic HSCT in CR1 [67–69]. These three meta-analyses included 41 studies and they came to the following conclusions: (1) myeloablative MSD allografts had absolute survival benefit of 10–15% at 5 years compared to chemotherapy alone or chemotherapy followed by autologous HSCT, (2) MSD allografts improve survival in patients younger than 35 years and are the optimal post-remission therapy in ALL patients ≥15 years old, (3) no beneficial effect of autologous HSCT in comparison to chemotherapy, and (4) MSD allografts offer superior OS as well as DFS and significantly reduce the risk of relapse but carry increased risk of NRM [67–69]. For patients with relapsed and refractory ALL, allogeneic HSCT is the only potentially curative therapeutic modality [68]. Three major studies that included 1419 patients with relapsed ALL in adults showed that the prognosis of relapsed ALL in adults was very poor and that the 5-year OS of adults with relapsed ALL not subjected to allogeneic HSCT ranged between 0.0 and 10% [70–72].

**1.Philadelphia chromosome [t9,22]:** The commonest cytogenetic abnormality. Encountered in 15–30% of adults and 5% of children with ALL

**1. Age:** <1 year and >35 years

• > 30,000 in B-lineage • > 100,000 in T-lineage

**4. Immunophenotyping:** • CD 20 positivity

logic remission.

• Deletion 6q

• Low hypodiploidy • Near triploidy

• Translocation 8,14 • Translocation 4,11 • Translocation 1,19 • Translocation 9,22 • Philadelphia-like

• Complex cytogenetics

• +8 • −7

**2. White blood cell count at presentation:**

**3. Cell type:** pro-B; early and mature T

• CD 10 negative pre-B ALL. **5. Poor performance status:** >1 **6. Poor response to prednisolone**

**7. Peripheral blood blasts ≥5% on day: 8–15**

**9. Involvement of central nervous system 10. Clinical relapse:** >First complete remission

**12. High-risk cytogenetic and molecular abnormalities:**

• Immunoglobulin H gene rearrangement

• Intrachromosomal amplification of chromosome 21

**8. Failure to achieve remission** >**4 weeks of induction chemotherapy**

**11. Minimal residual disease:** Detectable molecular and immunophenotypic evidence of disease while in morpho-

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	- t4,11

**3.Chromosomal abnormalities that are associated with:**


**4.Other common cytogenetic encountered in patients with ALL:**


ALL, acute lymphoblastic leukemia and MLL, mixed lineage leukemia.

**Table 1.** The most common chromosomal abnormalities in patients with ALL.

Either MAC therapies or RIC regimens can be offered according to the age and comorbid medical conditions of the HSCT recipient [73, 74]. In patients with acute leukemia, the following stem cell sources have been utilized in allogeneic HSCT: MSD, MUD, and UCB [73, 75].

#### **2.6. Focus on haploidentical HSCT**

Haploidentical HSCT evolved several decades ago, and it has undergone several modifications and remarkable developments in relation to: conditioning therapy, post-transplantation immunosuppression, and graft manipulation [73, 76]. Historically, the main obstacles to successful haploidentical HSCT were graft failure, intractable GVHD, decreased GVL effect, and delayed immune reconstitution [75, 76]. This form of HSCT is readily available for the majority of patients with acute leukemia and is an acceptable alternative to other donor sources of stem cells [75–77]. Techniques that are used to improve the outcome of haploidentical HSCT include: (1) CD3/CD19 depletion to reduce GVHD, (2) KIR B haplotype donors

#### **1. Age:** <1 year and >35 years

#### **2. White blood cell count at presentation:**


#### **4. Immunophenotyping:**

	- +8
	- −7

Either MAC therapies or RIC regimens can be offered according to the age and comorbid medical conditions of the HSCT recipient [73, 74]. In patients with acute leukemia, the following stem cell sources have been utilized in allogeneic HSCT: MSD, MUD, and UCB [73, 75].

**1.Philadelphia chromosome [t9,22]:** The commonest cytogenetic abnormality. Encountered in 15–30% of adults and

**2.Chromosomal abnormalities that are associated with higher risk of central nervous system involvement:**

Haploidentical HSCT evolved several decades ago, and it has undergone several modifications and remarkable developments in relation to: conditioning therapy, post-transplantation immunosuppression, and graft manipulation [73, 76]. Historically, the main obstacles to successful haploidentical HSCT were graft failure, intractable GVHD, decreased GVL effect, and delayed immune reconstitution [75, 76]. This form of HSCT is readily available for the majority of patients with acute leukemia and is an acceptable alternative to other donor sources of stem cells [75–77]. Techniques that are used to improve the outcome of haploidentical HSCT include: (1) CD3/CD19 depletion to reduce GVHD, (2) KIR B haplotype donors

**2.6. Focus on haploidentical HSCT**

5% of children with ALL

166 Stem Cells in Clinical Practice and Tissue Engineering

• High risk of relapse

**3.Chromosomal abnormalities that are associated with:** • High white cell and blast cell counts at presentation

**4.Other common cytogenetic encountered in patients with ALL:**

ALL, acute lymphoblastic leukemia and MLL, mixed lineage leukemia.

**Table 1.** The most common chromosomal abnormalities in patients with ALL.

• t4,11 • t8,14 • t14q+

• t9,22 • t4,11

• t10,14 • t1,14

• Deletion 11q22

• Hypodiploidy • Hyperdiploidy

• Deletion 11q23 [MLL]


#### **13. High-risk genetic mutations:**


**Table 2.** High-risk features that predict poor long-term outcome even with intensive chemotherapy in patients with acute lymphoblastic leukemia.

In patients with Ph− ALL in CR1, studies have shown that (1) outcomes of haploidentical HSCT are comparable to MSD and MUD allografts and (2) outcomes of HR patients are comparable to those of low-risk patients once haploidentical allografts are used. Therefore, haploidentical HSCT represents a valuable alternative for patients with Ph− ALL lacking MSDs [79, 80]. In adult patients with HR-ALL in CR1, haploidentical HSCT performed with post-transplantation cyclophosphamide-based GVHD prophylaxis has produced 52% DFS at

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Also in adults with HR-ALL in CR1 and CR2 or beyond, unmanipulated haploidentical transplants have been associated with 3-year OS and DFS of 33 and 31%, respectively; thus, unmanipulated haploidentical allografts can be considered a valid option for adults with HR-ALL lacking HLA-identical donors particularly if performed in early disease status [74]. Compared to HLA-matched related donor allografts, haploidentical HSCT has produced similar rates of long-term survival and NRM but lower relapse rates in patients with Ph+ ALL, thus haploidentical HSCT represents a valid therapeutic option for patients who lack a suitable HLA-

T-cell ALL is an aggressive neoplasm derived from malignant transformation of lymphoblasts committed to T-cell lineage [83]. It accounts for 10–25% of all cases of ALL [84–86]. Given the rarity of T-cell ALL, patients are typically treated in a similar fashion to B-cell ALL with pediatric inspired dose-intense multi-agent chemotherapy regimens in addition to central nervous system (CNS) prophylaxis [83–85]. T-cell ALL carries a poor prognosis compared with B-cell ALL due to: (1) higher relapse rates even if they respond to chemotherapy and achieve CR and (2) more extensive involvement of bone marrow and extramedullary sites, particularly the mediastinum [83, 84, 86]. Even with the current intensive chemotherapeutic regimens, the 5-year event-free survival (EFS) is 80%, whereas the 10-year EFS is only

Allogeneic HSCT is a potentially curative therapeutic option for patients with T-cell ALL, but relapse after allogeneic HSCT is a major cause of treatment failure [86]. Patients with T-cell ALL who lack an HLA-matching donor for allogeneic HSCT should preferably have prolonged maintenance chemotherapy [83]. Studies have shown that (1) in children with T-cell ALL in CR2 subjected to allogeneic HSCT, the 3-year OS is about 50% and (2) in adults with T-cell ALL including the aggressive early-thymic precursor (ETP) subtype subjected to allogeneic HSCT in CR1, the 3-year OS is 62% and those transplanted in CR2 or beyond, the 3-year OS is 24% indicating the better outcome of allogeneic HSCT in CR1 in adults [84, 85]. Other studies on adults with T-cell ALL subjected to allogeneic HSCT have shown the following results: (1) allogeneic HSCT is safe and effective in overcoming the poor prognosis particularly when applied early, (2) there was controversy regarding the use of TBI in the conditioning therapies as some studies highlighted the importance of having TBI as part of the conditioning regimen, while other studies showed no difference between TBI-based and busulfan-based conditioning therapies, and (3) MRD status at transplantation is highly predictive of disease relapse, suggesting that novel therapies

3 years, thus providing a suitable alternative to HLA-matched transplantation [68].

matched donor [81, 82].

**2.7. HSCT in T-cell ALL**

15% [84].

confer rapid natural killer cell proliferation soon after HSCT resulting in lower relapse rates due to GVL effect, and (3) infusion of high numbers of CD34+ cells to improve immune reconstitution [77].

Historically, mega doses of stem cells had been used after T-cell depletion in order to avoid development of GVHD, but this maneuver had been associated with high incidence of graft failure and disease relapse [73, 78]. Recently, unmanipulated allografts and post-transplantation cyclophosphamide have been used with high success [73, 74, 78]. Also, it has been shown that the outcome of unmanipulated haploidentical HSCT in adult patients with acute leukemia are comparable to those of unrelated UCBT and MUD allografts [74, 78].


ALL, acute lymphoblastic leukemia; CR, complete remission; MLL, mixed lineage leukemia; and MRD, minimal residual disease.

**Table 3.** Indications of allogeneic HSCT in patients with ALL.

In patients with Ph− ALL in CR1, studies have shown that (1) outcomes of haploidentical HSCT are comparable to MSD and MUD allografts and (2) outcomes of HR patients are comparable to those of low-risk patients once haploidentical allografts are used. Therefore, haploidentical HSCT represents a valuable alternative for patients with Ph− ALL lacking MSDs [79, 80]. In adult patients with HR-ALL in CR1, haploidentical HSCT performed with post-transplantation cyclophosphamide-based GVHD prophylaxis has produced 52% DFS at 3 years, thus providing a suitable alternative to HLA-matched transplantation [68].

Also in adults with HR-ALL in CR1 and CR2 or beyond, unmanipulated haploidentical transplants have been associated with 3-year OS and DFS of 33 and 31%, respectively; thus, unmanipulated haploidentical allografts can be considered a valid option for adults with HR-ALL lacking HLA-identical donors particularly if performed in early disease status [74]. Compared to HLA-matched related donor allografts, haploidentical HSCT has produced similar rates of long-term survival and NRM but lower relapse rates in patients with Ph+ ALL, thus haploidentical HSCT represents a valid therapeutic option for patients who lack a suitable HLAmatched donor [81, 82].

#### **2.7. HSCT in T-cell ALL**

confer rapid natural killer cell proliferation soon after HSCT resulting in lower relapse rates due to GVL effect, and (3) infusion of high numbers of CD34+ cells to improve immune

**Table 2.** High-risk features that predict poor long-term outcome even with intensive chemotherapy in patients with

Historically, mega doses of stem cells had been used after T-cell depletion in order to avoid development of GVHD, but this maneuver had been associated with high incidence of graft failure and disease relapse [73, 78]. Recently, unmanipulated allografts and post-transplantation cyclophosphamide have been used with high success [73, 74, 78]. Also, it has been shown that the outcome of unmanipulated haploidentical HSCT in adult patients with acute leuke-

ALL, acute lymphoblastic leukemia; CR, complete remission; MLL, mixed lineage leukemia; and MRD, minimal residual

**1.**Severe hypodiploidy **2.**Persistent MRD

**4.**Primary induction failure

extramedullary relapse

**3.**T-cell ALL with poor response to prednisolone

**5.**MLL gene rearrangement in infants with ALL **6.**Relapsed ALL [ALL in CR2]: bone marrow or

mia are comparable to those of unrelated UCBT and MUD allografts [74, 78].

