Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders that are more common in patients aged ≥ 60 years and are incurable with conventional therapies. Reduced-intensity conditioning (RIC) ...allogeneic hematopoietic stem-cell transplantation is potentially curative but has additional mortality risk. We evaluated RIC transplantation versus nontransplantation therapies in older patients with MDS stratified by International Prognostic Scoring System (IPSS) risk.
A Markov decision model with quality-of-life utility estimates for different MDS and transplantation states was assessed. Outcomes were life expectancy (LE) and quality-adjusted life expectancy (QALE). A total of 514 patients with de novo MDS aged 60 to 70 years were evaluated. Chronic myelomonocytic leukemia, isolated 5q- syndrome, unclassifiable, and therapy-related MDS were excluded. Transplantation using T-cell depletion or HLA-mismatched or umbilical cord donors was also excluded. RIC transplantation (n = 132) stratified by IPSS risk was compared with best supportive care for patients with nonanemic low/intermediate-1 IPSS (n = 123), hematopoietic growth factors for patients with anemic low/intermediate-1 IPSS (n = 94), and hypomethylating agents for patients with intermediate-2/high IPSS (n = 165).
For patients with low/intermediate-1 IPSS MDS, RIC transplantation LE was 38 months versus 77 months with nontransplantation approaches. QALE and sensitivity analysis did not favor RIC transplantation across plausible utility estimates. For intermediate-2/high IPSS MDS, RIC transplantation LE was 36 months versus 28 months for nontransplantation therapies. QALE and sensitivity analysis favored RIC transplantation across plausible utility estimates.
For patients with de novo MDS aged 60 to 70 years, favored treatments vary with IPSS risk. For low/intermediate-1 IPSS, nontransplantation approaches are preferred. For intermediate-2/high IPSS, RIC transplantation offers overall and quality-adjusted survival benefit.
Summary Background Although umbilical cord blood is an accepted alternative to bone marrow for transplantation, allele-matched bone marrow is generally regarded as the preferred graft source. Our aim ...was to assess leukaemia-free survival after transplantations of these alternatives compared with present HLA-matching practices, and to assess the relative effect of cell dose and HLA match, and their potential interaction on leukaemia-free survival after cord-blood transplantation. Methods Outcomes of 503 children (<16 years) with acute leukaemia and transplanted with umbilical cord blood were compared with outcomes of 282 bone-marrow recipients. All transplantation took place in the USA. Recipients of umbilical cord blood were transplanted with grafts that were HLA-matched (n=35) or HLA-mismatched for one (n=201) or two antigens (n=267) (typing at antigen level for HLA-A and HLA-B, and allele level for HLA-DRB1). Bone-marrow recipients were transplanted with grafts that were matched at the allele level for HLA-A, HLA-B, HLA-C, and HLA-DRB (n=116), or mismatched (n=166). The primary endpoint was 5-year leukaemia-free survival. Findings In comparison with allele-matched bone-marrow transplants, 5-year leukaemia-free survival was similar to that after transplants of umbilical cord blood mismatched for either one or two antigens and possibly higher after transplants of HLA-matched umbilical cord blood. Transplant-related mortality rates were higher after transplants of two-antigen HLA-mismatched umbilical cord blood (relative risk 2·31, p=0·0003) and possibly after one-antigen HLA-mismatched low-cell-dose umbilical-cord-blood transplants (1·88, p=0·0455). Relapse rates were lower after two-antigen HLA-mismatched umbilical-cord-blood transplants (0·54, p=0·0045). Interpretation These data support the use of HLA-matched and one- or two-antigen HLA-mismatched umbilical cord blood in children with acute leukaemia who need transplantation. Because better HLA matching and higher cell doses significantly decrease the risk of transplant-related mortality after umbilical-cord-blood transplantation, greater investment in large-scale banking is needed to increase HLA diversity.
Grades 2-4 acute graft-versus-host disease (GVHD) occurs in approximately 35% of matched, related donor (MRD) allogeneic hematopoietic cell transplantation (HCT) recipients. We sought to determine if ...the combination of tacrolimus and sirolimus (Tac/Sir) was more effective than tacrolimus and methotrexate (Tac/Mtx) in preventing acute GVHD and early mortality after allogeneic MRD HCT in a phase 3, multicenter trial. The primary end point of the trial was to compare 114-day grades 2-4 acute GVHD-free survival using an intention-to-treat analysis of 304 randomized subjects. There was no difference in the probability of day 114 grades 2-4 acute GVHD-free survival (67% vs 62%, P = .38). Grades 2-4 GVHD was similar in the Tac/Sir and Tac/Mtx arms (26% vs 34%, P = .48). Neutrophil and platelet engraftment were more rapid in the Tac/Sir arm (14 vs 16 days, P < .001; 16 vs 19 days, P = .03). Oropharyngeal mucositis was less severe in the Tac/Sir arm (peak Oral Mucositis Assessment Scale score 0.70 vs 0.96, P < .001), but otherwise toxicity was similar. Chronic GVHD, relapse-free survival, and overall survival at 2 years were no different between study arms (53% vs 45%, P = .06; 53% vs 54%, P = .77; and 59% vs 63%, P = .36). Based on similar long-term outcomes, more rapid engraftment, and less oropharyngeal mucositis, the combination of Tac/Sir is an acceptable alternative to Tac/Mtx after MRD HCT. This study was funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; and the trial was registered at www.clinicaltrials.gov as #NCT00406393.
