Comparison of Chronic Graft-Versus-Host Disease Severity and Functional Status after Cord Blood, Haploidentical Related and 1-Allele Mismatched Unrelated Donor Hematopoietic Cell Transplantation

Abstract Hematopoietic cell transplantation (HCT) can be accomplished with grafts from alternative donors for patients lacking an HLA-matched related or unrelated donor. The optimal choice of an alternative donor stem cell source remains an open question and is influenced by several factors including chronic graft-versus-host disease (cGVHD). Chronic GVHD is a heterogeneous syndrome with major morbidity and adverse effects on quality of life (QoL) among long-term allogeneic HCT survivors. The aim of this study was to analyze the incidence of cGVHD and manifestations associated with severe morbidity and poor functional outcomes among recipients with alternative HCT donors. Methods: This retrospective study included adults who received a first alternative donor HCT for any diagnosis between 2006 and 2015 in Seattle and subsequently developed cGVHD. The alternative grafts included unrelated 4-6/6-HLA-matched single or double cord blood units (UCB), related HLA-haploidentical bone marrow or mobilized blood stem cells with post-transplant cyclophosphamide (R-HAPLO), and mobilized blood cells from unrelated donors with 1-allele mismatching at an HLA-A, B, C or DR locus at any HLA-typing resolution (1-mMUD). Endpoints were cumulative incidence frequencies (CI) of cGVHD and the CI of manifestations associated with severe morbidity (i.e., grade 2 or 3 keratoconjunctivitis sicca, scleroderma-like skin features, grade 2 or 3 myofasciitis, bronchiolitis obliterans, or esophageal stricture requiring dilation) and the CI of functional outcomes (i.e., return to work/school after the diagnosis of cGVHD, discontinuation of systemic immunosuppressive therapy, and change in KPS). We also compared the 2014 NIH overall severity of cGVHD at initial diagnosis, the incidence of new systemic immunosuppression after first-line therapy for cGVHD, non-relapse mortality and overall survival after cGVHD diagnosis. Results: Of 396 alternative donor HCT recipients, 129 developed cGVHD and were included in this study. Chronic GVHD developed in 29 of 163 UCB recipients (3-year CI, 18%), 21 of 88 R-HAPLO recipients (24%) and 79 of 145 1-mMUD recipients (55%) HCT (Fig. 1A). The median follow-up times after onset of cGVHD were 48 (range 4-121) months for UCB, 60 (range <1-123) for R-HAPLO, and 46 (range 4-131) for 1-mMUD. Table 1 displays characteristics of cGVHD according to the alternative donor groups. The CI of any manifestation of severe morbidity at 3 years after a cGVHD diagnosis is shown in Fig. 1B and was significantly lower in UCB (14%) and R-HAPLO (23%) compared to the 1-mMUD group (58%) [hazard ratio (HR) 0.13 (95% Confidence Interval 0.1-0.4), p=<0.0001, and HR 0.31 (0.1-0.7), p=0.007, respectively]. Compared to the 1-mMUD group, a higher proportion of recipients of UCB (68% vs. 35%) returned to work/school at 3 years after cGVHD [HR 2.54 (1.1-5.7), p=0.02], and a similar trend was observed in R-HAPLO (62% vs. 35% [HR 2.38 (1.0-5.9), p=0.06)] (Fig. 1C). The CI of discontinued systemic immunosuppression at 3 years was significantly lower in the 1-mMUD (15%) compared to the UCB (45%) and R-HAPLO (50%) groups [HR 3.96 (1.9-8.4), p=0.0003, and HR 4.93 (2.2-11.1), p=0.0001, respectively], (Fig. 1D). We found trends suggesting improved annualized KPS change from cGVHD onset to 3.5 years in the UCB [+5 (range -12 to +44)] and R-HAPLO [+11 (range -14 to +64)] groups compared to the 1-mmUD group [0 (range -81 to +46)] (p=0.05 and p=0.06, respectively). The proportion of patients in each group requiring change in systemic therapy for control of cGVHD at 3 years after first line treatment was: 17% for UCB, 25% for R-HAPLO and 39% for 1-mMUD, and was significantly lower for UCB compared to the 1-mMUD group [HR 0.30 (0.1-0.8), p=0.01]. Non-relapse mortality and overall survival were similar among the 3 groups. Conclusions: Compared to 1-mMUD group, UCB and R-HAPLO HCT recipients were less likely to develop cGVHD. Among those with cGVHD, UCB and R-HAPLO HCT recipients were less likely to develop manifestations of severe morbidity, had less protracted cGVHD (a shorter duration of systemic treatment), and higher likelihood of resuming work or school, suggesting better QoL compared to 1-mMUD HCT recipients. Our results will help better counsel patients about alternative HCT donors. A randomized study (NCT01597778) comparing UCB with R-HAPLO HCT is underway to determine which of these donors may be associated with superior outcomes. Disclosures Lee: Mallinckrodt: Honoraria; Amgen: Other: One-time advisory board member; Bristol-Myers-Squibb: Other: One-time advisory board member; Kadmon: Other: One-time advisory board member. Martin: Pfizer: Consultancy; Procter and Gamble: Equity Ownership; Incyte: Consultancy; Fresenius, Neovii: Research Funding. Cheng: Gilead Sciences, Inc.: Consultancy. Flowers: Pharmacyclics: Consultancy.

