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1.
Donor selection for KIR alloreactivity is associated with superior survival in haploidentical transplant with PTCy
Zou, J., Kongtim, P., Srour, S. A., Greenbaum, U., Schetelig, J., Heidenreich, F., Baldauf, H., Moore, B., Saengboon, S., Carmazzi, Y., et al
Frontiers in immunology. 2022;13:1033871
Abstract
With the continuous increase in the use of haploidentical donors for transplantation, the selection of donors becomes increasingly important. Haploidentical donors have been selected primarily based on clinical characteristics, while the effects of killer cell immunoglobulin-like receptors (KIRs) on outcomes of haploidentical-hematopoietic stem cell transplantation (haplo-HSCT) with post-transplant cyclophosphamide (PTCy) remain inconclusive. The present study aimed to thoroughly evaluate the effect of KIRs and binding ligands assessed by various models, in addition to other patient/donor variables, on clinical outcomes in haplo-HSCT. In a cohort of 354 patients undergoing their first haplo-HSCT, we found that a higher Count Functional inhibitory KIR score (CF-iKIR) was associated with improved progression-free survival (adjusted hazard ratio [HR], 0.71; P = .029) and overall survival (OS) (HR, 0.66; P = .016), while none of the other models predicted for survival in these patients. Moreover, using exploratory classification and regression tree analysis, we found that donor age <58 years combined with cytomegalovirus-nonreactive recipient was associated with the best OS, whereas donor age >58 years was associated with the worst OS. In the rest of our cohort (80%), cytomegalovirus-reactive recipients with a donor <58 years old, a higher CF-iKIR was associated with superior OS. The 3-year OS rates were 73.9%, 54.1% (HR, 1.84; P = .044), 44.5% (HR, 2.01; P = .003), and 18.5% (HR, 5.44; P <.001) in the best, better, poor, and worse donor groups, respectively. Our results suggest that KIR alloreactivity assessed by CF-iKIR score can help optimize donor selection in haplo-HSCT.
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2.
HLA Factors Versus Non-HLA Factors for Haploidentical Donor Selection
Mehta, R. S., Cao, K., Saliba, R. M., Al-Atrash, G., Alousi, A. M., Lontos, K., Marcoux, C., Carmazzi, Y., Rondon, G., Bashir, Q., et al
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
When multiple haploidentical donors are available for transplantation, those of younger generations are generally selected over those of older generations. However, it is unclear who is the optimal donor when selecting candidates from within a generation, such as a father vs mother, son vs daughter, or brother vs sister. Although traditionally, male donors are favored over female donors, particularly for male recipients and significant associations of individual HLA mis(matches) on outcomes are being recognized, the hierarchy of factors for donor selection is indeterminate. To assess whether HLA factors take precedence over non-HLA factors and to isolate the influence of specific characteristics on outcomes, we analyzed 412 patients stratified by donor relationship: child donor [son (n=202) vs daughter (n=96)]; parent [(father: n=28 vs mother: n=29)] and sibling [non-inherited maternal (NIMA, n=29) vs paternal (NIPA, n=28)-mismatched]. Among siblings, NIMA-mismatch was associated with a lower risk of acute graft-versus-host disease (aGVHD); B-leader mismatch was associated with high non-relapse mortality (NRM), poor progression-free survival, and a trend towards poor overall survival (OS); A-mismatch was associated with lower aGVHD. Among parent donors, the relationship did not impact any outcome; B-leader mismatch was associated with higher NRM and a trend towards poor OS; A-mismatch was associated with lower NRM and improved PFS and OS. Among child donors, no individual HLA mismatch predicted any outcome, and daughter donors were not associated with any adverse outcomes in multivariate analyses. Our data suggest that certain HLA factors may be more significant in some cases and should be given priority than simply selecting a donor based on relationship/gender.
