HLA mismatch combinations associated with decreased risk of relapse: implications for the molecular mechanism

Blood ◽  
2009 ◽  
Vol 113 (12) ◽  
pp. 2851-2858 ◽  
Author(s):  
Takakazu Kawase ◽  
Keitaro Matsuo ◽  
Koichi Kashiwase ◽  
Hidetoshi Inoko ◽  
Hiroh Saji ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Hematologic Malignancy ◽  
Human Leukocyte ◽  
Hematologic Malignancies ◽  
Hematopoietic Stem ◽  
Clinical Issue ◽  
Leukocyte Antigen ◽  
Unrelated Donors ◽  
Risk Of Relapse ◽  
Made In

Abstract The finding that the risk of relapse in hematologic malignancy decreases after allogeneic hematopoietic stem cell transplantation (HSCT) has lead to the concept of a graft-versus-leukemia (GVL) effect. However, this beneficial effect is considered to be frequently offset by graft-versus-host disease (GVHD). Thus, improving HSCT outcomes by separating GVL from GVHD is a key clinical issue. This cohort study registered 4643 patients with hematologic malignancies who received transplants from unrelated donors. Six major human leukocyte antigen (HLA) loci were retrospectively genotyped. We identified 4 HLA-Cw and 6 HLA-DPB1 mismatch combinations responsible for a decreased risk of relapse; of these, 8 of 10 combinations were different from those responsible for severe acute GVHD, including all 6 of the HLA-DPB1 combinations. Pairs with these combinations of HLA-DPB1 were associated with a significantly better overall survival than were completely matched pairs. Moreover, several amino acid substitutions on specific positions responsible for a decreased risk of relapse were identified in HLA-Cw, but not in HLA-DPB1. These findings might be crucial to elucidating the mechanism of the decreased risk of relapse on the basis of HLA molecule. Donor selection made in consideration of these results might allow the separation of GVL from acute GVHD, especially in HLA-DPB1 mismatch combinations.

Superior Outcomes with Matched Unrelated Donors Compared with One Human Leukocyte Antigen Mismatched Related Donors In Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 907-907
Author(s):  
Stefan O. Ciurea ◽  
Rima M. Saliba ◽  
Gabriela Rondon ◽  
Poliana A. Patah ◽  
Fleur Aung ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Resolution ◽  
Graft Failure ◽  
Human Leukocyte ◽  
Hla Typing ◽  
Class I ◽  
Hematopoietic Stem ◽  
Leukocyte Antigen ◽  
Unrelated Donors ◽  
Related Donor

Abstract Abstract 907 Most candidates for hematopoietic stem cell transplantation lack a human leukocyte antigen (HLA)-identical sibling donor; however, many patients may have a related donor with whom they are mismatched at one antigen/allele. It is not known whether such a match is preferable to a matched unrelated donor (MUD). We hypothesized that, in transplantation using related donors, adding a single HLA antigen/allele mismatch, identified through high resolution HLA typing at HLA-A, -B, -C, -DRB1 and -DQB1, would be associated with worse outcomes than transplantation using matched unrelated donors. Patients and Methods: To test this hypothesis, we analyzed outcomes (survival, relapse, non-relapse mortality) of 367 patients who received transplants from either a 10/10 MUD (n=318) or a one-antigen/allele mismatched related donor (MRD) by 7/8 HLA typing (n=49) treated during the same period of time (1995-2009) at our institution. All patients had intermediate/high-resolution HLA typing at all 5 loci either prospectively or retrospectively, if treated after or before year 2002. Of the 49 patients treated with mismatched related donors, 28 patients (57%) had one antigen/allele mismatched at HLA class I or II loci (or 9/10), 18 patients (37%) had 2 alleles mismatched (or 8/10), and 3 patients (6%) had 3 alleles mismatched (or 7/10). From the 28 patients with a one-allele mismatch, 24 had class I mismatches at either HLA-A or -B loci, and 4 had class II mismatches at either HLA-DR or -DQ loci. Characteristics between the MUD group and 9/10 MRD group were similar [median age 53 vs. 47 years (p=0.08); AML/MDS diagnosis 84% vs. 82% (p=0.5); active disease at transplant 59% vs. 57% (p=0.9); myeloablatie conditioning 63% vs. 75% (p=0.2); bone marrow stem cells 58% vs. 70% (p=0.2); pentostatin use 14% vs. 11% (p=0.4); median year of transplant 2006 vs. 2004, respectively] except more patients in the MUD group received ATG (96% vs. 68%, p=0.02). Results: Outcomes at 3-years were analyzed for the 28 consecutive patients who had received a transplant from a 9/10 MRD based on 5-loci (including -DQB1) HLA typing. Graft failure was more common in patients treated from 9/10 related donors than from MUD. The incidences of primary and secondary graft failure for the 9/10 MRD were 7% and 14%, respectively, whereas none of the MUD transplant recipients had either primary or secondary graft failure (p= 0.02). Cumulative incidence of progression was 40% vs. 25% (p=0.02, HR 1.9, CI 1.1–3.9), non-relapse mortality 40% vs. 26% (p=0.05, HR 1.9, CI 1.0–3.6) and grade II-IV a GVHD was 27% vs. 38% (p=0.4, HR 0.7, CI 0.3–2.5) for the two groups, respectively. Median survival was 6 months for the 9/10 MRD vs. 18 months for the MUD group. The overall survival and progression-free survival rates were 19% and 45% (p=0.007, HR 1.8, CI 1.2–2.9) and 19% vs. 42% (p=0.006, HR1.8, CI 1.2–2.9), respectively. Outcomes for 9/10 MRD transplant patients with class I mismatches (n=24) were significantly worse than outcomes in those with MUD transplants (n=318). The 2-year actuarial OS rate was 27% for the 9/10 MRD and 48% for the MUD transplant group (HR 1.9; 95% CI 1.1 – 3.1; p=0.01). Conclusion: These results indicate that transplant outcomes for patients treated from a one-antigen/allele mismatch related donor are significantly worse than from a MUD, primarily due to increased non-relapse mortality. Patients receiving transplants form a 9/10 related donors, at least with a class I mismatch, should be treated on investigational protocols. Disclosures: No relevant conflicts of interest to declare.