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Composite GRFS and CRFS Outcomes After Adult Alternative Donor HCT

Journal of Clinical Oncology ◽

10.1200/jco.19.00396 ◽

2020 ◽

Vol 38 (18) ◽

pp. 2062-2076 ◽

Cited By ~ 1

Author(s):

Rohtesh S. Mehta ◽

Shernan G. Holtan ◽

Tao Wang ◽

Michael T. Hemmer ◽

Stephen R. Spellman ◽

...

Keyword(s):

Multiple Testing ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Multivariable Analysis ◽

Pairwise Comparison ◽

Unrelated Donor ◽

Relapse Free Survival ◽

Free Survival ◽

Graft Versus Host ◽

Alternative Donor

PURPOSE There is no consensus on the best choice of an alternative donor (umbilical cord blood [UCB], haploidentical, one-antigen mismatched [7/8]–bone marrow [BM], or 7/8-peripheral blood [PB]) for hematopoietic cell transplantation (HCT) for patients lacking an HLA-matched related or unrelated donor. METHODS We report composite end points of graft-versus-host disease (GVHD)–free relapse-free survival (GRFS) and chronic GVHD (cGVHD)–free relapse-free survival (CRFS) in 2,198 patients who underwent UCB (n = 838), haploidentical (n = 159), 7/8-BM (n = 241), or 7/8-PB (n = 960) HCT. All groups were divided by myeloablative conditioning (MAC) intensity or reduced intensity conditioning (RIC), except haploidentical group in which most received RIC. To account for multiple testing, P < .0071 in multivariable analysis and P < .00025 in direct pairwise comparisons were considered statistically significant. RESULTS In multivariable analysis, haploidentical group had the best GRFS, CRFS, and overall survival (OS). In the direct pairwise comparison of other groups, among those who received MAC, there was no difference in GRFS or CRFS among UCB, 7/8-BM, and 7/8-PB with serotherapy (alemtuzumab or antithymocyte globulin) groups. In contrast, the 7/8-PB without serotherapy group had significantly inferior GRFS, higher cGVHD, and a trend toward worse CRFS (hazard ratio [HR], 1.38; 95% CI, 1.13 to 1.69; P = .002) than the 7/8-BM group and higher cGVHD and trend toward inferior CRFS (HR, 1.36; 95% CI, 1.14 to 1.63; P = .0006) than the UCB group. Among patients with RIC, all groups had significantly inferior GRFS and CRFS compared with the haploidentical group. CONCLUSION Recognizing the limitations of a registry retrospective analysis and the possibility of center selection bias in choosing donors, our data support the use of UCB, 7/8-BM, or 7/8-PB (with serotherapy) grafts for patients undergoing MAC HCT and haploidentical grafts for patients undergoing RIC HCT. The haploidentical group had the best GRFS, CRFS, and OS of all groups.

