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A. Nagler et al.
was associated with inferior GvHD-free/relapse-free survival. Compared to bone marrow grafts, peripheral grafts were associated with higher rates of GvHD. In patients with acute lymphoblastic leukemia undergoing unmanipulated haploidentical hematopoietic cell transplantation, PTCy for GvHD prevention resulted in a lower incidence of relapse and improved leukemia-free survival and overall sur- vival, compared to ATG.
Introduction
Despite significant advances in the management of adult acute lymphoblastic leukemia (ALL), disease relapse remains a significant impediment to long-term leukemia- free survival,1 especially in adult patients aged >20 years and in those with advanced (relapsed/refractory) disease.2 Although fraught with challenges of disease relapse and non-relapse mortality, allogeneic hematopoietic cell transplantation (HCT) is a potentially curative option for these patients, and is often considered in high-risk and advanced ALL.2-4 In the absence of a suitable HLA- matched donor, allogeneic transplantation from a related haploidentical donor can be considered and such donors are a readily available source of grafts for most patients irrespective of racial/ethnic background. Indeed, the use of haploidentical HCT has increased steadily over the years in various hematologic malignancies including acute leukemia.4,5 To mitigate the risk of greater HLA-dis- parity and resultant graft rejection and graft-versus-host disease (GvHD) which were seen with haploidentical HCT, T-cell depletion was used historically, but this strategy was associated with higher risks of non-relapse mortality, disease relapse and delayed immune reconsti- tution.6-9
The use of unmanipulated, T-cell-replete grafts has revived haploidentical transplantation. Immunosuppression using anti-thymocyte globulin (ATG) in this setting has shown favorable results.10,11 Wang et al. conducted a biolog- ically randomized trial, specifically in ALL patients in first complete remission, comparing matched sibling donor ver- sus haploidentical donor transplantation using ATG-based GvHD prophylaxis and reported a similar 3-year leukemia- free survival (60% vs. 61% by the intention-to-treat analy- sis). The administration of post-transplant cyclophos- phamide (PTCy) after an unmanipulated haploidentical allograft has shown favorable results and has become wide- ly utilized in the past decade.12,13 Registry data also support unmanipulated haploidentical HCT as a viable treatment option for ALL patients.14,15
Although both strategies are effective as GvHD pro- phylaxis, there is a paucity of comparative data on ATG versus PTCy in haploidentical transplantation. Ruggeri et al. conducted a retrospective study using data from the European Society for Blood and Marrow Transplantation (EBMT) registry on 308 patients with acute myeloid leukemia, and compared outcomes between those given ATG (n=115) or PTCy (n=193) as a GvHD prevention strategy. On multivariate analysis, compared to ATG, PTCy use was associated with significantly better leukemia-free survival (P=0.03) and GvHD-free/relapse- free survival (GRFS) (P=0.03). To our knowledge, no stud- ies have reported comparative data between ATG and PTCy platforms in ALL patients undergoing haploidenti- cal transplantation.16 We used the EBMT database to con- duct a comparative analysis between ATG and PTCy strategies in ALL patients undergoing haploidentical HCT
using bone marrow or peripheral blood as the source of hematopoietic cells for the graft.
Methods
Data source and patients
This is a retrospective multicenter analysis using the dataset of the Acute Leukemia Working Party of the EBMT group registry. The EBMT is a voluntary working group of more than 600 trans- plant centers that are required to report, annually, all consecutive hematopoietic cell transplants and follow-ups. Audits are per- formed routinely to determine the accuracy of the data. The study was planned and approved by the Acute Leukemia Working Party of the EBMT. In addition, the study protocol was approved by the institutional review board at each site and complied with country- specific regulatory requirements. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.
The subjects included in this analysis were adults (≥18 years) with ALL who underwent their first haploidentical HCT between 2007 and 2017, were reported to the ''Promise'' database of the EBMT and received either ATG or PTCy as a GvHD prevention strategy. Recipients of haploidentical transplantation (mismatched by at least two or more HLA-loci to donors) received unmanipu- lated, bone marrow or peripheral blood grafts with additional GvHD prophylaxis, which consisted predominantly of a cal- cineurin inhibitor plus mycophenolate mofetil or a calcineurin inhibitor plus methotrexate. Patients who received grafts that had been manipulated ex vivo (T-cell-depleted or CD34-selected grafts) or who received both ATG and PTCy (n=37) were excluded.
Study endpoints and definitions
The primary endpoint for this study was leukemia-free survival. Secondary endpoints were acute GvHD, chronic GvHD, relapse incidence, non-relapse mortality, GRFS and overall survival. Refined GRFS was defined as survival without the following events: grade III or IV acute GvHD, severe chronic GvHD, disease relapse, or death from any cause after haploidentical HCT.17,18 Leukemia-free survival was calculated until the date of first relapse, death from any cause or the last follow-up for patients alive in complete remission. Relapse was defined as disease recur- rence and appearance of blasts in the peripheral blood or bone marrow (>5%) after having achieved complete remission. Non- relapse mortality was defined as death from any cause other than relapse. Acute GvHD was graded according to the modified Seattle Glucksberg criteria19 and chronic GvHD according to the revised Seattle criteria.20 The conditioning regimen was defined as myeloablative when it contained total body irradiation (TBI) at a dose >6 Gray or a total dose of busulfan >8 mg/kg (orally) or >6.4 mg/kg (intravenously). All other conditioning regimens were defined as reduced intensity.21 Neutrophil engraftment was defined as the first of 3 successive days with an absolute neu- trophil count ≥500/mL.
Statistical analysis
Patient-, disease-, and transplant-related characteristics for the
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