No Influence of Post-Transplant Anti-HLA Antibodies on Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation from HLA-Mismatched Unrelated Donors

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5538-5538
Author(s):  
Anna Koclega ◽  
Miroslaw Markiewicz ◽  
Sylwia Mizia ◽  
Urszula Siekiera ◽  
Alicja Dobrowolska ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Hla Antigens ◽  
Negative Group ◽  
Hla Antibodies ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Unrelated Donors

Abstract Introduction: Although anti-HLA Antibodies (Abs) are considered an important factor of graft failure in solid organ transplants, their role in allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still undiscovered. Large polymorphism and immunogenicity of HLA-antigens and heterogeneity of anti-HLA Abs warrant the need of such investigation. The purpose of this study was to define the presence of anti-HLA Abs after allo-HSCT from HLA-mismatched unrelated donors and their impact on outcomes of allo-HSCT. Material and methods: 68 HLA-mismatched donor/recipient pairs entered the study. Indication for allo-HSCT was: ALL, AML, CML, SAA, PNH, MDS and CLL. Preparative regimen was myeloablative in 66(97%)pts and reduced in 2(3%)pts. Standard GVHD prophylaxis consisted of cyclosporine, methotrexate and pre-transplant anti-thymocyte globulin (67pts) or Alemtuzumab (1pt). HLA A,B,C,DR,DQ alleles were PCR-typed. Single HLA-antigen was mismatched in 44pts, single HLA-allele in 16pts, double antigens or alleles in 2 pts and another 2 pts had combined antigenic/allelic HLA mismatches. Anti-HLA A,B,C,DR,DQ,DP Abs were identified in sera collected at +30, +100 days and 1 year post-transplant with use of automated DynaChip assay utilizing microchips bearing purified class I and class II HLA antigens. Post-transplant chimerism was analyzed using STR-PCR method at 30, 100-days and 1-year after allo-HSCT. Results: Anti-HLA Abs were detected post-transplant in 49(72.1%) patients at least at one of three examined time-points. They were directed against HLA class I, II or both in: 22(32.4%), 7(10.3%) or 20(29.4%) patients, respectively. In 3 (4.4%) patients antibodies for many specificities were detected. Anti-HLA antibodies detected during the first year after transplantation did not impact the donor's chimerism. Full donor's chimerism was observed in 22/48 (46%) patients without versus 7/18 (39%) patients with anti-HLA Abs, p=0.615). Anti-HLA Abs present after transplantation also did not impact the risk of developing aGVHD, grades neither I-IV (36/49, 73% in positive versus 17/19, 89% in negative group, p=0.270), nor II-IV (15/49, 31% in positive versus 8/19, 42% in negative group, p=0.372). Chronic GVHD and extensive cGVHD also were not influenced by anti-HLA Abs detected post-transplant (23/49, 47% versus 10/19, 53%, p=0.676) and (13/49, 27% versus 5/19, 26%, p=0.986), respectively. Post-transplant anti-HLA Abs did not influence the recurrence of the disease, which was observed in 9/49 (18.3%) patients with versus 1/19 (5.2%) patients without anti-HLA antibodies, p=0.323, nor the overall survival at 3-years (54% in anti-HLA Abs positive versus 46% in anti-HLA Abs negative patients, p=0.207). Conclusions: Our results indicate, that anti-HLA Abs can be detected post-transplant in HLA-mismatched allo-HSCT recipients. Presence of anti-HLA antibodies detected after allo-HSCT was not associated with occurrence of aGVHD, cGVHD, relapse nor overall survival. Disclosures No relevant conflicts of interest to declare.

The Influence Of Anti-HLA Antibodies On Engraftment and Donor’s Chimerism Following Allogeneic Hematopoietic Stem Cell Transplantation From HLA-Mismatched Unrelated Donors

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4542-4542
Author(s):  
Miroslaw Markiewicz ◽  
Anna Koclega ◽  
Sylwia Mizia ◽  
Urszula Siekiera ◽  
Alicja Dobrowolska ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Graft Failure ◽  
Hla Antigens ◽  
Class I ◽  
Hla Antibodies ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Unrelated Donors