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Amphiregulin Improves Stratification of the Refined Minnesota Acute Graft-Versus-Host Disease Risk Score: Results from BMT CTN 0302/0802

Blood ◽

10.1182/blood.v130.suppl_1.72.72 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 72-72

Author(s):

Shernan G. Holtan ◽

Todd E. DeFor ◽

Joseph Pidala ◽

Nandita Khera ◽

Stephanie J. Lee ◽

...

Keyword(s):

Risk Score ◽

Research Funding ◽

Board Member ◽

Chronic Gvhd ◽

Threshold Level ◽

Advisory Board ◽

First Line ◽

Advisory Committees ◽

Graft Versus Host ◽

Hazard Ratios

Abstract Introduction: Amphiregulin (AREG) is an epidermal growth factor receptor (EGFR) ligand that can restore integrity to damaged intestinal mucosa in murine models of acute graft-versus-host disease (aGVHD). We previously described AREG as a circulating biomarker of late-onset aGVHD, but its relevance combined with clinical risk factors has not yet been tested in a large cohort of patients with aGVHD occurring prior to day 100 post-transplant. We therefore tested samples from two aGVHD first-line treatment trials, Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0302 and 0802, and identified a clinically relevant threshold level of circulating AREG at aGVHD onset. We then investigated whether incorporating AREG into the refined Minnesota Risk Score could further risk-stratify patients. Patients and Methods: Blood samples were obtained at the onset of systemic aGVHD treatment within BMT CTN 0302 (serum) and BMT CTN 0802 (plasma). All patients with response data and samples for analysis from both trials were included (N=251). We determined the association of AREG with clinical outcomes, including risk stratification by the refined Minnesota criteria, day 28 complete/partial response (CR/PR) to first-line therapy, 2-year overall survival (OS) and 6-month and 2-year non-relapse mortality (NRM). We investigated the effect of AREG on clinical endpoints per a doubling in the value of AREG, defined a clinically relevant threshold level in the AREG values using two-fold cross-validation, and confirmed the clinical relevance of this cut-point in independent samples (N=92) from pooled from drawn from the Chronic GVHD Consortium and the Mount Sinai Acute GVHD International Consortium (MAGIC). Results: In patients enrolled in BMT CTN 0302/0802, AREG levels were 1.7-fold higher in patients with Minnesota high-risk (HR) compared to standard-risk (SR) aGVHD (HR median 53.4 vs SR 31 pg/ml, p<0.01). Every 2-fold increase in AREG was associated with a 33% decrease in the likelihood of day 28 CR/PR (odds ratio [OR] 0.67, p<0.01, table). Clinical factors alone, as determined by the refined Minnesota Risk Score, were associated with day 28 CR/PR (p=0.02, table). Adding AREG to the Minnesota Risk Score could further risk-stratify patients. Minnesota SR patients with elevated AREG ≥ 33 pg/mL showed a 59% lower odds of day 28 CR/PR than SR patients with low AREG (OR 0.41, p=0.02). Patients with Minnesota HR aGVHD with AREG ≥ 33 pg/mL had the worst outcomes, with an 82% lower odds of day 28 CR/PR in comparison to HR with low AREG (OR 0.18, p<0.01). High AREG was associated with worse OS and NRM in both Minnesota SR (hazard ratios 2-year OS 2.3, p<0.01 and 6 month NRM 2.95, p=0.01, respectively) and HR patients (hazard ratios 2-year OS 3.35, p<0.01 and 6-month NRM 9.38, p<0.01 respectively, figure). Finally, in independent samples from the Chronic GVHD Consortium/MAGIC we confirmed that high AREG was associated with worse day 28 CR/PR (55.2% vs. 79.4%, p=0.02) and significantly worse 6-month survival after the onset of aGVHD (57.1% vs. 82.5%, p=0.01). Conclusion: AREG is elevated in patients with poor aGVHD outcomes and adds to the accuracy of risk stratification when combined with the refined Minnesota Risk Score. AREG ≥33 pg/mL at aGVHD onset is associated with lower day 28 CR/PR and higher mortality in samples from 4 multicenter cohorts. The mechanism of elevated circulating AREG in severe aGVHD is not yet known, although we hypothesize the degree of AREG elevation reflects the intensity of immune-mediated tissue injury resulting in AREG release. With accumulating evidence of altered EGFR ligands in aGVHD, further investigation into epithelial repair pathways involving AREG may lead to new adjunctive therapies to overcome poor steroid response in high-risk aGVHD. Disclosures Holtan: Incyte: Other: One-time advisory board member. Khera: Novartis: Consultancy. Lee: Mallinckrodt: Honoraria; Amgen: Other: One-time advisory board member; Bristol-Myers-Squibb: Other: One-time advisory board member; Kadmon: Other: One-time advisory board member. Chen: Immudex: Research Funding. Arora: Takeda Oncology: Consultancy. Flowers: Pharmacyclics: Consultancy. Cutler: Pfizer: Consultancy; Kite: Consultancy; Incyte: Consultancy; Bristol-Myers Squibb: Consultancy; Pharmacyclics: Consultancy; Astellas: Consultancy. Jagasia: Janssen: Consultancy, Research Funding; Therakos: Consultancy, Research Funding; Mallinckrodt: Consultancy. Hexner: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Levine: Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. MacMillan: Magenta Therapeutics: Research Funding.

