*2.1.1 Low risk, intermediate risk AML and the role of minimal residual disease (MRD)*

The European Leukemia Network (ELN) has recently redefined the risk categories for AML into three risk-groups: favourable, intermediate and adverse according to karyotype and somatic mutations harboring prognostic significance (**Table 1**) [6]. The EBMT has provided guidance on indications for transplantation based on clinical evidence and current practice which was updated in 2019 [7]. According to EBMT indications for transplant-eligible patients with favorable risk in first complete remission, the autologous stem cell transplantation may be an option instead of repeated consolidation cycles if MRD is negative. Allogeneic HSCT (from HLAidentical sibling or unrelated donor) remains an option in case of MRD positivity. A growing body of evidence indicates that the pre-transplant evaluation of minimal residual disease (MRD) has a prognostic significance [8–10] and it hasto be considered for the transplant choice. Pre-transplantation positivity of MRD is associated with worse overall survival, disease free-survival and relapse incidence [10]. For Intermediate-risk patients in 1st CR allogeneic transplant from an HLA identical sibling is considered as "standard" while autologous transplantation and HSCT from unrelated-donor and alternative donor are considered clinical options [7]. Mannis et al. retrospectively analyzed data from 334 consecutive adult AML patients who underwent to autologous transplantation between 1988 and 2013. Among these patients, 133 were classified as intermediate-risk according to karyotype. Median relapse-free survival (RFS) was three years and 45% of patients maintain a complete remission at five years. Fifty-four patients relapsed after auto-SCT and of whom 26 underwent to allo-HSCT. Among allografted patients 35% (9/26) died of NRM, 35% (9/26) died of progressive disease, 12% (3/26) lived relapse-free at a


**Table 1.** *ELN Risk stratification by genetics.*

#### *Stem Cell Transplantation in Acute Myeloid Laeukemia DOI: http://dx.doi.org/10.5772/intechopen.94416*

For patients in complete remission of the disease, also, the status of minimal residual disease must be considered [5] so that the most appropriate conditioning regimen and modulation of immunosuppressive therapy post-transplant can be chosen.

**2. Indications to allogeneic transplantation for acute myeloid leukemia**

*2.1.1 Low risk, intermediate risk AML and the role of minimal residual disease (MRD)*

The European Leukemia Network (ELN) has recently redefined the risk categories for AML into three risk-groups: favourable, intermediate and adverse according to karyotype and somatic mutations harboring prognostic significance (**Table 1**) [6]. The EBMT has provided guidance on indications for transplantation based on clinical evidence and current practice which was updated in 2019 [7]. According to EBMT indications for transplant-eligible patients with favorable risk in first complete remission, the autologous stem cell transplantation may be an option instead of repeated consolidation cycles if MRD is negative. Allogeneic HSCT (from HLAidentical sibling or unrelated donor) remains an option in case of MRD positivity. A growing body of evidence indicates that the pre-transplant evaluation of minimal residual disease (MRD) has a prognostic significance [8–10] and it hasto be considered for the transplant choice. Pre-transplantation positivity of MRD is associated with worse overall survival, disease free-survival and relapse incidence [10]. For Intermediate-risk patients in 1st CR allogeneic transplant from an HLA identical sibling is considered as "standard" while autologous transplantation and HSCT from unrelated-donor and alternative donor are considered clinical options [7]. Mannis et al. retrospectively analyzed data from 334 consecutive adult AML patients who underwent to autologous transplantation between 1988 and 2013. Among these patients, 133 were classified as intermediate-risk according to karyotype. Median relapse-free survival (RFS) was three years and 45% of patients maintain a complete remission at five years. Fifty-four patients relapsed after auto-SCT and of whom 26 underwent to allo-HSCT. Among allografted patients 35% (9/26) died of NRM, 35% (9/26) died of progressive disease, 12% (3/26) lived relapse-free at a

**2.1 AML-risk categories**

*Acute Leukemias*

**Risk category**

*Ref. [6].*

**Table 1.**

**186**

*ELN Risk stratification by genetics.*

**Genetic abnormalities**

mutated CEBPA.

Mutated RUNX1; Mutated ASXL1; Mutated TP53.

Favourable t(8;21)(q22;q22.1); RUNX1-RUNX1T1 inv.(16)(p13.1q22) or t(16;16)(p13.1;q22);

Cytogenetic abnormalities not classified as favorable or adverse.

(5q); 27; 217/abn(17p) Complex karyotype, monosomal karyotype;

Wild-type NPM1 and FLT3-ITD high;

Intermediate Mutated NPM1 and FLT3-ITDhigh; Wild-type NPM1 without FLT3-ITD or with FLT3-

Adverse t(6;9)(p23;q34.1); DEK-NUP214 t(v;11q23.3); KMT2A rearranged t(9;22)(q34.1;q11.2);

CBFB-MYH11; Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow; Biallelic

ITDlow (without adverse-risk genetic lesions); t(9;11)(p21.3;q23.3); MLLT3-KMT2A;

