Effect of donor age and kinship on outcomes in haplo-identical stem cell transplantation may be modulated by GVHD prophylaxis strategies
Bone marrow transplantation. 2020
Patterns of infection and infectious-related mortality in patients receiving post-transplant high dose cyclophosphamide as graft-versus-host-disease prophylaxis: impact of HLA donor matching
Bone marrow transplantation. 2020;:1-10
Post-transplant cyclophosphamide (PTCy) has become a promising option after allo-SCT, but infections may be more common than in traditional protocols. We herein report 117 consecutive adults who received PTCy-based alloSCT in our hospital: HaploSCT (34%), MRD (19%), and VUD (47%), respectively. The 18-month incidence of severe bacterial, viral, and IFI was 56%, 69%, and 8.7%, without differences between donor type, except for CMV infection and viral hemorrhagic cystitis, which had a higher incidence in the haploSCT cohort (58% vs. 43% and 30% vs. 8% on day +90, p < 0.05). Late infections by conventional respiratory viruses were common in all groups [33/87 (38%)]. The 2-year survival was 72% and did not differ by donor type. IRM at day 30, day 100, and 18 months was 1.7%, 4.4%, and 12%, without differences by donor type (p = 0.7). The primary cause of IRM was bacterial infection (42%). Grade 2-4 acute GvHD was the only independent predictor of IRM. Donor type had no impact on IRM or on survival. In our study, severe infections were common in all donor types using PTCy, with higher rates of early post-engraftment CMV-I and viral HC in haploSCT recipients, although lethal infections were uncommon and similar in all donor types.
Effect of donor characteristics on haploidentical transplantation with posttransplantation cyclophosphamide
Blood advances. 2018;2(3):299-307
We studied the association between non-HLA donor characteristics (age, sex, donor-recipient relationship, blood group [ABO] match, and cytomegalovirus [CMV] serostatus) and transplant outcomes after T-cell-replete HLA-haploidentical transplantation using posttransplantation cyclophosphamide (PT-Cy) in 928 adults with hematologic malignancy transplanted between 2008 and 2015. Siblings (n = 358) and offspring (n = 450) were the predominant donors, with only 120 patients having received grafts from parents. Although mortality risks were higher with donors aged 30 years or older (hazard ratio, 1.39; P < .0001), the introduction of patient age to the Cox regression model negated the effect of donor age. Two-year survival adjusted for CMV seropositivity, disease, and disease risk index was lower in patients aged 55 to 78 years after transplantation of grafts from donors younger than 30 years (53%) or aged at least 30 years (46%) compared with younger patients who received grafts from donors younger than 30 years (61%) and at least 30 years (60%; P < .0001). Similarly, 2-year survival in patients aged 55 to 78 years was lower after transplantation of grafts from siblings (45%) or offspring (48%) compared with patients aged 18 to 54 years after transplantation of grafts from siblings (62%), offspring (58%), and parents (61%; P < .0001). Graft failure was higher after transplantation of grafts from parents (14%) compared with siblings (6%) or offspring (7%; P = .02). Other non-HLA donor characteristics were not associated with survival or graft failure. The current analyses suggest patient and disease, rather than non-HLA donor characteristics, predominantly influence survival in adults.