**Adults Children**

**5.**Primary refractory disease [ALL refractory to induction or first-line chemotherapy]; once CR is achieved following salvage therapy, al-

**6.**Presence of MRD at any stage during the course of the disease, regardless their initial risk group [standard risk or high risk]

**7.**MLL [mixed lineage leukemia] gene rearrangement

**Table 3.** Indications of allogeneic HSCT in patients with ALL.

**1.**Philadelphia chromosome-positive ALL in CR1 **2.**ALL with Philadelphia-like molecular signature

**3.**High-risk or very high-risk ALL in CR1 **4.**Relapsed ALL [ALL in CR2 or beyond]

logeneic HSCT can be performed

disease.

reconstitution [77].

acute lymphoblastic leukemia.

**13. High-risk genetic mutations:** • IKZF1 deletion [IKAROS] • Unmutated NOTCH1

168 Stem Cells in Clinical Practice and Tissue Engineering

• RAS-PTEN altered • JAK 2 mutation • KMT2A rearrangement

• CREBBP • CRLF2 • ETP • PBX-E2A+ • BAALC+

• MLL [mixed lineage leukemia] gene rearrangement: 11q23

T-cell ALL is an aggressive neoplasm derived from malignant transformation of lymphoblasts committed to T-cell lineage [83]. It accounts for 10–25% of all cases of ALL [84–86]. Given the rarity of T-cell ALL, patients are typically treated in a similar fashion to B-cell ALL with pediatric inspired dose-intense multi-agent chemotherapy regimens in addition to central nervous system (CNS) prophylaxis [83–85]. T-cell ALL carries a poor prognosis compared with B-cell ALL due to: (1) higher relapse rates even if they respond to chemotherapy and achieve CR and (2) more extensive involvement of bone marrow and extramedullary sites, particularly the mediastinum [83, 84, 86]. Even with the current intensive chemotherapeutic regimens, the 5-year event-free survival (EFS) is 80%, whereas the 10-year EFS is only 15% [84].

Allogeneic HSCT is a potentially curative therapeutic option for patients with T-cell ALL, but relapse after allogeneic HSCT is a major cause of treatment failure [86]. Patients with T-cell ALL who lack an HLA-matching donor for allogeneic HSCT should preferably have prolonged maintenance chemotherapy [83]. Studies have shown that (1) in children with T-cell ALL in CR2 subjected to allogeneic HSCT, the 3-year OS is about 50% and (2) in adults with T-cell ALL including the aggressive early-thymic precursor (ETP) subtype subjected to allogeneic HSCT in CR1, the 3-year OS is 62% and those transplanted in CR2 or beyond, the 3-year OS is 24% indicating the better outcome of allogeneic HSCT in CR1 in adults [84, 85]. Other studies on adults with T-cell ALL subjected to allogeneic HSCT have shown the following results: (1) allogeneic HSCT is safe and effective in overcoming the poor prognosis particularly when applied early, (2) there was controversy regarding the use of TBI in the conditioning therapies as some studies highlighted the importance of having TBI as part of the conditioning regimen, while other studies showed no difference between TBI-based and busulfan-based conditioning therapies, and (3) MRD status at transplantation is highly predictive of disease relapse, suggesting that novel therapies can be offered before and after allogeneic HSCT to improve the outcome of this group of patients [85–88]. Patients with refractory T-cell ALL can be treated successfully with unmanipulated allografts from HLA-mismatched haploidentical siblings as haploidentical HSCT offers higher GVL effect [89, 90].

of allogeneic HSCT are superior to chemotherapy alone, (2) MSD and MUD allografts have yielded equivalent outcomes, (3) in patients subjected to allogeneic HSCT, age, WBC count at presentation, and early response to treatment have been shown to be independent prognostic indicators, (4) early allogeneic HSCT is recommended once morphologic remission is achieved as this form of treatment has shown to produce durable remissions in patients with CR1, and (5) in children with Ph+ ALL, two studies showed advantage of allogeneic HSCT in protection against late disease relapses and in achieving 5-year OS and DFS of 80.2 and 72.9%,

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In patients with Ph+ ALL, achievement of complete molecular remission (CMR) prior to allogeneic HSCT reduces the risk of leukemia relapse post-allogeneic HSCT even though TKIs may still rescue some patients who relapse after transplantation [109, 110]. Without TKIs, 30–50% of patients with Ph+ ALL relapse after allogeneic HSCT [96]. Even in the era of TKIs, relapse is still the main cause of allogeneic HSCT failure in HR patients Ph+ ALL [111]. Ph+ ALL patients, subjected to allogeneic HSCT, should ideally be (1) in CR and without MRD prior to transplantation and (2) below 60 years of age. However, only carefully selected patients ≥60 years old are candidates for allogeneic HSCT [100, 112]. In patients with Ph+ ALL, RIC allogeneic HSCT can be offered to older patients and those with comor-

Additional cytogenetic abnormalities, such as monosomy 7, and abnormalities of chromosomes 8 and 9 are common in patients with Ph+ ALL as they are encountered in two thirds of cases [113]. Pre-existing mutations in the ABL kinase domain are frequently associated with resistance to TKIs and are a common cause of post-HSCT relapse in patients with Ph+ ALL [101]. Pre-transplantation risk factors for relapse in patients with Ph+ ALL include: (1) expression of P190 transcript, (2) evidence of morphologic disease at the time of transplantation, and (3) type of donor, with recipients of autologous HSCT or MSD having the highest risk of relapse [96]. Post-transplantation risk factors for relapse in patients with Ph+ ALL include: (1) expression of P190 transcript which carries the highest risk of relapse, (2) detection of MRD by reverse transcription PCR for bcr-abl transcript, and (3) lack of chronic extensive GVHD [96]. These risk factors can be utilized to improve risk stratification for patients with Ph+ ALL undergoing HSCT in order to develop specific strategies or therapeutic plans [96]. In patients with Ph+ ALL subjected to allogeneic HSCT, TKI therapy tailored according to pre-transplantation TKI response, anticipated toxicities, and Abl-1 domain mutations is feasible and may

Approximately 20–25% of ALL patients experience relapses of their disease at 5 years from diagnosis and initial therapy despite receiving the standard chemotherapeutic regimens [114, 115]. The prognosis of children and young adults with relapsed ALL is poor [114, 115]. Only a minority of adults with ALL who relapse after first line therapy can be rescued [116]. Salvage chemotherapy in patients with relapsed ALL includes: (1) mitoxantrone, etoposide, and cytarabine or (2) fludarabine, cytarabine, pegylated-asparaginase, and granulocyte colony stimulating factor [116]. Salvage chemotherapy alone is not curative in relapsed ALL [115].

bidities, that is, patients who are ineligible for MAC therapy [100, 112].

reduce relapse rate and improve the outcome of patients [111].

**2.9. Relapse of ALL before and after HSCT**

respectively [105–108].

Nelarabine, a prodrug of Ara-G, has shown selective cytotoxicity against T-cell lymphoblasts and is usually used in relapsed and refractory T-cell ALL [83, 91]. Nelarabine is a valuable therapeutic option in patients with T-cell ALL relapsing after allogeneic HSCT as it has shown response rates reaching 81%; hence it should be considered in: (1) treating relapses post-allogeneic HSCT and (2) maintenance therapy following transplantation in HR patients [91].

Gamma delta subtype of precursor T-cell ALL is usually treated with the same intensive chemotherapeutic regimens like other types of ALL (T- and B-cell types) [92]. In this rare type of T-cell ALL, the preferred therapy is usually induction chemotherapy to achieve CR followed by upfront allogeneic HSCT to eradicate the potential residual disease by the GVT effect of allogeneic HSCT [92].

#### **2.8. HSCT in Ph+ ALL**

Philadelphia chromosome positivity is the most common recurrent cytogenetic abnormality observed in adult patients with ALL [93–95]. Approximately 20–25% of adults and only about 2% of children with ALL harbor Philadelphia chromosome and express the bcr-abl transcript [93, 96, 97]. In recent years, the most significant therapeutic advancement has been the introduction of TKIs into the therapeutic regimens of Ph+ ALL [94]. In the era before TKIs, patients with Ph+ ALL were having poor prognosis after standard chemotherapy with DFS rates ranging between 0.0% and 20% [94, 96]. Historically, adult Ph+ ALL had been associated with high relapse rates and short DFS and OS [98].

Results of autologous HSCT in adults with Ph+ ALL are still disappointing [99]. Studies have shown that (1) Ph+ ALL is incurable without allogeneic HSCT and (2) in patients with Ph+ ALL, particularly adults, who are eligible for HSCT and who have achieved CR allogeneic HSCT, has remained the consolidation therapy of choice and the only proven curative therapeutic strategy [94, 96, 98–101]. However, patients with Ph+ ALL planned for allogeneic HSCT can be divided into three risk groups or categories: (1) HR; positive MRD or overt clinical disease, (2) intermediate risk; molecular disease but without morphologic disease, and (3) low risk; no evidence of MRD [96].

In children and adolescents with Ph+ ALL, allogeneic HSCT is a controversial issue and there is increasing reluctance to offer allogeneic HSCT to children in the era of TKIs [94, 97, 102]. The children's Oncology Group reported the following results on the use of TKIs in children and adolescents with Ph+ ALL: (1) excellent outcomes of the combination of TKI and chemotherapy with OS of 88% at 3 years and 70% at 5 years, (2) achievement of complete hematological remission in approximately 95% of cases and molecular remission in >50% of patients, and (3) no advantage of subjecting patients to allogeneic HSCT [103, 104]. On the contrary, in children and young adults with Ph+ ALL, studies have shown that (1) results of allogeneic HSCT are superior to chemotherapy alone, (2) MSD and MUD allografts have yielded equivalent outcomes, (3) in patients subjected to allogeneic HSCT, age, WBC count at presentation, and early response to treatment have been shown to be independent prognostic indicators, (4) early allogeneic HSCT is recommended once morphologic remission is achieved as this form of treatment has shown to produce durable remissions in patients with CR1, and (5) in children with Ph+ ALL, two studies showed advantage of allogeneic HSCT in protection against late disease relapses and in achieving 5-year OS and DFS of 80.2 and 72.9%, respectively [105–108].

In patients with Ph+ ALL, achievement of complete molecular remission (CMR) prior to allogeneic HSCT reduces the risk of leukemia relapse post-allogeneic HSCT even though TKIs may still rescue some patients who relapse after transplantation [109, 110]. Without TKIs, 30–50% of patients with Ph+ ALL relapse after allogeneic HSCT [96]. Even in the era of TKIs, relapse is still the main cause of allogeneic HSCT failure in HR patients Ph+ ALL [111]. Ph+ ALL patients, subjected to allogeneic HSCT, should ideally be (1) in CR and without MRD prior to transplantation and (2) below 60 years of age. However, only carefully selected patients ≥60 years old are candidates for allogeneic HSCT [100, 112]. In patients with Ph+ ALL, RIC allogeneic HSCT can be offered to older patients and those with comorbidities, that is, patients who are ineligible for MAC therapy [100, 112].

Additional cytogenetic abnormalities, such as monosomy 7, and abnormalities of chromosomes 8 and 9 are common in patients with Ph+ ALL as they are encountered in two thirds of cases [113]. Pre-existing mutations in the ABL kinase domain are frequently associated with resistance to TKIs and are a common cause of post-HSCT relapse in patients with Ph+ ALL [101]. Pre-transplantation risk factors for relapse in patients with Ph+ ALL include: (1) expression of P190 transcript, (2) evidence of morphologic disease at the time of transplantation, and (3) type of donor, with recipients of autologous HSCT or MSD having the highest risk of relapse [96]. Post-transplantation risk factors for relapse in patients with Ph+ ALL include: (1) expression of P190 transcript which carries the highest risk of relapse, (2) detection of MRD by reverse transcription PCR for bcr-abl transcript, and (3) lack of chronic extensive GVHD [96]. These risk factors can be utilized to improve risk stratification for patients with Ph+ ALL undergoing HSCT in order to develop specific strategies or therapeutic plans [96]. In patients with Ph+ ALL subjected to allogeneic HSCT, TKI therapy tailored according to pre-transplantation TKI response, anticipated toxicities, and Abl-1 domain mutations is feasible and may reduce relapse rate and improve the outcome of patients [111].