BCR-ABL1 inv.(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1) 25 or del

follow-up of 3.8 years while the remaining five patients lost at follow-up. The authors conclude that ASCT in 1st CR may cure about 40% of patients affected by intermediate-risk AML. However, the study of Mannis et al. is limited by the absence of mutational testing for FLT3-ITD and NPM1 end CEBPA for the vast majority of patients and the risk stratification is based on cytogenetics only [11]. National Comprehensive Cancer Network (NCCN) guidelines do not recommend ASCT as a treatment option for intermediate-risk AML in 1st CR outside of a clinical trial [12]. The recent GIMEMA AML 1310 study evaluated a risk-oriented treatment in intermediate-risk (IR) patients in 1st CR: the patients underwent to autologous or to allogeneic transplantation according to post-consolidation negative or positive MRD respectively [13]. Overall survival (OS) and disease-free survival (DFS) in intermediate-risk MRD-positive patients who underwent to allo-HSCT were comparable to OS and DFS of favourable-risk (FR) patients that underwent to autologous transplantation (IR-MRD+: OS and DFS 70% and 67% respectively – FR: OS and DFS 74% and 61% respectively). In IR-MRD negative patients who underwent to autologous stem cells transplantation (ASCT) OS and DFS were 79% and 61% respectively [13]. MRD was evaluated by detecting Leukemia-associated phenotype (LAIP) by 8-colour multiparametric flow cytometry and the threshold was 3.5 x 10e-4 leukemic cells.

Based on the GIMEMA AML 1310 trial, the transplant choice in transplanteligible intermediate-risk AML patients in 1st CR should be taken according to postconsolidation MRD. Some difficulties limit the application of MRD in clinical practice: the cut-off levels, the absence of LAIP or genetic mutations evaluable as MRDmarkers in a portion of AML-patients, experience of the laboratory, the method used for molecular MRD assessment. As regard to cut off levels, a consensus from the ELN recommends 0,1% as the threshold level for MRD-positivity [14]. Some studies indicate that also MRD levels inferior to 0.1% are consistent with MRD [15, 16], although residual leukemic cells between 0.01% and 0.1% may define a good-prognosis sub-group of patients. Further studies are needed to address the prognostic significance of very low levels of MRD. As regards to the method used for molecular MRD assessment, the ELN consensus recommends real-time quantitative PCR (RQ-PCR) as the standard. RQ-PCR can detect up to 0.1% residual leukemic cells, although further improvements will come from more advanced approaches based on techniques not yet validated such as next-generation sequencing (NGS) and digital-PCR. Validated markers for MRD are *RUNX1-RUNX1T1*, *CBF-B/MYH11*, *PML-RARα*, *NPM1*-mutation. About 60% of AML-patients lacks a somatic mutation suitable for MRD monitoring and *WT1*is not recommended as a marker for MRD [14]. Mutations interesting *DNMT3A*,*TET2* and *ASXL1* loci may persist in CR without having a defined prognostic significance in terms of increased risk of relapse [17].

#### *2.1.2 High-risk AML*

The categories comprising high-risk acute myeloid leukaemias (i.e. AML harboring *FLT3-ITD*, monosomic karyotype or complex karyotype, abn(17p), 5q- or del(5), 7q- or del(7), inv.(3) or t(3;3), t(8;9), t(8;22), AML harboring mutated *RUNX1*, *ASXL1*,*TP53*, secondary and therapy-related AML) have a poor prognosis in the absence of allogeneic hematopoietic transplantation.

As regard to *FLT3*-mutated-AML, the mitigating effect of *NPM-1* mutation on outcome has been established [18, 19]. ELN has distinguished between two categories: AML harboring *NPM1*-mutated and *FLT3*-*ITD* at high allelic ratio or *FLT3-ITD* at low allelic ratio and wild-type *NPM1* are classified into intermediate-risk AML while AML harboring *FLT3-ITD* at high allelic ratio and wild-type *NPM1* are

classified as high-risk AML [6]. Given the high risk of relapse, a recent positionstatement by the EBMT recommends allo-HSCT for *FLT3*-mutated AML (also with *NPM*1-mutation) in 1st CR from related or alternative donors. The expert panel also recommends a maintenance treatment with *FLT3*-inhibitor: Sorafenib is the suggested option if the patient is treated outside of a clinical trial [19, 20].

In summary, allogeneic HSCT may rescue about 30% of patients with primary induction or re-induction failure and the improvements in recent years in HLAtyping, donor availability (i.e. haploidentical donors), conditioning regimen and supportive care expand the possibility to give allogeneic transplantation to this category of patients [32]. In primary refractory disease performing more than two induction courses before allogeneic transplantation has no benefit [28, 30]. Duval et al. developed a prognostic score for the outcome of allo-HSCT performed for AML refractory to chemotherapy (named Duval Score). They analyzed data from 1673 patients from CIBMTR registry and developed a score based on five variables: phase of disease at HSCT (PIF or refractory relapse after CR > 6 months versus refractory relapse after CR < 6 months), cytogenetic class of risk (good/intermediate vs. high), circulating blasts (absent vs. present), HLA match (HLA matched related vs. matched unrelated vs. mismatched unrelated vs. haploidentical) and Karnofsky Score (KS: > 90 vs. < 90). Four class of risk correlated with different survival were identified. Three-

*Stem Cell Transplantation in Acute Myeloid Laeukemia DOI: http://dx.doi.org/10.5772/intechopen.94416*

years OS varied from 40% for score 0 versus 6% for score ≥ 3 [33].

unfit for an alternative donor at the time of 1st CR).

