When the donor and recipient are mismatched at HLA-DPB1, the risk of graft-versus-host disease is high. The authors found that when the donor has a particular regulatory allele that lowers expression ...of HLA-DPB1, the risk of GVHD is lower.
Hematopoietic-cell transplantation from unrelated donors can cure blood disorders; however, graft-versus-host disease (GVHD) remains a major impediment to successful outcomes.
1
GVHD can occur after HLA-matched transplantation when the donor cells recognize polymorphic peptides (“minor histocompatibility antigens”) presented by the recipient’s HLA.
2
In HLA-mismatched transplantation, direct recognition of the recipient’s mismatched HLA by the donor’s cells provides a potent stimulus for graft-versus-host allorecognition
3
–
7
; recognition of the donor’s mismatched HLA by the recipient’s immune system leads to graft rejection.
8
,
9
The importance of HLA class II alloantigens was established early in the history of clinical transplantation.
10
Advances in understanding the . . .
Purpose The optimal regimen intensity before allogeneic hematopoietic cell transplantation (HCT) is unknown. We hypothesized that lower treatment-related mortality (TRM) with reduced-intensity ...conditioning (RIC) would result in improved overall survival (OS) compared with myeloablative conditioning (MAC). To test this hypothesis, we performed a phase III randomized trial comparing MAC with RIC in patients with acute myeloid leukemia or myelodysplastic syndromes. Patients and Methods Patients age 18 to 65 years with HCT comorbidity index ≤ 4 and < 5% marrow myeloblasts pre-HCT were randomly assigned to receive MAC (n = 135) or RIC (n = 137) followed by HCT from HLA-matched related or unrelated donors. The primary end point was OS 18 months post-random assignment based on an intent-to-treat analysis. Secondary end points included relapse-free survival (RFS) and TRM. Results Planned enrollment was 356 patients; accrual ceased at 272 because of high relapse incidence with RIC versus MAC (48.3%; 95% CI, 39.6% to 56.4% and 13.5%; 95% CI, 8.3% to 19.8%, respectively; P < .001). At 18 months, OS for patients in the RIC arm was 67.7% (95% CI, 59.1% to 74.9%) versus 77.5% (95% CI, 69.4% to 83.7%) for those in the MAC arm (difference, 9.8%; 95% CI, -0.8% to 20.3%; P = .07). TRM with RIC was 4.4% (95% CI, 1.8% to 8.9%) versus 15.8% (95% CI, 10.2% to 22.5%) with MAC ( P = .002). RFS with RIC was 47.3% (95% CI, 38.7% to 55.4%) versus 67.8% (95% CI, 59.1% to 75%) with MAC ( P < .01). Conclusion OS was higher with MAC, but this was not statistically significant. RIC resulted in lower TRM but higher relapse rates compared with MAC, with a statistically significant advantage in RFS with MAC. These data support the use of MAC as the standard of care for fit patients with acute myeloid leukemia or myelodysplastic syndromes.
Because the outcome of allogeneic hematopoietic cell transplantation (HCT) is predominantly influenced by disease type and status, it is essential to be able to stratify patients undergoing HCT by ...disease risk. The Disease Risk Index (DRI) was developed for this purpose. In this study, we analyzed 13 131 patients reported to the Center for International Blood and Marrow Transplant Research who underwent HCT between 2008 and 2010. The DRI stratified patients into 4 groups with 2-year overall survival (OS) ranging from 64% to 24% and was the strongest prognostic factor, regardless of age, conditioning intensity, graft source, or donor type. A randomly selected training subgroup of 9849 patients was used to refine the DRI, using a multivariable regression model for OS. This refined DRI had improved prediction ability for the remaining 3282 patients compared with the original DRI or other existing schemes. This validated and refined DRI can be used as a 4- or 3-group index, depending on the size of the cohort under study, for prognostication; to facilitate the interpretation of single-center, multicenter, or registry studies; to adjust center outcome data; and to stratify patients entering clinical trials that enroll patients across disease categories.
•The DRI successfully stratified patients in a very large allogeneic transplantation registry cohort.•The DRI was refined by using this cohort to build a more inclusive and conditioning intensity–independent index.
Results of 2 parallel phase 2 trials of transplantation of unrelated umbilical cord blood (UCB) or bone marrow (BM) from HLA-haploidentical relatives provided equipoise for direct comparison of these ...donor sources. Between June 2012 and June 2018, 368 patients aged 18 to 70 years with chemotherapy-sensitive lymphoma or acute leukemia in remission were randomly assigned to undergo UCB (n = 186) or haploidentical (n = 182) transplant. Reduced-intensity conditioning comprised total-body irradiation with cyclophosphamide and fludarabine for both donor types. Graft-versus-host disease prophylaxis for UCB transplantation was cyclosporine and mycophenolate mofetil (MMF) and for haploidentical transplantation, posttransplant cyclophosphamide, tacrolimus, and MMF. The primary end point was 2-year progression-free survival (PFS). Treatment groups had similar age, sex, self-reported ethnic origin, performance status, disease, and disease status at randomization. Two-year PFS was 35% (95% confidence interval CI, 28% to 42%) compared with 41% (95% CI, 34% to 48%) after UCB and haploidentical transplants, respectively (P = .41). Prespecified analysis of secondary end points recorded higher 2-year nonrelapse mortality after UCB, 18% (95% CI, 13% to 24%), compared with haploidentical transplantation, 11% (95% CI, 6% to 16%), P = .04. This led to lower 2-year overall survival (OS) after UCB compared with haploidentical transplantation, 46% (95% CI, 38-53) and 57% (95% CI 49% to 64%), respectively (P = .04). The trial did not demonstrate a statistically significant difference in the primary end point, 2-year PFS, between the donor sources. Although both donor sources extend access to reduced-intensity transplantation, analyses of secondary end points, including OS, favor haploidentical BM donors. This trial was registered at www.clinicaltrials.gov as #NCT01597778.
