Minor Histocompatibility Antigen Mismatch and Incidence of Graft Versus Host Disease, Event-Free, and Overall Survival in Patients Undergoing Unrelated Donor Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4201-4201
Author(s):  
Brian C Shaffer ◽  
Christine Tremblay ◽  
Daniel Peaceman ◽  
Jennifer Hsu ◽  
Seth M. Steinberg ◽  
...  
Keyword(s):  
Overall Survival ◽  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Histocompatibility Antigen ◽  
Unrelated Donor ◽  
Minor Histocompatibility Antigen ◽  
Graft Versus Host

Abstract Abstract 4201 Graft versus Host Disease (GvHD) is a potentially devastating complication of allogeneic hematopoietic cell transplantation (HCT) initiated in part due to donor-recipient disparities in immunoreactive proteins, or minor histocompatibility antigens (mHAgs). There are no established prognostic tools to predict which patients will get acute or chronic GvHD. Analysis of mHAg mismatch is a potential predictive tool for GvHD; however, previous studies attempting to establish a relationship between mHAg mismatch and GvHD have been largely equivocal. Here we tested the hypothesis that analysis of an expanded set of mHAgs for mismatch in the GvH direction can be predictive of acute or chronic GvHD by NIH criteria. We additionally analyzed event-free (EFS) and overall survival (OS) in the mHAg matched and mismatched subgroups. Recipient/donor pairs from 45 HLA-A, -B, -C, and DRB1 matched unrelated donor transplants from 2007–2011 were retrospectively typed for 19 mHAgs using an SSP-PCR typing kit (Minor Histocompatibility Antigen Typing Kit; Life Technologies, Carlsbad, CA). Genomic DNA was obtained from peripheral blood mononuclear cells. EFS and OS were estimated using the Kaplan-Meier method. The relationship between mismatch and acute or chronic GvHD was described using Fischer's Exact Test. Cumulative incidence of treatment related mortality (TRM) was calculated using the Gooley Method. Two patients expired of early TRM and were excluded from the GvHD analyses. The rate of acute GvHD grades II-IV was 6 of 14 in those without a mHAg mismatch and 21 of 29 in those with a mismatch (43% versus 72%, P = 0.062). The rate of chronic GvHD was 8 of 14 in those without a mismatch and 10 of 29 in those with a mismatch (53% versus 34%, P = 0.140). The presence of a mismatch did not significantly impact EFS (P = 0.42) or OS (P = 0.26). The cumulative incidence of TRM at 24 months post transplantation was greater in patients with a mismatch (36% versus 13%). Two year OS was superior in patients who were conditioned with alemtuzumab (N = 24) and had a lower degree of mismatch (0–1 mismatch = 72% versus 2+ mismatches = 38%, P = 0.038). This study suggests the possibility of a relationship between mHAg mismatch and acute GvHD and TRM. Further study using this expanded mHAg analysis on a larger cohort of individuals would more adequately define the potential benefit of mHAg mismatch analysis in the context of unrelated donor HCT. Disclosures: No relevant conflicts of interest to declare.

Graft Versus Host Disease Prophylaxis with Everolimus and Tacrolimus in Patients with Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukaemia (AML) Receiving Allogeneic Peripheral Blood Stem Cell Transplantation (PBSCT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2886-2886 ◽  
Author(s):  
Uwe Platzbecker ◽  
Caroline Pabst ◽  
Alexander Kiani ◽  
Johannes Schetelig ◽  
Martin Wermke ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Acute Gvhd ◽  
De Novo ◽  
Chronic Gvhd ◽  
Clinical Signs ◽  
Unrelated Donor ◽  
Peripheral Blood Stem Cells ◽  
Host Disease ◽  
Graft Versus Host

