Outcome of Allogeneic Hematopoietic Cell Transplantation in AML or MDS with a HLA-Mismatched Unrelated Donor: A Single Center Analysis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5940-5940
Author(s):  
Jörg Schmohl ◽  
Christiane Dorn ◽  
Sebastian P. Haen ◽  
Christoph Faul ◽  
Lothar Kanz ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Transplantation ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
High Dose ◽  
Single Center ◽  
Mismatched Donor

Abstract Introduction: In acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), allogeneic hematopoietic cell transplantation (HCT) can constitute a curative treatment option. Best results are reported using 10/10 HLA-matched donors, and several reports indicated inferior outcomes because of increased graft versus host disease (GVHD) and non-relapse mortality (NRM) if a HLA-mismatched donor is used. Methods: Here we present a single center analyses evaluating all patients (pts) with AML or MDS receiving allogeneic HCT with a mismatch unrelated donors (MMUD) between 2004 and 2014. Results:137 pts were evaluated. Median age was 51 years (range 18-76). For myeloablative conditioning (n=52) the following regimens were used: 12 Gy total body irradiation (TBI) and high-dose cyclophosphamide (n=40), or high-dose busulfan and cyclophosphamide (n=8); for reduced intensity conditioning (n=83) fludarabine with either busulfan (n=27), melphalan (n=6), treosulfan (n=7), cyclophosphamide (=15) or TBI (n=19) was used. Stem cell sources were either peripheral blood (n=134) or bone marrow (n=3). The donor/recipient match was a 9/10 alleleic mismatch in 41% and a 9/10 antigen-mismatch in 59% of cases. All but 21 patients received antithymocyte globuline prior to transplantation for GVHD prophylaxis. Post-transplant immunosuppression consisted of a combination of calcineurine inhibitors with either methotrexate (n=65) or mycophenolate mofetil (n=28). Kaplan-Meier estimated overall survival (OS) for all patients at 1 year was 70% and at 3 years 23%. Cumulative incidence of relapse was 32%. Median follow up of patients alive was 40 months (4-122 month). Engraftment with >500 neutrophils and >25.000 platelets was observed at a median of 20 and 20 days after HCT, respectively. Cumulative incidence of NRM until day 100, 1 year and 3 years was 16%, 27% and 28%, respectively. OS and NRM were not different in pts with allelic or antigen-mismatched donors (OS at 1 year/3 years: 65%/48% versus 48%/33% (p=0,2411), NRM at day 100, 1 year and 3 years: 21%, 24% and 33% versus 20%, 27% and 37% (p=0,6210) ). Acute GvHD mostly occurred at lower grades (grade I 34%, grade II 16%, ≥ grade III 10%). Risk of acute GVHD for patients with an antigen-mismatched donor was not different compared to those with an allelic-mismatched donors (51% versus 42%, p=0,4086). Conclusion: Stem cell treatment with mismatched donors in allogeneic HCT is a valuable and safe option for pts with missing matched stem cell source. Due to optimized pre- and-posttransplant treatment, satisfactory long term survival can be achieved. Disclosures No relevant conflicts of interest to declare.

scholarly journals Prediction of Graft-Versus-Host Disease in Recipients of Single Mismatched Unrelated Hematopoietic Cell Transplantation Donor Using a Highly Multiplexed Proteomic Assay, MHC-Pepseq

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1808-1808
Author(s):  
Karamjeet S. Sandhu ◽  
Ketevan Gendzekhadze ◽  
Dongyun Yang ◽  
Ryotaro Nakamura ◽  
Sally Mokhtari ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Advisory Committees ◽  
Graft Versus Host ◽  
Mismatched Donor