The current indications for allo-HSCT in 2nd CR include transplantation-eligible patients affected by low-risk AML relapsed after previous chemotherapy or autologous transplantation [7]. Allo-HSCT in 2nd CR may also be offered to patients for whom this procedure was previously considered not indicated or too risky (for example intermediate-risk AML for whom MRD was absent after consolidation chemotherapy, or patients lacking HLA-identical sibling donors and considered

Some retrospective analysis by ALWP of EBMT has addressed the role of allogeneic transplantation in 2nd CR of AML. Christopeit and coll. have analyzed 537 patients who have undergone allograft in 2nd CR or first relapse after ASCT: 3-years overall survival (OS), leukaemia-free survival (LFS) and non-relapse mortality (NRM) were respectively 39.5%, 31.5% and 33%. Cumulative incidence of relapse (CIR) was 34.6%. A longer survival correlated with allo-HSCT performed in complete remission than in chemo-refractory relapse, with favorable-risk cytogenetics and with a longer duration of 1st CR (more than ten months in median).NRM was higher in patients undergoing to allo—HSCT from alternative donors than HLAidentical sibling and in those who received Total-body Irradiation (TBI) as part of

Gilleece and coll. published a registry report by the EBMT on allo-HSCT in 2nd CR

of AML including 1879 patients transplanted between 2007 and 2016. The global outcome at 2 years were: LFS: 52%, OS: 58%, Relapse Incidence: 30%. NRM was 20%. The results were split by age < 50 or ≥ 50 years old and by the intensity of conditioning. OS and LFS for <50 yrs. old were 61% and 54% respectively (without differences due to conditioning regimen). For ≥50 years old OS was respectively 58% and 54% for myeloablative (MAC) and reduced-intensity conditioning (RIC) and LFS was 50% for both conditioning regimens. In multivariate analysis, the intensity of the conditioning regimen did have an impact on NRM that was lower for RIC in patients aged ≥50 years (HR 0.54, p < 0.001). Overall Survival, LFS, CIR and Graft-relapse free survival (GRFS) were better in patients with longer intervals from diagnosis to allo-HSCT. Performance status (PS) and the cytogenetic class of risk at diagnosis

(good, intermediate and adverse) also correlated with outcome [35].

Halaburda K et al. retrospectively analyzed 631 patients affected by Corebinding factor (CBF) AML who were allo-grafted in 2nd CR and reported to the EBMT registry between 2000 and 2014. Five-years OS and LFS were respectively 58% and 54% while relapse and NRM at were 22.5% and 23%. The composite

*2.1.5 Transplantation in 2nd CR*

the conditioning pre-ASCT [34].

**189**

As regards the high-risk categories harboring a particular adverse prognosis AML expressing del(5)/5q-, del(7)/7q-, abn(17p), monosomic karyotype, the EBMT have conducted a retrospective analysis on transplant outcome reporting two-year overall survival and leukaemia-free survival between 27% and 34% and between 20% and 24% respectively [21–23]. The worse outcome was observed in patients expressing both 5q- and abn(17p) [23].

#### *2.1.3 Secondary- and therapy-related AML*

Secondary AML (sAML) and therapy-related AML comprise a group of heterogeneous disease that, respect to de novo AML, occur more frequently in elderly patients, most often are chemo-resistant to cytotoxic chemotherapy and have a worse prognosis [24]. Sengsayadeth et al. have conducted a retrospective analysis on 3960 patients affected by sAML undergoing to allo-HSCT between 2000 and 2016. The two years overall survival and disease-free survival were respectively 45% and 39%. The subgroup of patients receiving HSCT not in complete remission experienced the worse outcome (2 years OS and DFS, respectively 35 and 29%) [25]. Recently the Acute Leukemia Working Party of the EBMT published a retrospective registry-based study comparing the outcome of allo-HSCT for sAML and de novo AML patients transplanted in the time interval 2000–2016. The three years overall survival, disease-free survival and cumulative incidence of relapse (CIR) were respectively 60%, 55%, 28% and 46%, 41% and 35% respectively for de novo AML and sAML. In multivariate analysis, sAML was associated with worse OS, DFS and CIR than de novo AML [26]. In patients fit for transplant affected by sAMLallo-HSCT must be offered upfront, preferably in 1st CR. Novel agent CPX351 (liposomal formulation of Cytarabine and Daunorubicine in a 5:1 ratio) has been recently approved as induction treatment for these patients and has demonstrated superiority compared to the conventional "7+3" schedule [27].

#### *2.1.4 Chemotherapy-refractory AML*

The prognosis of patients who fail to reach complete remission after induction chemotherapy is poor. In these patients, five years survival is <10%. Allogeneic transplantation may improve survival to 25–30% [28].

Jabbour et al. compared outcomes of 28 AML primary-induction failure (PIF) patients who underwent to allo-HSCT to that of 149 PIF patients who were treated with salvage chemotherapy alone: results were dramatically in favour of allo-HSCT with a three years OS rate of 39% for allo-grafted patients versus 2% for chemotherapy-only patients [29].

Ferguson et al. in a retrospective analysis on 8907 patients have found that patients who fail to achieve a reduction of myeloid blasts <50% with >15% residual blasts after one course of induction chemotherapy as well as patients who fail to achieve complete remission after two courses of induction chemotherapy have a very dismal prognosis if treated with further chemotherapy. Allogeneic stem cell transplantation may improve survival of these patients [28].