Abstract Introduction: The use of a calcineurin-inhibitor in combination with methotrexate is the current standard in the prophylaxis of graft versus host disease (GVHD). Everolimus is a newly developed m-TOR inhibitor, which, besides a potent immunosuppressive action including the stimulation of regulatory CD4+foxp3+ T-cells (Tregs), seems to mediate anti-neoplastic effects in MDS and AML. Methods: We report results of a prospective study investigating for the first time a combination of everolimus (days 0–56) with tacrolimus (starting day 0) in 16 patients with MDS (RCMD n=3, RAEB-1 n=3, RAEB-2 n=3, CMMOL-1 n=1, CMMOL-2 n=1, MDS/AML n=1) or de novo AML (n=4) undergoing allogeneic myeloablative conditioning (busulfan 16 mg/kg over 4 days, fludarabine 120 mg/m² over 4 days) followed by a median of 7.0 x 106/kg CD34+ peripheral blood stem cells (PBSC) from related (n=2) or unrelated donors (n=14). It is of note that 5 unrelated donor/recipient pairs displayed one allel-mismatch whereas all others were matched in 10 out 10 HLA characters. The median age of the patients was 61 years (range 47–69) and the majority (n=7) of MDS patients were classified INT-2 or HIGH according to IPSS. Results: All patients engrafted a median of 14 days (platelets) and 17 days (neutrophils) after transplant. On day 21 and 56 after PBSCT the median number of CD4+foxp3+ cells in the blood was not significantly different from normal donors (patients, n=5: 3.2 and 2.3 x 104/ul, controls n=4: 3.7 x 104/ul) Nevertheless, the rate of acute GVHD was moderate with five patients (31 %) developing acute GVHD grade II and only one patient experiencing grade IV GVHD after cessation of immunosuppression due to thrombotic-thrombocytopenic purpura (TTP). Decrease of thrombocytes together clinical signs of TTP were seen in two additional patients while four patients developed VOD of the liver, which was fatal in one case. Extensive chronic GVHD was seen in 50 % of evaluable patients. Mucositis CTC grade III was observed in 5 patients only. The total day 100 mortality rate was 19 % and currently eleven out of sixteen patients (69%) are alive and in remission. Conclusion: Everolimus and tacrolimus are highly efficient in preventing GVHD after unrelated PBSCT in older patients with MDS and AML, which seems not to be mediated by an increase in Tregs. Nevertheless, side effects associated with thrombotic microangiopathy might be more prevalent compared to other regimens.

Serious Acute or Chronic Graft-Versus-Host Disease after Hematopoietic Cell Transplantation: A Comparison of Myeloablative and Non-Myeloablative Conditioning Regimens.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 755-755
Author(s):  
Olga Sala-Torra ◽  
Paul J. Martin ◽  
Barry Storer ◽  
Mohamed Sorror ◽  
Rainer F. Storb ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Hematopoietic Cell ◽  
Host Disease ◽  
Graft Versus Host ◽  
Co Morbidity

Abstract We have previously described serious graft-versus-host disease (GVHD) as a highly undesirable outcome after allogeneic hematopoietic cell transplantation (HCT). Serious GVHD encompasses death, lengthy hospitalization, major disability, or recurrent major infections related to either acute or chronic GVHD. In a previous study, we found a 25% incidence of serious GVHD among 171 consecutive patients who had HCT after non-myeloablative (NMA) conditioning between January 1998 and May 2002. To put this observation into perspective, we applied the same criteria for serious GVHD in a cohort of 264 consecutive patients who had HCT after myeloablative (MA) conditioning during the same period of time and compared results with those of the previous study. The overall incidence of serious GVHD was 17% (44/264) in the MA group, compared to 25% (43/171) in the NMA group. There were no statistically significant differences in the incidence of grades III–IV GVHD, extensive chronic GVHD or nonrelapse mortality between the two groups (Table). Patients in the NMA group were older and had higher comorbidity scores than those in the MA group. In the univariate analysis, the hazard ratio (HR) of serious GVHD for the NMA group compared to the MA group was 1.71 (95% C.I., 1.1–2.6) (p = 0.01). After adjusting for patient age, patient and donor gender, donor type, HLA-mismatch, aggressive versus indolent malignancy at HCT, remission versus relapse at HCT, myeloid versus non–myeloid malignancy, HCT co–morbidity index, and prior donor lymphocyte infusion, the HR of serious GVHD was 1.50 (95% C.I., 0.8–2.7) (p = 0.17). After censoring for recurrent or progressive malignancy after HCT, the cumulative incidence of serious GVHD at 3 years was 21% for the NMA group and 14% for the MA group, and the HR was 1.33 (95% C.I., 0.7–2.6) (p = 0.40). Reasons for categorization of GVHD as serious (i.e., death, lengthy hospitalization, major disability, or recurrent major infections) were similar between the MA and NMA cohorts. Among the 44 patients with serious GVHD in the MA group, 19 (43%) had serious acute GVHD, and 25 (57%) had serious chronic GVHD. Among the 43 patients with serious GVHD in the NMA group, 20 (46%) had serious acute GVHD, and 30 (70%) had serious chronic GVHD. Among the 264 MA patients, 28 (11%) had grade III–IV acute GVHD and 147 (56%) had extensive chronic GVHD that did not meet the criteria for serious GVHD, compared to 7 (4%) and 84 (49%) of the 171 NMA patients, respectively. We conclude that the type of pretransplant conditioning regimen does not have a large effect on the incidence of serious GVHD after HCT. Assessment of serious GVHD provides additional useful information to acute GVHD grades and the classification of limited and extensive chronic GVHD in describing overall GVHD-related outcomes after HCT. MA NMA Outcome, n (%) n = 264 n = 171 Serious GVHD 44 (17) 43 (25) Grades III–IV acute GVHD 54 (20) 27 (16) Extensive chronic GVHD 174 (66) 114 (68) 2-year nonrelapse mortality 66 (25) 43 (25)