PICO Summary
Population
Adults with haematological malignancy who underwent haploidentical transplantation at a single centre in USA (n=412
Intervention
Sibling donor: non-inherited maternal mismatched (NIMA, n=29); non-inherited paternal mismatch (NIPA, n=28)
Comparison
Child donor: son (n=202), daughter (n=96); Parent donor: father, (n=28), mother, (n=29)
Outcome
Among siblings, NIMA-mismatch was associated with a lower risk of acute graft-versus-host disease (aGVHD); B-leader mismatch was associated with high non-relapse mortality (NRM), poor progression-free survival (PFS), and a trend towards poor overall survival (OS); A-mismatch was associated with lower aGVHD. Among parent donors, the relationship did not impact any outcome; B-leader mismatch was associated with higher NRM and a trend towards poor OS; A-mismatch was associated with lower NRM and improved PFS and OS. Among child donors, no individual HLA mismatch predicted any outcome, and daughter donors were not associated with any adverse outcomes in multivariate analyses.
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3.
Haploidentical vs Matched Unrelated vs Matched Sibling Donor HCT with Post-Transplantation Cyclophosphamide
Mehta, R. S., Saliba, R. M., Ghanem, S., Alousi, A. M., Rondon, G., Anderlini, P., Al-Atrash, G., Bashir, Q., Hosing, C. M., Im, J. S., et al
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
With the use of post-transplantation cyclophosphamide (PTCy), the outcomes of mismatched related donor hematopoietic cell transplantation (HCT) are now approaching that of matched donors. We compared haploidentical versus HLA-matched (MUD) versus HLA-identical sibling (MSD) donors, where all patients received PTCy for graft-versus-host disease (GVHD) prophylaxis. We included 661 patients (275 haploidentical, 246 MUD, and 140 MSD). The most common diagnoses were acute myeloid leukemia or myelodysplastic syndrome. In multivariate analysis, the haploidentical group was associated with a significantly higher non-relapse mortality (NRM; Hazard Ratio [HR] 3.2, 95% confidence interval [CI] 2-4.9, p<0.001), inferior progression-free survival (HR 1.8, 95% CI 1.4-2.4, p<0.001) and overall survival (HR 2.2, 95% CI 1.6-3, p<0.001) than the MUD group. Relapse was the most common cause of death in all groups. Among NRM causes, the haploidentical group had more infection-related deaths and fewer GVHD-related deaths than other groups. The haploidentical group had a higher risk of viral and fungal infections, grade ≥3 hemorrhagic cystitis and cardiovascular toxicities, and slower reconstitution of CD4, CD8, and regulatory T cells but faster reconstitution of NK cells. In an exploratory analysis, older patients with older donors (>50 years for both) appeared to be associated with particularly high NRM and lower OS in haploidentical than the other groups. Our data suggest that even with the use of PTCy, the outcomes of haploidentical HCT are inferior as compared to HLA-matched donor HCT.
PICO Summary
Population
Adults with acute myeloid leukaemia or myelodysplastic syndromes requiring hematopoietic cell transplantation in single centre in the USA (HCT, n=661)
Intervention
HCT from haploidentical donors (n=275)
Comparison
HCT from HLA-matched donors (MUD, n=246) or HLA-identical sibling donors (MSD, n=140)
Outcome
In multivariate analysis, the haploidentical group was associated with a significantly higher non-relapse mortality (NRM; Hazard Ratio [HR] 3.2, 95% confidence interval [CI] 2-4.9), inferior progression-free survival (HR 1.8, 95% CI 1.4-2.4) and overall survival (HR 2.2, 95% CI 1.6-3) than the MUD group. Relapse was the most common cause of death in all groups. Among NRM causes, the haploidentical group had more infection-related deaths and fewer GVHD-related deaths than other groups. The haploidentical group had a higher risk of viral and fungal infections, grade ≥3 hemorrhagic cystitis and cardiovascular toxicities, and slower reconstitution of CD4, CD8, and regulatory T cells but faster reconstitution of NK cells. In an exploratory analysis, older patients with older donors (>50 years for both) appeared to be associated with particularly high NRM and lower OS in haploidentical than the other groups.
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4.
