HLA-matched Unrelated Donor Hematopoietic Cell Transplantation Research Articles

Interplay between donor age and HLA-DP matching in 10/10 HLA-matched unrelated donor HCT

AbstractIn 10/10 HLA-matched unrelated donor (MUD) hematopoietic cell transplantation (HCT) with calcineurin-inhibitor (CNI)-based prophylaxis, T-cell epitope DP-matched and permissive mismatched donors are associated with similar overall survival (OS) whereas donors with nonpermissive mismatches should be avoided. Younger unrelated donors are also favored over older donors. We explored outcomes associated with different combinations of DP-matching and donor age (dichotomized at 35 years) to further guide donor selection. Using a Center for International Blood and Marrow Transplant Research data set, we categorized 10 783 patients into 6 groups: DP-matched/younger donor (n = 1591), DP-matched/older donor (n = 526), permissive-mismatched/younger donor (n = 3845), permissive-mismatched/older donor (n = 1184), nonpermissive mismatched/younger donor (n = 2659), and nonpermissive mismatched/older donor (n = 978). We noted that younger donor age, rather than DP matching, was associated with better OS. Younger donors with permissive mismatches were associated with improved OS compared with older matched donors. Furthermore, younger donors with nonpermissive mismatches were associated with improved OS compared with older donors with permissive mismatches. Our study adds further information about the association of DP matching and donor age with HCT outcomes. Donor age should be prioritized over DP matching in patients undergoing 10/10 HLA-MUD with CNI prophylaxis. Among those with younger donors, permissive-mismatched or DP-matched donors are preferred over nonpermissive mismatched donors.

The Adverse Event Landscape of Stem Cell Transplant: Evidence for aGVHD Driving Early Transplant Associated Toxicities

Although unrelated-donor (URD) hematopoietic cell transplantation (HCT) is associated with many toxicities, a detailed analysis of adverse events, as defined by the Common Terminology Criteria for Adverse Events (CTCAE), has not previously been curated. This represents a major unmet need, especially as it relates to assessing the safety of novel agents. We analyzed a detailed AE database from the "ABA2" randomized, double-blind, placebo-controlled clinical trial of abatacept for acute graft-versus-host disease (aGVHD) prevention, for which the FDA mandated a detailed AE assessment through Day +180, and weekly neutrophil and platelet counts through Day +100. These were analyzed for their relationship to key transplant outcomes, with a major focus on the impact of aGVHD on the development/severity of AEs. A total of 2102 AEs and 1816 neutrophil/platelet counts were analyzed from 142 8/8-HLA-matched URD HCT recipients on ABA2 (placebo cohort, n = 69, abatacept cohort, n = 73). This analysis resulted in 2 major observations. (1) Among graft source, conditioning intensity, age, and Grade 2 to 4 aGVHD, only aGVHD impacted Grade 3 to 5 AE acquisition after the first month post-transplant. (2) The development of Grade 3 to 4 aGVHD was associated with thrombocytopenia. We have created a detailed resource for the transplant community by which to contextualize clinical toxicities after transplant. It has identified aGVHD as a major driver of post-HCT Grade 3 to 5 AEs, and underscored a link between aGVHD and thrombocytopenia. This establishes a critical safety framework upon which the impact of novel post-transplant aGVHD therapeutics should be evaluated. This trial was registered at www.clinicaltrials.gov (#NCT01743131).

Cytotoxic T Lymphocyte Antigen 4 (CTLA4) Single Nucleotide Polymorphisms Do Not Impact Outcomes After Unrelated Donor Transplant: A Center For International Blood and Marrow Transplant Research Analysis