Abstract Graft-versus-host disease (GVHD) remains a major cause of treatment failure after allogeneic hematopoietic cell transplantation (alloHCT). In HLA-mismatched donor setting, indirect presentation of allogeneic peptides from recipient's mismatched HLA class I or II proteins by donor or recipient antigen presenting cells can be an immunogenic driver of GVHD. However, the potential diversity of such antigens is large, and predicting them in a systematic manner has proven challenging. Using a novel, highly-multiplexed peptide-MHC binding assay (MHC-PepSeq) we sought to 1) identify allogeneic peptides derived from mismatched HLA protein that can be efficiently presented by HLA-DR, and 2) explore the possibility that the frequency of these HLA-DRB1 binding allopeptides may be predictive of clinical GVHD in HLA-DPB1 mismatched donor/recipient pairs. Using publicly-available population allele frequency data (allelefrequencies.net), we identified a set of class I and II sequences that cover >95% of alleles at each of 9 human HLA-loci (-A, -B, -C, -DRA1,-DRB1, -DQA1, -DQB1, -DPA1, -DPB1) in 3 major US populations (European Caucasian, African American, Mexican Chicano). When represented in the form of densely overlapping tiled 15-mer peptides, 7,744 unique 15mers were identified. We encoded these peptides into DNA oligonucleotides and used the PepSeq parallel synthesis protocol to generate a library of the corresponding DNA-barcoded peptides. The library was incubated with recombinantly-expressed full-length HLA proteins, washed, eluted, amplified, and sequenced to identify the various HLA-derived peptides that bind to the assayed HLA proteins (Figure 1). In the current study, DPB1-derived allopeptides in the setting of HLA-A, B, C, DRB1, and DQB1 (10/10) matched unrelated (MUD) HCT donors with a mismatch in DPB1 were investigated. The peptide library was assayed for binding to the DRB1*07:01 protein, selected since it was the common allele in this cohort. We identified 327 patients who were transplanted at our center and met these criteria. For each case, we used comprehensive in silico tiling to identify HLA-DPA and DPB-derived peptides present in the recipient but absent in the donor. This set was intersected with the peptides identified as binders to HLA-DRB1*07:01 in the 7,744-plex MHC-PepSeq assay, to arrive at a donor-recipient pair-specific set of 'allopeptides' Overall, we identified such allopeptide at the median of 0 (range: 0-8) across the 327 cases. Next, we examined an association between the number of allopeptides and acute GVHD in the cohort of 94 patients with positive HLA-DRB1*07:01. Median age at alloHCT was 60 years (range: 19-78), 53% males, 1.% bone marrow graft and only 7% female to male donors. Ablative (TBI) conditioning was delivered to 34%) pts. 83% received Tacrolimus/Sirolimus-based, and 9% received post-transplant cyclophosphamide-based GVHD prophylaxis. Patient/HCT characteristics are summarized in Table 1. In this cohort, 18% had no DPB1 mismatch, 54% had a single and 28% had double mismatches, with 21% pts carrying non-permissive DPB1 mismatches. Allopeptide score was 0 in 75% of pts. Non-permissive mismatch 9 (39%) vs. 11 (16%) were more likely to have allopeptide score ≥1 and similarly double mismatches 11 (48%) vs. 15 (21%) were more likely to have allopeptide score of ≥1. Among pts with ≥1 allopeptide score 14 (61%) had DPB1 matched or permissive mismatch. The cumulative incidence of grade 2-4 acute GVHD was 40.8% (range: 29-52) in pts with no allopeptides from DPB1 compared with 56% (range: 34-74) in those with ≥1 allopeptides (p=0.259) (Figure 2). The cumulative incidence of grade 3-4 acute GVHD and chronic GVHD were similar between allopeptide 0 vs. ≥1. Together, we show that the "MHC-PepSeq" assay can identify novel candidate HLA-derived allopeptides in 10/10 MUD HCTs. The number of such peptides are relatively low - with a majority having no allopeptide. In an exploratory analysis in a selected cohort of patients with HLA-DRB1*0701 in the setting of 10/10 MUD HCT, the number of allopeptides in our assay may be predictive of GVHD. The expanded analyses on other HLA-DRB1 restriction elements are underway. Figure 1 Figure 1. Disclosures Al Malki: CareDx: Consultancy; Hansa Biopharma: Consultancy; Neximmune: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; Rigel Pharma: Consultancy. Ali: BMS: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees. Forman: Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy.

scholarly journals HLA-mismatched donor and high ferritin level showed poor clinical outcomes after allogeneic hematopoietic cell transplantation in patients with advanced myelofibrosis

2020 ◽  
Vol 11 ◽  
pp. 204062072093693
Author(s):  
Jae-Ho Yoon ◽  
Gi June Min ◽  
Sung-Soo Park ◽  
Silvia Park ◽  
Sung-Eun Lee ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Ferritin Level ◽  
Chronic Gvhd ◽  
Human Leukocyte ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Mismatched Donor ◽  
Grade Iii