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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 ◽

10.1182/blood-2021-149686 ◽

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.

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Alternative Donor Hematopoietic Cell Transplantation for Patients with Fanconi Anemia.

Blood ◽

10.1182/blood.v120.21.3081.3081 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3081-3081

Author(s):

Margaret L. MacMillan ◽

Bruce R. Blazar ◽

Todd E. Defor ◽

Kathryn E. Dusenbery ◽

Arne Slungaard ◽

...

Keyword(s):

Relative Risk ◽

Cell Transplantation ◽

Fanconi Anemia ◽

Graft Failure ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Hematopoietic Cell ◽

Unrelated Donor ◽

Probability Of Survival ◽

Alternative Donor

Abstract Abstract 3081 Hematopoietic cell transplantation (HCT) is the only proven curative therapy for the hematological abnormalities in patients with Fanconi anemia (FA). In the mid-1990s, survival after alternative donor (AD)-HCT was reported to be 18% with excessive rates of regimen-related toxicity, graft failure, graft-versus-host-disease (GVHD) and opportunistic infections (OI). Between 1990 and 2010, 127 FA patients underwent AD-HCT at the University of Minnesota using one of 5 consecutive, prospective phase I-II total body irradiation (TBI) containing clinical trials, representing the largest single center experience. All patients received cyclophosphamide (CY, 40 mg/kg) and single fraction TBI. Sequential changes were made to prevent GVHD, graft failure and OI and ultimately enhance survival; in 1994, all patients received T cell depleted (TCD) bone marrow (BM) or umbilical cord blood (UCB) to reduce GVHD; in 1999, fludarabine (FLU) was added to enhance engraftment; in 2003, thymic shielding (TS) was added to reduce OI risk; and in 2006, TBI dose reduction was evaluated to reduce toxicity. Over this time period, HLA-matched unrelated donor BM was the donor of choice with partially HLA matched BM and UCB only used as alternatives. Neutrophil recovery was twice as likely after FLU-containing regimens than non-FLU containing regimens and was not deleteriously affected by TS or reducing TBI dose to 300cGy. Grade II-IV acute GVHD was significantly reduced by the use of TCD (18%) compared to T replete BM or UCB (50% and 38%, respectively: p<0.01). Similarly, chronic GVHD was significantly lower with TCD BM (9%) vs T replete BM or UCB (25% and 15%, respectively; p=0.04). For the entire cohort of 127 patients, the probability of survival was 61% at 1 year and 54% at 5 years with a median follow-up of 9 years. Mortality was higher in recipients who were older (>10 years) or CMV seropositive, received any transfusions before HCT, or developed OI before HCT (Table). Mortality was lowest using CY/FLU/ATG, TBI 300 cGy with TS (Trial 5, relative risk [RR] 0.1; p<0.01). For 10 patients on Trial 5 who had no prior history of transfusions or OI, incidences of neutrophil and platelet are 100% and 100%, acute and chronic GVHD 17% and 0%, and probability of survival is 92%. Table: Factors associated with 3 year mortality: Multivariate analysis Factors Relative Risk of Mortality (95% CI) P-value Trial* 2: CY/ATG/TBI 450-600, CSA/MP 1.0 3: CY/FLU/ATG/TBI 450, CSA/MP 0.3 (0.1–.7) <0.01 4: CY/FLU/ATG/TBI 450+TS, CSA/MP 0.2 (0.1–0.7) 0.01 5: CY/FLU/ATG/TBI 300+TS, CSA/MP or MMF 0.1 (0.04–0.3) <0.01 Donor Type Matched URD Marrow 1.0 Mismatched URD Marrow 0.3 (0.1–0.8) <0.01 Mismatched RD Marrow 0.3 (0.1–2.3) 0.22 Single or Double UCB 2.0 (0.9–4.6) 0.08 Age at Transplant <10 years 1.0 10–17 years 2.4 (1.2–5.0) 0.01 18+ years 3.1 (1.4–7.0) <0.01 Prior OI None 1.0 Yes 3.2 (1.5–6.9) <0.01 Prior Transfusions None Yes 2.4 (1.0–5.8) 0.05 CMV Serostatus Patient negative/donor negative 1.0 Patient negative/donor positive 1.5 (0.7–3.4) 0.34 Patient positive 2.2 (1.1–4.3) 0.03 * Trial 1 (CY/TBI 450, MTX/MP or CSA) was excluded as there were only 8 patients in this group and a number of demographic and disease factors were unknown. Substantial progress has been made in the successful application of AD-HCT for FA. These data support the urgency of transplant prior to the onset of severe pancytopenia when risk of OI and transfusions are more likely, particularly when a suitable BM donor is available. While other regimens are being explored, CY/FLU/ATG/TBI300 with TS should be considered a new standard of care for FA patients undergoing AD-HCT. Disclosures: No relevant conflicts of interest to declare.

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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 ◽

10.1182/blood.v120.21.4201.4201 ◽

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.

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Older Age, Use Of Myeloablative Regimens For Malignant Diseases and Chronic Graft-Versus-Host Disease Are Risk Factors For Avascular Necrosis Of Bone After Allogeneic Hematopoietic Cell Transplantation In Children and Adolescents

Blood ◽

10.1182/blood.v122.21.917.917 ◽

2013 ◽

Vol 122 (21) ◽

pp. 917-917

Author(s):

Xianxin Li ◽

Ruta Brazauskas ◽

Zhiwei Wang ◽

Amal Al-Seraihy ◽

K. Scott Baker ◽

...