Impact of Donor Type and Melphalan Dose on Allogeneic Transplant Outcomes for Patients with Lymphoma
Saini, N. Y., Saliba, R. M., Rondon, G., Maadani, F., Popat, U., Hosing, C. M., Betul, O., Bashir, Q., Olson, A., Nieto, Y., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
We analyzed 186 patients with lymphoma who received allogeneic stem cell transplant (ASCT) with fludarabine-melphalan (FM) conditioning and different donors [25 haploidentical (HD), 98 matched unrelated (MUD), and 63 matched related (MRD)] at our institution between 09/2009-01/2018. Patients received fludarabine 160 mg/m(2) (40 mg/m(2)/day x 4 days) in combination with one dose of melphalan 140 mg/m(2) (FM140) or 100 mg/m2 (FM100). Engraftment was similar between the 3 groups (92%, 89%, and 98%, respectively; p=0.7). The 6-months cumulative incidence of grade III-IV aGVHD was 4%, 14% and 8% (p=NS), and 3-year chronic GVHD was 5%, 16% and 26% (p=NS) for HD, MUD and MRD groups, respectively. The 3-year non-relapse mortality and relapse were 31%, 32% and 10% (HD vs. MUD, p=0.9, HD vs. MRD, p=0.02), and 15%, 21% and 39% (HD vs. MUD, p=0.4, HD vs. MRD, p=0.04) for HD, MUD and MRD groups, respectively. At 3 years, PFS was 59%, 44% and 46% (p=NS), OS was 52%, 54% and 67% (p=NS) and GVHD-free, relapse-free survival (GRFS) 39%, 31%, 24% for HD, MUD transplants (p=NS). No differences in the 3-year PFS [57% vs. 43% (p=0.3)] and OS [64% vs. 58% (p=0.7)] were seen for patients receiving FM100 versus FM140. In conclusion, HD transplants have similar outcomes compared with HLA matched transplants in patients with lymphoma, and FM100 appears to be at least as effective conditioning as FM140 regimen.
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5.
Haploidentical vs haplo-cord transplant in adults under 60 years receiving fludarabine and melphalan conditioning
van Besien, K., Artz, A., Champlin, R. E., Guarneri, D., Bishop, M. R., Chen, J., Gergis, U., Shore, T., Liu, H., Rondon, G., et al
Blood advances. 2019;3(12):1858-1867
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Editor's Choice
Abstract
Haplo-identical transplant with posttransplant cyclophosphamide (haplo) and umbilical cord blood transplant supported by third-party CD34 cells (haplo-cord) are competing approaches to alternative donor transplant. We compared, in adults younger than age 60 years, the outcomes of 170 haplo at 1 institution with that of 137 haplo-cord at 2 other institutions. All received reduced intensity conditioning with fludarabine and melphalan +/- total body irradiation. GVHD prophylaxis for haplo consisted of cyclophosphamide, tacrolimus, and mycophenolate, whereas haplo-cord received antithymocyte globulin, tacrolimus, and mycophenolate. Haplo transplant used mostly bone marrow, and peripheral blood stem cells were used in haplo-cord transplants. Haplo-cord were older and had more advanced disease. Haplo-cord hastened median time to neutrophil (11 vs 18 days, P = .001) and platelet recovery (22 vs 25 days, P = .03). At 4 years, overall survival (OS) was 50% for haplo-cord vs 49% for haplo. Progression-free survival (PFS) was 40% for haplo-cord vs 45% for haplo. In multivariate analysis, the disease risk index was significant for OS (hazard ratio, 1.8; 95% confidence interval, 1.48-2.17; P = .00) and PFS. Total body irradiation was associated with decreased recurrence and improved PFS, age >40 with increased nonrelapse mortality. The type of transplant had no effect on OS, PFS, relapse, or nonrelapse mortality. Cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) by day 100 was 16% after haplo-cord vs 33% after haplo (P < .0001), but grade 3-4 GVHD was similar. Chronic GVHD at 1 year was 4% after haplo-cord vs 16% after haplo (P < .0001). Haplo or haplo-cord results in similar and encouraging outcomes. Haplo-cord is associated with more rapid neutrophil and platelet recovery and lower acute and chronic GVHD. Institutional review board authorization for this retrospective study was obtained at each institution. Some patients participated in trials registered at www.clinicaltrials.gov as #NCT01810588 and NCT01050946.