Antithymocyte Globulin-Based Prophylaxis for Graft Versus Host Disease Compared to Post-Transplant Cyclophosphamide-Based Prophylaxis in Matched Unrelated Donor Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2307-2307
Author(s):  
Sara Redondo Velao ◽  
Mi Kwon ◽  
Diana Champ ◽  
MJ Pascual Cascon ◽  
Pascual Balsalobre ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Antithymocyte Globulin ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis

Abstract INTRODUCTION Post-transplant high-dose cyclophosphamide (PTCy) has shown to prevent graft versus host disease (GvHD) after haploidentical allogeneic hematopoietic cell transplantation (HSCT). Although less extended, its use after matched unrelated donor (MUD) HSCT in combination with additional immunosuppression has been encouraging. The aim of this study was to analyze and compare outcomes of antithymocyte globulin based (ATG) versus PTCy-based GvHD prophylaxis in matched unrelated donor HSCT. MATERIAL AND METHODS We retrospectively analyzed 51 MUD (8/8 HLA-matched) transplants performed in two Spanish centers: 25 received ATG-based prophylaxis and were performed from 2010 to 2013, and 26 received PTCy-based prophylaxis and were performed from 2013 to 2016. RESULTS Characteristics of patients and post-HSCT complications are detailed in Table 1. There were no significant differences in age, gender, diagnosis and Disease risk index. For the ATG group, conditioning regimen consisted of fludarabine combined with busulfan (80%) or melphalan (12%), and TBI plus cyclophosphamide (8%). All patients received ATG 2 mg/kg from day -4 to day -2 followed by methotrexate and cyclosporine (CsA). Conditioning regimen for patients from the PTCy group consisted of fludarabine and busulfan (85%) and thiotepa combined with busulfan and fludarabine (15%). GvHD prophylaxis consisted of PTCy 50 mg/kg on days +3 and +4, combined with: CsA plus MMF in 57%, CsA alone in 31%, or tacrolimus plus MMF or sirolimus in 8%, and tacrolimus alone in 4%. With a median follow-up of 58 months for the ATG group and 12 months for the PTCy group, there were no statistically significant differences in overall survival at 18 months (56% vs 85%, p=0.08), in event free survival (56% vs 68%, p=0.5), and in cumulative incidence of relapse (12% vs 18%, p=0.3). Non-relapse mortality at 12 months was significantly higher in the ATG group (32% vs 10%, p = 0.04). The ATG group presented more cases of hepatic toxicity grades I-IV and hemorrhagic cystitis than PTCy group (Table 1). Cumulative incidence of acute GvHD grades II-IV was higher in the ATG group as well as acute GvHD grades III-IV, with no differences in moderate/severe chronic GvHD incidence (Figure A). CONCLUSION In our experience, albeit differences in follow-up and limited number of patients, we conclude that PTCy combined with additional immunosuppression after MUD allogeneic HSCT offers lower rates of acute GvHD together with less toxicity and non-relapse mortality compared to ATG-based prophylaxis. Further analysis including larger series and follow-up are needed to confirm these observations. Disclosures No relevant conflicts of interest to declare.

