**5. Treatment of the AYA group**

This group is considered as a "superimposed" population since pediatric schemes have improved their degrees of response compared to adult designed schemes. Initially, the treatment regimens in this group of patients were based on regimens for adults, showing complete remissions in a low percentage, a couple of examples are the UKALLXII/ECOG [41] case study that reported complete remission (CR) nearly 51% after 1 chemotherapy cycle with increase to 91% after 2 induction cycles and the CALGB8811 [42] study that reported RC of 62–86% after 1 and 2 cycles of induction to remission respectively; On the other hand, the LALA-94 [43] study reported CR rate of 72% after one treatment cycle up to 84% after 2 treatment cycles, thus we have to mention the Hyper-CVAD scheme with a CR rate in the first cycle reported in 81% with increase after 2 cycles to 92% [44]; the DFCI45 pilot study showed an RC of 82% in the first induction cycle. Due to the above, it's clear that treatment schemes based on adults'schemes are ineffective to achieve CR, for these reasons the AYA Group was separated looking for different treatment schemes which includes two large groups, those based on pediatric schemes with expansion in the group of age and modified pediatric inspiration schemes (**Tables 6** and **7**).

By reviewing the pediatric regimens with extension to the age group of treatment was possible to increase the degree of response in this group classified as AYA; in adult regimens, complete remissions ranging from 51% to a maximum of 82% were reported after 1 cycle of treatment, however, in **Table 1** we observe that pediatric regimens in general achieved a higher percentage of complete response or remission after applying 1 cycle of induction, showing with the highest degree of complete response in 98% of the cases for the studies: TOTAL TERAPY IV, 46 PETHEMA ALL 96.47 DCOG, 58 ALL97.59, however, it should be noted that the study with greater robustness in this group that showed the highest CR is the


#### **Table 6.**

*No comparative studies of pediatric regimens.*

proliferation and survival, have been associated with refractoriness of chemother-

The most recent classification of the World Health Organization (WHO) for

The evolution in treatment of patients with ALL has progressed over time, this in order to achieve better survival, relapse-free rates and the quest to achieve cure. We will divide this issue into two large groups: AYA group (adolescents and young adults) and the group of people over 40 years old; and subdivided focusing on

Chemotherapy treatment is divided into treatment phases with different goals:

Induction: it is the phase that seeks to achieve remission normalizing the parameters of the blood count (Hb >10 gr/dl, Neutrophils >1000 /mm3, platelets >100,000/mm3) as well normalization of the organs affected by diagnosis (liver,

Consolidation: in this phase, the aim is to keep the patient in remission and achieve a negative minimal residual disease (MRD) that will impact the prognosis. Maintenance: this phase seeks to avoid relapse of the disease and prepare for an

Recurrent chromosomal and molecular abnormalities characterize ALL subtypes in adults and children (**Table 3**) and often provide prognostic information that can influence risk stratification and treatment decisions (**Table 4**). The frequency of certain subtypes differs between adult and child ALL, what partially explains the difference in clinical outcomes between patient populations [6, 30, 34, 36].

apy and should be considered as poor prognosis markers [35, 36].

Provisional entity: Natural killer (NK) cell lymphoblastic leukemia/lymphoma

B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2);BCR-ABL1 B-lymphoblastic leukemia/lymphoma with t(v;11q23.3);KMT2A rearranged B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1);ETV6-RUNX1

B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3) IL3-IGH B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3);TCF3-PBX1 Provisional entity: B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like Provisional entity: B-lymphoblastic leukemia/lymphoma with iAMP21

Provisional entity: Early T-cell precursor lymphoblastic leukemia

B-lymphoblastic leukemia/lymphoma with hyperdiploidy B-lymphoblastic leukemia/lymphoma with hypodiploidy

acute lymphoblastic leukemia ins shown in **Table 5**.

**B-lymphoblastic leukemia/lymphoma** B-lymphoblastic leukemia/lymphoma, NOS

*Acute Leukemias*

**T-lymphoblastic leukemia/lymphoma**

*WHO classification of lymphoblastic leukemia.*

*Modified of D´Angelo, 2006 [37].*

**Table 5.**

status of Philadelphia chromosome (positive and negative).

**4. Treatment**

[38, 39].

**130**

kidney, lung).

elective suspension [38–40].

#### *Acute Leukemias*


#### **Table 7.**

*Pediatric inspired schemes.*


respectively, is recorded. Likewise, the DFS reported in the MODIFIED TPOG group is lower, being 47% of the cases at 2 years. In this same table we observe the two studies with the largest number of patients, the GRAALL2003 / 200,554 study with a number of subjects analyzed of 502 cases and for the GAMALL55 study 887 cases, with a similarity in the DFS reported for the GRAALL2003 / 2005 of 59% at 5 years and for GMALL07 / 03 from 61% at 5 years and similar OS in both groups from 65% at 5 years; the aforementioned has generated improvement in responses and survival in the AYA groups, so the current recommendations are aimed at treating pediatric schemes or modified schemes of pediatric-inspired