Single-Antigen-Mismatched Unrelated Hematopoietic Stem Cell Transplantation Using High-Dose Post-Transplantation Cyclophosphamide is a Suitable Alternative for Patients Lacking HLA-Matched Donors
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
The optimal prophylaxis regimen for graft-versus-host disease (GVHD) in the setting of mismatched unrelated donor (MMUD) allogeneic hematopoietic stem cell transplantation (alloSCT) is not defined. The use of high-dose post-transplant cyclophosphamide (PTCy) in haploidentical transplantation has proven feasible and effective in overcoming the negative impact of HLA-disparity on survival. We hypothesized that PTCy could also be effective in the setting of MMUD transplantation. We retrospectively analyzed 86 consecutive adult recipients of alloHSCT in our institution, comparing two contemporaneous groups: PTCyMMUD (n=26) vs. matched unrelated donor (MUD) (n=60). Graft source was primarily peripheral blood (92%). All PTCyMMUD were HLA 7/8 (differences in HLA-class I loci in 92% of patients), and received PTCy plus tacrolimus + mofetil mycophenolate as GVHD prophylaxis. No differences were observed between PTCyMMUD and MUD in the 100-day cumulative incidence of acute GVHD grades II-IV (31% vs. 22%, respectively, P=0.59) and III-IV (8% vs. 10%, P=0.67). There was a trend for a lower incidence of moderate/severe chronic GVHD at 1-year after PTCyMMUD in comparison with MUD (22% vs. 41%, P=0.098). No differences between PTCyMMUD and MUD were found regarding non-relapse mortality (25% vs. 18%; P=0.52) or relapse rate (11% vs. 19%, P=0.18). Progression-free survival and overall survival at 2-year were similar in both cohorts (67% vs. 54%, HR 0.84, 95% CI 0.38-1.88; P= 0.68; and 72% vs. 57%, HR 0.71; 95% CI 0.31-1.67; P=0.44, respectively). The 2-year cumulative incidence of survival free of moderate-severe chronic GVHD and relapse tended to be higher in the PTCyMMUD group (47% vs. 24%; HR 0.60, 95% CI 0.31-1.14, P=0.12). We conclude that HLA 7/8 MMUD transplantation using PTCy plus tacrolimus is a suitable alternative for those patients who lack a MUD.
Similar outcomes after haploidentical transplantation with post-transplant cyclophosphamide versus HLA-matched transplantation: a meta-analysis of case-control studies
BACKGROUND Outcomes of haploidentical hematopoietic cell transplantation (haplo-HCT) with post-transplant cyclophosphamide (PT-Cy) have greatly improved. It remains unknown whether haplo-HCT with PT-Cy was associated with poor outcomes when compared with HLA-matched HCT. To address this issue, we performed a meta-analysis to compare outcomes of haplo-HCT with PT-Cy with those of HLA-matched HCT. METHODS A systematic search for case-control studies were performed in PubMed, Embase and Cochrane Library databases. Using a random model, the risk ratios (RRs) and 95% confidence intervals (95% CI) were pooled for the final analysis. RESULTS Nine case-control studies including 2258 patients (827 patients in the haplo-HCT with PT-Cy group, 748 controls from HLA-matched related donors (MRD), and 683 controls from HLA-matched unrelated donors (MUD)) met the inclusion criteria. No differences were found between haplo-HCT with PT-Cy and HLA-matched HCT with regard to acute graft-versus-host-disease (GVHD), non-relapse mortality, relapse, progression free survival and overall survival. However, haplo-HCT with PT-Cy was found to be associated with a lower incidence of moderate to severe chronic GVHD (Haplo vs MRD: RR=0.54; 95% CI=0.39-0.75; Haplo vs MUD: RR=0.70; 95% CI=0.56-0.88). CONCLUSIONS The results of this meta-analysis suggest that haplo-HCT with PT-Cy can achieve comparable outcomes with those of HLA-matched HCT. Haploidentical donors can be a feasible and valid alternative when conventional HLA-matched donors are unavailable.