Introduction Although anti-HLA Antibodies (Abs) are considered an important factor of graft failure in solid organ transplants, their role in allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still undiscovered. Large polymorphism and immunogenicity of HLA-antigens and heterogeneity of anti-HLA Abs warrant the need of such investigation. The purpose of this study was to define the presence of anti-HLA Abs before allo-HSCT from HLA-mismatched unrelated donors and their impact on engraftment and post-transplant full donor’s chimerism. Material and Methods 70 HLA-mismatched donor/recipient pairs entered the study. Indication for allo-HSCT was: ALL, AML, CML, SAA, PNH, MDS and CLL. Preparative regimen was myeloablative in 68pts (97%) and reduced in 2pts (2.3%). Standard GVHD prophylaxis consisted of cyclosporine, methotrexate and pre-transplant anti-thymocyte globulin (69pts) or Alemtuzumab (1pt). HLA A,B,C,DR,DQ alleles were PCR-typed. Single HLA-antigen was mismatched in 46pts, single HLA-allele in 16pts, double antigens or alleles in 2 pts and another 2 pts had combined antigenic/allelic HLA mismatch. Anti-HLA A,B,C,DR,DQ,DP Abs were identified in sera collected prior to the conditioning treatment with use of automated DynaChip assay utilizing microchips bearing purified class I and class II HLA antigens. Post-transplant chimerism was analyzed using STR-PCR method at 30, 100-days and 1-year after allo-HSCT. Results Anti-HLA Abs pre-formed before allo-HSCT were detected in 32pts: against class I, II or both in 13(18.6%), 7(10%) and 12(17.1%) pts. Anti-HLA Abs were detected after allo-HSCT in 49pts: against class I, II or both in 22(32.4%), 7(10.3%) and 20(29.4%) pts, respectively. Anti-HLA Abs directed against the mismatched HLA antigens were observed in 4 pts before allo-HSCT. Although no Abs specific to mismatched HLA alleles were detected, Abs belonging to the same Cross-Reactive Groups (CREGs) were present in 5pts. No graft failure has been observed (graft failure was defined as absence of neutrophil recovery by day 30 after allo-HSCT or loss of donor’s chimerism). The detection of anti-HLA Abs before allo-HSCT was associated with decrease of post-transplant donor’s chimerism (18/31 vs 11/35, p=0.03). Anti-HLA Abs had no significant impact on engraftment of platelets and neutrophils. The median time to neutrophils engraftment was 16.9 days (range 7-31 days) in pts with and 18.9 days (range 13-30 days) in pts without anti-HLA Abs (p=0.188). The median time to platelets engraftment was 16.9 days (range 9-31 days) in patients with and 18.3 days (range 10-32 days) in pts without anti-HLA Abs (p=0.274). Conclusions Our preliminary results indicate, that anti-HLA Abs are present before transplantation in mismatched allo-HSCT recipients. They influence the post-transplant full donor’s chimerism, but they did not influence engraftment and graft failure. Disclosures: No relevant conflicts of interest to declare.

Anti-HLA Antibodies in Allogeneic Hematopoietic Stem Cell Transplantation From HLA-Mismatched Unrelated Donors

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4475-4475
Author(s):  
Anna Koclega ◽  
Miroslaw Markiewicz ◽  
Urszula Siekiera ◽  
Alicja Dobrowolska ◽  
Sylwia Mizia ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Hla Antigens ◽  
Class I ◽  
Hla Antibodies ◽  
Hematopoietic Stem ◽  
Unrelated Donors