Those patients over 40 years old are considered as "adults" an represent totally different group when comparing with the pediatric and AYA groups when talking about prognosis and treatment. The age by itself is a conditioning factor for a lower response rate, lower DFS, and poorer OS compared to the AYA group, this data is summarized in **Table 8**. This group have hematological remission variable and those with lesser degree of Response rate are adults over 65 years, with a percentage of CR ranging from 41 to 60% according to the ALL-07FRAIL72 studies and the SMOG 841964 study. As illustrated in **Table 3**, in the Edouard Herriot Lyon Hospital, the population of 35–60 years old reached a CR of 85% but this was lower in the group over 60 years with CR reported in 58% [69]; as well as the study of the MD Anderson with the HyperCVAD [62] scheme where the age groups of 30 to 49 years, 50 to 59 years and over 60 years reached a CR of 98%, 83%, 79% respectively [70]. In the same way, the DFS and OS for the Hyper CVAD group of the GIMEMA study 028865 was lower in the older groups, 39% at 5 years and an OS with a longer duration of 27% at 9, in general we conclude that the older age could

All those previously described have been mainly in the groups cataloged as Phi negative ALL, as they are not carriers of the BCR / ABL oncogene, however, in the group that is a carrier of these genetic alteration treatment will be describe in

protocols.

**133**

**Table 9.**

be related to lower rate of CR, DFS and OS.

**Studies Number of**

*DOI: http://dx.doi.org/10.5772/intechopen.94886*

PETHEMA ALL0PH07

GIMEMA LAL0201-B

GIMEMA LAL1205 (Dasatinib)

*ALL Phi positive treatment.*

(Imatinib)

(Imatinib)

**cases**

*Acute Lymphoblastic Leukemia in Adolescents and Young Adults*

**Age (rank)**

GMALL (Imatinib) 28 54-79 96 2/19 2/42 [72]

HyperCVAD + Imatinib 54 17-84 93 5/43 5/35 [74]

EWAL-PH-01 (Dasatinib) 71 59-83 96 5/27 5/36 [76]

HyperCVAD plus Dasatinib. 72 21-80 96 5/42 5/52 [78] EWALL-PH-02 Nilotinib 65 55-85 87 NR NR [79] Korean study Nilotinib 90 17-77 91 2/72 2/72 [80] HyperCVAD + Ponatinib 37 27-55 100 2/81 2/80 [81] GIMEMA + Ponatinib 42 27-85 91 3/69 3/83 [82] *CR: Complete Remission, Ref. Reference, DFS: Disease Free Survival, OS: Overall Survival, NR: Not Reported.*

**% CR**

**DFS (years/%)**

53 56-88 87 38months 37.3 months [73]

29 61-83 100 1/48 1/74 [75]

53 18-77 100 2/51 2/69 [77]

**OS (years/%)** **Ref.**

#### **Table 8.**

*Treatment schemes for ALL in adults.*

PETHEMA ALL 96.47 study, which shows a reported follow-up at 5 years with evidence of DFS of 61% OS of 69% at 6 years. On the other hand, it is important to mention that the Intergroup C1040351 study observed a 2-year DFS of 66% and an OS of 79%. In all the groups referred to in **Table 8**, the degree of CR registered was greater than 90%, but with different DFS and OS times, the longest DFS time for the DCOG study, which was 69% at 5 years and OS of 79% at 5 years.

Of the pediatric inspiration schemes, we refer to those registered in **Table 9**, all of them report CR greater than 90%, with the exception of studies DFCI01–17552 and MODIFIED TPOG 56 where the lowest degree of CR of 86 and 89%,


*Acute Lymphoblastic Leukemia in Adolescents and Young Adults DOI: http://dx.doi.org/10.5772/intechopen.94886*

#### **Table 9.**

*ALL Phi positive treatment.*

respectively, is recorded. Likewise, the DFS reported in the MODIFIED TPOG group is lower, being 47% of the cases at 2 years. In this same table we observe the two studies with the largest number of patients, the GRAALL2003 / 200,554 study with a number of subjects analyzed of 502 cases and for the GAMALL55 study 887 cases, with a similarity in the DFS reported for the GRAALL2003 / 2005 of 59% at 5 years and for GMALL07 / 03 from 61% at 5 years and similar OS in both groups from 65% at 5 years; the aforementioned has generated improvement in responses and survival in the AYA groups, so the current recommendations are aimed at treating pediatric schemes or modified schemes of pediatric-inspired protocols.

Those patients over 40 years old are considered as "adults" an represent totally different group when comparing with the pediatric and AYA groups when talking about prognosis and treatment. The age by itself is a conditioning factor for a lower response rate, lower DFS, and poorer OS compared to the AYA group, this data is summarized in **Table 8**. This group have hematological remission variable and those with lesser degree of Response rate are adults over 65 years, with a percentage of CR ranging from 41 to 60% according to the ALL-07FRAIL72 studies and the SMOG 841964 study. As illustrated in **Table 3**, in the Edouard Herriot Lyon Hospital, the population of 35–60 years old reached a CR of 85% but this was lower in the group over 60 years with CR reported in 58% [69]; as well as the study of the MD Anderson with the HyperCVAD [62] scheme where the age groups of 30 to 49 years, 50 to 59 years and over 60 years reached a CR of 98%, 83%, 79% respectively [70]. In the same way, the DFS and OS for the Hyper CVAD group of the GIMEMA study 028865 was lower in the older groups, 39% at 5 years and an OS with a longer duration of 27% at 9, in general we conclude that the older age could be related to lower rate of CR, DFS and OS.