The FLAMSA regimen has been designed for patients with active disease who undergo allo-HSCT. It comprises an initial debulk with Aracytin, Fludarabine and Amsacrine followed by a reduced-intensity conditioning and HSCT [30, 31].

*Stem Cell Transplantation in Acute Myeloid Laeukemia DOI: http://dx.doi.org/10.5772/intechopen.94416*

In summary, allogeneic HSCT may rescue about 30% of patients with primary induction or re-induction failure and the improvements in recent years in HLAtyping, donor availability (i.e. haploidentical donors), conditioning regimen and supportive care expand the possibility to give allogeneic transplantation to this category of patients [32]. In primary refractory disease performing more than two induction courses before allogeneic transplantation has no benefit [28, 30]. Duval et al. developed a prognostic score for the outcome of allo-HSCT performed for AML refractory to chemotherapy (named Duval Score). They analyzed data from 1673 patients from CIBMTR registry and developed a score based on five variables: phase of disease at HSCT (PIF or refractory relapse after CR > 6 months versus refractory relapse after CR < 6 months), cytogenetic class of risk (good/intermediate vs. high), circulating blasts (absent vs. present), HLA match (HLA matched related vs. matched unrelated vs. mismatched unrelated vs. haploidentical) and Karnofsky Score (KS: > 90 vs. < 90). Four class of risk correlated with different survival were identified. Threeyears OS varied from 40% for score 0 versus 6% for score ≥ 3 [33].

#### *2.1.5 Transplantation in 2nd CR*

classified as high-risk AML [6]. Given the high risk of relapse, a recent positionstatement by the EBMT recommends allo-HSCT for *FLT3*-mutated AML (also with *NPM*1-mutation) in 1st CR from related or alternative donors. The expert panel also

As regards the high-risk categories harboring a particular adverse prognosis AML expressing del(5)/5q-, del(7)/7q-, abn(17p), monosomic karyotype, the EBMT have conducted a retrospective analysis on transplant outcome reporting two-year overall survival and leukaemia-free survival between 27% and 34% and between 20% and 24% respectively [21–23]. The worse outcome was observed in patients

Secondary AML (sAML) and therapy-related AML comprise a group of heterogeneous disease that, respect to de novo AML, occur more frequently in elderly patients, most often are chemo-resistant to cytotoxic chemotherapy and have a worse prognosis [24]. Sengsayadeth et al. have conducted a retrospective analysis on 3960 patients affected by sAML undergoing to allo-HSCT between 2000 and 2016. The two years overall survival and disease-free survival were respectively 45% and 39%. The subgroup of patients receiving HSCT not in complete remission experienced the worse outcome (2 years OS and DFS, respectively 35 and 29%) [25]. Recently the Acute Leukemia Working Party of the EBMT published a retrospective registry-based study comparing the outcome of allo-HSCT for sAML and de novo AML patients transplanted in the time interval 2000–2016. The three years overall survival, disease-free survival and cumulative incidence of relapse (CIR) were respectively 60%, 55%, 28% and 46%, 41% and 35% respectively for de novo AML and sAML. In multivariate analysis, sAML was associated with worse OS, DFS and CIR than de novo AML [26]. In patients fit for transplant affected by sAMLallo-HSCT must be offered upfront, preferably in 1st CR. Novel agent CPX351 (liposomal formulation of Cytarabine and Daunorubicine in a 5:1 ratio) has been recently approved as induction treatment for these patients and has demonstrated superior-

The prognosis of patients who fail to reach complete remission after induction chemotherapy is poor. In these patients, five years survival is <10%. Allogeneic

Jabbour et al. compared outcomes of 28 AML primary-induction failure (PIF) patients who underwent to allo-HSCT to that of 149 PIF patients who were treated with salvage chemotherapy alone: results were dramatically in favour of allo-HSCT

Ferguson et al. in a retrospective analysis on 8907 patients have found that patients who fail to achieve a reduction of myeloid blasts <50% with >15% residual blasts after one course of induction chemotherapy as well as patients who fail to achieve complete remission after two courses of induction chemotherapy have a very dismal prognosis if treated with further chemotherapy. Allogeneic stem cell

The FLAMSA regimen has been designed for patients with active disease who undergo allo-HSCT. It comprises an initial debulk with Aracytin, Fludarabine and Amsacrine followed by a reduced-intensity conditioning and HSCT [30, 31].

with a three years OS rate of 39% for allo-grafted patients versus 2% for

recommends a maintenance treatment with *FLT3*-inhibitor: Sorafenib is the suggested option if the patient is treated outside of a clinical trial [19, 20].

expressing both 5q- and abn(17p) [23].

*Acute Leukemias*

*2.1.3 Secondary- and therapy-related AML*

ity compared to the conventional "7+3" schedule [27].

transplantation may improve survival to 25–30% [28].

transplantation may improve survival of these patients [28].

*2.1.4 Chemotherapy-refractory AML*

chemotherapy-only patients [29].

**188**

The current indications for allo-HSCT in 2nd CR include transplantation-eligible patients affected by low-risk AML relapsed after previous chemotherapy or autologous transplantation [7]. Allo-HSCT in 2nd CR may also be offered to patients for whom this procedure was previously considered not indicated or too risky (for example intermediate-risk AML for whom MRD was absent after consolidation chemotherapy, or patients lacking HLA-identical sibling donors and considered unfit for an alternative donor at the time of 1st CR).