Cytotoxic T Lymphocyte Antigen 4 (CTLA4) is a critical T cell molecule that inhibits T cell activation and plays an essential role in T cell homeostasis and immune responses. Genetic variations in the CTLA4 gene have been hypothesized to be possible biologic markers that are predictive of transplant outcomes. Previous investigators have studied single nucleotide polymorphisms (SNPs) of the CTLA4 gene and its impact on hematopoietic cell transplantation (HCT) outcomes with discordant results. AA and AG genotypes in the donor CTLA4 regulatory region involving SNP rs4553808 in patients after unrelated donor (URD) HCT have recently been shown to be an independent predictor of improved relapse free survival (RFS) and overall survival (OS) compared to the GG genotype. To validate these preliminary findings, a Center for International Blood and Marrow Research (CIBMTR) study was performed in a larger, more homogenous cohort of patients.Adult patients with acute myeloid leukemia (AML) and advanced myelodysplastic syndrome (MDS) undergoing a first 8/8 or 7/8 HLA matched URD HCT after myeloablative, non-myeloablative, or reduced intensity conditioning from 2002 to 2007 in first or second complete remission with available donor research samples from the National Marrow Donor Program research repository were included. The primary goal was to evaluate the impact of SNP rs4553808 on RFS, OS, and NRM and the cumulative incidence of acute graft-versus-host disease (aGVHD), and chronic graft-versus-host disease (cGVHD). Any GVHD prophylaxis could be used except in vitro T-cell depletion or use of in vivo/in vitro alemtuzumab. Patients receiving T cell depletion with anti-thymocyte globulin (ATG) were oversampled to allow analysis of any effects on outcomes. An exploratory analysis of 9 other tagSNPs that encompass the entire CTLA4 gene (rs231775, rs231779, rs11571315, rs231777, rs3087243, rs16840252, rs231725, rs10197010, rs11571316) was performed to evaluate for any additional potential associations with clinical outcomes.Each SNP was analyzed in multivariable models adjusting for clinically significant variables using the Cox proportional hazards model. Due to multiple testing, p-values <0.005 were considered significant. The interaction with CTLA4 SNPs and use of ATG was also specifically analyzed. The final analysis included 780 patients with a median followup of 63 months. Median age of recipients and donors was 50 and 34, respectively. 90% of recipients were identified to be of Caucasian descent (N=709). 80% of patients had AML (N=624) and 20% MDS (N=156). Conditioning was 61% ablative, 28% reduced intensity and 11% non-myeloablative, with 74% receiving peripheral blood grafts. 75% were HLA-matched and 25% single locus mismatched. Tacrolimus with methotrexate or mycophenolate mofetil GVHD prophylaxis was given to 62%, cyclosporine-based prophylaxis to 15% while 23% received other regimens. By design, 50% of patients received ATG. Genotyping showed that 552 (71%) were AA, 208 (27%) were AG and 19 (2%) were GG (AG, and particularly GG, were associated with worse outcomes in the prior study). Multivariable analysis adjusting for significant donor and recipient characteristics showed no significant association between SNP rs4553808 and OS (p=0.07), RFS (p=0.41), NRM (p=0.25), and incidence of acute and chronic GVHD (Figure 1). Multivariable analysis of the other 9 tagSNPs also showed no association with transplant outcomes (p>0.005). No interaction was found between the CTLA4 SNPs and use of ATG on outcomes. These results indicate that CTLA4 SNPS do not have impact on outcomes. Other genomic or cellular biomarkers need to be studied to risk stratify patients at high risk of negative clinical events, especially as therapies targeting CTLA4 and PD-1 evolves. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Alternative donor transplantation for myelodysplastic syndromes: haploidentical relative and matched unrelated donors

AbstractWe compared outcomes in 603 patients with myelodysplastic syndrome (MDS) after HLA-haploidentical relative (n = 176) and HLA-matched unrelated (n = 427) donor hematopoietic cell transplantation (HCT) from 2012 to 2017, using the Center for International Blood and Marrow Transplant Research database. All transplantations used reduced-intensity conditioning regimens. Total-body irradiation plus cyclophosphamide and fludarabine was the predominant regimen for HLA-haploidentical relative donor HCT, and graft-versus-host disease (GVHD) prophylaxis was uniformly posttransplantation cyclophosphamide, calcineurin inhibitor, and mycophenolate. Fludarabine with busulfan or melphalan was the predominant regimen for HLA-matched unrelated donor HCT, and GVHD prophylaxis was calcineurin inhibitor with mycophenolate or methotrexate. Results of multivariate analysis revealed higher relapse (hazard ratio [HR], 1.56; P = .0055; 2-year relapse rate, 48% vs 33%) and lower disease-free survival (DFS) rates after HLA-haploidentical relative donor HCT (HR, 1.29; P = .042; 2-year DFS, 29% vs 36%). However, overall survival (OS) rates did not differ between donor type (HR, 0.94; P = .65; 2-year OS, 46% for HLA-haploidentical and 44% for HLA-matched unrelated donor HCT) because of mortality associated with chronic GVHD. Acute grade 2 to 4 GVHD (HR, 0.44; P < .0001) and chronic GVHD (HR, 0.36; P < .0001) were lower after HLA-haploidentical relative donor HCT. By 2 years, probability of death resulting from chronic GVHD was lower after HLA-haploidentical relative compared with HLA-matched unrelated donor HCT (6% vs 21%), negating any potential survival advantage from better relapse control. Both donor types extend access to transplantation for patients with MDS; strategies for better relapse control are desirable for HLA-haploidentical relative donor HCT, and effective GVHD prophylaxis regimens are needed for unrelated donor HCT.