#### **2.9. Relapse of ALL before and after HSCT**

can be offered before and after allogeneic HSCT to improve the outcome of this group of patients [85–88]. Patients with refractory T-cell ALL can be treated successfully with unmanipulated allografts from HLA-mismatched haploidentical siblings as haploidentical

Nelarabine, a prodrug of Ara-G, has shown selective cytotoxicity against T-cell lymphoblasts and is usually used in relapsed and refractory T-cell ALL [83, 91]. Nelarabine is a valuable therapeutic option in patients with T-cell ALL relapsing after allogeneic HSCT as it has shown response rates reaching 81%; hence it should be considered in: (1) treating relapses post-allogeneic HSCT and (2) maintenance therapy following transplantation in

Gamma delta subtype of precursor T-cell ALL is usually treated with the same intensive chemotherapeutic regimens like other types of ALL (T- and B-cell types) [92]. In this rare type of T-cell ALL, the preferred therapy is usually induction chemotherapy to achieve CR followed by upfront allogeneic HSCT to eradicate the potential residual disease by the GVT effect of

Philadelphia chromosome positivity is the most common recurrent cytogenetic abnormality observed in adult patients with ALL [93–95]. Approximately 20–25% of adults and only about 2% of children with ALL harbor Philadelphia chromosome and express the bcr-abl transcript [93, 96, 97]. In recent years, the most significant therapeutic advancement has been the introduction of TKIs into the therapeutic regimens of Ph+ ALL [94]. In the era before TKIs, patients with Ph+ ALL were having poor prognosis after standard chemotherapy with DFS rates ranging between 0.0% and 20% [94, 96]. Historically, adult Ph+ ALL had been associated with high

Results of autologous HSCT in adults with Ph+ ALL are still disappointing [99]. Studies have shown that (1) Ph+ ALL is incurable without allogeneic HSCT and (2) in patients with Ph+ ALL, particularly adults, who are eligible for HSCT and who have achieved CR allogeneic HSCT, has remained the consolidation therapy of choice and the only proven curative therapeutic strategy [94, 96, 98–101]. However, patients with Ph+ ALL planned for allogeneic HSCT can be divided into three risk groups or categories: (1) HR; positive MRD or overt clinical disease, (2) intermediate risk; molecular disease but without morphologic disease, and (3)

In children and adolescents with Ph+ ALL, allogeneic HSCT is a controversial issue and there is increasing reluctance to offer allogeneic HSCT to children in the era of TKIs [94, 97, 102]. The children's Oncology Group reported the following results on the use of TKIs in children and adolescents with Ph+ ALL: (1) excellent outcomes of the combination of TKI and chemotherapy with OS of 88% at 3 years and 70% at 5 years, (2) achievement of complete hematological remission in approximately 95% of cases and molecular remission in >50% of patients, and (3) no advantage of subjecting patients to allogeneic HSCT [103, 104]. On the contrary, in children and young adults with Ph+ ALL, studies have shown that (1) results

HSCT offers higher GVL effect [89, 90].

170 Stem Cells in Clinical Practice and Tissue Engineering

relapse rates and short DFS and OS [98].

low risk; no evidence of MRD [96].

HR patients [91].

allogeneic HSCT [92].

**2.8. HSCT in Ph+ ALL**

Approximately 20–25% of ALL patients experience relapses of their disease at 5 years from diagnosis and initial therapy despite receiving the standard chemotherapeutic regimens [114, 115]. The prognosis of children and young adults with relapsed ALL is poor [114, 115]. Only a minority of adults with ALL who relapse after first line therapy can be rescued [116]. Salvage chemotherapy in patients with relapsed ALL includes: (1) mitoxantrone, etoposide, and cytarabine or (2) fludarabine, cytarabine, pegylated-asparaginase, and granulocyte colony stimulating factor [116]. Salvage chemotherapy alone is not curative in relapsed ALL [115]. Allogeneic HSCT offers the best and may be the only chance for cure in relapsed ALL, particularly in adult patients [114–116]. Allogeneic HSCT can be performed using either a sibling donor or an unrelated donor [114, 115].

patients with Ph+ ALL, TKIs have been incorporated into: (1) the induction phase in conjunction with cytotoxic chemotherapy, (2) in the consolidation and maintenance phases in conjunction with cytotoxic chemotherapy in patients who are not eligible for allogeneic HSCT, and (3) in the post-transplantation maintenance therapy in recipients of allogeneic HSCT and their incorporation into the treatment regimens at various stages of the disease has signifi-

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Studies in children with Ph+ ALL have shown that (1) the incorporation of imatinib into the chemotherapeutic regimens has improved the prognosis and (2) TKIs administered in the early phases of therapy can dramatically reduce MRD and improve the outcome of patients [12, 94, 124, 125]. Also, several groups have reported that the combination of imatinib and high dose chemotherapy has significantly improved the outcome of children and adults with Ph+ ALL with CR rates reaching 86–95% and 1-year OS reaching 75% [94, 124]. The 4-year OS in Ph+ ALL subjected to allogeneic HSCT in the era of imatinib has increased significantly to reach 52% [94]. Imatinib maintenance following allogeneic HSCT may further improve the

Dasatinib is a second-generation TKI with dual Src and Abl kinase inhibition activity [126, 127]. It is active against all imatinib-resistant kinase domain mutations apart from T315I mutation, thus having superior potency for inhibiting bcr-abl fusion protein compared to imatinib [126, 127]. The use of dasatinib is associated with the following adverse effects: bone marrow suppression, fluid retention, pleural effusion, skin eruptions, cardiac conduction disturbances, and colitis that may be hemorrhagic, immune-mediated, or cytomegalovirus-

Dasatinib is usually used in combination with cytotoxic chemotherapy such as hyper-CVAD regimen to control Ph+ ALL prior to allogeneic HSCT [126]. It can also be used in the setting of post-HSCT as maintenance therapy to prevent disease relapse or to eliminate MRD [127]. In older adults who are not candidates for allogeneic HSCT or younger patients who are unable to tolerate intensive chemotherapy, an induction regimen composed of targeted therapies such as dasatinib and corticosteroids may offer the potential of greater and longer responses, thus avoiding the morbidity associated with the use of cytotoxic chemotherapy [128, 129]. In this combination, dasatinib inhibits Scr-Abl kinase while corticosteroids modulate Bcl2 family of proteins leading to apoptosis [128]. The combination of dasatinib and corticosteroids is associated with relapses mainly due to T315I mutations that can be further treated with

The use of TKIs, including the second-generation drugs such as nilotinib, in the post-HSCT setting in patients with Ph+ ALL could potentially reduce relapse rates [130, 131]. Studies

cantly improved the outcomes of patients [10–12, 93, 124].

outcome of patients with Ph+ ALL [125].

*3.1.1. Imatinib*

*3.1.2. Dasatinib*

induced [127].

ponatinib [129].

*3.1.3. Nilotinib*

In patients with ALL, relapse after HSCT remains the main cause of treatment failure due to the limited therapeutic options and the associated poor outcome [117–119]. Factors that affect the occurrence as well as the outcome of ALL relapse after HSCT include: GVHD, MRD, intrinsic factors of the disease, and transplantation characteristics [120]. The prognosis of patients with ALL who relapse after HSCT is extremely poor with long-term survival <10%, and there is no difference in short-term survival between patients with isolated EMR and systemic relapse, suggesting that all disease relapses should be treated systemically [118]. EMR after allogeneic HSCT poses significant challenge for transplantation physicians as it carries poor outcome and has limited therapeutic options [119]. The risk factors for EMR, particularly CNS relapse, after allogeneic HSCT include: HR cytogenetics, advanced disease status, male gender, history of EMD before HSCT, hyperleukocytosis at diagnosis, and receiving peripheral blood stem cells [119]. However, prophylactic IT chemotherapy and maintenance treatment after HSCT may reduce the rate of CNS relapse post-HSCT [119].

Treatment of ALL relapse post-HSCT includes: (1) continuation of low-dose immunosuppressive therapy may be the optimal approach as abrupt discontinuation of immune suppression does not lead to any clinical benefit and may result in aggravation of GVHD, (2) re-induction or salvage therapy followed by second allogeneic HSCT in highly selected patients may offer the best chance of prolonged survival, and (3) other interventions, such as frequent MRD monitoring, pre-emptive immunotherapy in the form of DLI, post-transplantation maintenance therapy, use of novel and targeted therapies in post-HSCT, and enrollment in clinical trials [117, 118, 120].

Prerequisites for successful management of ALL post-HSCT relapse by either second allogeneic HSCT or experimental non-transplant approaches include: good clinical condition of the patient and the capacity to achieve hematological remission by the salvage therapy [117]. For patients with acute leukemia who relapse after the first allogeneic HSCT, only a second allograft can provide a realistic chance of long-term disease remission [121]. The second allogeneic HSCT used in the treatment of relapse after the first allograft can be obtained from HLA-MSD, MUD, or HLA-mismatched alternative donor [122]. Based on the rapid donor availability as compared to MUD, a haploidentical second allogeneic HSCT might be considered as an alternative therapeutic option for relapse after the first allograft [122, 123].

### **3. Novel and targeted therapies in ALL**

#### **3.1. Tyrosine kinase inhibitors**

The introduction of TKIs has revolutionized the therapy of patients with Ph+ ALL [94, 107]. Over the past 12 years, administration of TKIs before allogeneic HSCT has significantly improved the long-term outcome of allogeneic HSCT in adults with Ph+ ALL [93, 107]. In patients with Ph+ ALL, TKIs have been incorporated into: (1) the induction phase in conjunction with cytotoxic chemotherapy, (2) in the consolidation and maintenance phases in conjunction with cytotoxic chemotherapy in patients who are not eligible for allogeneic HSCT, and (3) in the post-transplantation maintenance therapy in recipients of allogeneic HSCT and their incorporation into the treatment regimens at various stages of the disease has significantly improved the outcomes of patients [10–12, 93, 124].

#### *3.1.1. Imatinib*

Allogeneic HSCT offers the best and may be the only chance for cure in relapsed ALL, particularly in adult patients [114–116]. Allogeneic HSCT can be performed using either a sibling

In patients with ALL, relapse after HSCT remains the main cause of treatment failure due to the limited therapeutic options and the associated poor outcome [117–119]. Factors that affect the occurrence as well as the outcome of ALL relapse after HSCT include: GVHD, MRD, intrinsic factors of the disease, and transplantation characteristics [120]. The prognosis of patients with ALL who relapse after HSCT is extremely poor with long-term survival <10%, and there is no difference in short-term survival between patients with isolated EMR and systemic relapse, suggesting that all disease relapses should be treated systemically [118]. EMR after allogeneic HSCT poses significant challenge for transplantation physicians as it carries poor outcome and has limited therapeutic options [119]. The risk factors for EMR, particularly CNS relapse, after allogeneic HSCT include: HR cytogenetics, advanced disease status, male gender, history of EMD before HSCT, hyperleukocytosis at diagnosis, and receiving peripheral blood stem cells [119]. However, prophylactic IT chemotherapy and maintenance treat-

Treatment of ALL relapse post-HSCT includes: (1) continuation of low-dose immunosuppressive therapy may be the optimal approach as abrupt discontinuation of immune suppression does not lead to any clinical benefit and may result in aggravation of GVHD, (2) re-induction or salvage therapy followed by second allogeneic HSCT in highly selected patients may offer the best chance of prolonged survival, and (3) other interventions, such as frequent MRD monitoring, pre-emptive immunotherapy in the form of DLI, post-transplantation maintenance therapy, use of novel and targeted therapies in post-HSCT, and enrollment in clinical

Prerequisites for successful management of ALL post-HSCT relapse by either second allogeneic HSCT or experimental non-transplant approaches include: good clinical condition of the patient and the capacity to achieve hematological remission by the salvage therapy [117]. For patients with acute leukemia who relapse after the first allogeneic HSCT, only a second allograft can provide a realistic chance of long-term disease remission [121]. The second allogeneic HSCT used in the treatment of relapse after the first allograft can be obtained from HLA-MSD, MUD, or HLA-mismatched alternative donor [122]. Based on the rapid donor availability as compared to MUD, a haploidentical second allogeneic HSCT might be consid-

ered as an alternative therapeutic option for relapse after the first allograft [122, 123].