Some retrospective analysis by ALWP of EBMT has addressed the role of allogeneic transplantation in 2nd CR of AML. Christopeit and coll. have analyzed 537 patients who have undergone allograft in 2nd CR or first relapse after ASCT: 3-years overall survival (OS), leukaemia-free survival (LFS) and non-relapse mortality (NRM) were respectively 39.5%, 31.5% and 33%. Cumulative incidence of relapse (CIR) was 34.6%. A longer survival correlated with allo-HSCT performed in complete remission than in chemo-refractory relapse, with favorable-risk cytogenetics and with a longer duration of 1st CR (more than ten months in median).NRM was higher in patients undergoing to allo—HSCT from alternative donors than HLAidentical sibling and in those who received Total-body Irradiation (TBI) as part of the conditioning pre-ASCT [34].

Gilleece and coll. published a registry report by the EBMT on allo-HSCT in 2nd CR of AML including 1879 patients transplanted between 2007 and 2016. The global outcome at 2 years were: LFS: 52%, OS: 58%, Relapse Incidence: 30%. NRM was 20%. The results were split by age < 50 or ≥ 50 years old and by the intensity of conditioning. OS and LFS for <50 yrs. old were 61% and 54% respectively (without differences due to conditioning regimen). For ≥50 years old OS was respectively 58% and 54% for myeloablative (MAC) and reduced-intensity conditioning (RIC) and LFS was 50% for both conditioning regimens. In multivariate analysis, the intensity of the conditioning regimen did have an impact on NRM that was lower for RIC in patients aged ≥50 years (HR 0.54, p < 0.001). Overall Survival, LFS, CIR and Graft-relapse free survival (GRFS) were better in patients with longer intervals from diagnosis to allo-HSCT. Performance status (PS) and the cytogenetic class of risk at diagnosis (good, intermediate and adverse) also correlated with outcome [35].

Halaburda K et al. retrospectively analyzed 631 patients affected by Corebinding factor (CBF) AML who were allo-grafted in 2nd CR and reported to the EBMT registry between 2000 and 2014. Five-years OS and LFS were respectively 58% and 54% while relapse and NRM at were 22.5% and 23%. The composite

end-point of Graft-relapse free survival (GRFS) at 2 and 5 years was 40 and 34% respectively. In multivariate analysis, GRFS was associated with three or more additional cytogenetic abnormalities and in vivo T-cell depletion (HR 1.6, P = 0.03). A trend for a better GRFS was associated with a transplant from a CMVseronegative donor and for MRD –negative status at allo-HSCT [36].

development of the Disease Risk Index, conducting a retrospective study involving

It does not take into account factors like age and comorbidities. It categorizes patients into four risk groups with different OS and PFS based on differences in the

Sorror et al., through a retrospective analysis study, developed the Hematopoietic cell transplantation-specific comorbidity index (HCT-CI) (**Table 4**) [40]. Initially developed in 2005, as an adaptation of the Charlson Comorbidity Index to HSCT, it was revised in 2014 to include the age variable [41]. Compared to the previous scores, the HCT-CI places much emphasis on the patient's general health and organ dysfunctions, analyzing 17 comorbidities as described in **Table 2**. It defines 3 risk groups: score 0 (low risk), score 1–2 (intermediate risk), >= 3 (high risk).HSCT-CI was subsequently validated in an independent cohort of patients by Raimondi et al. in 2012 [42]. It is an independent predictor of both NRM and OS. 2 years NRM is 14.7%, 21.3%, and 27.3% in patients having ad HSCT score of 0, 1–2 and > 3 respectively and OS was 56.4%, 21.3% and 41.3% respectively. Patients with low scores should be enrolled in randomized clinical trials or undergoing high intensity conditioning regimens (total busulfan dose>8 mg / kg, or cyclophosphamide dose>120 mg / kg or > 60 mg/kg in combination with other drugs, or melphalan dose>140 mg/mq or total body irradiation dose>6 Gy), while patients with a high score should be candidates for the reduced intensity/non myeloablative condi-

Another score widely used in transplantation practice is the EBMT risk score [43]. It was introduced more than ten years ago initially for patients with chronic myeloid leukaemia (CML), the most frequent indication for allogeneic stem cell transplantation in those years, and subsequently extended to other haematological diseases. Each of the five factors taken into consideration has the same "weight" and importance on the global risk: age, stage of the disease, time from diagnosis, donor type and donor-recipient gender. The score allows us to predict approximately the 5-year probability of OS and TRM for any disease. The novelty, compared to the HSCT-CI, is the introduction of the concept of the disease stage to improve the

1.By age, 3 categories are identified: <20 years (0 score points), 20–40 years (1 score point) and > 40 years (2 score points). The introduction of lowintensity conditioning regimes has opened access to allogeneic transplantation also to elderly patients, but this does not take away the fact that mortality is

2.For disease stage, three categories are defined: early disease stage (0 score point) represented by acute leukaemia in first CR, intermediate disease stage (1 score point) in which acute leukaemia in second CR and late-stage disease

3.The time interval from diagnosis to transplant provides a cut-off of 12 months. If the elapsed time is <12 months 0 score points if>12 months one score point.

(2 score points) are included with advanced leukaemia.

For acute leukaemias in the first CR we arbitrarily set as 0.

1539 patients analyzing information about the disease and its status [39].

relapse risk as described in **Tables 2** and **3**.