Abstract Abstract 4475 Introduction: Anti-HLA Antibodies (Abs) are considered an important factor in solid organ transplants and transfusion medicine, but role of humoral arm of immunological response to HLA antigens in allogeneic hematopoietic stem cell transplantation (allo-HSCT) is unknown. Large polymorphism and immunogenicity of HLA-antigens and heterogeneity of anti-HLA Abs warrant the need of such investigation. The purpose of this study was to define presence and profiles of anti-HLA Abs detected before or after allo-HSCT from HLA-mismatched unrelated donors and their impact on allo-HSCT results. Material and methods: 35 HLA-mismatched donor/recipient pairs entered the study. Indication for allo-HSCT was: ALL (7pts), AML(18pts), CML(5pts), SAA(2pts), CLL(1pt), MDS(1pt) and PNH (1pt). Preparative regimen was myeloablative in 33pts (94.3%) and reduced in 2pts (5.7%). Standard GVHD prophylaxis consisted of cyclosporine, methotrexate and pre-transplant anti-thymocyte globulin (34pts) or Alemtuzumab (1pt). HLA A, B, C, DR, DQ alleles were PCR-typed. 21(60%) pts had mismatch of single HLA-antigen: A-4(11.4%), B-1(2.8%), C-13(37%), DQ-3(8,5%); 10(28.5%) pts had mismatch of single HLA-allele: A-3(8.5%), B(11.4%), DQ-3(8.5%); 4 pts had double antigenic (A+C and A+DQ) or combined antigenic/allelic (A/B and C/A) HLA mismatches. Anti-HLA A, B, C, DR, DQ, DP Abs were identified in sera collected before start of the conditioning treatment and +30 days, +100 days and 1 year after allo-HSCT with use of automated DynaChip assay utilizing microchips bearing purified class I and class II HLA antigens. Results: Anti-HLA Abs pre-formed before allo-HSCT were detected in 17(48.5%) pts: against class I, II or both in 6(35%), 4(24%) and 7(41%) pts. Anti-HLA Abs were detected after allo-HSCT in 25(71.4%) pts, against class I, II or both in 9(36%), 3(12%) and 13(52%) pts, respectively. In 7 pts anti-HLA Abs were not detected neither before nor after allo-HSCT. Anti-HLA Abs directed against the mismatched HLA antigens were observed in 4 pts before and in 10 pts after allo-HSCT, no anti-HLA Abs specific against mismatched alleles were detected. Allo-HSCT results obtained in studied subgroups are presented in the Table below: Conclusions: Our preliminary results indicate that anti-HLA Abs are present pre- or post-transplant in mismatched allo-HSCT recipients and may be potentially responsible for the occurrence of complications, what needs to be further investigated and analyzed. Disclosures: No relevant conflicts of interest to declare.

Pre-Transplant Rituximab Therapy Is Associated with Improved Progression-Free and Overall Survival in Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation for Diffuse Large B-Cell Lymphoma (DLBCL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 19-19 ◽  
Author(s):  
Timothy S. Fenske ◽  
Parameswaran Hari ◽  
Jeanette Carreras ◽  
Mei-Jie Zhang ◽  
Rammurti Kamble ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
B Cell Lymphoma ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Conditioning Therapy

Abstract Outcomes following first-line therapy for patients (pts) with DLBCL have improved significantly with the availability of the chimeric anti-CD20 monoclonal antibody rituximab (R). Despite this progress, many pts develop refractory or recurrent DLBCL and are considered candidates for autologous hematopoietic stem cell transplantation (AuHCT). For such pts, it is possible that R given pre-transplant and/or during conditioning therapy affects the natural history of DLBCL, such that traditional methods of risk assessment and patient selection for AuHCT may need revision. We therefore studied the outcomes of 1,006 pts who underwent peripheral blood AuHCT for DLBCL between 1996 and 2003 reported to the CIBMTR, analyzed according to whether R was (n=188, “+R” group) or was not (n=818, “-R” group) administered prior to AuHCT. Using the chi-square statistic for categorical and the Kruskal-Wallis for continuous variables, there were no significant differences between the +R and -R groups with regard to gender, pre-transplant performance status, disease status at transplant, pre-transplant chemosensitivity, second-line aa-IPI score distribution, Ann Arbor stage at transplant, interval from diagnosis to transplant, bulky disease, bone marrow involvement, post-transplant radiation therapy, or post-transplant myeloid growth factor therapy. The +R group had a higher proportion of pts age 61 or older (40% vs. 23%, p<0.001). AuHCT occurred between 1999–2003 in 96% of pts in the +R group, and between 1996–2001 in 93% of the -R pts (p<0.001). For the +R pts, 94% received R only with pretransplant chemotherapy, 3% only with conditioning therapy, and 3% with both pretransplant chemotherapy and conditioning therapy. Conditioning regimens were similar in the +R and -R groups, with the majority receiving the BEAM regimen. In univariate analysis, platelet and neutrophil engraftment were not affected by use of R. Treatment-related mortality (TRM) at 1, 3, or 5 years did not differ significantly between the +R and -R groups. Progression-free survival (PFS) at 1 and 3 years was superior in the +R group (62% vs. 49% at 1 year, p=0.002; 49% vs. 38% at 3 years, p=0.010). Overall survival (OS) was superior in the +R group (68% vs. 60% at 1 year, p=0.032; 57% vs. 45% at 3 years, p=0.003). In multivariate analysis, later year of transplant (2000–2003) and age <55 were associated with lower TRM, but pre-transplant R was not. Conversely, pre-transplant R, age <55, and fewer than 3 lines of chemotherapy were associated with improved PFS, while year of transplant was not. Finally, pre-transplant R, age <55, fewer than 3 lines of chemotherapy, and year of transplant 2000–2003, were all associated with improved OS. We conclude that pre-transplant rituximab is associated with improved PFS and OS following AuHCT for DLBCL, with no evidence of impaired engraftment or increased TRM.