The introduction of TKIs has revolutionized the therapy of patients with Ph+ ALL [94, 107]. Over the past 12 years, administration of TKIs before allogeneic HSCT has significantly improved the long-term outcome of allogeneic HSCT in adults with Ph+ ALL [93, 107]. In

**3. Novel and targeted therapies in ALL**

**3.1. Tyrosine kinase inhibitors**

ment after HSCT may reduce the rate of CNS relapse post-HSCT [119].

donor or an unrelated donor [114, 115].

172 Stem Cells in Clinical Practice and Tissue Engineering

trials [117, 118, 120].

Studies in children with Ph+ ALL have shown that (1) the incorporation of imatinib into the chemotherapeutic regimens has improved the prognosis and (2) TKIs administered in the early phases of therapy can dramatically reduce MRD and improve the outcome of patients [12, 94, 124, 125]. Also, several groups have reported that the combination of imatinib and high dose chemotherapy has significantly improved the outcome of children and adults with Ph+ ALL with CR rates reaching 86–95% and 1-year OS reaching 75% [94, 124]. The 4-year OS in Ph+ ALL subjected to allogeneic HSCT in the era of imatinib has increased significantly to reach 52% [94]. Imatinib maintenance following allogeneic HSCT may further improve the outcome of patients with Ph+ ALL [125].

#### *3.1.2. Dasatinib*

Dasatinib is a second-generation TKI with dual Src and Abl kinase inhibition activity [126, 127]. It is active against all imatinib-resistant kinase domain mutations apart from T315I mutation, thus having superior potency for inhibiting bcr-abl fusion protein compared to imatinib [126, 127]. The use of dasatinib is associated with the following adverse effects: bone marrow suppression, fluid retention, pleural effusion, skin eruptions, cardiac conduction disturbances, and colitis that may be hemorrhagic, immune-mediated, or cytomegalovirusinduced [127].

Dasatinib is usually used in combination with cytotoxic chemotherapy such as hyper-CVAD regimen to control Ph+ ALL prior to allogeneic HSCT [126]. It can also be used in the setting of post-HSCT as maintenance therapy to prevent disease relapse or to eliminate MRD [127]. In older adults who are not candidates for allogeneic HSCT or younger patients who are unable to tolerate intensive chemotherapy, an induction regimen composed of targeted therapies such as dasatinib and corticosteroids may offer the potential of greater and longer responses, thus avoiding the morbidity associated with the use of cytotoxic chemotherapy [128, 129]. In this combination, dasatinib inhibits Scr-Abl kinase while corticosteroids modulate Bcl2 family of proteins leading to apoptosis [128]. The combination of dasatinib and corticosteroids is associated with relapses mainly due to T315I mutations that can be further treated with ponatinib [129].

#### *3.1.3. Nilotinib*

The use of TKIs, including the second-generation drugs such as nilotinib, in the post-HSCT setting in patients with Ph+ ALL could potentially reduce relapse rates [130, 131]. Studies on the use of nilotinib have shown the following results: (1) safety and efficacy of nilotinib prophylaxis to prevent relapse of Ph+ ALL after allogeneic HSCT, (2) effectiveness of nilotinib to control MRD and to convert patients to CMR, and (3) achievement of prolongation of survival without jeopardizing immune function or reconstitution following HSCT [130–133]. However, side effects such as prolongation of QT interval on electrocardiogram and early disease relapse post-HSCT may limit its use [132, 134].

of blinatumomab include: fever, febrile neutropenia, headache, neurotoxicity, such as apha-

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Chimeric antigen receptors (CAR) consist of an extracellular antigen recognition domain linked to an intracellular signaling domain [152, 153]. An important part of CAR design in choosing an optimal tumor-associated antigen to target [152]. A patient's own T-cells may be genetically modified to express an artificial T-cell receptor termed CAR designed to be specific to a tumor-associated antigen [154]. CARs are artificial receptors that redirect antigen specificity, activate T-cells, and further enhance T-cell function through their costimulatory component [155]. Ideally, the target antigen should only be expressed on tumor cells and not on normal cells in order to ensure that there is no (on-target-off tumor) activity that could result in toxicity [152]. The most extensively investigated CAR in clinical setting targets CD19, which is expressed not only in most B-cell malignancies but also in normal B-cells. Thus, CAR-mediated tumor destruction is accompanied by CAR-mediated destruction of normal B-cells resulting in

**Viral transduction Conditioning therapy Cytokine** 

No conditioning therapy

No conditioning therapy

ALL, acute lymphoblastic leukemia; R/R, relapsed/refractory; CR, complete remission; HSCT, hematopoietic stem cell

**release syndrome (%)**

Cyclophosphamide **18** • 88% CR

**Outcome**

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**27** • 90% morphologic remission • 73% MRD by flow cytometry • 6 patients relapsed

Cyclophosphamide **33.3** • 7 patients had CR with 5

• Molecular CR: 70%

having MRD

**30** • 10 patients achieved CR at 5 months

sia, and cytokine release syndrome (CRS) [140].

**3.4. CAR T-cells**

B-cell aplasia [152].

**Center Patients** 

Memorial Sloan Kettering Cancer Center

University of Pennsylvania and Children Hospital of Philadelphia

Fred Hutchinson Cancer Research Center

MD Anderson Cancer Center

**(number and diagnosis)**

> Retroviral transduction

> Lentiviral transduction

> Lentiviral transduction

Sleeping beauty transposon electroporation

transplantation; CAR, chimeric receptor antigen; and MRD, minimal residual disease.

**Table 4.** Clinical trials on the use of CAR-T cells in ALL patients.

**27** Relapsed B-ALL

**25** Pediatric R/R B-ALL

**9** Phase I

**10** CAR T-cells infused following allogeneic HSCT

#### *3.1.4. Ponatinib*

Ponatinib is a pan-bcr/abl TKI which is capable of inhibiting T315I kinase domain mutation that confers resistance to other TKIs and dismal prognosis [95, 129]. Ponatinib can be given prior to HSCT as bridging therapy to control disease and to prevent disease relapse following HSCT [95, 135]. Rapid hematological responses can be obtained in almost all patients but morphologic and molecular responses can unfortunately be short-lived [95]. One study showed that patients with Ph+ ALL who underwent allogeneic HSCT had better survival than those who received ponatinib alone [136].

#### **3.2. Nelarabine**

Nelarabine is a purine nucleoside analogue and a soluble prodrug of Ara-G with specific cytotoxicity against T-lymphocytes [136–145]. It has significant activity in patients with T-cell ALL and T-cell lymphoblastic lymphoma (LBL) [137, 140, 142, 143, 146]. In October 2005, nelarabine gained an accelerated approval by the food and drug authority (FDA) in the USA for the treatment of children and adults with T-cell ALL and T-cell LBL who are in relapse or refractory to at least two chemotherapeutic regimens [137–145]. It has been used as a single agent or in combination with intensive chemotherapy or P13K inhibitors [138, 142, 143, 146–148]. The use of nelarabine in the treatment of patients having T-cell ALL relapsing after allogeneic HSCT has been associated with 90% OS at 1 year [144]. The adverse effects of nelarabine include: (1) myelosuppression with neutropenia and thrombocytopenia and (2) neurotoxicity, which is the commonest side effect, may be transient and reversible and can manifest as depression in the level of consciousness, sensory and motor neuropathies, and Guillain-Barre syndrome [139–145]. The mechanisms of resistance to nelarabine include: (1) reduced drug incorporation into DNA and (2) anti-apoptosis [149]. Other novel purine analogues, such as clofarabine and forodesine, have demonstrated significant anti-tumor activity in relapsed/ refractory T-cell ALL and T-cell LBL [138].

#### **3.3. Blinatumomab**

Blinatumomab is a bispecific T-cell engager monoclonal antibody construct that is designed to direct cytotoxic T-cells to CD19-expressing B-cells [150, 151]. It is indicated (1) in the treatment of Ph− relapsed/refractory pre-B ALL, (2) to induce GVL reaction in patients with pre-B ALL relapsing post-allogeneic HSCT, and (3) in the treatment of HR patients with Ph+ ALL [150, 151]. In a phase II single arm multicenter study that included 45 patients with HR-Ph+ ALL patients who had relapsed or were refractory to TKIs, single agent blinatumomab showed remarkable anti-leukemic activity as 88% of patients achieved CR or CR with partial hematologic recovery and a median OS of 7.1 months [151]. The adverse effects of blinatumomab include: fever, febrile neutropenia, headache, neurotoxicity, such as aphasia, and cytokine release syndrome (CRS) [140].

#### **3.4. CAR T-cells**

on the use of nilotinib have shown the following results: (1) safety and efficacy of nilotinib prophylaxis to prevent relapse of Ph+ ALL after allogeneic HSCT, (2) effectiveness of nilotinib to control MRD and to convert patients to CMR, and (3) achievement of prolongation of survival without jeopardizing immune function or reconstitution following HSCT [130–133]. However, side effects such as prolongation of QT interval on electrocardiogram and early

Ponatinib is a pan-bcr/abl TKI which is capable of inhibiting T315I kinase domain mutation that confers resistance to other TKIs and dismal prognosis [95, 129]. Ponatinib can be given prior to HSCT as bridging therapy to control disease and to prevent disease relapse following HSCT [95, 135]. Rapid hematological responses can be obtained in almost all patients but morphologic and molecular responses can unfortunately be short-lived [95]. One study showed that patients with Ph+ ALL who underwent allogeneic HSCT had better survival than those

Nelarabine is a purine nucleoside analogue and a soluble prodrug of Ara-G with specific cytotoxicity against T-lymphocytes [136–145]. It has significant activity in patients with T-cell ALL and T-cell lymphoblastic lymphoma (LBL) [137, 140, 142, 143, 146]. In October 2005, nelarabine gained an accelerated approval by the food and drug authority (FDA) in the USA for the treatment of children and adults with T-cell ALL and T-cell LBL who are in relapse or refractory to at least two chemotherapeutic regimens [137–145]. It has been used as a single agent or in combination with intensive chemotherapy or P13K inhibitors [138, 142, 143, 146–148]. The use of nelarabine in the treatment of patients having T-cell ALL relapsing after allogeneic HSCT has been associated with 90% OS at 1 year [144]. The adverse effects of nelarabine include: (1) myelosuppression with neutropenia and thrombocytopenia and (2) neurotoxicity, which is the commonest side effect, may be transient and reversible and can manifest as depression in the level of consciousness, sensory and motor neuropathies, and Guillain-Barre syndrome [139–145]. The mechanisms of resistance to nelarabine include: (1) reduced drug incorporation into DNA and (2) anti-apoptosis [149]. Other novel purine analogues, such as clofarabine and forodesine, have demonstrated significant anti-tumor activity in relapsed/

Blinatumomab is a bispecific T-cell engager monoclonal antibody construct that is designed to direct cytotoxic T-cells to CD19-expressing B-cells [150, 151]. It is indicated (1) in the treatment of Ph− relapsed/refractory pre-B ALL, (2) to induce GVL reaction in patients with pre-B ALL relapsing post-allogeneic HSCT, and (3) in the treatment of HR patients with Ph+ ALL [150, 151]. In a phase II single arm multicenter study that included 45 patients with HR-Ph+ ALL patients who had relapsed or were refractory to TKIs, single agent blinatumomab showed remarkable anti-leukemic activity as 88% of patients achieved CR or CR with partial hematologic recovery and a median OS of 7.1 months [151]. The adverse effects

disease relapse post-HSCT may limit its use [132, 134].

who received ponatinib alone [136].

174 Stem Cells in Clinical Practice and Tissue Engineering

refractory T-cell ALL and T-cell LBL [138].

**3.3. Blinatumomab**

*3.1.4. Ponatinib*

**3.2. Nelarabine**

Chimeric antigen receptors (CAR) consist of an extracellular antigen recognition domain linked to an intracellular signaling domain [152, 153]. An important part of CAR design in choosing an optimal tumor-associated antigen to target [152]. A patient's own T-cells may be genetically modified to express an artificial T-cell receptor termed CAR designed to be specific to a tumor-associated antigen [154]. CARs are artificial receptors that redirect antigen specificity, activate T-cells, and further enhance T-cell function through their costimulatory component [155]. Ideally, the target antigen should only be expressed on tumor cells and not on normal cells in order to ensure that there is no (on-target-off tumor) activity that could result in toxicity [152]. The most extensively investigated CAR in clinical setting targets CD19, which is expressed not only in most B-cell malignancies but also in normal B-cells. Thus, CAR-mediated tumor destruction is accompanied by CAR-mediated destruction of normal B-cells resulting in B-cell aplasia [152].