All those previously described have been mainly in the groups cataloged as Phi negative ALL, as they are not carriers of the BCR / ABL oncogene, however, in the group that is a carrier of these genetic alteration treatment will be describe in

PETHEMA ALL 96.47 study, which shows a reported follow-up at 5 years with evidence of DFS of 61% OS of 69% at 6 years. On the other hand, it is important to mention that the Intergroup C1040351 study observed a 2-year DFS of 66% and an OS of 79%. In all the groups referred to in **Table 8**, the degree of CR registered was greater than 90%, but with different DFS and OS times, the longest DFS time for

Of the pediatric inspiration schemes, we refer to those registered in **Table 9**, all of them report CR greater than 90%, with the exception of studies DFCI01–17552

the DCOG study, which was 69% at 5 years and OS of 79% at 5 years.

**Studies Number of**

MODIFIED DFCI

*Pediatric inspired schemes.*

HOSPITAL EDOUARD HERRIOT, LYON

*Treatment schemes for ALL in adults.*

**Table 8.**

**132**

**Studies Number of**

CALGB 280

MD ANDERSON, HOUSTON 65

91-01

*Acute Leukemias*

**Table 7.**

**cases**

**Age (rank)**

DFCI 01-175 74 18-50 86 4/58 4/67 [55]

GRAALL2003/2005 502 15-35 95 5/59 5/65 [57] GMALL 07/03 887 15-35 91 5/61 5/65 [58] MODIFIED TPOG 35 15-39 89 2/47 2/50 [59] LALIN 20 15-25 90 5/70 NR [60] NOPHO-92 144 10-14 99 5/65 NR [61] *CR: Complete Remission, Ref. Reference, DFS: Disease Free Survival, OS: Overall Survival, NR: Not Reported.*

**cases**

350 129

195 118 66

> 64 31 44

**Age (rank)**

> <30 30-59 >60

> <35 35-60 >60

<30 30-49 50-59 >60

Hyper-CVAD 185 >60 91 5/39% 5/10 [62] SMOG 8419 85 50-84 41 5/32 5/<10 [63] GIMEMA 0288 778 12-59 82 2/50 9/27 [64]

PETHEMA ALL96 33 56-67 58 2/39 2/46 [66] MRC UKALLXII/ECOG2993 100 55-64 70 5/19 5/21 [67] GMALL 268 55-85 76 NR 5/23 [68]

ALL-07FRAIL 72 57-89 54 6.9 month 7.6 month [71] *CR: Complete Remission, Ref. Reference, DFS: Disease Free Survival, OS: Overall Survival, NR: Not Reported.*

**% CR**

> 90 81 57

84 85 58

**DFS (years/%)**

> 3/47 3/38 3/18

3/35 3/31 3/11

3/53 3/55 3/34 3/36

**OS (years/%)**

> 3/58 3/38 3/18

3/39 3/34 3/11

5/54 5/42 5/29 5/17

**Ref.**

[65]

[69]

[70]

**% CR**

**DFS (years/%)**

42 18-35 98 3/77 3/83 [56]

**OS (years/%)** **Ref.**

and MODIFIED TPOG 56 where the lowest degree of CR of 86 and 89%,

**Table 9**, where the different percentages of response between these and those Phi negatives are observed.

In the GMALL73 study the benefit of adding a tyrosine kinase inhibitor (TKI) to non-intensive regimens in elderly patients was initially observed. In this study a group was randomized to receive chemotherapy (CT) + TKI vs. CT, and was observed that adding an TKI achieved a CR of 96%, the double from the RC of 50% seeing in patients who were not treated with imatinib. In this patient group it is striking that adding TKI to a conventional chemotherapy scheme offers the benefit of even higher CR than those presented in populations older than 40 years, as reported in the studies of the Italian group (GIMEMA, LAL0201-B and GIMEMA LAL1205) [75, 77]with CR of 100% with 1st and 2nd generation inhibitor of TKI, however, the DFS and OS were brief in both groups, being higher in the group that received dasatinib (2nd generation TKI) as induction therapy and with a younger population that predicts the higher degree of response. It is worth mentioning that the second-generation TKI dasatinib has Central Nervous System (CNS) penetration showing improved response and survival of cases with CNS infiltration compared to imatinib that fails to cross the blood–brain barrier. **Table 4** records the treatment given by the MD Anderson group, which showed that adding a 3rd generation TKI as ponatinib to the HyperCVAD scheme achieved 100% CR in the group aged 27 to 55 with DFS and OS at 2 years of 81 and 80% respectively [81]. It should be mentioned that ponatinib has good CNS penetration as does dasatinib, however ponatinib is indicated in patients with the T315I resistance mutation.

chemotherapy with a single drug or with steroid-based triplet plus cytarabine and methotrexate at same time as systemic CT is being administrated. With these measures the relapse rate can be reduced from 10 to 5%. Irradiation as a single dose of 24 Gy is recommended as unique therapy to the skull without involving the neuroaxis to avoid cytopenia associated with concurrent CT [86]. In cases of ALL Phi +, although dasatinib and ponatinib are not part of prophylaxis therapy these have been shown to cross the blood–brain barrier and secondarily reduced the risk