A single-center analysis of chronic graft-versus-host disease-free, relapse-free survival after alternative donor stem cell transplantation in children with hematological malignancies
International Journal of Hematology. 2017;105(5):676-685
We assessed the clinical outcomes of allogeneic hematopoietic stem cell transplantation (SCT) from alternative donors for pediatric patients with hematological malignancies, defining graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) as a composite endpoint. We also defined chronic GVHD-free, relapse-free survival (cGRFS) as survival without severe chronic GVHD, relapse, or death. The probabilities of 2-year disease-free survival from a human leukocyte antigen (HLA) matched unrelated donor (n = 57), related donor with HLA-1 antigen mismatch in the graft-versus-host direction (1Ag-GvH-MMRD, n = 28), and unrelated umbilical cord blood (n = 35) were 52.2, 38.5, and 40.4%, respectively (P = 0.14), and for 2-year GRFS were 26.2, 13.4, and 30.4%, respectively (P = 0.089), and for 2-year cGRFS were 36.2, 16.7, and 40.4%, respectively (P = 0.015). Of the three groups, the 1Ag-GvH-MMRD group showed a significantly higher cumulative incidence of severe cGVHD, and was identified as a significant risk factor for worse cGRFS. These results suggest that intensification of GVHD prophylaxis may be needed for SCT from 1Ag-GvH-MMRD. As with GRFS, cGRFS should be used as an endpoint of the clinical study to predict long-term morbidity and mortality for patients who need longer follow-up such as pediatric SCT recipients.
Post-transplant high-dose cyclophosphamide after HLA-matched vs haploidentical hematopoietic cell transplantation for AML
Bone Marrow Transplantation. 2016;51(12):1561-1564
Post-transplant cyclophosphamide (PT-Cy) is the backbone of GvHD prophylaxis following haploidentical hematopoietic cell transplantation (haplo-HCT). PT-Cy has also been used in matched related (MRD) and unrelated (MUD) settings. It is not known whether outcomes are similar between haplo-HCT and MRD/MUD HCT when PT-Cy is used. We performed a retrospective analysis of 83 patients with AML who underwent HCT (using PT-Cy-based GvHD prophylaxis) from MRD, MUD or haploidentical donors. The groups were similar in baseline characteristics with the exception of older age in the MRD/MUD group (P=0.012). In multivariate analysis, the effect of donor type (MRD/MUD vs haploidentical) on transplant outcomes was not significant in any of the models except for faster neutrophil recovery after MRD/MUD transplants (hazard ratio: 2.21; 95% confidence interval: 1.31-3.72, P=0.002). In conclusion, we showed similar outcomes in MRD/MUD vs haploidentical HCT (except slower count recovery following haplo-HCT) when PT-Cy is used for GvHD prophylaxis. Although slower count recovery following haplo-HCT (compared with MRD/MUD transplants without PT-Cy) has been attributed to using PT-Cy, our results suggest that HLA disparity is the primary cause of this difference. Furthermore, our analysis supports PT-Cy as a viable option for GvHD prophylaxis after MRD/MUD transplants.
Prognostic factors affecting outcome after allogeneic transplantation for hematological malignancies from unrelated donors: results from a randomized trial
Biol Blood Marrow Transplant. 2012;18(11):1716-26
Several prognostic factors for the outcome after allogeneic hematopoietic stem-cell transplant (HSCT) from matched unrelated donors have been postulated from registry data; however, data from randomized trials are lacking. We present analyses on the effects of patient-related, donor-related, and treatment-related prognostic factors on acute GVHD (aGVHD), chronic GVHD (cGVHD), relapse, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS) in a randomized, multicenter, open-label, phase III trial comparing standard graft-versus-host-disease (GVHD) prophylaxis with and without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before HSCT from HLA-A, HLA-B antigen, HLA-DRB1, HLA-DQB1 allele matched unrelated donors. High-resolution testing (allele) of HLA-A, HLA-B, and HLA-C were obtained after study closure, and the impact of an HLA 10/10 4-digit mismatch on outcome and on the treatment effect of ATG-F versus control investigated. Advanced disease was a negative factor for relapse, DFS, and OS. Donor age >40 adversely affected the risk of aGVHD III-IV, extensive cGVHD, and OS. Younger donors are to be preferred in unrelated donor transplantation. Advanced disease patients need special precautions to improve outcome. The degree of mismatch had no major influence on the positive effect of ATG-F on the reduction of aGVHD and cGVHD.Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.