•There is no significant difference in PFS between UCB and haploidentical transplantation for leukemia or lymphoma.•Lower nonrelapse mortality and superior OS favor haploidentical marrow over UCB transplantation.
Display omitted
The National Marrow Donor Program (NMDP) has increased the availability of suitable HLA-matched donors of bone marrow and cord blood, such that more than 90% of people of European or African American ...ancestry in need of a donor will have one.
Hematopoietic stem-cell transplantation (HSCT) is a potentially curative therapy for several life-threatening blood cancers and other diseases. Although an HLA-matched sibling is the preferred donor, only about 30% of patients who may benefit from HSCT have such a donor available. To address this issue, registries of adult volunteers and, more recently, umbilical cord–blood banks have been developed around the globe. In the United States, the National Marrow Donor Program (NMDP) was established in 1986 and has grown to include more than 10.5 million adult volunteers and nearly 200,000 cord-blood units. With contracts from the federal government, the NMDP currently operates . . .
Single-cycle melphalan 200 mg/m
and autologous hematopoietic cell transplantation (AHCT) followed by lenalidomide (len) maintenance have improved progression-free survival (PFS) and overall survival ...(OS) for transplantation-eligible patients with multiple myeloma (MM). We designed a prospective, randomized, phase III study to test additional interventions to improve PFS by comparing AHCT, tandem AHCT (AHCT/AHCT), and AHCT and four subsequent cycles of len, bortezomib, and dexamethasone (RVD; AHCT + RVD), all followed by len until disease progression.
Patients with symptomatic MM within 12 months from starting therapy and without progression who were age 70 years or younger were randomly assigned to AHCT/AHCT + len (n = 247), AHCT + RVD + len (n = 254), or AHCT + len (n = 257). The primary end point was 38-month PFS.
The study population had a median age of 56 years (range, 20 to 70 years); 24% of patients had high-risk MM, 73% had a triple-drug regimen as initial therapy, and 18% were in complete response at enrollment. The 38-month PFS rate was 58.5% (95% CI, 51.7% to 64.6%) for AHCT/AHCT + len, 57.8% (95% CI, 51.4% to 63.7%) for AHCT + RVD + len, and 53.9% (95% CI, 47.4% to 60%) for AHCT + len. For AHCT/AHCT + len, AHCT + RVD + len, and AHCT + len, the OS rates were 81.8% (95% CI, 76.2% to 86.2%), 85.4% (95% CI, 80.4% to 89.3%), and 83.7% (95% CI, 78.4% to 87.8%), respectively, and the complete response rates at 1 year were 50.5% (n = 192), 58.4% (n = 209), and 47.1% (n = 208), respectively. Toxicity profiles and development of second primary malignancies were similar across treatment arms.
Second AHCT or RVD consolidation as post-AHCT interventions for the up-front treatment of transplantation-eligible patients with MM did not improve PFS or OS. Single AHCT and len should remain as the standard approach for this population.
Risk factors for acute GVHD (AGVHD), overall survival, and transplant-related mortality were evaluated in adults receiving allogeneic hematopoietic cell transplants (1999-2005) from HLA-identical ...sibling donors (SDs; n = 3191) or unrelated donors (URDs; n = 2370) and reported to the Center for International Blood and Marrow Transplant Research, Minneapolis, MN. To understand the impact of transplant regimen on AGVHD risk, 6 treatment categories were evaluated: (1) myeloablative conditioning (MA) with total body irradiation (TBI) + PBSCs, (2) MA + TBI + BM, (3) MA + nonTBI + PBSCs, (4) MA + nonTBI + BM, (5) reduced intensity conditioning (RIC) + PBSCs, and (6) RIC + BM. The cumulative incidences of grades B-D AGVHD were 39% (95% confidence interval CI, 37%-41%) in the SD cohort and 59% (95% CI, 57%-61%) in the URD cohort. Patients receiving SD transplants with MA + nonTBI + BM and RIC + PBSCs had significantly lower risks of grades B-D AGVHD than patients in other treatment categories. Those receiving URD transplants with MA + TBI + BM, MA + nonTBI + BM, RIC + BM, or RIC + PBSCs had lower risks of grades B-D AGVHD than those in other treatment categories. The 5-year probabilities of survival were 46% (95% CI, 44%-49%) with SD transplants and 33% (95% CI, 31%-35%) with URD transplants. Conditioning intensity, TBI and graft source have a combined effect on risk of AGVHD that must be considered in deciding on a treatment strategy for individual patients.