ALL, acute lymphoblastic leukemia; R/R, relapsed/refractory; CR, complete remission; HSCT, hematopoietic stem cell transplantation; CAR, chimeric receptor antigen; and MRD, minimal residual disease.

**Table 4.** Clinical trials on the use of CAR-T cells in ALL patients.

**1.Monoclonal antibodies, immunotoxins, and immunoconjugate antibodies:**

genetic modification with CD19-specific CAR to target tumor in addition to cell expansion, (4) lymphodepletion by administration of pre-infusion conditioning therapy in the form cyclophosphamide or cyclophosphamide and fludarabine, (5) CAR T-cell infusion to target CD 19+ B-cells, and (6) cell death or apoptosis of CD19+ lymphoblasts [152–154, 156]. Indication for CAR T-cell therapy include: (1) relapsed and refractory B-cell ALL, (2) chronic lymphocytic leukemia, (3) acute myeloid leukemia, (4) follicular lymphoma, (5) diffuse large B-cell lymphoma, (6) multiple myeloma, (7) Waldenstrom's macroglobulinemia, and (8) treatment of relapse post-allogeneic HSCT for B-cell malignancies [152, 157, 158]. Studies have shown that treatment options in relapse after allogeneic HSCT for lymphoid malignancies including ALL include: (1) DLI, (2) salvage chemotherapy followed by a second allogeneic HSCT, and (3) CAR T-cell infusions, a cell-based immunotherapy that can effectively enhance and maintain

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Adverse effects or complications of CAR T-cell therapy in relapsed and refractory ALL include: (1) CRS, which can be severe and life-threatening, may manifest with: hyperpyrexia, hypotension, capillary leak syndrome, neurological manifestations, myalgia, and respiratory as well as renal insufficiency, (2) neurotoxicity in the form of delirium and seizures, (3) macrophage activation syndrome, (4) aplasia of normal B-lymphocytes, and (5) death that may occasionally be encountered [155, 159–165]. Serum biochemical markers of CRS following CAR T-cell therapy in relapsed and refractory ALL include C-reactive protein and ferritin [155, 159, 165]. Management of CRS includes: supportive care, corticosteroids, vasopressors, ventilatory support, and anti-interleukin-6 receptor antibody (tocilizumab) therapy [165]. The main clinical trials on the use of CAR T-cells are shown in **Table 4** [152, 156]. Novel and targeted therapies that can be used in the treatment of patients with ALL are shown in **Table 5** [1–3, 56, 160, 161].

Recently, management of patients with ALL has improved dramatically due to several reasons such as improvements in our understanding of the disease biology; improvements in the diagnostic techniques, including molecular genetics, that help in disease stratification; improvements in supportive care; adoption of dose-intense pediatric-inspired chemotherapeutic regimens in AYAs; progress in HSCT including donor selection, conditioning therapies, and prevention as well as treatment of GVHD; monitoring of MRD; and the availability of several novel agents and targeted therapies in addition to cellular and immunotherapies. The availability of the modern therapeutic interventions has translated into improved response rates and outcomes including OS. The integration of various novel and targeted therapies before and after transplantation has further improved the outcomes of patients with ALL.

Different therapeutic interventions available for treating children and adults with ALL should be considered complementary to each other. Future studies should focus on the optimal integration of these novel therapies into the treatment paradigm of this malignancy in order to achieve higher rates of response, disease control as well as long-term survival. Risk stratification of ALL will help in tailoring the management of patients according to their risk category taking into consideration their clinical manifestations, laboratory findings, including cytoge-

netic and molecular profiles, as well as responses to therapeutic interventions.

antitumor GVL response after transfusion into patients [152, 157, 158].

**4. Future directions**

	- Rituximab
	- Obinutuzumab
	- Ofatumumab
	- REGN 1979
	- Epratuzumab
	- Inotuzumab ozogamicin (IO)
	- Moxetumomab pasudotox, reformulation of BL22
	- Coltuximab ravtansine [SAR3419]
	- Denintuzumab mafodotin [SGN-CD19A]
	- ADC-402, newest CD19 monoclonal antibody
	- Combotox: Anti-CD19 and anti- CD22
	- Bispecific T cell engager (BITE) construct: Blinatumomab [anti-CD3; CD 19 construct]

#### **5.P13K- mTOR inhibitors:**


#### **6.Chimeric antigen receptor T-cells (CAR T-cells)**

**Table 5.** Novel and targeted therapies in acute lymphoblastic leukemia.

CAR T-cell therapy involves several laboratory, technical, and clinical procedures that include: (1) obtaining peripheral blood mononuclear cells by leukapheresis, (2) CD3 (T-cell) separation, (3) engineering of T-cells to express CAR by gene transfer technology, viral transduction, or genetic modification with CD19-specific CAR to target tumor in addition to cell expansion, (4) lymphodepletion by administration of pre-infusion conditioning therapy in the form cyclophosphamide or cyclophosphamide and fludarabine, (5) CAR T-cell infusion to target CD 19+ B-cells, and (6) cell death or apoptosis of CD19+ lymphoblasts [152–154, 156]. Indication for CAR T-cell therapy include: (1) relapsed and refractory B-cell ALL, (2) chronic lymphocytic leukemia, (3) acute myeloid leukemia, (4) follicular lymphoma, (5) diffuse large B-cell lymphoma, (6) multiple myeloma, (7) Waldenstrom's macroglobulinemia, and (8) treatment of relapse post-allogeneic HSCT for B-cell malignancies [152, 157, 158]. Studies have shown that treatment options in relapse after allogeneic HSCT for lymphoid malignancies including ALL include: (1) DLI, (2) salvage chemotherapy followed by a second allogeneic HSCT, and (3) CAR T-cell infusions, a cell-based immunotherapy that can effectively enhance and maintain antitumor GVL response after transfusion into patients [152, 157, 158].

Adverse effects or complications of CAR T-cell therapy in relapsed and refractory ALL include: (1) CRS, which can be severe and life-threatening, may manifest with: hyperpyrexia, hypotension, capillary leak syndrome, neurological manifestations, myalgia, and respiratory as well as renal insufficiency, (2) neurotoxicity in the form of delirium and seizures, (3) macrophage activation syndrome, (4) aplasia of normal B-lymphocytes, and (5) death that may occasionally be encountered [155, 159–165]. Serum biochemical markers of CRS following CAR T-cell therapy in relapsed and refractory ALL include C-reactive protein and ferritin [155, 159, 165]. Management of CRS includes: supportive care, corticosteroids, vasopressors, ventilatory support, and anti-interleukin-6 receptor antibody (tocilizumab) therapy [165]. The main clinical trials on the use of CAR T-cells are shown in **Table 4** [152, 156]. Novel and targeted therapies that can be used in the treatment of patients with ALL are shown in **Table 5** [1–3, 56, 160, 161].

### **4. Future directions**

CAR T-cell therapy involves several laboratory, technical, and clinical procedures that include: (1) obtaining peripheral blood mononuclear cells by leukapheresis, (2) CD3 (T-cell) separation, (3) engineering of T-cells to express CAR by gene transfer technology, viral transduction, or

**1.Monoclonal antibodies, immunotoxins, and immunoconjugate antibodies:**

• CD20:

• CD 22:

• CD 19:

○ Rituximab ○ Obinutuzumab ○ Ofatumumab ○ REGN 1979

○ Epratuzumab

○ Inotuzumab ozogamicin (IO)

176 Stem Cells in Clinical Practice and Tissue Engineering

**a.** Single CD 19 monoclonal antibodies: ○ Coltuximab ravtansine [SAR3419]

○ Denintuzumab mafodotin [SGN-CD19A] ○ ADC-402, newest CD19 monoclonal antibody

○ Combotox: Anti-CD19 and anti- CD22

**6.Chimeric antigen receptor T-cells (CAR T-cells)**

**Table 5.** Novel and targeted therapies in acute lymphoblastic leukemia.

**2.Proteasome inhibitors:** Bortezomib

**4.Hypomethylating agents:** Decitabine

**3.JAK inhibitors:** Ruxolitinib

**5.P13K- mTOR inhibitors:**

• NVP-BEZ 235 • NCT01756118 • NCT 02484430 • NCT 01523977 • NCT 01403415 • NCT 01614197 • NCT 01184885

**b.** Dual monoclonal antibodies including anti-CD19 activity:

○ Bispecific T cell engager (BITE) construct: Blinatumomab [anti-CD3; CD 19 construct]

○ Moxetumomab pasudotox, reformulation of BL22

Recently, management of patients with ALL has improved dramatically due to several reasons such as improvements in our understanding of the disease biology; improvements in the diagnostic techniques, including molecular genetics, that help in disease stratification; improvements in supportive care; adoption of dose-intense pediatric-inspired chemotherapeutic regimens in AYAs; progress in HSCT including donor selection, conditioning therapies, and prevention as well as treatment of GVHD; monitoring of MRD; and the availability of several novel agents and targeted therapies in addition to cellular and immunotherapies. The availability of the modern therapeutic interventions has translated into improved response rates and outcomes including OS. The integration of various novel and targeted therapies before and after transplantation has further improved the outcomes of patients with ALL.

Different therapeutic interventions available for treating children and adults with ALL should be considered complementary to each other. Future studies should focus on the optimal integration of these novel therapies into the treatment paradigm of this malignancy in order to achieve higher rates of response, disease control as well as long-term survival. Risk stratification of ALL will help in tailoring the management of patients according to their risk category taking into consideration their clinical manifestations, laboratory findings, including cytogenetic and molecular profiles, as well as responses to therapeutic interventions.

In children with ALL, the role of HSCT has decreased due to the use of intensified chemotherapeutic regimens and the incorporation of novel and targeted therapies into the upfront treatment. However, patients with HR features, those with MRD, and patients with relapsed or refractory disease should be considered for HSCT and novel therapies should be administered whenever indicated.

[6] Larson RA. Induction therapy for Philadelphia chromosome negative acute lymphoblastic leukemia in adults. Edited by: Loweberg B, Rosmarin AG. Up To Date 2017 [7] Spiekerman K.Therapeutic management of acute lymphoblastic leukemia. In: Hiddemann W, editor. Handbook of Acute Leukemia. Switzerland: Springer International Publishing;

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[8] Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, et al., ECOG; MRC/ NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: Results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005;**106**(12):3760-3767. DOI: 10.1182/blood-2005-04-

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Blood. 2001;**98**(6):1982-1984. DOI: org/10.1182/blood.V98.6.1982

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10.1200/JCO.2008.20.8959 (Epub Oct 5, 2009)

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bbmt.2007.06.001 (Epub Jul 20, 2007)

1623 (Epub Aug 16, 2005)

10.1007/s11899-011-0093-y

### **5. Conclusion**

Intensified pediatric chemotherapeutic regimens show poor outcome of ALL in adults compared to children particularly in patients with HR features or disease relapse. Thus, allogeneic HSCT has more indications in adults than in children. However, the integration of other therapeutic interventions into the management of ALL, before and after transplantation, is likely to improve the outcome of patients further.