**Classification Lymphoblasts in CSF Leucocytes in CSF**

SNC 2 Present <5 SNC 3 Present ≥5 TLP Present Variable

*CSF, cerebrospinal fluid; CNS, central nervous system; traumatic lumbar puncture (TLP).*

*Classification of the CNS infiltration according to the CSF characteristics.*

Hematopoietic stem cell transplant (HSCT) in patients with Acute Lymphoblas-

The modality of transplant recommended is allogenic after the first complete

It is preferred a matched sibling donor or an unrelated donor very well matched,

The choice of conditioning is based on the patient's physical status, for those fit without relevant comorbidity the recommended regimens are the combination of

Haploidentical transplant is always an option in patients without a matched donor, this type of transplant is nowadays frequently used because it allows almost all patients in need for an allo-SCT to undergo allo-SCT without a

tic Leukemia is a therapeutic option in those with high risk disease that have reached complete response (CR) and those who are candidates by the Predictive Models of Risk (Disease Risk Index (DRI), EBMT Risk Score, HCT-Comorbidity Index). the patients could be classified in 3 different risk groups (0 points = low risk, 1–2 points = intermediate risk, ≥ 3 = high risk) and this correlated with two

response (CR1) in high-risk patients (**Table 12**) and in patients with second

Autologous HSCT is not recommended for an adult with ALL. It could be possible in high-risk patients with negative minimal residual disease (MRD) that are not considered for allo-HSCT, but there is insufficient data to support this option,

of isolated relapse to the CNS [87, 88].

**Table 10.**

complete response (CR2) [90].

including Phi + ALL [91].

matched-donor [96].

**7.2 Conditioning**

**135**

**7. Hematopoietic stem cell transplant**

SNC 1 None

*DOI: http://dx.doi.org/10.5772/intechopen.94886*

*Acute Lymphoblastic Leukemia in Adolescents and Young Adults*

years NRM (non relapse mortality (**Table 11**) [90–93].

**7.1 Indication for the different modalities of allo-HSCT**

these options are considered equivalent in terms of results [91, 92].

fractionated TBI (Total Body Irradiation) 12Gy in 6 fractions, plus

A meta-analysis of 15 studies with a total of 11,040 patients with ALL Phi positive shown that the highest prevalence of Phi positive is seeing in those between 11 and 40 years old (25.8% to 26.2%.) By age subgroup the reported prevalence was: 1–10 years 15.6%, 10–20 years 25.6%, 21–40 years of age 26.2% and in the group over 40 years of age 16.9%. In this meta-analysis, the overall 5-year survival rate was 42.8% (CI 95% CI, 23.9–64.1, I2 93) [83].

#### **6. Prophylaxis to CNS**

Intrathecal chemotherapy is pivotal in the treatment of ALL since the CNS is a site of relevance in this pathology. In adult ALL involvement of the CNS at diagnosis is reported in 5–7% of cases, mainly with meningeal involvement. The risk factors related to initial infiltration are elevated Lactic Dehydrogenase (LDH), hyperleukocytosis and ALL B subtype at diagnosis, the latter showing CNS involvement in up to 18% of cases. Other factors that contribute to the initial infiltration are increased blast replication rate, mediastinal mass, and positive Phi [84]. These same factors contribute to the early relapse of the disease, systemically or in isolation to the CNS. For the diagnosis of infiltration, the microscopic examination of cerebrospinal fluid (CSF) obtained from a lumbar puncture continues to be the standard and classified the cases into risk groups according to the number of leukocytes, and the presence of blasts (**Table 10**) and the nature of the lumbar puncture, as well as determination by flow cytometry.

Traumatic Lumbar puncture (TLP) is defined as a result of CSF with erythrocyte count>10 /uL. The Stevenherz/Bleyer algorithm evaluates traumatic puncture if the patient has leukemic cells in peripheral blood and the lumbar puncture is traumatic and contains >5 leukocytes/uL and blasts, the following algorithm should be followed to distinguish between CNS2 disease and CNS3: CSF leukocytes/ erythrocytes >2 x leukocytes in blood/red blood cells [84, 85].

Effective prophylaxis to prevent CNS relapse is an essential part of ALL regimens, the most used modalities are based on CNS irradiation, intrathecal *Acute Lymphoblastic Leukemia in Adolescents and Young Adults DOI: http://dx.doi.org/10.5772/intechopen.94886*