The Effect of Granulocyte Colony-Stimulating Factor Use on Hospital Length of Stay after Allogeneic Hematopoietic Cell Transplantation: A Retrospective Multicenter Cohort Study.

Granulocyte colony-stimulating factor (G-CSF) is administered after allogeneic hematopoietic cell transplantation (HCT) to aid neutrophil recovery. We compared the effect of empiric G-CSF administration on the duration of index inpatient hospitalization stay after HCT for patients aged ≥18 years with a hematologic malignancy. G-CSF was considered empiric if administered between day -3 and day +6 in relation to graft infusion. We studied 3562 HCTs (1487 HLA-matched sibling donor HCTs and 2075 HLA-matched unrelated donor HCTs) between 2007 and 2016. Three hundred and thirteen (21%) recipients of HLA-matched sibling donor HCT and 417 (20%) recipients of HLA-matched unrelated donor HCT received empiric G-CSF therapy. The effect of G-CSF therapy on the index hospitalization stay was examined in generalized linear models (GLMs) with adjustment for other patient, disease, and transplantation characteristics and acute graft-versus-host disease and infection post-transplantation. The duration of index hospitalization by treatment group did not differ for HLA-matched sibling donor HCT but was shorter with G-CSF for HLA-matched unrelated donor HCT (15 days versus 19 days; P < .001). Our GLMs confirmed shorter hospitalization with the use of G-CSF therapy for HLA-matched unrelated donor HCT (P=.01). G-CSF therapy was not associated with early survival for either donor type, and there was no benefit or disadvantage of giving G-CSF to promote neutrophil recovery.

Allogeneic Transplantation for Myelodysplastic Syndrome in Adults over 50 Years Old Using Reduced Intensity/Non-Myeloablative Conditioning: Haploidentical Relative Versus Matched Unrelated Donor