Desensitization for Mismatched Hematopoietic Stem Cell Transplantation (HSCT)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1955-1955 ◽  
Author(s):  
Douglas Edward Gladstone ◽  
Andrea Zachary ◽  
Ephraim J. Fuchs ◽  
Leo Luznik ◽  
Yvette L. Kasamon ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Hla Antigens ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Specific Antibodies ◽  
Post Transplant

Abstract Abstract 1955 Introduction: Sensitization to donor HLA antigens is associated with an increased risk of engraftment failure in HLA mismatched hematopoietic stem cell transplantation (HSCT). However, the use of partially mismatched donors is increasing since, at best, only 30% of patients have an HLA identical sibling donor available for transplantation, and many are unable to find a matched unrelated donor in a timely fashion. A non-myeloablative, T cell replete regimen for HSCT that utilizes post-transplant high dose, cyclophosphamide for graft-versus-host-disease (GVHD) prophylaxis was pioneered at Johns Hopkins and has permitted transplantation of over 200 patients with HLA-haploidentical related donors. The use of HLA haplo-identical donors greatly increases the numbers of potential donors for most HSCT candidates. Review of the evaluations of 148 consecutive candidates for haplotransplantation revealed that 95% had at least one haplo-identical donor with an average of 2.7 donors/patient. However donor specific HLA antibody (DSHA) was observed in 10.8% of patients. We report here, successful desensitization of (DHSA) to levels safe for HSCT in six broadly sensitized patients who had poor-risk hematologic malignancies and for whom there were no other donors for whom HLA specific antibodies were not an issue. Methods: The desensitization protocol was modified from that developed for renal transplant patients at the Johns Hopkins University Comprehensive Transplant Center and included alternate day, single volume plasmapheresis (PP) with low dose, 100mg/kg, anti-CMV hyper immune immunoglobulin (IVIg) under immunosuppression with tacrolimus and mycophenolate mofetil. Varying numbers of PP/IVIg treatments were scheduled prior to the non-myeloablative conditioning regimen according to each patient's DHSA level. PP/IVIg was stopped during conditioning. All but one patient received one additional PP/IVIg at transplant day −1. HLA antibodies were assessed by solid phase immunoassays using panels of pooled HLA antigens, HLA phenotypes, and single HLA antigens in microbead suspension array immunoassays (GenProbe Lifecodes Inc., San Diego, CA; One Lambda, Inc., Canoga Park, CA) Results and conclusions: All six patients prior to desensitization had DHSA at levels sufficient to yield positive flow cytometric crossmatch (FCXM) tests defined as 12K molecules of equivalent soluble fluorochromes (MESFs). The donor specific antibodies were reduced to levels well below a positive FXCM in all six patients by the end of the PP/IVIG treatments and before transplantation through an average of 4.2 PP/IVIg treatments. The average reduction in the donor specific antibody strength was 71.5% (range: 52–91%). In three patients, the DHSA levels were reduced to negative by time of transplant. A fourth patient was transplanted with a DHSA level just below that consistent with a positive FCXM, but by three months post-transplant had completely eliminated the DHSA. Two patients received one additional post-transplant PP/IVIg, resulting in stable DSA levels well below a +FCXM. Sufficient post-transplant follow-up of more than four months was available for four patients of which 3 received grafts from haploidentical donors and 1 from an HLA-mismatched unrelated donor. All four of these fully engrafted with no acute GVHD episodes. These results demonstrate that desensitization can extend the opportunity for HSCT to sensitized patients with no other donor options. Disclosures: Luznik: Otsuka Pharmaceuticals: Research Funding.

scholarly journals Implementation of allogeneic hematopoietic stem cell transplantation from unrelated donors from Russian and foreign registries

2020 ◽  
Vol 65 (3) ◽  
pp. 299-311
Author(s):  
V. A. Vasilyeva ◽  
L. A. Kuzmina ◽  
E. N. Parovichnikova ◽  
M. Yu. Drokov ◽  
A. A. Dmitrova ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Russian Federation ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
The Past ◽  
Unrelated Donors ◽  
The Russian Federation