#### **Table 10.**

**Table 9**, where the different percentages of response between these and those Phi

In the GMALL73 study the benefit of adding a tyrosine kinase inhibitor (TKI) to non-intensive regimens in elderly patients was initially observed. In this study a group was randomized to receive chemotherapy (CT) + TKI vs. CT, and was observed that adding an TKI achieved a CR of 96%, the double from the RC of 50% seeing in patients who were not treated with imatinib. In this patient group it is striking that adding TKI to a conventional chemotherapy scheme offers the benefit of even higher CR than those presented in populations older than 40 years, as reported in the studies of the Italian group (GIMEMA, LAL0201-B and GIMEMA LAL1205) [75, 77]with CR of 100% with 1st and 2nd generation inhibitor of TKI, however, the DFS and OS were brief in both groups, being higher in the group that received dasatinib (2nd generation TKI) as induction therapy and with a younger population that predicts the higher degree of response. It is worth mentioning that the second-generation TKI dasatinib has Central Nervous System (CNS) penetration showing improved response and survival of cases with CNS infiltration compared to imatinib that fails to cross the blood–brain barrier. **Table 4** records the treatment given by the MD Anderson group, which showed that adding a 3rd generation TKI as ponatinib to the HyperCVAD scheme achieved 100% CR in the group aged 27 to 55 with DFS and OS at 2 years of 81 and 80% respectively [81]. It should be mentioned that ponatinib has good CNS penetration as does dasatinib, however ponatinib is indicated in patients with the T315I resistance mutation. A meta-analysis of 15 studies with a total of 11,040 patients with ALL Phi positive shown that the highest prevalence of Phi positive is seeing in those between 11 and 40 years old (25.8% to 26.2%.) By age subgroup the reported prevalence was: 1–10 years 15.6%, 10–20 years 25.6%, 21–40 years of age 26.2% and in the group over 40 years of age 16.9%. In this meta-analysis, the overall 5-year survival rate

Intrathecal chemotherapy is pivotal in the treatment of ALL since the CNS is a site of relevance in this pathology. In adult ALL involvement of the CNS at diagnosis is reported in 5–7% of cases, mainly with meningeal involvement. The risk factors related to initial infiltration are elevated Lactic Dehydrogenase (LDH), hyperleukocytosis and ALL B subtype at diagnosis, the latter showing CNS involvement in up to 18% of cases. Other factors that contribute to the initial infiltration are increased blast replication rate, mediastinal mass, and positive Phi [84]. These same factors contribute to the early relapse of the disease, systemically or in isolation to the CNS. For the diagnosis of infiltration, the microscopic examination of cerebrospinal fluid (CSF) obtained from a lumbar puncture continues to be the standard and classified the cases into risk groups according to the number of leukocytes, and the presence of blasts (**Table 10**) and the nature of the lumbar

Traumatic Lumbar puncture (TLP) is defined as a result of CSF with erythrocyte count>10 /uL. The Stevenherz/Bleyer algorithm evaluates traumatic puncture if the patient has leukemic cells in peripheral blood and the lumbar puncture is traumatic and contains >5 leukocytes/uL and blasts, the following algorithm should be followed to distinguish between CNS2 disease and CNS3: CSF leukocytes/

Effective prophylaxis to prevent CNS relapse is an essential part of ALL regimens, the most used modalities are based on CNS irradiation, intrathecal

negatives are observed.

*Acute Leukemias*

was 42.8% (CI 95% CI, 23.9–64.1, I2 93) [83].

puncture, as well as determination by flow cytometry.

erythrocytes >2 x leukocytes in blood/red blood cells [84, 85].

**6. Prophylaxis to CNS**

**134**

*Classification of the CNS infiltration according to the CSF characteristics.*

chemotherapy with a single drug or with steroid-based triplet plus cytarabine and methotrexate at same time as systemic CT is being administrated. With these measures the relapse rate can be reduced from 10 to 5%. Irradiation as a single dose of 24 Gy is recommended as unique therapy to the skull without involving the neuroaxis to avoid cytopenia associated with concurrent CT [86]. In cases of ALL Phi +, although dasatinib and ponatinib are not part of prophylaxis therapy these have been shown to cross the blood–brain barrier and secondarily reduced the risk of isolated relapse to the CNS [87, 88].

#### **7. Hematopoietic stem cell transplant**

Hematopoietic stem cell transplant (HSCT) in patients with Acute Lymphoblastic Leukemia is a therapeutic option in those with high risk disease that have reached complete response (CR) and those who are candidates by the Predictive Models of Risk (Disease Risk Index (DRI), EBMT Risk Score, HCT-Comorbidity Index). the patients could be classified in 3 different risk groups (0 points = low risk, 1–2 points = intermediate risk, ≥ 3 = high risk) and this correlated with two years NRM (non relapse mortality (**Table 11**) [90–93].

The modality of transplant recommended is allogenic after the first complete response (CR1) in high-risk patients (**Table 12**) and in patients with second complete response (CR2) [90].

Autologous HSCT is not recommended for an adult with ALL. It could be possible in high-risk patients with negative minimal residual disease (MRD) that are not considered for allo-HSCT, but there is insufficient data to support this option, including Phi + ALL [91].

#### **7.1 Indication for the different modalities of allo-HSCT**

It is preferred a matched sibling donor or an unrelated donor very well matched, these options are considered equivalent in terms of results [91, 92].

Haploidentical transplant is always an option in patients without a matched donor, this type of transplant is nowadays frequently used because it allows almost all patients in need for an allo-SCT to undergo allo-SCT without a matched-donor [96].