Keyword(s):

Risk Factors ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

High Dose ◽

Unrelated Donor ◽

Malignant Diseases ◽

Graft Versus Host ◽

History Of ◽

Donor Source

Abstract Avascular necrosis (AVN) of the bone is a painful and debilitating complication of allogeneic hematopoietic cell transplantation (HCT) that is associated with significant morbidity and often requires surgery. Risk factors for its development in pediatric allogeneic HCT recipients are not well described. To assess risk factors for AVN in children and adolescents following allogeneic HCT, we conducted a nested case-control study with a matched cohort of 638 patients reported to the Center of International Blood and Marrow Transplant Research who were ≤ 21 years of age, received their first allogeneic transplant between 1990 to 2008 in the United States and had survived ≥ 6 months from HCT. Overall, 160 cases with AVN were identified. Each case was matched with up to 3 controls by same year of HCT, similar length of follow-up and by transplant center (478 controls). Cases and controls were confirmed via central review of radiology, pathology and/or surgical procedure reports. The median age for cases was 15 (range 2-21) years, 49% were male, 65% had acute leukemia, 65% had received high-dose total body irradiation (TBI) based conditioning regimen, and 65% had received unrelated donor HCT. Among cases, 18% had a history of acute graft-versus-host disease (GVHD) while 56% had a history of chronic GVHD prior to development of AVN. Median time from HCT to diagnosis of AVN was 14 (range <1-172) months. We evaluated age, gender, diagnosis, conditioning regimen, TBI, donor source and GVHD as risk factors for AVN. On conditional logistic regression, increasing age at HCT, female gender and chronic GVHD were significantly associated with increased risks of AVN. Compared to patients receiving myeloablative regimens for malignant diseases, lower risks of AVN were seen in patients with non-malignant diseases and those who had received reduced intensity conditioning regimen for malignant diseases. (Table). Patients receiving unrelated donor transplant had lower risks of AVN compared to HLA-identical sibling donor HCT recipients; there was no significant interaction between donor source and GVHD status. Lack of data on pre- and post-HCT steroid exposure was a limitation of our study. Our findings suggest that children at high risk for AVN include those within the age group where rapid bone growth occurs as well as those who experience exposure to high-dose myeloablative conditioning regimens and immunosuppression post-HCT for the treatment of GVHD. Our study identifies important risk factors for AVN in a large cohort of pediatric HCT recipients. Future studies should evaluate the role of surveillance and preventive strategies for AVN in pediatric HCT recipients who are at high risk for development of AVN. Disclosures: No relevant conflicts of interest to declare.

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Efficacy of Post-Transplant Cyclophosphamide As Graft-Versus-Host Disease Prophylaxis after Peripheral Blood Stem Cell HLA-Mismatched Unrelated Donor Hematopoietic Cell Transplantation; A Prospective Pilot Trial

Blood ◽

10.1182/blood-2020-142807 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 49-50

Author(s):

Monzr M. Al Malki ◽

Ni-Chun Tsai ◽

Joycelynne Palmer ◽

Saloomeh Mokhtari ◽

Thai Cao ◽

...

Keyword(s):

Clinical Trial ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Pilot Trial ◽