•Tac/Sir prophylaxis provides equivalent GVHD-free survival when compared with Tac/Mtx in MRD transplantation.•Tac/Sir is associated with more rapid engraftment and reduced oropharyngeal mucositis after MRD transplantation.
Hematopoietic cell transplantation (HCT) from HLA-mismatched unrelated donors can cure life-threatening blood disorders, but its success is limited by graft-versus-host disease (GVHD). HLA-B leaders ...encode methionine (M) or threonine (T) at position 2 and give rise to TT, MT, or MM genotypes. The dimorphic HLA-B leader informs GVHD risk in HLA-B–mismatched HCT. If the leader influences outcome in other HLA-mismatched transplant settings, the success of HCT could be improved for future patients. We determined leader genotypes for 10 415 patients receiving a transplant between 1988 and 2016 from unrelated donors with one HLA-A, HLA-B, HLA-C, HLA-DRB1, or HLA-DQB1 mismatch. Multivariate regression methods were used to evaluate risks associated with patient leader genotype according to the mismatched HLA locus and with HLA-A, HLA-B, HLA-C, HLA-DRB1, or HLA-DQB1 mismatching according to patient leader genotype. The impact of the patient leader genotype on acute GVHD and mortality varied across different mismatched HLA loci. Nonrelapse mortality was higher among HLA-DQB1–mismatched MM patients compared with HLA-DQB1–mismatched TT patients (hazard ratio, 1.35; P = .01). Grades III to IV GVHD risk was higher among HLA-DRB1–mismatched MM or MT patients compared with HLA-DRB1–mismatched TT patients (odds ratio, 2.52 and 1.51, respectively). Patients tolerated a single HLA-DQB1 mismatch better than mismatches at other loci. Outcome after HLA-mismatched transplantation depends on the HLA-B leader dimorphism and the mismatched HLA locus. The patient's leader variant provides new information on the limits of HLA mismatching. The success of HLA-mismatched unrelated transplantation might be enhanced through the judicious selection of mismatched donors for a patient's leader genotype.
•The HLA-B leader dimorphism informs survival after unrelated donor HCT.•The risks associated with HLA mismatching depend on the HLA-B leader genotype.
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Summary Background The importance of matching at the HLA C locus has not been well defined for unrelated umbilical-cord blood transplantation. The selection algorithm for umbilical-cord blood units ...generally considers intermediate resolution HLA typing at A and B and allele-level typing at DRB1. We aimed to establish the relative importance of additional matching at HLA C. Methods We used Cox regression to assess retrospectively the effect of donor–recipient HLA matching on outcomes of single umbilical-cord blood transplantations for leukaemia and myelodysplastic syndrome. Our primary endpoint was transplant-related mortality. HLA typing was done with molecular techniques with a minimum of intermediate resolution for HLA A, B, and C, and at the allele-level for DRB1. Findings The median age of our study population was 10 years (range <1–62) and 552 (69%) of 803 patients were aged 16 years or younger at transplantation. Compared with transplantations matched at HLA A, B, C, and DRB1 (n=69), transplant-related mortality risk was higher after transplantations matched at HLA A, B, and DRB1 and mismatched at HLA C (n=23; HR 3·97, 95% CI 1·27–12·40; p=0·018). Transplant-related mortality risk was also higher after transplantations with a single mismatch at HLA A, B, or DRB1 and mismatched at HLA C (n=234; 1·70, 1·06–2·74; p=0·029) compared with transplantations matched at HLA C with a single mismatch at HLA A, B, or DRB1 (n=127). Assessing the overall effect of HLA disparity on transplant-related mortality, risks were higher with units mismatched at two (n=259; 3·27, 1·42–7·54; p=0·006), three (n=253; 3·34, 1·45–7·71; p=0·005), or four (n=75; 3·51, 1·44–8·58; p=0·006) loci compared with matched units (n=69). Interpretation Our data suggest that the present strategy for umbilical-cord blood unit selection should be reassessed; matching at HLA C for units that are matched at HLA A, B, or DRB1 or in the presence of a single locus mismatch at HLA A, B, or DRB1 should be included to minimise mortality risks. Funding National Cancer Institute, National Heart Lung and Blood Institute, National Institute for Allergy and Infectious Diseases, Leukemia and Lymphoma Society, US Department of the Navy, Children's Leukemia Research Association, and INSERM.