PICO Summary
Population
We compared, in adults younger than age 60 years, the outcomes of 170 haplo at 1 institution with that of 137 haplo-cord at 2 other institutions
Intervention
Haploidentical transplantation with post-transplant cyclophosphamide (n=170)
Comparison
Umbilical cord blood transplant supported by third-party CD34 cells (haplo-cord) (n=137)
Outcome
The type of transplant had no effect on OS, PFS, relapse, or nonrelapse mortality. Cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) by day 100 was 16% after haplo-cord vs 33% after haplo, but grade 3-4 GVHD was similar. Chronic GVHD at 1 year was 4% after haplo-cord vs 16% after haplo.
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6.
Is a matched unrelated donor search needed for all allogeneic transplant candidates?
Ciurea, S. O., Bittencourt, M. C. B., Milton, D. R., Cao, K., Kongtim, P., Rondon, G., Chen, J., Konopleva, M., Perez, J. M. R., El Shazly, M. F., et al
Blood advances. 2018;2(17):2254-2261
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Abstract
Donor availability for allogeneic transplantation remains an important factor in determining outcomes of a successful transplant. We examined outcomes of 242 patients treated over 3 years who had a matched unrelated donor (MUD) search at our institution. One hundred sixty patients (66%) had a 10 of 10 MUD identified, and 85 (53%) proceeded to MUD transplantation. White patients and those with common haplotypes were more likely to have a MUD identified (odds ratio [OR], 7.4 [P < .0001]; OR, 41.6 [P < .0001]), and were more likely to proceed to transplantation with a MUD (OR, 11.2 [P < .0001]; OR, 85.1 [P = .002]). In addition, patients who were newly diagnosed/in remission at the time of MUD search had a higher probability of receiving a transplant (OR, 2.01 [P = .013]) and better progression-free survival (PFS; P < .0001). In multivariate analysis for patients who received a transplant, donor type did not influence PFS at 3 years, which was 40% for MUD and 57% for haploidentical transplants, respectively (hazard ratio, 1.2 [P = .50]). In conclusion, race, haplotype frequency, and disease status at the time of MUD search influence the probability of identifying a MUD and receiving a transplant. Patients with a low likelihood of receiving a MUD transplant may proceed to a haploidentical transplant as soon as indicated, as this approach does not appear to compromise transplant outcomes.
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7.
Effect of non-permissive HLA-DPB1 mismatches after unrelated allogeneic transplantation with in vivo T cell depletion
Oran, B., Saliba, R. M., Carmazzi, Y., de Lima, M., Rondon, G., Ahmed, S., Alousi, A., Andersson, B. S., Anderlini, P., Alvarez, M., et al
Blood. 2018
Abstract
We investigated the impact of donor-recipient HLA-DPB1 matching on outcomes of allogeneic hematopoietic stem cell transplantation with in vivo T cell depletion using ATG for patients with hematological malignancies. All donor-recipient pairs had high resolution typing for HLA-A, -B, -C, -DRB1, -DQB1, -DPB1 and -DRB3/4/5 and were matched at HLA-A, -B, -C and -DRB1. HLA-DPB1 mismatches were categorized by immunogenicity of the DPB1 matching using the DPB T-cell epitope tool. Of 1004 donor-recipient pairs, 210 (21%) were DPB1 matched, 443 (44%) had permissive mismatches, 184 (18%) non-permissive mismatches, in graft versus host (GvH) direction and 167 (17%) non-permissive mismatches in host versus graft (HvG) direction. Compared with HLA-DPB1 permissive mismatched pairs, non-permissive GvH mismatched pairs had the highest risk of grade II-IV acute graft versus host disease (aGvHD) (HR=1.4, p=0.01) while matched pairs had the lowest risk (HR=0.5, p<0.001). Grade III-IV aGvHD was only increased with non-permissive GvH mismatched (HR=2.3, p=0.005). The risk of disease progression was lower with any HLA-DPB1 mismatches, permissive or non-permissive However the favorable prognosis of HLA-DPB1 mismatches on disease progression was observed only in peripheral blood stem cell recipients that were in the intermediate risk group by the disease risk index (HR=0.4, p=0.001) but no other risk groups. Our results suggest avoidance of non-permissive GvH HLA-DPB1 mismatches for lowering the risk of grade II-IV and III-IV aGvHD. Permissive or non-permissive HvG HLA-DPB1 mismatches may be preferred over HLA-DPB1 matched donors in the intermediate risk patients to decrease the risk of disease progression.