scholarly journals Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria

Blood ◽  
2011 ◽  
Vol 117 (11) ◽  
pp. 3214-3219 ◽  
Author(s):  
Mary E. D. Flowers ◽  
Yoshihiro Inamoto ◽  
Paul A. Carpenter ◽  
Stephanie J. Lee ◽  
Hans-Peter Kiem ◽  
...  
Keyword(s):  
Risk Factors ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Human Leukocyte ◽  
National Institutes Of Health ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Abstract Risk factors for grades 2-4 acute graft-versus-host disease (GVHD) and for chronic GVHD as defined by National Institutes of Health consensus criteria were evaluated and compared in 2941 recipients of first allogeneic hematopoietic cell transplantation at our center. In multivariate analyses, the profiles of risk factors for acute and chronic GVHD were similar, with some notable differences. Recipient human leukocyte antigen (HLA) mismatching and the use of unrelated donors had a greater effect on the risk of acute GVHD than on chronic GVHD, whereas the use of female donors for male recipients had a greater effect on the risk of chronic GVHD than on acute GVHD. Total body irradiation was strongly associated with acute GVHD, but had no statistically significant association with chronic GVHD, whereas grafting with mobilized blood cells was strongly associated with chronic GVHD but not with acute GVHD. Older patient age was associated with chronic GVHD, but had no effect on acute GVHD. For all risk factors associated with chronic GVHD, point estimates and confidence intervals were not significantly changed after adjustment for prior acute GVHD. These results suggest that the mechanisms involved in acute and chronic GVHD are not entirely congruent and that chronic GVHD is not simply the end stage of acute GVHD.

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 Randomized Trial of Tacrolimus and Methotrexate Versus Tacrolimus, Reduced Dose Methotrexate, and Mycophenolate Mofetil for Prevention of Graft-Versus-Host Disease after Myeloablative Related and Unrelated Donor Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 99-99
Author(s):  
Betty K. Hamilton ◽  
Lisa A. Rybicki ◽  
Taylor Lucas ◽  
Donna Corrigan ◽  
Matt Kalaycio ◽  
...  
Keyword(s):  
Research Funding ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Toxicity Profile ◽  
Advisory Committees ◽  
Graft Versus Host ◽  
Reduced Dose ◽  
Grade 3