### **Author details**

Eshrak Alshibani1 , Zeyad AlShaibani2 and Khalid Ahmed Al-Anazi<sup>1</sup> \*

\*Address all correspondence to: kaa\_alanazi@yahoo.com

1 Department of Hematology and Hematopoietic, Stem Cell Transplantation, Oncology Center, King Fahad Specialist Hospital, Dammam, Saudi Arabia

2 Allogeneic Blood and Marrow Transplant Section, Princess Margaret Cancer Center, Toronto, Canada

### **References**


[6] Larson RA. Induction therapy for Philadelphia chromosome negative acute lymphoblastic leukemia in adults. Edited by: Loweberg B, Rosmarin AG. Up To Date 2017

In children with ALL, the role of HSCT has decreased due to the use of intensified chemotherapeutic regimens and the incorporation of novel and targeted therapies into the upfront treatment. However, patients with HR features, those with MRD, and patients with relapsed or refractory disease should be considered for HSCT and novel therapies should be adminis-

Intensified pediatric chemotherapeutic regimens show poor outcome of ALL in adults compared to children particularly in patients with HR features or disease relapse. Thus, allogeneic HSCT has more indications in adults than in children. However, the integration of other therapeutic interventions into the management of ALL, before and after transplantation, is

1 Department of Hematology and Hematopoietic, Stem Cell Transplantation, Oncology

2 Allogeneic Blood and Marrow Transplant Section, Princess Margaret Cancer Center,

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178 Stem Cells in Clinical Practice and Tissue Engineering

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\*Address all correspondence to: kaa\_alanazi@yahoo.com

Center, King Fahad Specialist Hospital, Dammam, Saudi Arabia

**5. Conclusion**

**Author details**

Eshrak Alshibani1

Toronto, Canada

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**Chapter 9**

**Provisional chapter**

**Provisional chapter**

**Post-Transplantation Management Strategies**

Relapse is an overwhelmingly difficult and tragic event for patients suffering from hematologic malignancies that have been treated with bone marrow transplantation. More often than not, treatment options are fairly limited in each disease. Selecting the appropriate maintenance therapy gives a chance to delay or avoid these recurrences entirely.Althoughnoperfect combinationofdrugshasyetbeenestablishedas amainstay maintenance therapy post-transplant, the authors here discuss the most effective and

**Keywords:** post-transplant management, graft versus host disease, graft versus

strategies employed for prevention of relapse post-transplant in different diseases.

The transplantation of multipotent hematopoietic stem cells that are usually derived from bone marrow, umbilical cord, or peripheral blood is a process known as hematopoietic stem cell transplantation (HSCT). It may be autologous or allogeneic and although life-saving, this procedure is not without its drawbacks. Major complications associated with HSCT include graft versus host disease (GVHD), infections, and relapse. Our current discussion is based on

and reproduction in any medium, provided the original work is properly cited.

distribution, and reproduction in any medium, provided the original work is properly cited.

distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

**Post-Transplantation Management Strategies**

**Post-Transplantation Management Strategies**

Muhammad Waqas Khan, Ahmed Elmaaz and

Muhammad Waqas Khan, Ahmed Elmaaz and

Muhammad Waqas Khan, Ahmed Elmaaz and

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

safest drugs available for different diseases.

leukemia, hematopoietic stem cell transplant

Zartash Gul

Zartash Gul

Zartash Gul

http://dx.doi.org/10.5772/65239

**Abstract**

**1. Introduction**


#### **Post-Transplantation Management Strategies Post-Transplantation Management Strategies Post-Transplantation Management Strategies**

Muhammad Waqas Khan, Ahmed Elmaaz and Muhammad Waqas Khan, Ahmed Elmaaz and Muhammad Waqas Khan, Ahmed Elmaaz and

Zartash Gul Zartash Gul Zartash Gul

[162] Tasian SK, Gardner RA. CD19-redirected chimeric antigen receptor-modified T cells: A promising immunotherapy for children and adults with B-cell acute lymphoblastic leukemia (ALL). Therapeutic Advances in Hematology. 2015;**6**(5):228-2241. DOI:

[163] Tang XY, Sun Y, Zhang A, Hu GL, Cao W, Wang DH, et al. Third-generation CD28/4- 1BB chimeric antigen receptor T cells for chemotherapy relapsed or refractory acute lymphoblastic leukaemia: A non-randomised, open-label phase I trial protocol. BMJ

[164] Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. The Journal of Clinical Investigation. 2016;**126**(6):2123-2138. DOI: 10.1172/JCI85309 (Epub Apr 25,

[165] Jackson HJ, Rafiq S, Brentjens RJ. Driving CAR T-cells forward. Nature Reviews Clinical Oncology. 2016;**13**(6):370-383. Published online Mar 22, 2016. DOI: 10.1038/

Open. 2016;**6**(12):e013904. DOI: 10.1136/bmjopen-2016-013904

10.1177/2040620715588916

194 Stem Cells in Clinical Practice and Tissue Engineering

2016)

nrclinonc.2016.36

Additional information is available at the end of the chapter Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/65239

#### **Abstract**

Relapse is an overwhelmingly difficult and tragic event for patients suffering from hematologic malignancies that have been treated with bone marrow transplantation. More often than not, treatment options are fairly limited in each disease. Selecting the appropriate maintenance therapy gives a chance to delay or avoid these recurrences entirely.Althoughnoperfect combinationofdrugshasyetbeenestablishedas amainstay maintenance therapy post-transplant, the authors here discuss the most effective and safest drugs available for different diseases.

**Keywords:** post-transplant management, graft versus host disease, graft versus leukemia, hematopoietic stem cell transplant

### **1. Introduction**

The transplantation of multipotent hematopoietic stem cells that are usually derived from bone marrow, umbilical cord, or peripheral blood is a process known as hematopoietic stem cell transplantation (HSCT). It may be autologous or allogeneic and although life-saving, this procedure is not without its drawbacks. Major complications associated with HSCT include graft versus host disease (GVHD), infections, and relapse. Our current discussion is based on strategies employed for prevention of relapse post-transplant in different diseases.

© 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **2. Multiple myeloma**

The use of autologous hematopoietic stem cell transplantation (A-HSCT) preceded by highdose chemotherapy is a widely accepted modality for management of multiple myeloma (MM) in patients under the age of 65 years [1–3]. Since recurrence still remains a concern, a need for long-term regimen after transplantation to extend the response and prevent relapse is warranted. Allogenic HSCT has been associated with decreased relapse rates, in part due to its graft versus myeloma effect, but its use is limited by its complications [4]. Thalidomide [5–8], lenalidomide [9–13], proteasome inhibitors, and bortezomib [14–16] are being used as a maintenance therapy following AHSCT. They have shown to significantly decrease the relapse as well as improve the progression free survival (PFS) and overall survival (OS) rates. They have gradually replaced conventional and interferon-based therapy over the past decade due to their limited adverse effect profiles and positive impact on PFS and OS [17]. The mean survival associated with the new modalities approaches eight years post-transplant from the previous duration of three years in the past decades [18]. Several studies have been conducted to comprehensively evaluate the use of these novel agents including the assessment of their degree of response, their depth of response, and their long-term complications.

indicating that thalidomide should not be used in those individuals (Hazard ratio [HR] 4.55,

Post-Transplantation Management Strategies

http://dx.doi.org/10.5772/65239

197

A number of other studies have evaluated the use of thalidomide with a corticosteroid in comparison to using a corticosteroid alone. A study of 243 patients by Spencer et al. demonstrated a three-year survival rate; 86% with the thalidomide and corticosteroid group versus 75% in the lone steroid group (*P* = 0.004). The PFS was 42 and 23%, respectively, with a *P*-value of less than 0.001) [21]. In the Brazilian trial, Maiolino et al. studied 108 patients for duration of 2 years and demonstrated a PFS of 64% in the thalidomide and steroid containing group compared with 30% in dexamethasone only group (*P* = 0.002) [22]. No significant difference was found between both groups in terms of OS (*P* = 0.27). In a similar study by Stewart et al., the PFS in the thalidomide containing group was 32%, while the control group had it at 14% after a median follow-up for 4 years [8]. The survival rate in the thalidomide containing group was 68% in comparison to 60% in the lone dexamethasone group. No significant difference

Despite the significant improvement in PFS, EFS, and the variable responses in OS rates, the most common long-term complication for thalidomide is peripheral neuropathy, in particular after long-term usage [6, 8, 9, 21]. No optimal duration of thalidomide post-transplant has been

Due to its higher efficacy and a lower toxicity profile the use of lenalidomide surpasses in tolerance when compared with thalidomide [7]. Although its exact mechanism is not fully understood, several hypotheses have been put forward. One such theory suggests that lenalidomide acts as a natural killer against tumor cells due to their increased cytokine production [23]. Lenalidomide is proven to decrease the production of tumor necrosis factor alpha that in turn tends to increase MM cell growth. It also inhibits the binding of MM cells to the bone marrow cells [24]. Various studies have been conducted to study the effect of lenalidomide on PFS and OS rates post AHSCT in MM. The Cancer and Leukemia Group B (CALGB) conducted a trial labeled CALGB 100104 in which 460 were randomly divided into two groups; one group receiving lenalidomide and the other a placebo with no previous consolidation therapy [12]. The time to progression (TTP) was 46 months in the lenalidomide group compared with 27 months in the placebo group (*P* < 0.001). The OS was significantly higher in patients receiving lenalidomide as compared with those receiving a placebo, 85 and 77%, respectively, (*P* = 0.028). After 36 months of follow-up, the PFS was 66% in the lenalidomide group and 39% in the placebo group. In the IFM 05-02 trial conducted by Attal et al., 614 patients received lenalidomide for a duration of 2 months after AHSCT. They were then divided into two groups: a placebo group and a lenalidomide group [10]. The lenalidomide group had a 41-month TTP versus 23 months in the placebo group with a *P*-value of <0.001. No difference in OS was found between both the groups, an OS of 73 and 75% in lenalidomide and placebo groups, respectively (*P* = 0.7). Following 45 months of follow-up, the PFS was 43 and 22% (*P* < 0.001), EFS of 40 and 23 months (*P* < 0.001), in the lenalidomide and placebo groups, respectively. The difference in OS in both trials was thought to be due to the difference

*P* = 0.02) [5].

was observed (*P* = 0.18).

**2.2. Lenalidomide**

suggested by either of the trials.

#### **2.1. Thalidomide**

Thalidomide is the first and one of the most widely studied drug following the study and evaluation of post-AHST maintenance therapies in MM. In a Phase II study conducted by Intergroupe Francophone du Myélome (IFM), 597 patients—all younger than 65 years—were divided into three groups [9]. Arm-A did not receive any maintenance therapy, while arm-B received pamidronate. Patients who received a combination of pamidronate and 400 micrograms (mcg) of Thalidomide (once daily following AHSCT) were placed in arm-C. The results showed a 36% PFS in arm-A, 37% in arm-B, and 52% in arm-C (*P* < 0.009). With a median followup of 39 months, the OS was 77% in arm-A, 74% in arm-B, and 87% in arm-C with a *P*-value of <0.04. In another study conducted by Barlogie et al., 7668 patients were divided into two groups; thalidomide versus non-thalidomide. The event-free survival (EFS) was 64% in thalidomide users versus 43% in non-thalidomide group (*P* < 0.001). The OS in the thalidomide group was 57% with 44% in the non-thalidomide group after a 72 months median follow-up (*P* = 0.09). A Phase III trial by Lokhorst et al. [6] compared the EFS between a thalidomidebased regimen and an Interferon-alpha-based regimen with a follow-up of 34 and 22 months, respectively, *P* < 0.001. The results showed no significant difference in the OS between both groups (*P* = 0.77).

The UK Medical Research Council (MRC)—Myeloma XI study divided patients into two separate groups: those with transplant and those without. The PFS was noted to be significantly higher in the transplant group following a median follow-up of 22 months and 15 months, respectively (*P* < 0.0001). No significant difference was noted in the OS between both groups (*P* = 0.7) [5–19]. This may in part be due to a difference in the cytogenetic analysis into highand low-risk cytogenetic involving chromosome 13 [20]. A detailed analysis showed patients with a chromosome 17p deletion have decreased OS when being treated with thalidomide indicating that thalidomide should not be used in those individuals (Hazard ratio [HR] 4.55, *P* = 0.02) [5].

A number of other studies have evaluated the use of thalidomide with a corticosteroid in comparison to using a corticosteroid alone. A study of 243 patients by Spencer et al. demonstrated a three-year survival rate; 86% with the thalidomide and corticosteroid group versus 75% in the lone steroid group (*P* = 0.004). The PFS was 42 and 23%, respectively, with a *P*-value of less than 0.001) [21]. In the Brazilian trial, Maiolino et al. studied 108 patients for duration of 2 years and demonstrated a PFS of 64% in the thalidomide and steroid containing group compared with 30% in dexamethasone only group (*P* = 0.002) [22]. No significant difference was found between both groups in terms of OS (*P* = 0.27). In a similar study by Stewart et al., the PFS in the thalidomide containing group was 32%, while the control group had it at 14% after a median follow-up for 4 years [8]. The survival rate in the thalidomide containing group was 68% in comparison to 60% in the lone dexamethasone group. No significant difference was observed (*P* = 0.18).