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8.
Haploidentical Transplantation for Older Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome
Ciurea, S. O., Shah, M. V., Saliba, R. M., Gaballa, S., Kongtim, P., Rondon, G., Chen, J., Wallis, W., Cao, K., Konopleva, M., et al
Biology of Blood & Marrow Transplantation. 2017
Abstract
Allogeneic stem cell transplantation with HLA-matched donors is increasingly used for older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). It remains unclear if haploidentical stem cell transplantation (haploSCT) is a suitable option for older patients with this disease. We analyzed 43 patients with AML/MDS (median age, 61 years) who underwent a haploSCT at our institution. All patients received a fludarabine-melphalan-based reduced-intensity conditioning regimen and post-transplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis. Except for 1 patient who had early death, the remaining 42 patients (98%) engrafted donor cells. The cumulative incidences of grades II to IV and III to IV acute GVHD at 6 months were 35% and 5%, respectively, and chronic GVHD at 2 years was 9%. After a median follow-up of 19 months, 2-year overall survival, progression-free survival (PFS), and relapse incidence were 42%, 42%, and 24%, respectively. Best PFS (74% at 2 years) was seen in patients with intermediate-/good-risk cytogenetics, in first or second remission (hazard ratio, .4; P=.05), and with a younger donor (<=40 years; hazard ratio, .2; P=.01). In conclusion, these data suggest that haploidentical transplantation is safe and effective for older AML/MDS patients. Disease status, cytogenetics, and younger donor age are predictors for improved survival in older patients receiving a haploidentical transplant. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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Specific combinations of donor and recipient KIR-HLA genotypes predict for large differences in outcome after cord blood transplantation
Sekine, T., Marin, D., Cao, K., Li, L., Mehta, P., Shaim, H., Sobieski, C., Jones, R., Oran, B., Hosing, C., et al
Blood. 2016;128(2):297-312
Abstract
The ability of cord blood transplantation (CBT) to prevent relapse depends partly on donor natural killer (NK) cell alloreactivity. NK effector function depends on specific killer-cell immunoglobulin-like receptors (KIR) and HLA interactions. Thus, it is important to identify optimal combinations of KIR-HLA genotypes in donors and recipients that could improve CBT outcome. We studied clinical data, KIR and HLA genotypes, and NK-cell reconstitution in CBT patients (n = 110). Results were validated in an independent cohort (n = 94). HLA-KIR genotyping of recipient germline and transplanted cord blood (CB) grafts predicted for large differences in outcome. Patients homozygous for HLA-C2 group alleles had higher 1-year relapse rate and worse survival after CBT than did HLA-C1/C1 or HLA-C1/C2 (HLA-C1/x) patients: 67.8% vs 26.0% and 15.0% vs 52.9%, respectively. This inferior outcome was associated with delayed posttransplant recovery of NK cells expressing the HLA-C2-specific KIR2DL1/S1 receptors. HLA-C1/x patients receiving a CB graft with the combined HLA-C1-KIR2DL2/L3/S2 genotype had lower 1-year relapse rate (6.7% vs 40.1%) and superior survival (74.2% vs 41.3%) compared with recipients of grafts lacking KIR2DS2 or HLA-C1 HLA-C2/C2 patients had lower relapse rate (44.7% vs 93.4%) and better survival (30.1% vs 0%) if they received a graft with the combined HLA-C2-KIR2DL1/S1 genotype. Relapsed/refractory disease at CBT, recipient HLA-C2/C2 genotype, and donor HLA-KIR genotype were independent predictors of outcome. Thus, we propose the inclusion of KIR genotyping in graft selection criteria for CBT. HLA-C1/x patients should receive an HLA-C1-KIR2DL2/L3/S2 CB graft, while HLA-C2/C2 patients may benefit from an HLA-C2-KIR2DL1/S1 graft. Copyright © 2016 by The American Society of Hematology.