Page 119 - 2019_03-Haematologica-web

Introduction
Haploidentical versus unrelated donor HSCT for active AML Methods
After initiation of intensive chemotherapy for acute myelogenous leukemia (AML), failure to respond is a major unfavorable prognostic factor.1,2 Obtaining a mor- phological complete remission (CR) after induction has been defined as a prognostic factor and even, until recently, considered as a prerequisite for allogeneic stem cell transplantation (HSCT). However, up to 30% of adults with newly diagnosed AML fail to achieve CR after two courses of intensive chemotherapy.1 Moreover, once a first or second CR has been obtained, approximately half of younger patients and 80% of older patients relapse.1,3,4 In both clinical situations, refractory and/or relapsed AML, active disease remains a major therapeutic challenge. Consequently, the accu- mulating evidence that HSCT can deliver long-term dis- ease-free survival in a proportion of patients with AML with active disease represents an importance advance in the treatment in this very high-risk patient population.5- 9 Defining the impact of donor selection is still a major issue. It has been demonstrated that HSCT from matched sibling donors is a valid option, leading to a disease-free survival rate in the range of 20-30% for this very high-risk patient population.7,10-13 More recently, HSCT from unrelated donors (UD) was used for patients with primary refractory AML, with an overall survival (OS) rate of about 22%.13-15 Since 2010, the use of hap- loidentical HSCT has surged by about 300% among European Society of Blood and Marrow Transplantation (EBMT) centers.16,17 Indeed, over recent years, haploiden- tical donors have been increasingly adopted as a valid source of donor cells for HSCT in AML in the absence of HLA-compatible matched sibling donors or matched UD. Based on several non-randomized comparative studies evaluating HSCT from haploidentical donors (Haplo HSCT),18-21 the combined data suggest similar outcomes for Haplo and UD HSCT.22,23 However, only small series are available for patients with resistant and/or relapsed AML undergoing HSCT from alterna- tive donors. Craddock et al. reported that the OS rate of 36 patients who received an UD transplant with a reduced-intensity conditioning regimen (RIC) was 36% at 5 years, which was similar to that of 18 patients given myeloablative conditioning (MAC).14 For patients with active leukemia, HSCT from alternative or mismatched donors may, theoretically, be of advantage, as HLA dis- parities may augment donor/recipient alloreactivity.
However, relatively few data are available for the very high-risk population of patients with refractory or relapsing AML transplanted from alternative donors while in active disease. In view of the fact that the development of Haplo HSCT is significantly influenced by the use of post-transplantation cyclophosphamide (PTCy), and because advances in supportive care influ- ence outcomes, a safety and efficacy update comparison between Haplo and UD HSCT in a large cohort of patients with active disease is highly warranted to fur- ther support decision-making. With this aim, the present study, based on the EBMT - Acute Leukemia Working Party (ALWP) database, was conducted in order to com- pare outcomes of AML patients with active disease after Haplo HSCT versus 10/10 or 9/10 HLA-matched UD HSCT.
Study design and data retrieval
This is a retrospective, multicenter, registry-based analysis. Data for this study were provided and approved by the ALWP of the EBMT group registry. The EBMT registry is a voluntary work- ing group of more than 600 transplant centers, mostly located in Europe, which are required to report all consecutive stem-cell transplantations and follow-up data once a year. Data are entered, managed, and maintained in a central database with internet access; each EBMT center is represented in this database. There are no restrictions on centers for reporting data, except for those required by law on patients’ consent, data confidentiality and accuracy. Quality control measures include several independent systems: confirmation of the validity of the entered data by the reporting team, selective comparison of the survey data with MED-A data sets in the EBMT registry database, cross-checking with national registries, and regular in-house and external data audits. All patients provided informed consent to the use of their data in retrospective studies. The Review Board of the ALWP as well as the ethics committee of the EBMT approved this study.
Eligibility criteria for this analysis included adult patients (aged >18 years) with active AML including primary refractory AML, AML in first relapse and second relapse who had received a first HSCT from a 10/10 HLA allele-matched UD (UD 10/10), or a 9/10 HLA allele-mismatched UD (UD 9/10) or a haploidentical donor (≥2 antigen mismatches or more out of 8) with post-transplant cyclophosphamide (Haplo PTCy) as graft-versus-host disease (GvHD) prophylaxis. Active AML was defined by the failure to achieve CR (bone marrow blasts >5%) despite induction chemotherapy. Cytogenetic groups were defined according to Grimwade et al.24 The source of stem cells could be either bone marrow or granulocyte colony-stimulating factor-mobilized peripheral blood stem cells. All UD were HLA-matched (10/10) or mismatched at one loci (9/10) (-A, -B, -C, -DRB1, -DQB1). We excluded patients who had undergone umbilical cord blood HSCT, so that the analysis was restricted to a more homogeneous study population. MAC was defined, according to the EBMT, as a regimen containing total body irradiation with a dose >6Gy, a total dose of oral busulfan >8 mg/kg or a total dose of intravenous busulfan >6.4mg/kg.25 The FLAMSA sequential conditioning regi- men consisted of a combination of a short course of intensive chemotherapy using fludarabine 30 mg/m2/day, intermediate-dose cytosine arabinoside 2 g/m2/day, and amsacrine 100 mg/m2/day from day –12 to –9, followed, after a 3-day rest, by RIC using 4 Gy total body irradiation on day –5, cyclophosphamide 40 to 60 mg/kg/day on days –4 and –3, and antithymocyte globulin from days –4 to –2; the 4Gy total body irradiation could have been replaced by a total dose of intravenous busulfan of 6.4mg/kg (or an equivalent oral dose).26-28
Endpoints
OS was calculated from the date of transplantation until death or last observation alive. Leukemia-free survival (LFS) was calcu- lated from the date of transplantation until relapse or last disease- free follow-up. Relapse and death from any cause were considered events. Non-relapse mortality (NRM) was defined as death with- out prior relapse. Neutrophil recovery was defined as achieving absolute neutrophil counts greater than or equal to 0.5×109/L for three consecutive days. The diagnosis and grading of acute29 and chronic GvHD30 were performed by transplant centers using the standard criteria. Cytogenetic abnormalities were classified according to Medical Research Centre criteria, and graft-versus- host-free, relapse-free survival (GRFS) as previously published.31
haematologica | 2019; 104(3)
525