Despite the significant improvement in PFS, EFS, and the variable responses in OS rates, the most common long-term complication for thalidomide is peripheral neuropathy, in particular after long-term usage [6, 8, 9, 21]. No optimal duration of thalidomide post-transplant has been suggested by either of the trials.

#### **2.2. Lenalidomide**

**2. Multiple myeloma**

196 Stem Cells in Clinical Practice and Tissue Engineering

**2.1. Thalidomide**

groups (*P* = 0.77).

The use of autologous hematopoietic stem cell transplantation (A-HSCT) preceded by highdose chemotherapy is a widely accepted modality for management of multiple myeloma (MM) in patients under the age of 65 years [1–3]. Since recurrence still remains a concern, a need for long-term regimen after transplantation to extend the response and prevent relapse is warranted. Allogenic HSCT has been associated with decreased relapse rates, in part due to its graft versus myeloma effect, but its use is limited by its complications [4]. Thalidomide [5–8], lenalidomide [9–13], proteasome inhibitors, and bortezomib [14–16] are being used as a maintenance therapy following AHSCT. They have shown to significantly decrease the relapse as well as improve the progression free survival (PFS) and overall survival (OS) rates. They have gradually replaced conventional and interferon-based therapy over the past decade due to their limited adverse effect profiles and positive impact on PFS and OS [17]. The mean survival associated with the new modalities approaches eight years post-transplant from the previous duration of three years in the past decades [18]. Several studies have been conducted to comprehensively evaluate the use of these novel agents including the assessment of their

degree of response, their depth of response, and their long-term complications.

Thalidomide is the first and one of the most widely studied drug following the study and evaluation of post-AHST maintenance therapies in MM. In a Phase II study conducted by Intergroupe Francophone du Myélome (IFM), 597 patients—all younger than 65 years—were divided into three groups [9]. Arm-A did not receive any maintenance therapy, while arm-B received pamidronate. Patients who received a combination of pamidronate and 400 micrograms (mcg) of Thalidomide (once daily following AHSCT) were placed in arm-C. The results showed a 36% PFS in arm-A, 37% in arm-B, and 52% in arm-C (*P* < 0.009). With a median followup of 39 months, the OS was 77% in arm-A, 74% in arm-B, and 87% in arm-C with a *P*-value of <0.04. In another study conducted by Barlogie et al., 7668 patients were divided into two groups; thalidomide versus non-thalidomide. The event-free survival (EFS) was 64% in thalidomide users versus 43% in non-thalidomide group (*P* < 0.001). The OS in the thalidomide group was 57% with 44% in the non-thalidomide group after a 72 months median follow-up (*P* = 0.09). A Phase III trial by Lokhorst et al. [6] compared the EFS between a thalidomidebased regimen and an Interferon-alpha-based regimen with a follow-up of 34 and 22 months, respectively, *P* < 0.001. The results showed no significant difference in the OS between both

The UK Medical Research Council (MRC)—Myeloma XI study divided patients into two separate groups: those with transplant and those without. The PFS was noted to be significantly higher in the transplant group following a median follow-up of 22 months and 15 months, respectively (*P* < 0.0001). No significant difference was noted in the OS between both groups (*P* = 0.7) [5–19]. This may in part be due to a difference in the cytogenetic analysis into highand low-risk cytogenetic involving chromosome 13 [20]. A detailed analysis showed patients with a chromosome 17p deletion have decreased OS when being treated with thalidomide Due to its higher efficacy and a lower toxicity profile the use of lenalidomide surpasses in tolerance when compared with thalidomide [7]. Although its exact mechanism is not fully understood, several hypotheses have been put forward. One such theory suggests that lenalidomide acts as a natural killer against tumor cells due to their increased cytokine production [23]. Lenalidomide is proven to decrease the production of tumor necrosis factor alpha that in turn tends to increase MM cell growth. It also inhibits the binding of MM cells to the bone marrow cells [24]. Various studies have been conducted to study the effect of lenalidomide on PFS and OS rates post AHSCT in MM. The Cancer and Leukemia Group B (CALGB) conducted a trial labeled CALGB 100104 in which 460 were randomly divided into two groups; one group receiving lenalidomide and the other a placebo with no previous consolidation therapy [12]. The time to progression (TTP) was 46 months in the lenalidomide group compared with 27 months in the placebo group (*P* < 0.001). The OS was significantly higher in patients receiving lenalidomide as compared with those receiving a placebo, 85 and 77%, respectively, (*P* = 0.028). After 36 months of follow-up, the PFS was 66% in the lenalidomide group and 39% in the placebo group. In the IFM 05-02 trial conducted by Attal et al., 614 patients received lenalidomide for a duration of 2 months after AHSCT. They were then divided into two groups: a placebo group and a lenalidomide group [10]. The lenalidomide group had a 41-month TTP versus 23 months in the placebo group with a *P*-value of <0.001. No difference in OS was found between both the groups, an OS of 73 and 75% in lenalidomide and placebo groups, respectively (*P* = 0.7). Following 45 months of follow-up, the PFS was 43 and 22% (*P* < 0.001), EFS of 40 and 23 months (*P* < 0.001), in the lenalidomide and placebo groups, respectively. The difference in OS in both trials was thought to be due to the difference in the duration of follow-ups. In a study by Alisna et al., 18 months of follow-up post an AHSCT, 30 patients were started on lenalidomide at a median of 96 days [11]. The PFS was noted to be 63% (95%CI, 43–77%), the OS at 78% (95% CI, 58–90%). A similar study by Kneppers et al. showed a PFS of 60% and an OS of 93%, in 30 patients who were newly diagnosed with MM (HOVON 76 trial) [13]. Lenalidomide was started 12 weeks post an AHSCT for a duration of 24 months.

be 16 versus 48% in the PAD group receiving bortezomib, proving the effective use of Borte-

We do not know the exact dose at which bortezomib may be effective during maintenance therapy; we suspect that lower doses might be effective in achieving the desired results.

In another Phase 1 trial by Abidi et al., 12 out of the 15 patients were studied to determine the safest and best-tolerated maintenance dosing of bortezomib post-HSCT [28]. The median duration of follow-up for the entire cohort was 33 months ranging from 12 to 62 months. The

neously on day(s) 1, 8, and 15 in a 28-day cycle was the best-tolerated maintenance dosing and

Allogenic stem cells transplantation (SCT) used to be the first line in management of chronic myeloid leukemia (CML). The survival rate following SCT depends on the phase of the disease in which HSCT was performed; 80% in chronic phase (CP), 40% in accelerated phase (AP), and 20% in blast crisis phase (BP) [29]. Due to the fact that relapses had been a significant problem following SCT, donor leukocyte infusion (DLI) was used to augment the graft versus leukemia (GVL) effect [30]. The introduction of tyrosine kinase inhibitors (TKIs) has replaced the use of DLI due to its effects on bone marrow suppression and GVHD induction. TKIs have proven to greatly improve survival following SCT [31, 32]. Detection of the BCR-ABL transcript levels (the enzyme affected by tyrosine kinase) early on after SCT with the aid of reverse transcriptase polymerase chain reaction (RT-PCR), the probability of relapse after SCT can be predicted giving us an idea regarding the efficacy of TKI post-transplant. High-level positive BCR-ABL is associated with highest relapse probabilities, while negative BCR-ABL has the lowest chances of relapse. Low-level positive BCR-ABL is associated with intermediate risk (total number of BCR-ABL transcripts was <100 per mg RNA and/or the BCR-ABL/ABL ratio was

The efficacy of TKIs following SCT depends on the phase of the disease; prognosis is better if TKIs were used for relapsed CP phase; however, substantially less if used for relapse in the AP

The efficacy of imatinib mesylate (IM), the first TKI to be studied has been reported by many studies [35]. Wright et al. studied the response of IM after SCT in CML relapsing patients [36]. Out of 22 patients who received IM for relapse, eight were in CP, while 14 were in AP posttransplant. A complete hematological response was observed in 19 patients, while a complete cytogenetic response was observed in 17 patients. After a 31.5-month follow-up postrelapse, the OS was at 64%. Wright concluded that a complete molecular response following relapse was a predictive factor of the OS (95% CI, 2.3–182). Similarly, Palandri et al. used IM in a total of 16 patients with CML who relapsed post-transplant either in CP or AP for average 31 months. Seventy-five percent of patients achieved a complete molecular response [37],

administered intravenously and may be subcuta-

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zomib as a maintenance therapy in renal impaired patients suffering from MM.

can be safely given beginning around the hundredth day post-ASCT.

study concluded that bortezomib 1 mg/m2

**3. Chronic myeloid leukemia (CML)**

<0.02%) [33].

or BP phases [31, 32, 34].

These studies concluded lenalidomide as an effective maintenance therapy following an AHSCT having significant impact on improving the PFS and OS, particularly on the elderly, patients with an increased risk of MM, and patients receiving a lenalidomide-based induction regimen [25]. Long-term usage was found to be associated with an elevated risk of hematologic complications. A grade 3–4 neutropenia was found in 51% of the patients in comparison with 18% receiving a placebo [10]. Thromboembolic complications were also noted to be markedly higher in comparison to the placebo using group (2% compared with 6%, respectively, *P* = 0.01). The risk of second primary malignancies (SPMs) as acute myeloblastic leukemias (AML) or myelodysplastic syndromes (MDS) has also been reported in various studies [10, 12]. The risk of SPM was significantly higher in patients receiving Melphalan as part of their lenalidomide treatment [27]. A few other studies noted that a lenalidomide-based maintenance therapy post AHSCT was not feasible due to the development of a GVHD [11, 13].

#### **2.3. Bortezomib**

A first of its kind, proteasome inhibitor has been used as a maintenance therapy in MM posttransplant. Trials have shown bortezomib's efficacy and its well-defined toxicity profile [14– 16]. In a trial by Sonneveld et al. (HOVON 65/GMMG-HD4), 827 patients were divided into two groups; those taking Bortezomib for 2 years after induction (with bortezomib, adriamycin, dexamethasone [PAD]) and HSCT, and a non-Bortezomib group (who took vincristine, adriamycin, and dexamethasone [VAD]) followed by thalidomide [15]. A significant increase in PFS and OS was found on a multivariate analysis (35 and 28 months, respectively, *P* = 0.002), with a hazard ratio (HR) of 0.77 (95% CI, 0.6–1.0, *P* = 0.048) after a 41-month follow-up in the bortezomib group.

In a study conducted by Rosinol et al., 386 patients were divided into three groups in depending on their induction treatment regimens post-HSCT [14]. Thalidomide/dexamethasone (TD), versus bortezomib/thalidomide/dexamethasone (VTD), versus alternate chemotherapy using different regimens in patients <65 years of age who then received a maintenance therapy using bortezomib and thalidomide (VT) versus thalidomide (T) versus interferon, respectively, for 3 years. PFS in the VT group was significantly elevated in comparison with the other groups, although no difference was noted in the OS rates between the three groups. A more recent study by Scheid et al. evaluated the effect of bortezomib post-HSCT in patients with MM and renal impairment using the same management regimen used in the HONOVO 65 trial, using bortezomib for the PAD group and thalidomide for the VAD group [16]. In 746 patients, the serum creatinine was <2 mg/dL, while 81 patients had a serum creatinine of more than 2 mg/dL. The response in the VAD was 63% compared with a response of 81% in the PAD group in patients whose serum creatinine was >2 mg/dL. PFS in the VAD group was noted to be 16 versus 48% in the PAD group receiving bortezomib, proving the effective use of Bortezomib as a maintenance therapy in renal impaired patients suffering from MM.

We do not know the exact dose at which bortezomib may be effective during maintenance therapy; we suspect that lower doses might be effective in achieving the desired results.