Clinical- and biomarker-based tools may identify a lower-risk acute graft-versus-host disease (GVHD) population amenable to novel, reduced-intensity treatments. Previous data suggest sirolimus may ...rival standard of care prednisone. We conducted a National Heart, Lung, and Blood Institute/National Cancer Institute-funded Blood and Marrow Transplant Clinical Trials Network multicenter, open-label, randomized phase 2 trial to estimate the difference in day 28 complete response (CR)/partial response (PR) rates for sirolimus vs prednisone as initial treatment of patients with standard risk (SR) acute GVHD as defined by the Minnesota (MN) GVHD Risk Score and Ann Arbor (AA1/2) biomarker status. A total of 127 MN-SR patients were randomized (1:1), and 122 were AA1/2 (sirolimus, n = 58; prednisone, n = 64). Others were AA3 (n = 4), or AA status missing (n = 1). The day 28 CR/PR rates were similar for sirolimus 64.8% (90% confidence interval CI, 54.1%-75.5%) vs 73% (90% CI, 63.8%-82.2%) for prednisone. The day 28 rate of CR/PR with prednisone ≤0.25 mg/kg/day was significantly higher for sirolimus than prednisone (66.7% vs 31.7%; P < .001). No differences were detected in steroid-refractory acute GVHD, disease-free survival, relapse, nonrelapse mortality, or overall survival. Sirolimus was associated with reduced steroid exposure and hyperglycemia, reduced grade 2 to 3 infections, improvement in immune suppression discontinuation and patient-reported quality of life, and increased risk for thrombotic microangiopathy. For patients with clinical- and biomarker-based SR acute GVHD, sirolimus demonstrates similar overall initial treatment efficacy as prednisone. In addition, sirolimus therapy spares steroid exposure and allied toxicity, does not compromise long-term survival outcomes, and is associated with improved patient-reported quality of life. This trial was registered at www.clinicaltrials.gov as #NCT02806947.
•Sirolimus provides similar day 28 complete/partial response rates as prednisone in initial therapy of standard-risk acute GVHD.•Sirolimus therapy was associated with reduced steroid exposure, greater immune suppression discontinuation, and improved quality of life.
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Calcineurin inhibitors (CNI) are standard components of graft-versus-host disease (GVHD) prophylaxis after hematopoietic cell transplantation (HCT). Prior data suggested that CNI-free approaches ...using donor T-cell depletion, either by ex vivo CD34 selection or in vivo post-transplant cyclophosphamide (PTCy) as a single agent, are associated with lower rates of chronic GVHD (cGVHD).
This multicenter phase III trial randomly assigned patients with acute leukemia or myelodysplasia and an HLA-matched donor to receive CD34-selected peripheral blood stem cell, PTCy after a bone marrow (BM) graft, or tacrolimus and methotrexate after BM graft (control). The primary end point was cGVHD (moderate or severe) or relapse-free survival (CRFS).
Among 346 patients enrolled, 327 received HCT, 300 per protocol. Intent-to-treat rates of 2-year CRFS were 50.6% for CD34 selection (hazard ratio HR compared with control, 0.80; 95% CI, 0.56 to 1.15;
= .24), 48.1% for PTCy (HR, 0.86; 0.61 to 1.23;
= .41), and 41.0% for control. Corresponding rates of overall survival were 60.1% (HR, 1.74; 1.09 to 2.80;
= .02), 76.2% (HR, 1.02; 0.60 to 1.72;
= .95), and 76.1%. CD34 selection was associated with lower moderate to severe cGVHD (HR, 0.25; 0.12 to 0.52;
= .02) but higher transplant-related mortality (HR, 2.76; 1.26 to 6.06;
= .01). PTCy was associated with comparable cGVHD and survival outcomes to control, and a trend toward lower disease relapse (HR, 0.52; 0.28 to 0.96;
= .037).
CNI-free interventions as performed herein did not result in superior CRFS compared with tacrolimus and methotrexate with BM. Lower rates of moderate and severe cGVHD did not translate into improved survival.
In this trial, 1-year GVHD-free, relapse-free survival after stem-cell transplantation was 52.7% in the cyclophosphamide–tacrolimus–mycophenolate mofetil group and 34.9% in the ...tacrolimus–methotrexate group.
Selection of a suitable graft for allogeneic hematopoietic stem cell transplantation involves consideration of both donor and recipient characteristics. Of primary importance is sufficient ...donor-recipient HLA matching to ensure engraftment and acceptable rates of GVHD. In this Perspective, the National Marrow Donor Program and the Center for International Blood and Marrow Transplant Research provide guidelines, based on large studies correlating graft characteristics with clinical transplantation outcomes, on appropriate typing strategies and matching criteria for unrelated adult donor and cord blood graft selection.
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