The use of two units of cord blood to reconstitute hematopoiesis in transplantation for relapsed hematologic cancers in patients 1 to 21 years of age proved to be no better and was in some ways worse ...than the standard one-unit transplant.
Since 1993, unrelated-donor umbilical-cord blood has been used as the source of hematopoietic stem cells for transplantation in an estimated 30,000 patients with malignant and nonmalignant diseases.
1
As compared with stem-cell grafts from adult donors, cord blood has the advantages of more rapid availability, relative absence of donor attrition, and, after transplantation, a reduced risk of graft-versus-host disease (GVHD) despite donor–recipient HLA disparity.
2
,
3
In addition, less restriction on HLA matching permits greater use of cord blood for members of racial minorities, who are less likely to have a suitably HLA-matched volunteer adult donor.
4
However, the use of cord blood . . .
There are >24 million registered adult donors, and the numbers of unrelated donor transplantations are increasing. The optimal strategy for prioritizing among comparably HLA-matched potential donors ...has not been established. Therefore, the objective of the current analyses was to study the association between donor characteristics (age, sex, parity, cytomegalovirus serostatus, HLA match, and blood group ABO match) and survival after transplantation for hematologic malignancy. The association of donor characteristics with transplantation outcomes was examined using either logistic or Cox regression models, adjusting for patient disease and transplantation characteristics associated with outcomes in 2 independent datasets: 1988 to 2006 (N = 6349; training cohort) and 2007 to 2011 (N = 4690; validation cohort). All donor-recipient pairs had allele-level HLA typing at HLA-A, -B, -C, and -DRB1, which is the current standard for selecting donors. Adjusting for patient disease and transplantation characteristics, survival was better after transplantation of grafts from young donors (aged 18-32 years) who were HLA matched to recipients (P < .001). These findings were validated for transplantations that occurred between 2007 and 2011. For every 10-year increment in donor age, there is a 5.5% increase in the hazard ratio for overall mortality. Increasing HLA disparity was also associated with worsening survival. Donor age and donor-recipient HLA match are important when selecting adult unrelated donors. Other donor characteristics such as sex, parity, and cytomegalovirus serostatus were not associated with survival. The effect of ABO matching on survival is modest and must be studied further before definitive recommendations can be offered.
•Donor age and donor-recipient HLA match predict survival after hematopoietic cell transplantation.
Summary Background Umbilical-cord blood (UCB) is increasingly considered as an alternative to peripheral blood progenitor cells (PBPCs) or bone marrow, especially when an HLA-matched adult unrelated ...donor is not available. We aimed to determine the optimal role of UCB grafts in transplantation for adults with acute leukaemia, and to establish whether current graft-selection practices are appropriate. Methods We used Cox regression to retrospectively compare leukaemia-free survival and other outcomes for UCB, PBPC, and bone marrow transplantation in patients aged 16 years or over who underwent a transplant for acute leukaemia. Data were available on 1525 patients transplanted between 2002 and 2006. 165 received UCB, 888 received PBPCs, and 472 received bone marrow. UCB units were matched at HLA-A and HLA-B at antigen level, and HLA-DRB1 at allele level (n=10), or mismatched at one (n=40) or two (n=115) antigens. PBPCs and bone-marrow grafts from unrelated adult donors were matched for allele-level HLA-A, HLA-B, HLA-C, and HLA-DRB1 (n=632 and n=332, respectively), or mismatched at one locus (n=256 and n=140, respectively). Findings Leukaemia-free survival in patients after UCB transplantation was comparable with that after 8/8 and 7/8 allele-matched PBPC or bone-marrow transplantation. However, transplant-related mortality was higher after UCB transplantation than after 8/8 allele-matched PBPC recipients (HR 1·62, 95% CI 1·18–2·23; p=0·003) or bone-marrow transplantation (HR 1·69, 95% CI 1·19–2·39; p=0·003). Grades 2–4 acute and chronic graft-versus-host disease (GvHD) were lower in UCB recipients compared with allele-matched PBPC (HR 0·57, 95% 0·42–0·77; p=0·002 and HR 0·38, 0·27–0·53; p=0·003, respectively), while the incidence of chronic, but not acute GvHD, was lower after UCB than after 8/8 allele-matched bone-marrow transplantation (HR 0·63, 0·44–0·90; p=0·01). Interpretation These data support the use of UCB for adults with acute leukaemia when there is no HLA-matched unrelated adult donor available, and when a transplant is needed urgently. Funding National Cancer Institute, National Heart Lung and Blood Institute, National Institute of Allergy and Infectious Disease ( U24-CA76518 ); Health Resources and Services Administration ( HHSH234200637015C ); Office of Naval Research, Department of Navy ( N00014-08-1-1207 ); Children's Leukemia Research Association; and a Scholar in Clinical Research Award from the Leukemia and Lymphoma Society.
PDF