*Stem Cell Transplantation in Acute Myeloid Laeukemia DOI: http://dx.doi.org/10.5772/intechopen.94416*

**3.2 HSCT-Comorbidity Index (HCT-CI)**

tioning regimens.

**3.3 EBMT score**

score predictivity.

**191**

higher in this category of patients.

Passweg and coll. conducted a retrospective study to compare the impact of a previous ASCT versus chemotherapy consolidation without ASCT on the outcome of allo-HSCT performed in 2nd CR. The study included 2619 allo-grafted patients in 2nd CR between 2000 and 2017. Of these, 417 were previously treated in 1st CR with ASCT and 2202 with chemotherapy consolidation respectively. The patients were not evenly distributed among the two cohorts because patients treated with ASCT respect to those treated with chemotherapy consolidation were younger, had undergone transplantation earlier, had more often an unfavorable karyotype, more often received allo-HSCT from alternative donors than from HLA matched siblings and more often received a RIC than a MAC regimen. Two-years OS, LFS, GRFS and NRM were respectively 58, 50, and 21% for chemotherapy consolidations and 55, 46, 35 and 25% for ASCT-patients. In multivariate analysis risk of NRM, LFS and GRFS were higher for previous ASCT-patients than for previous chemotherapy consolidation patients. As well as in the study of Christopeit NRM of the allogeneic transplant was higher for patients in whom TBI was included in the pre-ASCT conditioning [37]. However, after first relapse, the attempt of a second complete remission is not always successful and if outcome is measured from the time-point of relapse, the overall results are very poor. Infact, only 10% of all AML patients that relapse and are treated with re-induction chemotherapy and subsequently with allogeneic hematopoietic transplantation are survivors at 5 years [38].

In summary, about 50% of patients in 2nd CR of AML, if eligible to transplantation, may be rescued by allo-graft, particularly when 1st CR has been longer than six months [33]. The chance to achieve a second remission after a first relapse is, however, limited. Furthermore, prior autologous transplantation is associated with an increased risk of NRM post allogeneic transplantation and this must be considered when choosing auto-transplantation in 1st CR, in particular for low and intermediate-risk AML.

#### **3. Risk assessment**

Allogeneic Hematopoietic Stem Cell Transplantation remains a procedure associated with significant mortality and morbidity.

Once the bone marrow transplant has been established as a therapeutic indication, the candidate has to be evaluated in order to define eligibility for treatment and to choose the most appropriate conditioning regimen.

The study of the factors related to the disease, to the donor characteristics and to the patient's general health allows us to evaluate the probability of post-HSCT nonrelapse mortality (NRM).

Here we describe the predictive models used in the clinical practice that quantify the post-HSCT risk profile by integrating all these different factors and therefore predict tolerability to allogeneic BM transplant.

#### **3.1 Disease risk index (DRI)**

The score arises from the evidence that the outcome of HCT depends on the state of the disease at the time of transplantation. Armand et al. led to the

*Stem Cell Transplantation in Acute Myeloid Laeukemia DOI: http://dx.doi.org/10.5772/intechopen.94416*

development of the Disease Risk Index, conducting a retrospective study involving 1539 patients analyzing information about the disease and its status [39].

It does not take into account factors like age and comorbidities. It categorizes patients into four risk groups with different OS and PFS based on differences in the relapse risk as described in **Tables 2** and **3**.

#### **3.2 HSCT-Comorbidity Index (HCT-CI)**

Sorror et al., through a retrospective analysis study, developed the Hematopoietic cell transplantation-specific comorbidity index (HCT-CI) (**Table 4**) [40]. Initially developed in 2005, as an adaptation of the Charlson Comorbidity Index to HSCT, it was revised in 2014 to include the age variable [41]. Compared to the previous scores, the HCT-CI places much emphasis on the patient's general health and organ dysfunctions, analyzing 17 comorbidities as described in **Table 2**. It defines 3 risk groups: score 0 (low risk), score 1–2 (intermediate risk), >= 3 (high risk).HSCT-CI was subsequently validated in an independent cohort of patients by Raimondi et al. in 2012 [42]. It is an independent predictor of both NRM and OS. 2 years NRM is 14.7%, 21.3%, and 27.3% in patients having ad HSCT score of 0, 1–2 and > 3 respectively and OS was 56.4%, 21.3% and 41.3% respectively. Patients with low scores should be enrolled in randomized clinical trials or undergoing high intensity conditioning regimens (total busulfan dose>8 mg / kg, or cyclophosphamide dose>120 mg / kg or > 60 mg/kg in combination with other drugs, or melphalan dose>140 mg/mq or total body irradiation dose>6 Gy), while patients with a high score should be candidates for the reduced intensity/non myeloablative conditioning regimens.

#### **3.3 EBMT score**

end-point of Graft-relapse free survival (GRFS) at 2 and 5 years was 40 and 34% respectively. In multivariate analysis, GRFS was associated with three or more additional cytogenetic abnormalities and in vivo T-cell depletion (HR 1.6, P = 0.03).