#### **7.2 Conditioning**

The choice of conditioning is based on the patient's physical status, for those fit without relevant comorbidity the recommended regimens are the combination of fractionated TBI (Total Body Irradiation) 12Gy in 6 fractions, plus


**7.3 Maintenance post allo-HSCT**

*High Risk Patients [91, 92, 94, 95].*

Time to CR >1 cycle

Age >40 years

*DOI: http://dx.doi.org/10.5772/intechopen.94886*

High WBC count at diagnosis >30 x 10<sup>9</sup> in B-ALL

ALL subtypes T-cell precursor ALL

Immunophenotype Pro-B/early and mature-T

**7.4 Status of minimal residual disease before HSCT**

Cytogenetics Hypodiploidy (< 44 chromosomes)

*Acute Lymphoblastic Leukemia in Adolescents and Young Adults*

CNS disease Central Nervous System involvement

t(9:22) (q34;q11.2):BCR-ABL1

High-risk genetics IKZF1 deletion in B precursor ALL, unmutated NOTCH1, Ph-like. MRD >1X10<sup>4</sup> after two courses of therapy, some groups post-induction.

t(4;11) (q21;q23) t(8;14) (q24.1q32)

>100 x 10<sup>9</sup> in T-ALL

Complex karyotype (5 or more chromosomal abnormalities)

treatment period [100].

**High Risk**

**Table 12.**

outcome [101–103].

**8. Novel Therapies**

**8.1 Blinatumomab**

children.

**137**

It is recommended for patients with Ph +, maintenance with TKI after allo-HSCT. The optimal treatment duration has not been defined. The described options are continuing the treatment until MRD negativity is confirmed by three consecutive tests or sustained for at least three months, or TKI administration for at least one year of continuous PCR negativity, and if a single positive result, then reset the

It is demonstrated that the presence of MRD positivity at the time of HSCT is a significant risk for relapse after the procedure; this asseveration applies for both B-ALL and T-ALL and suggests that novel therapies are a new option to improve the

It is a bispecific T-cell engager antibody construct that binds simultaneously to CD3-positive cytotoxic T cells and CD19-positive B cells, this reaction allows the patient's endogenous T cells to recognize and eliminate CD19-positive ALL blasts. It is indicated for the treatment of B- ALL in the first or second complete remission with MRD >/= 0.1% and in B-ALL relapse or refractory in adults and

In the TOWER study, eligible patients with pretreated B-ALL were randomly assigned to receive Blinatumomab or Standard Chemotherapy. The overall survival was significantly better in patients treated with Blinatumomab compared with those of the standard group. The median OS was 7.7 months (95% confidence interval [CI], 5.6 to 9.6) in the blinatumomab group versus 4.0 months (95% CI, 2.9

*EF = ejection fraction; ULN= upper limit of normal, AST = aspartate aminotransferase, ALT = alanine aminotransferase, BMI=body mass index, SLE = systemic lupus erythematosus, RA= rheumatoid arthritis, CTD = connective tissue disease, Dlco = diffusion capacity of carbon monoxide, FEV1= forced expiratory volume in one second.*

#### **Table 11.**

*HCT-Comorbidity Index [89].*

Cyclophosphamide (Cy) 120 mg/kg or Etoposide (VP) 60 mg/kg. The regimens with TBI seem to have better anti-leukemic activity than busulfan-based regimens [97].

For elderly patients should be considered reduced conditioning regimens as for patients with contraindications for myeloablative regimens [92].

For patients with an haploidentical donor the used scheme is: Cy 14.5 mg/kg/day IV on days 6 and 5, fludarabine 30 mg/m2 /day IV on days 6 to 2, and 200 cGy of TBI on day 1, on days +3 and + 4, 50 mg/kg Cy with Mesna [98, 99].

Other regimens for transplant with haploidentical donor recommended by the Acute Leukemia Working Party of EMBT are: 1) Myeloablative regimen TBF (thiotepa 10 mg/kg, fludarabine 150 mg/m2, busulfan 9.6 mg/kg IV. 2) RIC (reducedintensity chemotherapy) Thiotepa 5 mg/kg and busulfan 6.4 mg/kg. ATG and Cyclophosphamide are used as prophylaxis for Graft versus Host Disease (GVHD) at doses of ATG 10 mg/Kg (total dose), or Cy 50 mg/kg +3 and + 4 [96].



**Table 12.**

*High Risk Patients [91, 92, 94, 95].*

#### **7.3 Maintenance post allo-HSCT**

It is recommended for patients with Ph +, maintenance with TKI after allo-HSCT. The optimal treatment duration has not been defined. The described options are continuing the treatment until MRD negativity is confirmed by three consecutive tests or sustained for at least three months, or TKI administration for at least one year of continuous PCR negativity, and if a single positive result, then reset the treatment period [100].

#### **7.4 Status of minimal residual disease before HSCT**

It is demonstrated that the presence of MRD positivity at the time of HSCT is a significant risk for relapse after the procedure; this asseveration applies for both B-ALL and T-ALL and suggests that novel therapies are a new option to improve the outcome [101–103].

### **8. Novel Therapies**

#### **8.1 Blinatumomab**

It is a bispecific T-cell engager antibody construct that binds simultaneously to CD3-positive cytotoxic T cells and CD19-positive B cells, this reaction allows the patient's endogenous T cells to recognize and eliminate CD19-positive ALL blasts.

It is indicated for the treatment of B- ALL in the first or second complete remission with MRD >/= 0.1% and in B-ALL relapse or refractory in adults and children.