Introduction. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a standard treatment for many patients with hematological malignancies. Over the past 20 years, an increase in transplantation activity has been noted throughout the world. About 50 % of all allo-HSCT are transplanted from unrelated donors. Aim: to present the dynamics and stages of the development of unrelated donation using the example of one transplant center.Materials and methods. This study analyzed Allo-HSCT performed from 2009 to March 2019 at the National Research Center for Hematology (NRCH). The work of the unrelated donor recruiting group and the tissue typing laboratory was analyzed for this period. 107 patient requests for unrelated donor search were dissected to identify search failures. The parameters of 206 unrelated donors were estimated depending on the register (Russian Federation/foreign). Results. The number of allo-HSCTs did not exceed more than 20 per year, in 2009–2011. Since 2012, the number of alloHSCT signifi cantly increased when the possibility for searching for unrelated donors abroad as well as in the Russian Federation (RF) databases appeared. During this time an increase by more than 50 % was noted in the number of allo-HSCTs. Allo-HSCs from unrelated donors of the Russian Federation make up 30–40 % of all unrelated allo-HSCs. 16 % of potential donors of hematopoietic stem cells included in the NRCH registry are donors of the human blood components. Despite the increasing number of unrelated donors in international and RF databases, 12 % of patients did not fi nd a compatible donor in any of the registers, due to a rare combination of HLA genes. It was revealed that among donors from the RF from whom alloHSCT was performed, there was not a signifi cant prevalence of men, compared to the foreign registry, 50.7 % and 66.7 %, respectively, despite the preference of donor-male by doctors. The 5-year overall survival in patients with acute leukemia in the fi rst complete remission, depending on the performance of allo-HSCT from a donor from the RF or foreign registers, are comparable, 40 % and 39.5 %, respectively.Conclusion. The number of allo-HSCT has increased 5 times over the past 10 years largely due to the development of unrelated donation: 30–40 % of allo-HSC transplants received from unrelated donors were performed from donors from the United database of the Russian Federation. The 5-year overall survival of these patients is comparable with the results of the overall survival patients who received transplants from donors from foreign registers.

Quantitative Assessment of WT1 Gene Transcript After Hematopoietic Stem Cell Transplantation Is a Powerful MRD Marker to Predict the Clinical Outcome in Acute Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4461-4461
Author(s):  
Bingrui Zhao ◽  
XiaoWen Tang ◽  
Jiannong Cen ◽  
Song Jin ◽  
Xiaolan Shi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Acute Leukemia ◽  
Cell Transplantation ◽  
Quantitative Assessment ◽  
Negative Group ◽  
Hematopoietic Stem ◽  
Positive Group ◽  
Post Transplant

Abstract Abstract 4461 Background WT1 is a panleukemic marker that is expressed in 90% of acute leukemias and has been used as MRD marker after chemotherapy or transplantation. However, the threshold of WT1 to predict relapse and outcome in acute leukemia (AL) patients post transplantation has not been well studied. Objective We evaluated the predictive value of quantitative Wilms’ tumor gene (WTl) assessment for relapse following hematopoietic stem cell transplantation (HSCT) in patients of AL. Methods The quantitative assessment of WT1 expression by real-time quantitative PCR (RQ-PCR) was measured in 63 AL patients (pts) with 326 bone marrow samples at the different time points post transplant. ROC (Receiver Operating Characteristic) curve was used to determine the WT1 threshold in order to predict clinical relapses. Furthermore, AL patients were divided into WT1 positive and negative groups according to the threshold of WT1, and the clinical outcomes of these patients post transplant were analysed retrospectively. Results BM samples from 19 pts who relapsed post transplanted showed significantly higher WT1 expression levels compared to the samples from 44 pts in remission (P<0.01), with a median expression level of 1270 (range 55–47596) and 132 (range 0–2959) copies WT1/104ABL, respectively. Ten of 18 relapsed patients died from recurrence, and had higher levels of WT1 expression than that of other 8 patients. Based on the ROC curve, the cut-off value of WT1 was 585 copies WT1/104ABL, dividing 63 patients into WT1-positive group (>585,n=21) and the negative group (≤585,n=42). The WT1-negative group had longer relapse- free survival (RFS) (P<0.01) and overall survival (OS) (P<0.01) than that of positive group. Conclusion Our data suggest that, in the HSCT setting, the sequential and quantitative analysis of WT1 may be useful as a leukemia marker for monitoring MRD, and predicting AL relapse post transplant. Disclosures: No relevant conflicts of interest to declare.

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