Passweg and coll. conducted a retrospective study to compare the impact of a previous ASCT versus chemotherapy consolidation without ASCT on the outcome of allo-HSCT performed in 2nd CR. The study included 2619 allo-grafted patients in 2nd CR between 2000 and 2017. Of these, 417 were previously treated in 1st CR with ASCT and 2202 with chemotherapy consolidation respectively. The patients were not evenly distributed among the two cohorts because patients treated with ASCT respect to those treated with chemotherapy consolidation were younger, had undergone transplantation earlier, had more often an unfavorable karyotype, more often received allo-HSCT from alternative donors than from HLA matched siblings and more often received a RIC than a MAC regimen. Two-years OS, LFS, GRFS and NRM were respectively 58, 50, and 21% for chemotherapy consolidations and 55, 46, 35 and 25% for ASCT-patients. In multivariate analysis risk of NRM, LFS and GRFS were higher for previous ASCT-patients than for previous chemotherapy consolidation patients. As well as in the study of Christopeit NRM of the allogeneic transplant was higher for patients in whom TBI was included in the pre-ASCT conditioning [37]. However, after first relapse, the attempt of a second complete remission is not always successful and if outcome is measured from the time-point of relapse, the overall results are very poor. Infact, only 10% of all AML patients that relapse and are treated with re-induction chemotherapy and subsequently with

A trend for a better GRFS was associated with a transplant from a CMVseronegative donor and for MRD –negative status at allo-HSCT [36].

allogeneic hematopoietic transplantation are survivors at 5 years [38].

intermediate-risk AML.

*Acute Leukemias*

**3. Risk assessment**

relapse mortality (NRM).

**3.1 Disease risk index (DRI)**

**190**

ciated with significant mortality and morbidity.

predict tolerability to allogeneic BM transplant.

and to choose the most appropriate conditioning regimen.

In summary, about 50% of patients in 2nd CR of AML, if eligible to transplantation, may be rescued by allo-graft, particularly when 1st CR has been longer than six months [33]. The chance to achieve a second remission after a first relapse is, however, limited. Furthermore, prior autologous transplantation is associated with an increased risk of NRM post allogeneic transplantation and this must be considered when choosing auto-transplantation in 1st CR, in particular for low and

Allogeneic Hematopoietic Stem Cell Transplantation remains a procedure asso-

Once the bone marrow transplant has been established as a therapeutic indication, the candidate has to be evaluated in order to define eligibility for treatment

The study of the factors related to the disease, to the donor characteristics and to the patient's general health allows us to evaluate the probability of post-HSCT non-

Here we describe the predictive models used in the clinical practice that quantify the post-HSCT risk profile by integrating all these different factors and therefore

The score arises from the evidence that the outcome of HCT depends on the

state of the disease at the time of transplantation. Armand et al. led to the

Another score widely used in transplantation practice is the EBMT risk score [43]. It was introduced more than ten years ago initially for patients with chronic myeloid leukaemia (CML), the most frequent indication for allogeneic stem cell transplantation in those years, and subsequently extended to other haematological diseases. Each of the five factors taken into consideration has the same "weight" and importance on the global risk: age, stage of the disease, time from diagnosis, donor type and donor-recipient gender. The score allows us to predict approximately the 5-year probability of OS and TRM for any disease. The novelty, compared to the HSCT-CI, is the introduction of the concept of the disease stage to improve the score predictivity.



**Disease Stage No. of**

*Stem Cell Transplantation in Acute Myeloid Laeukemia DOI: http://dx.doi.org/10.5772/intechopen.94416*

Mantle cell lymphoma

Mantle cell lymphoma

Myeloproliferative neoplasm

AML intermediate cytogenetics CR

Multiple myeloma CR/

Low-risk MDS adverse cytogenetics

Low-risk MDS Intermediate cytogenetics

Low-risk MDS intermediate cytogenetics

High-risk MDS intermediate cytogenetics

AML favorable cytogenetics

**193**

VGPR/PR

AML favorable cytogenetics CR

CR

PR

**patients**

CLL CR 81 0.47 Low Low

Indolent NHL CR 183 0.53 Low Low

Indolent NHL PR 276 0.71 Low Low CLL PR 400 0.78 Low Low CML chronic phase 1/2 390 0.82 Low Low

ALL CR1 1023 1.00 Int Int T-cell NHL CR 171 1.00 Int Int

Aggressive NHL CR 181 1.05 Int Int

T-cell NHL PR 164 1.06 Int Int

HL PR 225 1.09 Int Int

Indolent NHL Advanced† 128 1.21 Int Int CLL Advanced 265 1.22 Int Int

Aggressive NHL PR 205 1.26 Int Int

HL Advanced† 85 1.48 High High

T-cell NHL Advanced† 93 1.41 High 20 High 33 31–35

Hodgkin lymphoma CR 126 0.36 Int 14 Low 66 63–68

CML advanced phase 69 0.92 Int 63 Int 51 50–52

**HR\* Original DRI**

160 0.51 Int Low

190 0.64 Low Low

149 0.95 Int Int

3611 Ref Int Int

339 1.03 Int Int

Any 426 0.98 Int Int

Early† 103 1.06 High Int

Early† 516 1.09 Int Int

Advanced† 235 1.18 Int Int

Early 364 1.24 Int Int

Advanced† 34 1.42 Int High

**Percentage of patients**

**New DRI Group**

**2-y OS (%)** **95% CI**

*DLBCL, diffuse large B cell lymphoma; RIC, reduced intensity conditioning; MAC, myeloablative conditioning; other abbreviations are as in Table 1. Ref. [39].*