In the TOWER study, eligible patients with pretreated B-ALL were randomly assigned to receive Blinatumomab or Standard Chemotherapy. The overall survival was significantly better in patients treated with Blinatumomab compared with those of the standard group. The median OS was 7.7 months (95% confidence interval [CI], 5.6 to 9.6) in the blinatumomab group versus 4.0 months (95% CI, 2.9

Cyclophosphamide (Cy) 120 mg/kg or Etoposide (VP) 60 mg/kg. The regimens with TBI seem to have better anti-leukemic activity than busulfan-based

*EF = ejection fraction; ULN= upper limit of normal, AST = aspartate aminotransferase, ALT = alanine aminotransferase, BMI=body mass index, SLE = systemic lupus erythematosus, RA= rheumatoid arthritis, CTD = connective tissue disease, Dlco = diffusion capacity of carbon monoxide, FEV1= forced expiratory volume in*

**Comorbidity Points Comorbidity Points**

3 Obesity

3 Hepatic Mild

3 Psychiatric disturbance

3 Cerebrovascular Disease

2 Inflammatory bowel disease Crohn's disease or ulcerative colitis

2 Coronary artery disease

2 Arrhytmia

2 Diabetes

BMI of > 35 for adults

Chronic hepatitis, bilirubin>ULN to 1.5x ULN, or AST/ALT >ULN to 2.5x ULN

Depression/anxiety requiring psychiatric consult and/or treatment at the time of HCT

Transient ischemic attacks or cerebrovascular accident

Requiring treatment with insulin or oral hypoglycemic

congestive heart failure, myocardial infarction, or EF of ≤ 50%

Atrial fibrillation or flutter, sick sinus syndrome, or ventricular arrhythmias

1 Age ≥ 40 1

1

1

1

1

1

1

1

1

patients with contraindications for myeloablative regimens [92].

IV on days 6 and 5, fludarabine 30 mg/m2

For elderly patients should be considered reduced conditioning regimens as for

For patients with an haploidentical donor the used scheme is: Cy 14.5 mg/kg/day

200 cGy of TBI on day 1, on days +3 and + 4, 50 mg/kg Cy with Mesna [98, 99]. Other regimens for transplant with haploidentical donor recommended by the Acute Leukemia Working Party of EMBT are: 1) Myeloablative regimen TBF (thiotepa 10 mg/kg, fludarabine 150 mg/m2, busulfan 9.6 mg/kg IV. 2) RIC (reducedintensity chemotherapy) Thiotepa 5 mg/kg and busulfan 6.4 mg/kg. ATG and Cyclophosphamide are used as prophylaxis for Graft versus Host Disease (GVHD)

at doses of ATG 10 mg/Kg (total dose), or Cy 50 mg/kg +3 and + 4 [96].

/day IV on days 6 to 2, and

regimens [97].

*one second.*

**Table 11.**

**136**

Liver disease

*Acute Leukemias*

AST/ALT >2.5xULN

Severe pulmonary

oroxygen at home

skin cancer

dyspnea

Renal

Heart valve disease

Moderate pulmonary

kidney transplant

polymyalgia rheumatica

Rheumatologic

Peptic ulcer Requiring treatment

Previous infection

conditioning regimen

*HCT-Comorbidity Index [89].*

Previoussolid malignancy Treated at any time point in

Liver cirrhosis, bilirubin >1.5xULN, or

DLco and/or FEV1 ≤ 65%, dyspnea at rest

thepatient'shistory, excluding nonmelanoma

DLco and/or FEV1 66–80% or minimal stress

Creatinine >2mg/dl, dialysis, or previous

SLE, RA, polymyositis, mixed CTD, and

Documented infection or fever of unknown etiology requiring antimicrobial treatment before, during and after the start of

Diagnosed (except mitral prolapse)

to 5.3) in the chemotherapy group (hazard ratio for death, 0.71; 95% CI, 0.55 to 0.93; p = 0.01 [104].

#### **8.2 Inotuzumab ozogamicin (InO)**

It is a humanized anti-CD22 monoclonal antibody conjugated to calicheamicin, a potent cytotoxic antibiotic compound that induces double-strand DNA breaks. It is utilized in patients with relapsed or refractory (R/R) B-ALL [105].

Katarjian H. and cols published a phase 3 trial (INO-VATE ALL) where randomly assigned adults with R/R ALL to receive either inotuzumab ozogamicin or standard intensive chemotherapy. The rate of complete remission was 80.7% in the inotuzumab ozogamicin group than in the standard therapy group, 29.4% p < 0.001. In the survival analysis OS of 5.0 months vs. 1.8 months (HR0.45 [97.5% CI, 0.34 to 0.6)]; p < 0.001. The veno-occlusive disease occurred more frequently in the InO group [106].

#### **8.3 Tisagenlecleucel**

It is a CD19-directed, genetically modified, autologous T-cell immunotherapy. It is prepared from an apheresis collection of the patient's peripheral blood mononuclear cells. The autologous T cells are transduced using a lentiviral vector to express an anti-CD19 chimeric antigen receptor (CAR) [107]. Tisagenlecleucel was the first gene-modified cell therapy approved by the FDA for children and young adults with relapsed or refractory B-cell ALL.

These have proven highly efficient at inducing MRD-negative remissions. A CAR induced remission could offer a window to proceed to allo- HSCT [107, 108].

Maude and cols published this trial of tisagenlecleucel in children with R/R B-ALL, the overall remission rate was 81%. All patients with complete remission were negative for MRD. The rate of relapse-free survival in patients with a response to treatment was 80% at 6 months and 59% at 12 months. Neurologic events occurred in 40% [108].

