Stem Cell Transplantation in Acute Myeloid Laeukemia

*Salvatore Leotta, Annalisa Condorelli, Giovanni Schininà, Roberta Sciortino, Alessandra Cupri and Giuseppe Milone*

#### **Abstract**

Allogeneic hematopoietic stem cell transplantation represents the only potentially curative therapeutic approach for Acute Myeloid Leukemia. The choice to perform an allogeneic hematopoietic transplant is the result of a decision-making process that considers disease-related factors (AML-risk category and the state of disease at the time of transplant), the type of donor available and his characteristics (HLA compatibility, gender, CMV serostatus) and the individual risk associated with the procedure itself. The choice of the appropriate conditioning regimen depends on the patient's age and comorbidities. While the introduction of reduced intensity regimen and the availability of alternative donors allows more patients to be eligible for transplantation, myeloablative conditioning remains the standard of care for fit patients. Disease relapse is the leading cause of treatment failure and new strategies attempting at reducing the relapse incidence post transplantation are currently being investigated.

**Keywords:** acute myeloid leukemia, allogeneic stem cell transplantation, treatment-related mortality, donor selection, conditioning regimen

#### **1. Introduction**

Allogeneic hematopoietic stem cell transplantation (HSCT) represents the only potentially curative therapeutic approach for Acute-Myeloid Leukemias (AML) [1]. This approach is often limited by the patient's transplant-eligibility, which depends on age and comorbidities. Moreover, in patients considered at low risk of relapse, allogeneic transplantation can be offered in case of disease relapse rather than in first complete remission. The high percentage of relapse of leukemia is the leading cause for failure of transplant [2]. The outcome of patients who relapse after transplantation is poor, especially for those who relapse within six months after transplantation for which overall survival at two years is often inferior to 20% [3].

Allogeneic HSCT for AML in first CR is indicated, according to The European Leukemia Network (ELN), when the risk of relapse exceeds 30–40% and the advantage in disease-free survival (DFS) that can derive from it is greater than 10% [4].

The choice to perform an allogeneic hematopoietic transplant is the result of a decision-making process that considers the AML-risk category together with the transplant risk calculated by evaluating both age and comorbidities. In adjunct, the decision-making process comprises the assessment of the disease-status at the moment in which the patient comes to the observation of the transplant-physician. 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.

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

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

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

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

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

in the absence of allogeneic hematopoietic transplantation.

10e-4 leukemic cells.

risk of relapse [17].

*2.1.2 High-risk AML*

**187**