Background: Preconditioning intensity, donor choice and graft- versus-host disease (GVHD) prophylaxis of allogeneic hematopoietic cell transplantation (allo-HCT) for advanced myelofibrosis (MF) have not been fully elucidated. Methods: Thirty-five patients with advanced MF were treated with reduced-intensity conditioning (RIC) allo-HCT. We searched for matched sibling donors first, followed by matched or mismatched unrelated donors and familial mismatched donors. Preconditioning regimen consisted of fludarabine (total 150 mg/m2) and busulfan (total 6.4 mg/kg) with total body irradiation ⩽400cGy. Results: All showed engraftments, but four showed either leukemic relapse or delayed graft failure. Two-year overall survival (OS) and non-relapse mortality (NRM) was 60.0% and 29.9%, respectively. Acute GVHD was observed in 19 patients, and grade III–IV acute GVHD (eight grade III and four grade IV) was higher in human leukocyte antigen (HLA)-mismatched donor HCT compared with HLA-matched HCT (70% versus 20%). Chronic GVHD was observed in 16 patients, and a cumulative incidence of severe chronic GVHD was 33% in HLA-mismatched donor HCT and 7.7% in HLA-matched HCT. Significant hepatic GVHD was observed in nine patients (five acute, four chronic) and six of them died. Multivariate analysis revealed inferior OS in HLA-mismatched donor HCT (hazard ratio (HR) = 6.40, 95% confidence interval (CI) 1.6–25.7, p = 0.009) and in patients with high ferritin level at the time of pre-conditioning period (HR = 7.22, 95% CI 1.9–27.5, p = 0.004), which were related to higher incidence of hepatic GVHD with high NRM rate. Conclusion: RIC allo-HCT can be a valid choice providing graft- versus-fibrosis effect for advanced MF patients. However, HLA-mismatched donor and high pre-HCT ferritin level related to fatal hepatic GVHD should be regarded as poor-risk parameters.

Patterns of Acute and Chronic Graft-Versus-Host Disease Following ATG-Based Conditioning for Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4479-4479
Author(s):  
Nandita Khera ◽  
Amylou C. Dueck ◽  
Veena Devi Salem Fauble ◽  
Lisa Sproat ◽  
Pierre Noel ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Median Time ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Median Number ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Grade Ii

Abstract Abstract 4479 Background: In vivo T-cell depletion with antithymocyte globulin (ATG) is known to decrease the incidence of acute and chronic graft vs. host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). However, the detailed patterns of GVHD (incidence, severity, timing, and quality) after ATG-based conditioning have not been examined in large patient cohorts, and it is unknown whether they differ from those seen in patients who do not receive ATG during conditioning therapy. Patients and Methods: We analyzed the incidence and characteristics of acute and chronic GVHD, requirements for immunosuppressive therapy (IST) and survival in a cohort of 174 patients who underwent a first HCT for hematologic malignancy with ATG as a part of their conditioning regimen. The median age was 54 years (range 19–76); all but 5 pts received PBSC, and median follow-up of survivors was 16.9 months (range 3–70 months). Donors were matched related in 18% (n=32), matched unrelated in 44% (n=77), and mismatched unrelated in 37% (n=65). Conditioning regimens were myeloablative in 33% (n=57) and reduced intensity in 67% (n=117). Additional GVHD prophylaxis included tacrolimus in all patients combined with either methotrexate (42%) or MMF (58%). Results: The cumulative incidence of grade II-IV and III-IV acute GVHD at 100 days was 34% and 7%, respectively, with the median time of onset at 43 days (range 11–98 days) after transplant. Eleven patients (6.3%) required additional immunosuppressive treatment due to steroid refractory GVHD. Late/persistent acute GVHD without any evidence of chronic occurred in 25% of patients. NIH chronic GVHD developed in 25 patients, with a cumulative incidence of 24.4% at 2 years. Forty four percent of these patients were classified as classic chronic, and 56% as overlap. The onset of chronic GVHD was quiescent in 20 (80%), progressive in 3 (12%), and de-novo in 2 (8%) patients. The global severity was mild in 9 (36%), moderate in 11 (44%) and severe in 5 (20%) cases. The median time of onset for chronic GVHD was 185 days (range 99–763). In a multivariate analysis of factors predictive for development of chronic GVHD, the only factor associated with development of chronic GVHD was prior grade II-IV acute GVHD (HR 2.5, p =.03). The most common diagnostic organ was mouth (n=16), followed by skin (n=8) and eye (n=1). The median number of sites involved during the course of chronic GVHD was 4 (range 1–7), and the median number of systemic immunosuppressive agents for treatment was 2 (range 0–4). Among the 25 chronic GVHD patients, 5 have discontinued immunosuppression at a median time of 13.1 months (range 6–26) since the diagnosis of chronic GVHD. The cumulative incidence of discontinuation of IST was 23% at one year and 50% at two years. Three deaths in the overall cohort were attributed to complications related to acute (n=2) or chronic GVHD (n=1). At 2 years, the overall survival among all 174 pts was 62.4%, cumulative incidence of relapse was 23.1%, and non-relapse mortality was 22.7%. Conclusion: These data from a large, uniformly treated and graded, predominantly peripheral blood stem cell transplant recipient population, confirm that ATG decreases both the incidence and severity of acute and chronic GVHD. In particular, the rate of moderate to severe chronic GVHD is extremely low, resulting in minimal need for tertiary treatment and decreased duration of immunosupression. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Allogeneic Hematopoietic Cell Transplantation for Richter Syndrome: A Single-Center Experience