Allogeneic Marrow Stem-Cell Transplantation From Human Leukocyte Antigen–Identical Siblings Versus Human Leukocyte Antigen–Allelic–Matched Unrelated Donors (10/10) in Patients With Standard-Risk Hematologic Malignancy: A Prospective Study From the French Society of Bone Marrow Transplantation and Cell Therapy

2006 ◽  
Vol 24 (36) ◽  
pp. 5695-5702 ◽  
Author(s):  
Ibrahim Yakoub-Agha ◽  
Florence Mesnil ◽  
Mathieu Kuentz ◽  
Jean Michel Boiron ◽  
Norbert Ifrah ◽  
...  
Keyword(s):  
Stem Cell ◽  
Human Leukocyte Antigen ◽  
Myeloid Leukemia ◽  
Hematologic Malignancy ◽  
Human Leukocyte ◽  
Positive Serology ◽  
Leukocyte Antigen ◽  
Donor Type ◽  
Unrelated Donors ◽  
Standard Risk

Purpose To investigate the influence of donor type (human leukocyte antigen [HLA] -identical sibling donor versus HLA-A–, HLA-B–, HLA-Cw–, HLA-DRB1–, and HLA-DQB1–identical unrelated donors, or so-called 10/10) on the outcome of patients who underwent allogeneic stem-cell transplantation (alloSCT), adjusting for other prognostic factors, in patients with standard-risk hematologic malignancy. Patients and Methods Between March 2000 and January 2003, we prospectively investigated the outcome of 236 consecutive patients with standard-risk malignancy from 12 French centers. Fifty-five patients underwent alloSCT from an unrelated HLA-identical donor at the allelic level, whereas 181 patients received an alloSCT from an HLA-identical sibling. Diagnoses included acute leukemia (n = 175), chronic myeloid leukemia (n = 43), and myelodysplastic syndrome (MDS; n = 18). All patients received unmodified marrow graft following myeloablative conditioning with cyclophosphamide and total-body irradiation. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and short-course methotrexate in all patients. Results In multivariable analysis, overall survival and transplantation-related mortality were adversely influenced by recipient cytomegalovirus (CMV) -positive serology, age of donor older than 37 years, and the occurrence of acute grade ≥ II GVHD. Event-free survival rates were lower for patients with recipient CMV-positive serology. Acute grades II to IV GVHD rates were higher for patients with chronic myeloid leukemia (CML). No factor was found to influence either relapse or acute grades III to IV GVHD. The effect of donor type was nonsignificant for all criteria. Conclusion In patients with standard-risk malignancy, transplantation from unrelated HLA-allellically matched donors led to outcomes similar to those from HLA-identical sibling donors.