#### **9. Minimal residual disease (MRD)**

In the last decade, the measurement of minimal residual disease has become a necessary tool in the follow-up of patients since its impact on progression-free survival and overall survival has been demonstrated in multiple studies, that leads it to be currently an indicator of treatment for patients with acute leukemia.

**Author details**

de México, Mexico

**139**

Juan Manuel Pérez Zúñiga

Martha Alvarado-Ibarra\*, José Antonio De la Peña Celaya, Luara Luz Arana-Luna, Eleazar Hernández-Ruiz, José Luis Alvarez Vera, María Eugenia Espitia Ríos and

Servicio de Hematología Centro Médico Nacional 20 de Noviembre, ISSSTE Ciudad

© 2020 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,

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

*Acute Lymphoblastic Leukemia in Adolescents and Young Adults*

*DOI: http://dx.doi.org/10.5772/intechopen.94886*

provided the original work is properly cited.

There are several ways of measurement of MRD and each one presents different sensitivity as describe: New Generation Sequencing (NGS) present a sensitivity of 10<sup>6</sup> ; Flow cytometry with a 10<sup>4</sup> sensitivity for cytometers of 6 colors and 10<sup>6</sup> for cytometers of 8 colors or more; PCR for specific genes 10<sup>5</sup> of sensitivity. However, to achieve these sensitivity results, it is necessary to perform them on bone marrow samples considered in morphological remission [89, 109].

We have already discussed the prognostic value of having a negative MRD. The GRAALL group demonstrated that the presence of negative MRD at the end of induction was a better prognostic marker than the conventional ones, like the achievement of CR at first line therapy a transplantation in patients with pediatric schemes [109, 110].

In a meta-analysis published in 2017, including 13,637 patients in total, the progression-free survival for the pediatric group was 77% at 10 years in patients with negative MRD, and 64% for adults, while progression free survival for patients with positive MRD were 32% and 21% respectively [111].

*Acute Lymphoblastic Leukemia in Adolescents and Young Adults DOI: http://dx.doi.org/10.5772/intechopen.94886*

to 5.3) in the chemotherapy group (hazard ratio for death, 0.71; 95% CI, 0.55 to

utilized in patients with relapsed or refractory (R/R) B-ALL [105].

It is a humanized anti-CD22 monoclonal antibody conjugated to calicheamicin, a potent cytotoxic antibiotic compound that induces double-strand DNA breaks. It is

It is a CD19-directed, genetically modified, autologous T-cell immunotherapy. It is prepared from an apheresis collection of the patient's peripheral blood mononuclear cells. The autologous T cells are transduced using a lentiviral vector to express an anti-CD19 chimeric antigen receptor (CAR) [107]. Tisagenlecleucel was the first gene-modified cell therapy approved by the FDA for children and young adults

These have proven highly efficient at inducing MRD-negative remissions. A CAR induced remission could offer a window to proceed to allo- HSCT [107, 108]. Maude and cols published this trial of tisagenlecleucel in children with R/R B-ALL, the overall remission rate was 81%. All patients with complete remission were negative for MRD. The rate of relapse-free survival in patients with a response to treatment was 80% at 6 months and 59% at 12 months. Neurologic events occurred in 40% [108].

In the last decade, the measurement of minimal residual disease has become a necessary tool in the follow-up of patients since its impact on progression-free survival and overall survival has been demonstrated in multiple studies, that leads it

There are several ways of measurement of MRD and each one presents different sensitivity as describe: New Generation Sequencing (NGS) present a sensitivity of

; Flow cytometry with a 10<sup>4</sup> sensitivity for cytometers of 6 colors and 10<sup>6</sup> for cytometers of 8 colors or more; PCR for specific genes 10<sup>5</sup> of sensitivity. However, to achieve these sensitivity results, it is necessary to perform them on bone marrow

We have already discussed the prognostic value of having a negative MRD. The GRAALL group demonstrated that the presence of negative MRD at the end of induction was a better prognostic marker than the conventional ones, like the achievement of CR at first line therapy a transplantation in patients with pediatric

In a meta-analysis published in 2017, including 13,637 patients in total, the progression-free survival for the pediatric group was 77% at 10 years in patients with negative MRD, and 64% for adults, while progression free survival for patients

to be currently an indicator of treatment for patients with acute leukemia.

samples considered in morphological remission [89, 109].

with positive MRD were 32% and 21% respectively [111].

Katarjian H. and cols published a phase 3 trial (INO-VATE ALL) where randomly assigned adults with R/R ALL to receive either inotuzumab ozogamicin or standard intensive chemotherapy. The rate of complete remission was 80.7% in the inotuzumab ozogamicin group than in the standard therapy group, 29.4% p < 0.001. In the survival analysis OS of 5.0 months vs. 1.8 months (HR0.45 [97.5% CI, 0.34 to 0.6)]; p < 0.001. The veno-occlusive disease occurred more

0.93; p = 0.01 [104].

*Acute Leukemias*

**8.2 Inotuzumab ozogamicin (InO)**

frequently in the InO group [106].

with relapsed or refractory B-cell ALL.

**9. Minimal residual disease (MRD)**

**8.3 Tisagenlecleucel**

10<sup>6</sup>

**138**

schemes [109, 110].