2018 ◽  
Vol 18 (1) ◽  
pp. e35-e39 ◽  
Author(s):  
Mohamed A. Kharfan-Dabaja ◽  
Ambuj Kumar ◽  
Facundo E. Stingo ◽  
Farhad Khimani ◽  
Mohammad Hussaini ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Single Center ◽  
Single Center Experience ◽  
Richter Syndrome

High dose valacyclovir for cytomegalovirus prophylaxis following allogeneic hematopoietic cell transplantation

2021 ◽  
pp. 107815522110604
Author(s):  
Kelly G Hawks ◽  
Amanda Fegley ◽  
Roy T Sabo ◽  
Catherine H Roberts ◽  
Amir A Toor
Keyword(s):  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
High Dose ◽  
Cmv Infection ◽  
Allogeneic Hct ◽  
Clinically Significant ◽  
Cmv Disease ◽  
Cmv Prophylaxis

Introduction Cytomegalovirus (CMV) is one of the most common and clinically significant viral infections following allogeneic hematopoietic cell transplantation (HCT). Currently available options for CMV prophylaxis and treatment present challenges related to side effects and cost. Methods In this retrospective medical record review, the incidence of clinically significant CMV infection (CMV disease or reactivation requiring preemptive treatment) following allogeneic HCT was compared in patients receiving valacyclovir 1 g three times daily versus acyclovir 400 mg every 12 h for viral prophylaxis. Results Forty-five patients who received valacyclovir were matched based on propensity scoring to 35 patients who received acyclovir. All patients received reduced-intensity conditioning regimens containing anti-thymocyte globulin. Clinically significant CMV infection by day + 180 was lower in the valacyclovir group compared to the acyclovir group (18% vs. 57%, p = 0.0004). Patients receiving valacyclovir prophylaxis also had less severe infection evidenced by a reduction in CMV disease, lower peak CMV titers, delayed CMV reactivation, and less secondary neutropenia. Conclusion Prospective evaluation of valacyclovir 1 g three times daily for viral prophylaxis following allogeneic HCT is warranted. Due to valacyclovir's favorable toxicity profile and affordable cost, it has the potential to benefit patients on a broad scale as an option for CMV prophylaxis.

scholarly journals Poor Outcomes of HLA-Mismatched Allogeneic Hematopoietic Cell Transplantation and High Ferritin Levels after a Reduced-Intensity Conditioning Regimen in Patients with Advanced Myelofibrosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5742-5742
Author(s):  
Han Bi Lee ◽  
Jae-Ho Yoon ◽  
Gi June Min ◽  
Sung-Soo Park ◽  
Silvia Park ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cell Transplantation ◽  
Research Funding ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Reduced Intensity Conditioning ◽  
Advisory Committees ◽  
Reduced Intensity

Allogeneic hematopoietic cell transplantation (allo-HCT) preconditioning intensity, donor choice, and graft-versus-host disease (GVHD) prophylaxis for advanced myelofibrosis (MF) have not been fully elucidated. Thirty-five patients with advanced MF were treated with reduced-intensity conditioning (RIC) allo-HCT. We searched for matched sibling (n=16) followed by matched (n=10) or mismatched (n=5) unrelated and familial mismatched donors (n=4). Preconditioning regimen consisted of fludarabine (total 150 mg/m2) and busulfan (total 6.4 mg/kg) with total body irradiation≤ 400cGy. All showed engraftments, but four (11.4%) showed either leukemic relapse (n=3) or delayed graft failure (n=1). Two-year overall survival (OS) and non-relapse mortality (NRM) was 60.0% and 29.9%, respectively. Acute GVHD was observed in 19 patients, and grade III-IV acute GVHD was higher with HLA-mismatch (70% vs. 20%, p=0.008). Significant hepatic GVHD was observed in nine patients (5 acute, 4 chronic), and six of them died. Multivariate analysis revealed inferior OS with HLA-mismatch (HR=6.40, 95%CI 1.6-25.7, p=0.009) and in patients with high ferritin level at post-HCT D+21 (HR=7.22, 95%CI 1.9-27.5, p=0.004), which were related to hepatic GVHD and high NRM. RIC allo-HCT can be a valid choice for advanced MF. However, HLA-mismatch and high post-HCT ferritin levels related to significant hepatic GVHD should be regarded as poor-risk parameters. Disclosures Kim: Handok: Honoraria; Amgen: Honoraria; Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

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