Human leukocyte antigen (HLA) DR4 is not associated with differences in overall survival (OS), progression free survival (PFS), or graft-vs-host-disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo HSCT) for myeloid malignancies

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6552-6552
Author(s):  
S. Gupta ◽  
C. Aggarwal ◽  
T. Hahn ◽  
S. Padmanabhan ◽  
P. McCarthy ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Human Leukocyte ◽  
Progression Free Survival ◽  
Hematopoietic Stem ◽  
Myeloid Malignancies ◽  
Leukocyte Antigen ◽  
Hla Dr ◽  
Gvhd Prophylaxis ◽  
Total Body

6552 Background: HLA DR4 is associated with autoimmune disorders and with response to cyclosporine immunosuppression in T-cell Large Granular Lymphoproliferative Disorder (BJH 2003;123(3)). We have earlier reported association of DR 15 positivity with decreased acute GVHD (aGVHD) in patients undergoing allo HSCT for myeloid malignancies (Blood, 2005 Nov 10;Epub). Therefore we investigated the role of HLA DR4 on graft-versus-leukemia effect and GVHD in HLA-matched allo HSCT performed for myeloid malignancies. Methods: A retrospective review of 119 consecutive related and 48 consecutive unrelated allo HSCT patients (pts) treated between 1992 and 2003 at RPCI was performed to investigate the influence of HLA DR4 on OS, PFS and the incidence of grade 2–4 aGVHD and chronic GVHD (cGVHD). HLA DR B1 locus typing was determined by either molecular (n=108) or serologic (n=59) methods. The proportion of patients with one or two HLA DR4 antigens was 26% (43/167) which is similar to the range seen in general Caucasian population. Pt characteristics included: AML (n=84), CML (n=63), and MDS (n=20); median age 43 years (range 11–66); Male (n=104), Female (n=63); Caucasian (>95%); Total Body Irradiation (TBI) conditioning regimens (n=124); Busulfan (Bu)/Cyclophosphamide (Cy) (n=22), Bu/TBI (n=27), Cy/TBI (n=13), Etoposide/Cy/TBI (n=84), or other combinations (n=21). Results: There was no difference in OS and the PFS between the HLA DR4 positive vs negative groups in any disease or donor subgroups (p=0.4 and 0.6). GVHD prophylaxis was similar in the two groups but aGVHD and cGVHD incidence was not different in the two groups (p=0.8 and 0.9) Conclusions: HLA DR 4 is not associated with differences in GVHD or outcomes unlike the previous finding that HLA DR15 is associated with decreased acute GVHD in myeloid malignancies. These results suggest that there are differential effects of HLA DR antigens on the incidence of GVHD and outcomes in myeloid and lymphoid malignancies. Understanding these differences may facilitate the design of pt specific GVHD prophylaxis following allo HSCT. No significant financial relationships to disclose.

Hematopoietic Stem Cell Transplantation (SCT) for Hematologic Malignancy from 10/10 Matched Unrelated Donors (MUD) with a Myeloablative Once Daily IV Fludarabine (Flu)/Busulfan Based Regimen (FLUBUP) with Thymoglobulin: Outcomes According to Stem Cell Source.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3140-3140
Author(s):  
James A. Russell ◽  
M. Ahsan Chaudhry ◽  
Michelle Geddes ◽  
Nizar J. Bahlis ◽  
Mary Lynn Savoie ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Acute Gvhd ◽  
Hematologic Malignancy ◽  
Multiorgan Failure ◽  
Chronic Gvhd ◽  
Low Risk ◽  
Hematopoietic Stem ◽  
Platelet Recovery ◽  
Unrelated Donors