Advisory Board ◽

Board Meeting ◽

Reduced Intensity Conditioning ◽

Research Support ◽

Graft Versus Host ◽

Gvhd Prophylaxis

Mismatched unrelated donors (MMUD) has improved access to hematopoietic cell transplantation (HCT) for underrepresented minority groups. However, MMUD HCT is historically associated with inferior outcomes primarily due to the increased risk of graft-versus-host disease (GvHD), when conventional calcineurin inhibitor-based GvHD prophylaxis is used. Post-transplant cyclophosphamide (PTCy) is an established and effective agent as part of GvHD prophylaxis post haploidentical HCT, which has been increasingly used in the matched donor HCT setting. To date, there have been no prospective studies reporting the efficacy of PTCy after peripheral blood stem cell (PBSC) MMUD HCT. Here, we conducted a pilot trial to estimate the GVHD-free relapse/progression-free survival (GRFS) at one-year post HCT and to evaluate the efficacy of PTCy as GvHD prophylaxis using either an ablative or reduced intensity conditioning regimen after PBSC MMUD HCT (NCT 03128359). Patients with hematologic malignancies (n=38), who were ≤75 years old, had KPS of ≥70%, and were scheduled for HCT from a 7/8 HLA-matched (A-, B-, C-, and DR-) donor were eligible. Patients received myeloablative conditioning (MAC, n=19) using Fludarabine (90 mg/m2) and FTBI (1200 cGy), or reduced intensity conditioning (RIC, n=19) using Fludarabine (100 mg/m2) and Melphalan (140 mg/m2 or 100 mg/m2 if >60 years old). All patients received GCSF-mobilized PBSC as the graft source. GvHD prophylaxis consisted of PTCy (50mg/kg x2 days), Tacrolimus (1mg/d), and MMF (1g x3/d). Overall, patients' median age at HCT was 53 years (range: 21-72), and 50% were male. HCT indication was AML (n=17), ALL (n=8), MDS (n=6), CML (n=3), NHL (n=3), or CLL (n=1). DRI was low in 18 (47%), intermediate in 14 (37%) and high/very high in 6 (16%) patients. At HCT, 29 patients were in complete remission and 9 had active disease (Median BM blast: 3.4, range: 0-7). HCT-CI was >2 in 17 patients (45%). Donors (median age: 32 years, range: 19-53) were mismatched at HLA-A (n=15), -B (n=12), -C (n=8), or DR-loci (n=5) with the median number of mismatches of 2 (range: 1-4) out of 12. The median CD34+ cell dose was 5.45×106/kg (range: 2.39-9.35). Median time to neutrophil engraftment was 16 days (range: 13-35). Complete donor chimerism (>99% if PCR or 95% if STR) was achieved in 36 patients (95%) by day 30 ± 7 days. With a median follow-up period of 18.1 months (range: 4.6 - 25.0), 1-year overall survival (OS) and GRFS were 87% (95% CI: 71-94) and 68% (95% CI: 51-81), respectively (Figure). Non-relapse mortality and relapse rate at 1 year