Abstract Background: Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). The combination of tacrolimus (Tac) and methotrexate (MTX) is a standard regimen for GVHD prophylaxis; however, it is associated with several toxicities and patients are often not able to complete the full MTX regimen. The combination of Tac, reduced dose ("mini")-MTX, and mycophenolate mofetil (MMF) has been investigated with a well-tolerated toxicity profile and low incidence of GVHD, although comparison with standard dose MTX has not been done. We performed a randomized non-inferiority trial comparing Tac/MTX (Full-MTX) to Tac/mini-MTX/MMF (Mini-MTX) for prevention of GVHD after myeloablative related and unrelated donor HCT. Methods: Patients <70 years in age receiving first myeloablative allogeneic HCT using 8/8 HLA-matched related or unrelated donor were eligible; all diagnoses and both bone marrow and peripheral blood stem cell grafts were allowed. Full-MTX patients received MTX dose of 15 mg/m 2 day +1, and 10 mg/m 2 days +3, +6, and +11. Mini-MTX patients received doses of 5 mg/m 2 on days +1, +3, and +6 plus MMF 1000 mg BID. MTX and MMF doses were adjusted for body weight in pediatric recipients. Primary endpoints were incidence of acute GVHD, mucositis, and hematopoietic engraftment. Secondary endpoints included incidence of chronic GVHD, organ toxicity, infection, relapse, non-relapse mortality (NRM), and overall survival (OS). Based on our local incidence rates, 45 patients/arm were needed to detect a hazard ratio of at most 1.7 for acute GVHD (no difference between two arms) using a one-sided non-inferiority log-rank test with 5% significance and 80% power. Results: We enrolled 101 patients; 5 were excluded due to change in eligibility or withdrawal of consent prior to HCT. Analysis is based on 96 patients who were randomized to receive Full-MTX (N=49) or Mini-MTX (N=47). Patient characteristics are described in the Table, and were generally balanced between the two groups . All patients in the Mini-MTX arm received their 3 planned doses of MTX; in the Full-MTX arm, 71% received all 4 doses, 26% received 3 doses, and 1 patient received 2 doses of MTX. There was no significant difference in cumulative incidence of grade 2-4 acute GVHD by day 100 between arms (28% Mini-MTX vs 27% Full-MTX, P=0.41) (Figure 1); however, there was a trend toward higher grade 3-4 acute GVHD in Mini-MTX arm (13% vs 4%, P=0.07). Mini-MTX recipients had lower incidence of severe WHO grade 3-4 mucositis (57% vs 82%, P=0.010), shorter duration of mucositis (median 11 vs 18 days, P<0.001), and had faster engraftment of both neutrophils (median 15 vs 17 days, P<0.001) and platelets (median 23 vs 27 days, P=0.023), with resultant shorter hospital stay (median 27 vs 31 days, P<0.001). There were no significant differences between the two arms in any grade of chronic GVHD (36% vs 25%, P=0.09) or moderate-severe chronic GVHD at 1 year (23% vs 20%, P=0.14). There were also no differences in bacterial (P=0.18), viral (P=0.52) or fungal (P=0.74) infections. There were no significant differences in hepatotoxicity, but lower proportion of patients receiving Mini-MTX experienced nephrotoxicity (creatinine ≥3X upper limit of normal: 2% vs 26%, P<0.001). Mini-MTX recipients also had less respiratory failure in the first 6 months (6% versus 22%, P=0.026). There was no difference in relapse between arms (2-year incidence 22% vs 21%, P=0.89), although Mini-MTX was associated with lower NRM (11% vs 25% at 2 years) (Figure 2), and non-significant but higher OS (70% vs 52% at 2 years; P=0.06). Conclusions: Compared to Full-MTX, a Mini-MTX regimen that incorporates MMF was associated with no difference in acute or chronic GVHD incidence and a more favorable toxicity profile, with faster engraftment, less mucositis, less organ toxicity, and lower NRM. The combination of Tac/mini-MTX/MMF is an acceptable alternative to Tac/MTX after myeloablative related and unrelated donor HCT. Figure 1 Figure 1. Disclosures Hamilton: Syndax: Membership on an entity's Board of Directors or advisory committees; Equilium: Membership on an entity's Board of Directors or advisory committees. Gerds: Imago: Research Funding; AbbVie: Consultancy; Constellation: Consultancy; Brystol Myers Squibb: Consultancy; Sierra Oncology: Consultancy; Incyte: Research Funding; PharmaEssentia: Consultancy; Novartis: Consultancy; Constellation: Research Funding; Krtos: Research Funding; CTI Biopharma: Research Funding; Accutate: Research Funding. Hill: Gentenech: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene (BMS): Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding. Copelan: Amgen: Consultancy. Majhail: Anthem, Inc: Consultancy; Incyte Corporation: Consultancy.

scholarly journals Comparison of Post-Allogeneic Hematopoietic Cell Transplantation (HCT) Outcomes after Matched Related Donor Versus Matched Unrelated Donor HCT in Adults with Acute Lymphoblastic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2017-2017 ◽  
Author(s):  
Eric Segal ◽  
Michael Martens ◽  
Hai-Lin Wang ◽  
Ruta Brazauskas ◽  
Daniel Weisdorf ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Survival Outcomes ◽  
Unrelated Donor ◽  
Term Survival ◽  
Donor Source