Abstract Since 1999 we have used FLUBUP for all patients (pts) with hematologic malignancy including those who might be considered candidates for nonmyelablative SCT. Eighty-four pts were transplanted with marrow (BMT) or blood (BCT) from unrelated donors matched for HLA-A, -B, C, DR and DQ between 05/99 and 07/05. Chemotherapy comprised Flu 50mg/m2 on days -6 to -2 and IV Bu (Busulfex, PDL Pharma) 3.2 mg/kg daily days -5 to -2 inclusive. Thirty-four pts had additional TBI 200cGy x 2 on day -1 or 0. Prophylaxis for GVHD was cyclosporine A, methotrexate with folinic acid and Thymoglobulin (Genzyme) 4.5 mg/kg in divided doses over 3 consecutive days pretransplant finishing day (D) 0. Follow-up of survivors was 12–82 months (median 33). Two BMT pts were unevaluable for engraftment (died before D28), one relapsed before AGC engraftment and 2 had graft failure (GF). Two additional pts died of relapse and one of transplant-related causes without platelet engraftment. Granulocytes engrafted in all BCT recipients, 2 died before D28 and 2 later of relapse without platelet engraftment. Details of Recipients, SCT and Outcomes BMT BCT Number 49 35 Patient age median (range) 40 (16–60) 41 (19–61) ns Donor age median (range) 32 (19–51) 29 (20–57) ns Low risk (Acute leukemia (AL) CR1/2, CML CP1) 23 (47%) (AML 8 CR1, 4 CR2, ALL 5 CR1, 1 CR2, 5 CML CP1) 22 (62%) (AML 10 CR1, 8 CR2, ALL 2 CR1, 3 CR 2, AUL 1 CR1) ns High risk 26 (53%) ( 11 active AL, 2 CML AP, 3 CLL, 1 CMML, 4 MDS, 1 MF, 3 NHL) 13 (38%) (5 active AL, 1 CML AP, 1 MM/MDS, 2 MDS,1 MF, 1 HD/CLL, 1 HD, 1 CLL) ns CMV+ve Recipient or Donor D 35 (71%) 23 (66%) ns Female to male SCT 13 (27%) 3 (9%) 0.05 Male pt 29 (59%) 18 (51%) ns TBI (not TRM risk factor) 11 (22%) 23 (66%) 0.0001 CD34+ cell dose x 10e6/kg median (range) 2.7 (0.44–18.32) 7.47 (1.36–23.87) <0.0001 Median AGC recovery (D) (range) 19 (13–113) 15 (10–46) <0.0001 Median platelet recovery (D) (range) 28 (15–120) 18 (5–67) <0.0001 Acute GVHD II–IV 19±2% 21±7% ns Acute GVHD III–IV 9±4% 12±6% ns Chronic GVHD 77±8% 53±10% ns Low risk TRM (3 years) 22±9% 0 0.03 High risk TRM 43±12% 39±14% ns Primary cause of non-relapse death <D100 PTLD (1), sudden death cause unknown (1), HUS (1), aspiration pneumonia (1) Pneumonia (1), multiorgan failure (2), PTLD (1) Primary cause of non-relapse death >D100 GVHD related (5), primary GF (2), infection (2) Secondary GF (1) Low risk survival 70±10% 81±9% ns High risk survival 33±10% 54±14% ns In low-risk pts FLUBUP appears to be relatively well-tolerated and TRM is lower after BCT. Infection and PTLD contribute as much as GVHD to TRM so there may be little to gain by changing ATG dose or timing. Engraftment is faster after BCT as expected but there is no difference in acute or chronic GVHD. In general therefore, BCT seems preferable to BMT for MUD SCT with this protocol.

HLA-mismatched unrelated donors are a viable alternate graft source for allogeneic transplantation following alemtuzumab-based reduced-intensity conditioning

Blood ◽  
2010 ◽  
Vol 115 (25) ◽  
pp. 5147-5153 ◽  
Author(s):  
Adam J. Mead ◽  
Kirsty J. Thomson ◽  
Emma C. Morris ◽  
Sajir Mohamedbhai ◽  
Shari Denovan ◽  
...  
Keyword(s):  
Human Leukocyte ◽  
Allogeneic Transplantation ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Leukocyte Antigen ◽  
Unrelated Donors ◽  
Uniform Conditioning ◽  
The Impact ◽  
Reduced Intensity ◽  
Related Mortality

Abstract The impact of human leukocyte antigen (HLA) mismatch after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (RIT) using unrelated donors (UD) is unclear, and may be modulated by T-cell depletion. We therefore examined outcomes of 157 consecutive patients undergoing RIT after uniform conditioning with fludarabine, melphalan, and alemtuzumab (FMC). Donors were 10/10 HLA-matched (MUDs, n = 107) and 6 to 9/10 HLA-matched (MMUDs, n = 50), with no significant differences in baseline characteristics other than increased cytomegalovirus seropositivity in MMUDs. Rates of durable engraftment were high. Graft failure rates (persistent cytopenias with donor chimerism) were similar (8% vs 3%, P = .21), though rejection (recipient chimerism) was more frequent in MMUDs (8% vs 0%, P < .01). There were no significant differences between donors in the incidences of acute graft-versus-host disease (GVHD; 20% vs 22% grade 2-4, respectively, P = .83), chronic extensive GVHD (3-year cumulative incidence [CI] 23% vs 24%, P = .56), or treatment-related mortality (1-year CI 27% vs 27%, P = .96). Furthermore, there was no difference in 3-year overall survival (OS; 53% vs 49%, P = .44). Mismatch occurred at the antigenic level in 40 cases. The outcome in these cases did not differ significantly from the rest of the cohort. We conclude that RIT using HLA-mismatched grafts is a viable option using FMC conditioning.

Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation

Blood ◽  
2011 ◽  
Vol 117 (14) ◽  
pp. 3921-3928 ◽  
Author(s):  
Mauro Di Ianni ◽  
Franca Falzetti ◽  
Alessandra Carotti ◽  
Adelmo Terenzi ◽  
Flora Castellino ◽  
...  
Keyword(s):  
Immune Reconstitution ◽  
T Regulatory Cells ◽  
Human Leukocyte ◽  
Hematologic Malignancies ◽  
Experimental Models ◽  
Hematopoietic Stem ◽  
Leukocyte Antigen ◽  
Haploidentical Transplantation ◽  
The Impact ◽  
First Time

Abstract Hastening posttransplantation immune reconstitution is a key challenge in human leukocyte antigen (HLA)–haploidentical hematopoietic stem-cell transplantation (HSCT). In experimental models of mismatched HSCT, T-regulatory cells (Tregs) when coinfused with conventional T cells (Tcons) favored posttransplantation immune reconstitution and prevented lethal graft-versus-host disease (GVHD). In the present study, we evaluated the impact of early infusion of Tregs, followed by Tcons, on GVHD prevention and immunologic reconstitution in 28 patients with high-risk hematologic malignancies who underwent HLA-haploidentical HSCT. We show for the first time in humans that adoptive transfer of Tregs prevented GVHD in the absence of any posttransplantation immunosuppression, promoted lymphoid reconstitution, improved immunity to opportunistic pathogens, and did not weaken the graft-versus-leukemia effect. This study provides evidence that Tregs are a conserved mechanism in humans.

scholarly journals Hematopoietic Stem Cell Transplantation From a Related Donor with Human Leukocyte Antigen 1-Antigen Mismatch in the Graft-Versus-Host Direction Using Low-dose Anti-thymocyte Globulin

2020 ◽  
Vol 29 ◽  
pp. 096368972097656
Author(s):  
Junya Kanda ◽  
Toshihiko Ando ◽  
Shun-ichi Kimura ◽  
Shin-ichiro Fujiwara ◽  
Kazunori Imada ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Low Dose ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Human Leukocyte ◽  
Hematopoietic Stem ◽  
Leukocyte Antigen ◽  
Graft Versus Host ◽  
Related Donor

Hematopoietic stem cell transplantation (HSCT) from a related donor with an human leukocyte antigen (HLA) 1-antigen mismatch without in vivo T cell depletion is associated with an elevated risk of severe, acute, and chronic graft-versus-host (GVH) disease (GVHD) and poor survival. Therefore, we conducted a multicenter phase II trial of HSCT using low-dose anti-thymocyte globulin (ATG, thymoglobulin). We recruited patients aged 16–65 years with leukemia, myelodysplastic syndrome, or lymphoma who planned to receive HSCT from a related donor with HLA 1-antigen mismatch in the GVH direction at the HLA-A, -B, or -DR locus. Pretransplantation ATG was administered with standard GVHD prophylaxis consisting of tacrolimus and methotrexate. Thirty-eight patients were eligible for the analysis. The 1-year GVHD-free relapse-free survival (GRFS) was 47%. The 3-year overall survival (OS) was 57%. Age of less than 50 years was associated with better OS. OS in patients with high/very high refined disease risk indexes (rDRIs) was comparable to that in those with low/intermediate rDRIs. The 100-day cumulative incidences of grades II–IV and III–IV acute GVHD were 45% and 18%, respectively. HSCT from a related donor with two allele mismatches showed higher incidences of grades II–IV and III–IV acute GVHD. Three-year cumulative incidences of moderate to severe or severe chronic GVHD were 13% and 3%, respectively. HSCT from a related donor with one locus mismatch at the antigen level using low-dose ATG showed lower incidences of acute and chronic GVHD, which led to acceptable GRFS, OS, relapse, and nonrelapse mortality.

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