Page 174 - 2020_02-Haematologica-web

M.-A. Perales et al.
hematopoietic cell transplant from a matched sibling or an alternative donor such as a haploidentical or unrelated donor. The introduction of transplantation of T-cell replete bone marrow or peripheral blood from a haploidentical relative using post-transplant cyclophosphamide for graft- versus-host disease (GvHD) has gained broad acceptance with consistently favorable outcomes.1-5 Others have reported comparable outcomes after haploidentical donor compared to unrelated donor transplantation for AML.6-8 Yet in a recent report from the Center for International Blood and Marrow Transplant Research (CIBMTR) and the European Society for Blood and Marrow Transplant (EBMT), non-relapse mortality and overall mortality were higher after transplantation of grafts from haploidentical (offspring) donors compared to HLA-matched siblings for AML and acute lymphoblastic leukemia (ALL) in patients aged 55-76 years.9 An earlier study of allogeneic transplan- tation for older patients with hematologic malignancy concluded HLA-matched sibling donor transplants was associated with lower GvHD and better survival in patients with good performance scores compared to HLA- matched unrelated donor (MUD) who were younger than their recipients.10 Published reports have recorded better survival after transplantation of bone marrow or peripher- al blood grafts from unrelated adult donors aged ≤40 years.11 Thus with increasing numbers of transplants being performed for AML in older patients (≥50 years), a clinical- ly relevant question is whether to use a haploidentical rel- ative or a young MUD when considering alternative donor transplantation.
after seven consecutive days of no platelet transfusions. Grade II- IV acute GvHD and chronic GvHD were based on reports from each transplant center using standard criteria.12,13
Statistical analysis
Differences in patients', disease and transplant characteristics between the two groups (i.e. donor type) were compared using the χ2 statistic for categorical variables. The probabilities of over- all survival and leukemia-free survival were calculated using the Kaplan-Meier estimator.14 The probabilities of neutrophil and platelet recovery, acute and chronic GvHD, non-relapse mortality and relapse were calculated using the cumulative incidence esti- mator to accommodate competing risks.15 Cox regression models were built to study the effect of donor type (MUD vs. haploiden- tical) and other factors associated with overall mortality, grade II-IV acute GvHD, chronic GvHD, relapse, non-relapse mortality and treatment failure.16 Variables tested included: donor age (test- ed as a continuous variable), recipient age, sex, performance score, hematopoietic cell transplant co-morbidity (HCT-CI) score, cytomegalovirus (CMV) serostatus, disease status, cytogenetic risk, transplant conditioning regimen intensity and transplant peri- od. All variables that attained P≤0.05 were held in the final multi- variable model with the exception of the variable for donor type that was held in all steps of model building and the final model regardless of level of significance. There was no first order inter- action between donor type and other variables including condi- tioning regimen intensity. Transplant center effect on survival was tested using the frailty approach.17 All P-values are two-sided. All analyses were made using SAS version 9.4 (Cary, NC, USA).
Results
Patients’, disease and transplant characteristics
Characteristics of recipients of haploidentical (n=192) and MUD (n=631) transplants were similar except that recipients of haploidentical transplants were more likely to have favorable or intermediate risk cytogenetics (P=0.03), and to have received reduced intensity condi- tioning regimen (P<0.0001) (Table 1). The predominant reduced intensity conditioning regimen for haploidentical transplantation was low-dose total body irradiation (200 cGy), cyclophosphamide (29 mg/kg) and fludarabine (150 mg/m2). The predominant reduced intensity conditioning regimen for MUD transplantation was busulfan or mel- phalan with fludarabine. The median ages of recipients of haploidentical and MUD transplantations were 61 and 61 years, respectively. The median time to haploidentical transplantation from diagnosis for patients in CR1 and CR2 were 5 and 20 months, respectively. The correspon- ding time to MUD transplantation was 5 and 18 months. Bone marrow was the predominant graft for haploidenti- cal transplants and peripheral blood the predominant graft for MUD transplants. All recipients of haploidentical transplantation received a uniform GvHD prophylaxis regimen: post-transplant cyclophosphamide with a cal- cineurin inhibitor and mycophenolate. Recipients of MUD transplantation received a calcineurin inhibitor con- taining GvHD prophylaxis; calcineurin inhibitor with methotrexate was the predominant regimen. Haploidentical donors (25% siblings and 75% offspring) were mismatched at ≥2 HLA-loci and the median donor age was 37 years (range: 17-69). MUD were allele-level matched at HLA-A, -B, -C and -DRB1 and their median age was 27 years (range 18-40). The median follow up of
Methods
Patients
Data are reported to the CIBMTR from 195 transplant centers in the United States and 90 of these centers contributed data for the current analysis. Patients are followed longitudinally until death or lost to follow up. Eligible patients were aged 50-76 years with AML, transplanted in first or second remission in the United States between 2008 and 2015 and with commonly used condi- tioning regimens (Online Supplementary Table S1). Patients received bone marrow or peripheral blood from a haploidentical donor (sibling or offspring mismatched at ≥ 2 HLA loci) or an 8/8 HLA- matched MUD aged 18-40 years. Unrelated donors aged >40 years were excluded as over 90% of unrelated donors selected for recent transplants in the US are aged 18-40 years old.11 Excluded patients included those transplanted in relapse (n=248) and receiving trans- plant regimens that included anti-thymocyte globulin or alem- tuzumab (n=76) or CD34 selected peripheral blood (n=56) or ex vivo T-cell depletion (n=34). Patients provided written informed consent for research. The Institutional Review Board of the National Marrow Donor Program approved this study.
End points
The primary end point was overall mortality. Death from any cause was considered an event and surviving patients were cen- sored at last follow up. Relapse was defined as the first detection of one of the following: hematologic, cytogenetic or molecular leukemia recurrence, and non-relapse mortality was defined as death in remission. Treatment failure was defined as relapse or death (inverse of leukemia-free survival). Neutrophil recovery was defined as the first of three consecutive days of an achieved absolute neutrophil count ≥0.5x109/L and platelet recovery was defined as the first date of an achieved platelet count ≥20x109/L
408
haematologica | 2020; 105(2)