#### **Table 2.**

*Summary of disease and stage risk groups from original DRI.*


#### *Stem Cell Transplantation in Acute Myeloid Laeukemia DOI: http://dx.doi.org/10.5772/intechopen.94416*

**Disease Disease risk**

ALL Intermediate

AML adverse cytogenetics High

**Stage Stage risk** 1st Complete Remission Low

2nd or subsequent PR **(if MAC)** High

**Disease risk Stage risk DRI assignment**

Low High Intermediate

Low Low Low

Intermediate High High

High High Very high

*DLBCL, diffuse large B cell lymphoma; RIC, reduced intensity conditioning; MAC, myeloablative conditioning; other*

AML favorable cytogenetics Low

CLL CML

*Acute Leukemias*

Indolent B-cell NHL

Multiple Myeloma Hodgkin lymphoma

Mantle cell lymphoma T-cell lymphoma, nodal

MDS adverse cytogenetics T-cell lymphoma, extranodal

2nd or subsequent CR

Chronic Phase CML

Induction Failure Active Relapse

**Overall assignment**

*abbreviations are as in Table 1.*

*Ref. [39].*

**Table 2.**

**192**

2nd or subsequent PR **(if RIC)**

Accelerated or Blast Phase CML

Intermediate Low

High Low

*Summary of disease and stage risk groups from original DRI.*

1st PR Untreated

AML intermediate cytogenetics MDS intermediate cytogenetics Myeloproliferative neoplasms

DLBCL/Transformed indolent B-NHL

### *Acute Leukemias*


*Int, intermediate. Ref. [39].*

*\* Hazard ratio for mortality compared with AML intermediate cytogenetics in CR1.*

*† Advanced stage refers to induction failure or active relapse, including stable or progressive disease for NHL, HL, and CLL. ‡ Those categories were not included in the original DRI.*

underwent allograft from a CMV-seronegative donor, cases of CMV seropositivity of the donor and/or the recipient showed a significantly decreased 2-year leukemia-free survival (44% vs. 49%, P < .001) and overall survival (50% vs. 56%, P < .001), and increased nonrelapse mortality (23% vs. 20%, P < .001) [44]. In a CIBMTR analysis early CMV-reactivation was associated with lower overall survival (HR: 1.27) and it

*Comorbidity HCT-CI score* **N %** Arrhytmia 1 7 3 Cardiac 1 18 9 Inflammatory bowel disease 1 1 0.5 Diabetes 1 5 2 Cerebrovascular disease 1 1 0.5 Psychiatric disturbance 1 10 5 Hepatic-mild 1 10 5 Obesity 1 14 7 Infection 1 28 14 Rheumatologic 2 2 1 Peptic ulcer 2 2 1 Moderate/severe renal 2 8 4 Moderate pulmonary 2 30 15 Prior solid malignancy 3 12 6 Heart valve disease 3 4 2 Severe pulmonary 3 49 24 Moderate/severe hepatic 3 2 1 No comorbidities 0 65 32 *Abbreviation: HCT-CI, hematopoietic cell transplantation comorbidity index;* N*, number of patients. Ref. [40].*

*Stem Cell Transplantation in Acute Myeloid Laeukemia DOI: http://dx.doi.org/10.5772/intechopen.94416*

Also cytokine's encoding gene polymorphisms seem to have a prognostic impact.

was confirmed as a poor risk factor for post-transplant outcome [45].

described by Tvedt et al. [46].

hematopoietic cell transplantation (HCT).

*Definitions of comorbidities included in the HCT-CI score.*

**4. Donor selection**

**195**

**Table 4.**

It has been shown that single nucleotide polymorphisms (SNPs) in the IL-6 encoding gene influence outcome after allogeneic stem cell transplantation as

The selection of a donor is a critical element contributing to the success of

Among the many factors that influence the outcome of hematopoietic stem cell transplantation, polymorphism of the classical human leukocyte antigen represents the most important barrier [47]. The human Major Histocompatibility Antigens is located on the short arm of chromosome 6. The MHC falls into three main regions, class I, II and III. The most relevant genes for transplantation belong to class I (*HLA-A*, *HLA-B* and *HLA-C*) and class II (*HLA-DR*, *HLA-DQ* and *HLA-DP*). MCH genes are inheritedin a co-dominant manner following Mendelian rules. Therefore,

#### **Table 3.**

*Refinement of DRI.*


Also donor or recipient cytomegalovirus (CMV) seropositivity has a prognostic impact: recently a study showed that, compared to CMV-seronegative recipients who


#### *Stem Cell Transplantation in Acute Myeloid Laeukemia DOI: http://dx.doi.org/10.5772/intechopen.94416*

#### **Table 4.**

*Definitions of comorbidities included in the HCT-CI score.*

underwent allograft from a CMV-seronegative donor, cases of CMV seropositivity of the donor and/or the recipient showed a significantly decreased 2-year leukemia-free survival (44% vs. 49%, P < .001) and overall survival (50% vs. 56%, P < .001), and increased nonrelapse mortality (23% vs. 20%, P < .001) [44]. In a CIBMTR analysis early CMV-reactivation was associated with lower overall survival (HR: 1.27) and it was confirmed as a poor risk factor for post-transplant outcome [45].

Also cytokine's encoding gene polymorphisms seem to have a prognostic impact. It has been shown that single nucleotide polymorphisms (SNPs) in the IL-6 encoding gene influence outcome after allogeneic stem cell transplantation as described by Tvedt et al. [46].