Abstract Allogeneic hematopoietic cell transplantation (HCT) is a potentially life-saving treatment for patients with acute lymphoblastic leukemia (ALL). About one-third of patients have a human leukocyte antigen (HLA) matched related donor (MRD), while the remaining two-thirds have either a fully HLA-matched (HLA-A, -B, -C, -DRB1 [8/8]) unrelated donor (MUD) or a MUD with a single HLA mismatch (7/8). Previous analyses by the CIBMTR have shown that MRD and MUD transplants produce similar survival outcomes for patients with acute myelogenous leukemia (AML) (Blood 2012; 119(17):3908-16), while donor source was an important predictor of outcomes in patients with myelodysplastic syndrome (MDS) (Blood 2013; 122(11):1974-82). Given that ALL represents the second most common indication for HCT, and recognizing the disease-specific nature of the impact of donor source on post-HCT outcomes previously described, we performed an analysis of outcomes after MRD versus MUD HCT in 1458 patients with ALL who underwent allogeneic HCT from 2000-2011 (MRD n=440, 8/8 MUD n=729, 7/8 MUD n=289). Median age was 37 years (18-69). Thirty-four percent were Philadelphia chromosome positive.Ten percent received reduced intensity conditioning (RIC). Twenty-three percent were transplanted in second complete remission (CR2).Seventy-four percent received peripheral blood stem cells. At 100 days post-HCT, the incidence of acute GVHD Grade B-D was significantly lower in MRD recipients than in 8/8 MUD or 7/8 MUD recipients (26%, 45%, 50%, respectively; p<0.001). In multivariate analysis, 8/8 MUD recipients had similar rates of transplant-related mortality (TRM) and overall survival (OS) (hazard ratio [HR] 1.16, p=0.225and HR 1.01, p=0.93, respectively) compared to MRD recipients; 7/8 MUD recipients had inferior TRM and OS when compared to both MRD recipients (HR 1.92, p<0.001 and HR 1.29, p=0.01, respectively) and 8/8 MUD recipients (HR 1.66, p<0.001 and HR 1.28, p=0.008, respectively).Recipients of peripheral blood transplants had inferior long-term survival (>24 months post-HCT) (HR=2.13, p=0.003) compared to bone marrow transplants. Compared to MRD, 8/8 MUD recipients had superior relapse rates (HR 0.77, p=0.02), while 7/8 MUD recipients had no difference (HR 0.75, p=0.05). There were no differences in leukemia-free survival (LFS) comparing 8/8 MUD recipients (HR 0.95, p=0.55) and 7/8 MUD recipients (HR 1.20, p=0.07) to MRD recipients (Table 2, Figure 1).Differences in survival were likely due to higher rates of acute GVHD and TRM in the 7/8 MUD group. We conclude that MRD and 8/8 MUD recipients have similar survival outcomes post-HCT, while 7/8 MUD recipients suffer inferior survival, demonstrating that donor source plays a large role in the quality of outcomes. While MRD remains the ideal donor source due to its lower incidence of acute GVHD,HCT from an 8/8 MUD is a good alternative to MRD transplant, given its comparable long-term survival outcomes. Figure 1. 100-day Cumulative Incidence of Acute GVHD; 5-year Cumulative Incidence of chronic GVHD, relapse, and TRM; 5-year Probabilities of LFS and OS in Adult ALL Patients Receiving MRD, 8/8 MUD, or 7/8 MUD HCT from 2000-2011 *Overall point-wise comparison † Point-wise pair-wise comparison Figure 1. 100-day Cumulative Incidence of Acute GVHD; 5-year Cumulative Incidence of chronic GVHD, relapse, and TRM; 5-year Probabilities of LFS and OS in Adult ALL Patients Receiving MRD, 8/8 MUD, or 7/8 MUD HCT from 2000-2011 *Overall point-wise comparison † Point-wise pair-wise comparison Figure 2. Multivariate Analysis for Relapse, TRM, Treatment Failure (Inverse of LFS), and All-Cause Mortality (Inverse of Overall Survival) in Adult ALL Patients Receiving MRD, 8/8 MUD, or 7/8 MUD HCT from 2000-2011. Figure 2. Multivariate Analysis for Relapse, TRM, Treatment Failure (Inverse of LFS), and All-Cause Mortality (Inverse of Overall Survival) in Adult ALL Patients Receiving MRD, 8/8 MUD, or 7/8 MUD HCT from 2000-2011. Figure 3. Adjusted Overall Survival Estimatesfor Adult ALL Patients Receiving MRD, 8/8 MUD, or 7/8 MUD HCT Figure 3. Adjusted Overall Survival Estimatesfor Adult ALL Patients Receiving MRD, 8/8 MUD, or 7/8 MUD HCT Disclosures Sandmaier: Gilliad: Honoraria; ArevaMed: Honoraria; Jazz Pharmaceutical: Honoraria; Seattle Genetics: Honoraria; Abmit: Research Funding; Bellicum: Research Funding.