were 11% (95% CI:4-27) and 11% (95% CI: 4-27), respectively (Figure). Cumulative incidence of day 100 acute GvHD grade 2-4 and 3-4 were 51% (95% CI: 38-70) and 19% (95% CI: 10-37), respectively. By NIH criteria, 1-year chronic GvHD was 52% (95% CI: 37-72) with moderate/severe chronic GvHD in 3% (95% CI 0.4-19). By exploratory post-hoc univariable analysis, RIC (vs. MAC) and intermediate/high-risk DRI (vs. low risk) were associated with worse GRFS (HR=4.7, 95%CI: 1.3-16.8, p=0.01 and HR=3.8, 95%CI: 1.1-13.8, p=0.04, respectively). The class and number of HLA mismatch, CD34+ cell dose, and absolute lymphocyte count were not predictive of GRFS. Infectious complications from Day -9 to +100 included CMV viremia (n=16) respiratory infections (n=5, 2 patients with lower respiratory), and BK virus cystitis (n=5). Fifteen patients had bacteremia (6 with GNR) and 4 had C. difficile colitis. Correlative flow-cytometry data was available for 29 patients. T cells reconstitution (>300/ul) was seen in 17 patients (59%) by day 100 (n=11) or day 180 (n=6). NK cell recovery (>150/ul) was seen in 24 patients (85.7%) by day 28 (n=9), day 100 (n=11), or day 180 (n=4). NK cells were predominantly highly cytotoxic CD3-CD56dim. Regulatory T cell counts on day 30 was associated with GRFS: median: 0.20/ul (range: 0.04-2.21) in the group with GRFS event (n=8) compared with 0.68/ul (range: 0.08-23.0, p=0.03) in the group with no GRFS event (n=19). Our pilot trial showed highly promising OS/GRFS in patients receiving PBSC MMUD HCT, indicating that PTCy is an effective GvHD prophylaxis platform in this setting. Our data support further development of PTCy in MMUD HCT to improve the access to and outcome of HCT in patients with hematologic disorders who have otherwise no suitable donor. Figure Disclosures Al Malki: Neximmune: Consultancy; Rigel Pharma: Consultancy; Jazz Pharmacuticals, Inc: Consultancy. Ali:Incyte Corporation: Consultancy. Stein:Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau. Marcucci:Merck: Other: Research Support (Investigation Initiated Clinical Trial); Takeda: Other: Research Support (Investigation Initiated Clinical Trial); Novartis: Speakers Bureau; Pfizer: Other: Research Support (Investigation Initiated Clinical Trial); Abbvie: Speakers Bureau; Iaso Bio: Membership on an entity's Board of Directors or advisory committees. Nakamura:Merck: Other: advisory board meeting; NapaJen Pharma: Consultancy; Kadmon Corporation: Other: Advisory board meeting; Kyowa-Kirin: Other: Support on a meeting presentation; Alexion: Other: Support on a meeting presentation; Celgene: Other: Support on seminar; Magenta Therapeutics: Other: Advisory board meeting; Viracor: Consultancy.

