Page 82 - Haematologica August 2018

D. Salvatore et al.
grade II-IV acute GvHD was observed for Haplo in both high-risk (Hazard Ratio 2.20; P<0.01) and intermediate risk (Hazard Ratio 1.84; P<0.01). A trend for a lower Relapse-Incidence was observed in Haplo among high-risk acute myeloid leukemia (Hazard Ratio 0.56; P=0.06). The propensity score analysis confirmed results. Our results underline that matched sibling donor is the first choice for acute myeloid leukemia patients in first complete remission. On the other hand, results of Haplo transplants are similar to matched sibling donor transplants in acute myeloid leukemia patients with high risk cytogenetics.
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Introduction
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for patients with acute myeloid leukemia (AML).1 However, a human leukocyte antigen (HLA)-identical sibling2,3 is available in only 25-35% of the patients.4 For patients lacking a full matched sibling donor (MSD), other stem cell sources are available such as unrelated donors,5 umbilical cord blood units,6 or HLA-mismatched family donors (Haplo).7,8 The advantage of the latter is the rapid availability of the donors both for the transplant proce- dure and for subsequent adoptive immunotherapies. Initial concerns with the Haplo-HSCT were the high rate of graft failure, of severe graft-versus-host disease (GvHD) due to the multiple class I and II HLA disparities between donor and recipient, and the high non-relapse mortality (NRM).9,10,11 Advances in HLA typing, optimization of GvHD prophylaxis and other transplantation techniques allowed outcome improvements,8 such as the use of non T-cell depleted (TCD) unmanipulated grafts with new strategies to modulate donor T-cell alloreactivity. In par- ticular, the use of post-transplant high-dose cyclophos- phamide (PTCY) or the addition of anti thymocyte glob- ulin (ATG) to standard GvHD prophylaxis ensured higher rates of engraftment while keeping an acceptable inci- dence of GvHD.12,13,14
This contributed to the increase in the number of unmanipulated Haplo-HSCT performed in recent years.15 Single center or registry-based studies have reported similar outcomes between Haplo-HSCT and unrelated or cord blood allo-HSCT for patients with hematological
malignancies.14,16,17,18
Data comparing Haplo -HSCT to MSD-HSCT in AML
patients are limited. In a recent prospective multicenter non-randomized study from China, Wang et al.19 showed in a very young cohort of AML patients (median age of 28 years in the Haplo group) similar outcomes for Haplo and MSD-HSCT in AML patients in first complete remission (CR1). Similarly, Yoon et al.20 analyzed long-term out- comes of 561 patients with intermediate (n=417) or poor risk (n=144) AML that underwent HSCT in CR1 from various donors including from MSD and Haplo. In poor risk AML, the authors observed a 5-year disease-free sur- vival (DFS) of 47% versus 60% (P<0.01) for MSD and Haplo, respectively; while in intermediate risk AML, DFS was 66% and 68% (P=0.08) for MSD and Haplo, respec- tively.
Herein, we conducted a registry-based study of adult patients undergoing either an unmanipulated Haplo or a MSD allo-HSCT for high or intermediate risk AML in CR1, reported to the Acute Leukemia Working Party (ALWP) of EBMT.
Methods
We retrospectively analyzed adult patients (≥18 years) diag- nosed with AML with intermediate or unfavorable cytogenetics who underwent their first allo-HSCT in CR1 between 2007 and 2015, from either a MSD or Haplo donor, and whose data were reported to the ALWP of the EBMT.
The EBMT is a voluntary working group of more than 500 transplant centers that are required to report all consecutive stem cell transplantations and follow up once a year. Audits are routine- ly performed to determine the accuracy of the data. This study was approved by the ALWP of the EBMT institutional review board and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.
Patients were stratified according to cytogenetic status at diag- nosis in intermediate or high risk, according to the previous defi- nition from Grimwade et al.21 Of note, included in the Haplo group, were only patients receiving an unmanipulated graft with the use of in vivo TCD or PTCY. Ex vivo graft manipulation was an exclusion criteria.
Conditioning regimen was defined myeloablative (MAC) when containing total body irradiation (TBI) with a dose >6 Gray or a total dose of busulfan (Bu) >8 mg/kg or >6.4 mg/kg when admin- istered orally or intravenously, respectively. All other regimens were defined as RIC.22
Primary end-point was leukemia-free survival (LFS), defined as the probability of being alive and disease-free at any time point. Both death and relapse were considered events. Patients alive and in CR were censored at their last follow up. Overall survival (OS) was defined as the probability of being alive at any time point. Other secondary endpoints were engraftment, acute (aGvHD) and chronic (cGvHD) GvHD, relapse incidence (RI), non-relapse mor- tality (NRM) and refined graft-versus-host/relapse free survival (GRFS),23 defined as being alive with neither grade III-IV aGvHD, severe cGvHD nor disease relapse at any time point. Modified Glucksberg criteria and revised Seattle criteria were used to grade aGvHD24 and cGvHD,25 respectively. Engraftment was defined as achieving an absolute neutrophil count greater than or equal to 0.5×109/L for three consecutive days. NRM was defined as death from any cause without previous relapse or progression. Median values and ranges were used for continuous variables and percent- ages for categorical variables. Patient-, disease- and transplant- related variables were compared using χ2 or Fischer exact test for categorical variables, and Mann–Whitney test for continuous vari- ables. Probabilities of OS, LFS and GRFS were calculated using Kaplan-Meier method.26 Cumulative incidence functions (CIF) were used to estimate RI and NRM in a competing risks setting. To study GvHD, death and relapse were considered as competing events. Univariate analyses were performed using the log rank test for OS, LFS and GRFS, while the Gray test was used for CIF. Multivariate analyses adjusted for differences between the groups were performed using Cox proportional hazards regression model.27
haematologica | 2018; 103(8)