Naive T-Cell Depletion to Prevent Chronic Graft-Versus-Host Disease

2022 ◽  
Author(s):  
Marie Bleakley ◽  
Alison Sehgal ◽  
Stuart Seropian ◽  
Melinda A. Biernacki ◽  
Elizabeth F. Krakow ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Unrelated Donor ◽  
Host Disease ◽  
Graft Versus Host ◽  
Grade Iii

PURPOSE Graft-versus-host disease (GVHD) causes morbidity and mortality following allogeneic hematopoietic cell transplantation. Naive T cells (TN) cause severe GVHD in murine models. We evaluated chronic GVHD (cGVHD) and other outcomes in three phase II clinical trials of TN-depletion of peripheral blood stem-cell (PBSC) grafts. METHODS One hundred thirty-eight patients with acute leukemia received TN-depleted PBSC from HLA-matched related or unrelated donors following conditioning with high- or intermediate-dose total-body irradiation and chemotherapy. GVHD prophylaxis was with tacrolimus, with or without methotrexate or mycophenolate mofetil. Subjects received CD34-selected PBSC and a defined dose of memory T cells depleted of TN. Median follow-up was 4 years. The primary outcome of the analysis of cumulative data from the three trials was cGVHD. RESULTS cGVHD was very infrequent and mild (3-year cumulative incidence total, 7% [95% CI, 2 to 11]; moderate, 1% [95% CI, 0 to 2]; severe, 0%). Grade III and IV acute GVHD (aGVHD) occurred in 4% (95% CI, 1 to 8) and 0%, respectively. The cumulative incidence of grade II aGVHD, which was mostly stage 1 upper gastrointestinal GVHD, was 71% (95% CI, 64 to 79). Recipients of matched related donor and matched unrelated donor grafts had similar rates of grade III aGVHD (5% [95% CI, 0 to 9] and 4% [95% CI, 0 to 9]) and cGVHD (7% [95% CI, 2 to 13] and 6% [95% CI, 0 to 12]). Overall survival, cGVHD-free, relapse-free survival, relapse, and nonrelapse mortality were, respectively, 77% (95% CI, 71 to 85), 68% (95% CI, 61 to 76), 23% (95% CI, 16 to 30), and 8% (95% CI, 3 to 13) at 3 years. CONCLUSION Depletion of TN from PBSC allografts results in very low incidences of severe acute and any cGVHD, without apparent excess risks of relapse or nonrelapse mortality, distinguishing this novel graft engineering strategy from other hematopoietic cell transplantation approaches.

scholarly journals FK506 in combination with methotrexate for the prevention of graft- versus-host disease after marrow transplantation from matched unrelated donors

Blood ◽  
1996 ◽  
Vol 88 (9) ◽  
pp. 3634-3641 ◽  
Author(s):  
RA Nash ◽  
LA Pineiro ◽  
R Storb ◽  
HJ Deeg ◽  
WE Fitzsimmons ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Marrow Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Host Disease ◽  
Graft Versus Host ◽  
Short Course ◽  
Unrelated Donors

The safety and potential efficacy of FK506 in combination with a short course of methotrexate (MTX) for the prevention of acute graft-versus-host disease (GVHD) after marrow transplantation from HLA-matched unrelated donors was evaluated in a single-arm Phase II study conducted at two centers. Forty-three patients, 15 to 54 (median 41) years of age, were transplanted for hematologic malignancies. Thirty-seven of 43 evaluable patients had evidence of sustained marrow engraftment. Five patients died before day 17 after transplantation. The median time to an absolute neutrophil count of > 0.5 x 10(5)/L was 21 (range, 14 to 30) days. Nephrotoxicity (serum creatinine concentration > 2 mg/dL or doubling of baseline) occurred in 32 patients (74% cumulative incidence during the first 100 days after transplant). Other adverse effects included hypertension (n = 27), hyperglycemia (n = 27), neurotoxicity (n = 9) and thrombotic thrombocytopenic purpura (n = 2). Severe veno-occlusive disease of the liver occurred in 9 (21%) of the 43 patients. Eighteen patients (42%) developed grades II to IV acute GVHD and five (12%) developed grades III to IV acute GVHD. Twelve of 25 evaluable patients developed extensive chronic GVHD within 1 year of marrow transplantation resulting in an estimate of the probability of developing this complication of 48%. The cumulative incidence of transplant-related mortality during the first 100 days was 37%. Kaplan-Meier estimates of disease-free survival at 2 years for good-risk, poor-risk, and all patients were 65%, 4%, and 32%, respectively. FK506 in combination with a short course of MTX appears active in preventing acute GVHD after marrow transplantation from unrelated donors. Further studies comparing the combination of FK506 and MTX with cyclosporine and MTX for the prevention of acute GVHD are warranted.

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