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Mapping MHC haplotype effects in unrelated donor hematopoietic cell transplantation

Blood ◽

10.1182/blood-2012-11-465161 ◽

2013 ◽

Vol 121 (10) ◽

pp. 1896-1905 ◽

Cited By ~ 39

Author(s):

Effie W. Petersdorf ◽

Mari Malkki ◽

Mary M. Horowitz ◽

Stephen R. Spellman ◽

Michael D. Haagenson ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Graft Versus Host Disease ◽

Hematopoietic Cell Transplantation ◽

Unrelated Donor ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Graft Versus Host ◽

Key Points ◽

Mhc Haplotype ◽

Hla Haplotypes

Key Points HLA haplotypes encode single nucleotide polymorphisms (SNPs) that are associated with risks after HLA-mismatched unrelated donor HCT. SNPs associated with graft-versus-host disease (GVHD) are independent of those associated with relapse.

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Immune Mediated Cerebellar Ataxia: An Unknown Manifestation of Graft-versus-Host Disease

Acta Haematologica ◽

10.1159/000494423 ◽

2018 ◽

Vol 141 (1) ◽

pp. 19-22

Author(s):

Liat Shargian-Alon ◽

Pia Raanani ◽

Uri Rozovski ◽

Tali Siegal ◽

Shlomit Yust-Katz ◽

...

Keyword(s):

Cerebellar Ataxia ◽

Graft Versus Host Disease ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Cerebellar Atrophy ◽

Acid Decarboxylase ◽

High Dose ◽

Host Disease ◽

Graft Versus Host ◽

Aged Woman

Neurologic complications of allogeneic hematopoietic cell transplantation (allo-HCT) include infections, cerebrovascular events, therapy-induced neurotoxicity, recurrent malignancies, and neurologic manifestations of graft-versus-host disease (GVHD). Anti-glutamic acid decarboxylase (GAD) antibody-associated cerebellar ataxia is a well-established disorder of autoimmune origin, but there are no reports in the literature of its occurrence following allo-HCT. We describe a middle-aged woman with chronic GVHD after allo-HCT who presented with a rapidly progressive cerebellar syndrome. Thorough investigation revealed only cerebellar atrophy on brain imaging and positive anti-GAD65 antibodies in serum and cerebrospinal fluid suggesting the diagnosis of anti-GAD antibody-associated cerebellar ataxia. Despite prompt treatment with high-dose corticosteroids, intravenous immunoglobulins, and rituximab, the patient’s condition rapidly deteriorated, and she died 4 months later. This case suggests that anti-GAD antibody-associated cerebellar ataxia may be a rare manifestation of chronic GVHD.

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