In another Phase 1 trial by Abidi et al., 12 out of the 15 patients were studied to determine the safest and best-tolerated maintenance dosing of bortezomib post-HSCT [28]. The median duration of follow-up for the entire cohort was 33 months ranging from 12 to 62 months. The study concluded that bortezomib 1 mg/m2 administered intravenously and may be subcutaneously on day(s) 1, 8, and 15 in a 28-day cycle was the best-tolerated maintenance dosing and can be safely given beginning around the hundredth day post-ASCT.

### **3. Chronic myeloid leukemia (CML)**

in the duration of follow-ups. In a study by Alisna et al., 18 months of follow-up post an AHSCT, 30 patients were started on lenalidomide at a median of 96 days [11]. The PFS was noted to be 63% (95%CI, 43–77%), the OS at 78% (95% CI, 58–90%). A similar study by Kneppers et al. showed a PFS of 60% and an OS of 93%, in 30 patients who were newly diagnosed with MM (HOVON 76 trial) [13]. Lenalidomide was started 12 weeks post an AHSCT for a duration

These studies concluded lenalidomide as an effective maintenance therapy following an AHSCT having significant impact on improving the PFS and OS, particularly on the elderly, patients with an increased risk of MM, and patients receiving a lenalidomide-based induction regimen [25]. Long-term usage was found to be associated with an elevated risk of hematologic complications. A grade 3–4 neutropenia was found in 51% of the patients in comparison with 18% receiving a placebo [10]. Thromboembolic complications were also noted to be markedly higher in comparison to the placebo using group (2% compared with 6%, respectively, *P* = 0.01). The risk of second primary malignancies (SPMs) as acute myeloblastic leukemias (AML) or myelodysplastic syndromes (MDS) has also been reported in various studies [10, 12]. The risk of SPM was significantly higher in patients receiving Melphalan as part of their lenalidomide treatment [27]. A few other studies noted that a lenalidomide-based maintenance therapy

A first of its kind, proteasome inhibitor has been used as a maintenance therapy in MM posttransplant. Trials have shown bortezomib's efficacy and its well-defined toxicity profile [14– 16]. In a trial by Sonneveld et al. (HOVON 65/GMMG-HD4), 827 patients were divided into two groups; those taking Bortezomib for 2 years after induction (with bortezomib, adriamycin, dexamethasone [PAD]) and HSCT, and a non-Bortezomib group (who took vincristine, adriamycin, and dexamethasone [VAD]) followed by thalidomide [15]. A significant increase in PFS and OS was found on a multivariate analysis (35 and 28 months, respectively, *P* = 0.002), with a hazard ratio (HR) of 0.77 (95% CI, 0.6–1.0, *P* = 0.048) after a 41-month follow-up in the

In a study conducted by Rosinol et al., 386 patients were divided into three groups in depending on their induction treatment regimens post-HSCT [14]. Thalidomide/dexamethasone (TD), versus bortezomib/thalidomide/dexamethasone (VTD), versus alternate chemotherapy using different regimens in patients <65 years of age who then received a maintenance therapy using bortezomib and thalidomide (VT) versus thalidomide (T) versus interferon, respectively, for 3 years. PFS in the VT group was significantly elevated in comparison with the other groups, although no difference was noted in the OS rates between the three groups. A more recent study by Scheid et al. evaluated the effect of bortezomib post-HSCT in patients with MM and renal impairment using the same management regimen used in the HONOVO 65 trial, using bortezomib for the PAD group and thalidomide for the VAD group [16]. In 746 patients, the serum creatinine was <2 mg/dL, while 81 patients had a serum creatinine of more than 2 mg/dL. The response in the VAD was 63% compared with a response of 81% in the PAD group in patients whose serum creatinine was >2 mg/dL. PFS in the VAD group was noted to

post AHSCT was not feasible due to the development of a GVHD [11, 13].

of 24 months.

198 Stem Cells in Clinical Practice and Tissue Engineering

**2.3. Bortezomib**

bortezomib group.

Allogenic stem cells transplantation (SCT) used to be the first line in management of chronic myeloid leukemia (CML). The survival rate following SCT depends on the phase of the disease in which HSCT was performed; 80% in chronic phase (CP), 40% in accelerated phase (AP), and 20% in blast crisis phase (BP) [29]. Due to the fact that relapses had been a significant problem following SCT, donor leukocyte infusion (DLI) was used to augment the graft versus leukemia (GVL) effect [30]. The introduction of tyrosine kinase inhibitors (TKIs) has replaced the use of DLI due to its effects on bone marrow suppression and GVHD induction. TKIs have proven to greatly improve survival following SCT [31, 32]. Detection of the BCR-ABL transcript levels (the enzyme affected by tyrosine kinase) early on after SCT with the aid of reverse transcriptase polymerase chain reaction (RT-PCR), the probability of relapse after SCT can be predicted giving us an idea regarding the efficacy of TKI post-transplant. High-level positive BCR-ABL is associated with highest relapse probabilities, while negative BCR-ABL has the lowest chances of relapse. Low-level positive BCR-ABL is associated with intermediate risk (total number of BCR-ABL transcripts was <100 per mg RNA and/or the BCR-ABL/ABL ratio was <0.02%) [33].

The efficacy of TKIs following SCT depends on the phase of the disease; prognosis is better if TKIs were used for relapsed CP phase; however, substantially less if used for relapse in the AP or BP phases [31, 32, 34].

The efficacy of imatinib mesylate (IM), the first TKI to be studied has been reported by many studies [35]. Wright et al. studied the response of IM after SCT in CML relapsing patients [36]. Out of 22 patients who received IM for relapse, eight were in CP, while 14 were in AP posttransplant. A complete hematological response was observed in 19 patients, while a complete cytogenetic response was observed in 17 patients. After a 31.5-month follow-up postrelapse, the OS was at 64%. Wright concluded that a complete molecular response following relapse was a predictive factor of the OS (95% CI, 2.3–182). Similarly, Palandri et al. used IM in a total of 16 patients with CML who relapsed post-transplant either in CP or AP for average 31 months. Seventy-five percent of patients achieved a complete molecular response [37], indicating that IM could be tolerated for longer period of time post-transplant with no major hematological drawbacks. However, peripheral blood counts should be monitored during the duration of treatment for pancytopenia, a leading side effect of TKIs [37]. A study by DeAngelo et al. evaluated 15 patients who received IM for relapse post-transplant, 10 of whom were in CP, one in AP, and four patients in BP [34]. Nine of the ten patients who received IM in CP achieved a complete cytogenetic response after six months. The OS rate was at one 100% after 25 months of follow-up. Kantarjian et al. studied 28 CML relapse patient post-SCT [32], all of whom received IM in a dose range of 400–1000 mg/day. Five patients were in CP, 15 in AP, and 8 in BP. Thirteen patients received DLI at an average of 4 months prior to the use of IM. Complete hematologic response was seen in 100% of the CP patients, 83% in AP, and 43% in BP. The OS was 74% after 1 year of follow-up. The study concluded that no difference was detected in complete response between patients who had received IM and DLI, in comparison to patients who received IM alone. A study by Hess et al. evaluated 44 patients, 37 of whom were in CP before SCT, 18 patients had molecular relapse, while 19 had cytogenetic relapse [38]. IM started post-SCT on an average of 2.1 years yielded a complete molecular response in 62% of the patients after 9 months that further improved with subsequent follow-ups. They also recommended the use of molecular end point in clinical decision making. On the other hand, a study by Olavarria et al. showed that standard PCR techniques were lacking; however, complete molecular response had been significantly high, especially in CP patients [31]. In another study by Olavarria et al., IM was administrated 35 days postrelapse in 22 patients. In a year, all patients had achieved complete molecular remission without cytogenetic relapse during the entire length of IM therapy [33]. Relapse had only been detected after the discontinuation of IM therapy. The length of IM use post-transplant is yet to be determined. These various studies have recommended IM as a feasible, effective, and well-tolerated treatment for relapsing CML patients after SCT. Currently, there is a paucity of data to determine the efficacy of using TKI after SCT for maintenance. However, given its efficacy in relapsed disease, many physicians use this strategy for maintenance.

**4. Philadelphia chromosome positive acute lymphoblastic leukemia**

Before the use of allogeneic SCT for the treatment of Philadelphia chromosome positive Acute Lymphoblastic Leukemia (Ph + ALL), patients were usually treated with induction chemotherapy alone. It had poor outcomes in regard to the long-term survival with a median diseasefree survival (DFS) range of 5–9 months [43]. SCT has been used as a curative treatment for Ph + ALL postinduction chemotherapy to improve the long-term survival [44]. One such retrospective study compared patients treated with chemotherapy alone, with patients being treated with chemotherapy followed by SCT [45]. The study reported significant survival improvement in patients treated with chemotherapy followed by SCT than patients treated

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Detection of BCR-ABL post-SCT using RT-PCR was found to be a good predictor of minimal residual disease (MRD). Relapse with RT-PCR turned positive 4–6 months prior to the occurrence of relapse in patients who achieved remission after chemotherapy with and without

In a study by Chen et al., the effects of TKI IM on DFS post-SCT in patients with Ph + ALL, 82 patients were evaluated of which 62 patients had received IM at a median of 70 days post-SCT for a median duration of 90 days. In 14 patients, BCR-ABL was positive prior to the use of IM, while 8 patients turned negative after a 1 month use of IM. Relapse rate was 10.2% in the group using IM, while it was 33.1% in non-IM group. The 5-year DFS was 81.5% in IM group in comparison to 33.5% in the non-IM group. Multivariate analysis proved the use of IM post-SCT as a prognostic factor for DFS and OS (*P* = 0.000) [47]. Twenty-two patients were studied by Carpenter et al. to assess the tolerance of IM use post-SCT [48]: 15 patients with Ph + ALL and seven patients with CML. IM was easily tolerated by 17 out of the 19 adult patients at doses of 400 mg/day. In the pediatric age group, it was tolerated by three children at doses of

/day in the first 90 days post-SCT (doses compared with those used in primary

therapy for Ph + leukemia). Fourteen patients had positive BCR-ABL before SCT. After an average 1.4-year follow-up, 17 patients were alive with negative BCR-ABL transcripts. In the Ribera et al. study, 30 patients newly diagnosed Ph + ALL received IM with chemotherapy followed by SCT [49]. Transplant was then followed by IM for a median duration of 3.9 months. Twenty-seven patients achieved remission of which 21 patients underwent SCT. Twelve patients received IM after transplant. After a follow-up of 4.1 years, the DFS and the OS were 30 and 30%, respectively. Contrary to previous studies, Ribera et al. showed that adverse effects due to transplant limited the early use of IM post-SCT despite the efficacy of combined IM and

In another study by Teng et al., a similar TKI, dasatinib was evaluated for the same purpose [50]. Six patients with Ph + ALL were enrolled in the study and received SCT along with 100 mg/ day dasatinib for 1 year. All patients achieved complete remission prior to SCT with relapse occurring in three patients only (all extramedullary). Only two patients had adverse effects from dasatinib which was improved by dividing the dose of dasatinib into two 50 mg doses. This study showed that dasatinib was effective and tolerated by Ph + ALL patients after SCT.

**(Ph + ALL)**

with chemotherapy alone.

combination with SCT [46].

chemotherapy as a primary treatment for Ph + ALL.

260 mg/m2

The available data about the use of second generation TKI, such as dasatinib, is still limited [39]. A study by Klyuchnikov et al. used second-generation TKI dasatinib post HST in 11 patients; out of whom nine had CML, two were in AP, and seven in BP [40]. All the patients had received TKI prior to their SCT-IM, dasatinib, or nilotinib (sometimes in combination). Dasatinib was administrated at a median interval of 1 year post-SCT with a median duration of treatment of 8 months (it was discontinued in one patient due to gastrointestinal bleeding that was thought due to drug-related thrombocytopenia). Responses to dasatinib posttransplant were seen in four out of the nine patients. Five patients failed to respond to dasatinib, while three passed away due to disease progression. One patient had a CNS relapse. The study concluded that second-generation TKI dasatinib is effective in the treatment of relapse of CML post-transplant and is generally well tolerated despite the hematological side effects. Contrary to IM, dasatinib was able to penetrate extramedullary tissues and CNS [41, 42].