Background: Allogeneic hematopoietic cell transplantation (HCT) has been a successful strategy to treat myelodysplastic syndrome (MDS). With only approximately one-third of patients having an HLA matched sibling, most transplants use mismatched relative (haploidentical) or unrelated donors. In the current analysis we sought to study outcomes after haploidentical related compared to HLA-matched unrelated donor HCT for MDS (de novo or therapy-related). Methods: We retrospectively studied 176 recipients of haploidentical related donor and 427 recipients of 8/8 HLA-matched unrelated donor HCT in the United States between 2012 and 2017. The primary outcome was overall survival. The effect of donor type on survival and other transplant outcomes were studied using a Cox regression model. Results: Patient and disease characteristics are presented in Table 1. Most transplants (85%) were for de novo MDS in both donor groups. Although all patients received reduced intensity regimens, the predominant conditioning regimens were confounded by donor type. Total body irradiation (TBI) 200 cGy/cyclophosphamide/fludarabine (TBI/Cy/Flu; 82%) was the predominant regimen for haploidentical HCT and fludarabine with busulfan or melphalan (Flu/Bu or Flu/Mel; 79%) without in vivo T-cell depletion was the predominant regimen for unrelated donor HCT. Similarly, graft-versus-host disease (GVHD) prophylaxis was also confounded by donor type. Posttransplant cyclophosphamide/calcineurin inhibitor/mycophenolate (PT-Cy/CNI/MMF) was the prophylaxis regimen for all haploidentical transplants. CNI/MMF (31%) or CNI/methotrexate (69%) was used for unrelated donor transplants. Peripheral blood was the predominant graft for both donor types. The median follow-up was 24 months (range 3-77) after haploidentical and 36 months (range 3-74) after unrelated donor HCT. Results of multivariate analysis, adjusted for HCT-CI, prior treatment with hypomethylating agents (HMAs), and IPPS-R did not show differences in survival by donor type (HR 0.98, p=0.85; 40% vs. 37%), Figure 1. However, the relapse rate (adjusted for prior HMAs, IPSS-R, and recipient sex) was higher after haploidentical compared to unrelated donor HCT (HR 1.60, p=0.002, 53% vs. 34%), which led to lower disease-free survival after haploidentical HCT (HR 1.30, p=0.03; 21% vs. 32%), Figure 1. To further test the effect of regimen intensity, low dose TBI regimens were compared to Flu/Bu and Flu/Mel; we did not observe a difference in relapse risk (HR 0.95, p=0.76). Non-relapse mortality did not differ by donor type (HR 0.88, p=0.46). Interval between diagnosis and transplant was also not associated with outcomes. Acute grade II-IV acute GVHD (HR 0.46, p&lt;0.001) and chronic GVHD (HR 0.34, p&lt;0.001) was less common after haploidentical HCT. The 1-year graft failure rate was higher after haploidentical compared to unrelated donor HCT (15% and 8%, respectively, p=0.02). Conclusion: Although the current analysis did not show differences in survival between haploidentical related and matched unrelated donor HCT, the higher relapse and consequently lower disease-free survival associated with the haploidentical HCT approach in this analysis (primarily TBI/Cy/Flu with PT-Cy/CNI/MMF) warrants caution. A more definitive comparison of the two donor types can be accomplished only if more haploidentical transplants were to use Flu/Bu or Flu/Mel conditioning. Figure 1 Disclosures Grunwald: Celgene: Consultancy; Pfizer: Consultancy; Agios: Consultancy; Merck: Consultancy; Abbvie: Consultancy; Medtronic: Equity Ownership; Incyte: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Amgen: Consultancy; Trovagene: Consultancy; Cardinal Health: Consultancy; Janssen: Research Funding; Genentech/Roche: Research Funding; Novartis: Research Funding; Forma Therapeutics: Research Funding. Bolanos-Meade:Incyte Corporation: Other: DSMB fees. Bredeson:Otsuka: Research Funding. Gupta:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding. Mussetti:Takeda: Honoraria; BMS: Honoraria; Novartis: Honoraria; Italfarmaco: Honoraria. Nakamura:Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: support for an academic seminar in a university in Japan; Alexion: Other: support to a lecture at a Japan Society of Transfusion/Cellular Therapy meeting ; Kirin Kyowa: Other: support for an academic seminar in a university in Japan. Nishihori:Novartis: Research Funding; Karyopharm: Research Funding. Solh:Celgene: Speakers Bureau; Amgen: Speakers Bureau; ADC Therapeutics: Research Funding. Weisdorf:Fate Therapeutics: Consultancy; Pharmacyclics: Consultancy; Incyte: Research Funding.

Killer Immunoglobulin-Like Receptor-Ligand Interactions Predict Clinical Outcomes following Unrelated Donor Transplantations.

Killer immunoglobulin-like receptor (KIR) and KIR ligand (KIRL) interactions play an important role in natural killer (NK) cell-mediated graft-versus-leukemia effect following hematopoietic cell transplantation (HCT). However, there is considerable heterogeneity in the KIR gene and KIRL content in individuals, making it difficult to estimate the full clinical impact of NK cell reconstitution following HCT. Here we present a novel adaptive mathematical model designed to quantify these interactions to better assess the influence of NK cell-mediated alloreactivity on transplant outcomes. Ninety-eight HLA- matched unrelated donor (URD) HCT recipients were studied retrospectively. The KIR-KIRL interactions were quantified using a system of matrix equations. Unit values were ascribed to each KIR-KIRL interaction, and the directionality of interactions was denoted by either a positive (activating) or negative (inhibition) symbol; these interactions were then summed. The absolute values of both the missing KIRL and inhibitory KIR-KIRL interactions were significantly associated with overall survival and relapse. These score components were initially used to develop a weighted score (w-KIR score) and subsequently a simplified, nonweighted KIR-KIRL interaction score (IM-KIR score). Increased w-KIR score and IM-KIR score were predictive of all-cause mortality and relapse (w-KIR score: hazard ratio [HR], .37 [P=.001] and .44 [P=.044], respectively; IM-KIR score: HR, .5 [P=.049] and .44 [P=.002], respectively). IM-KIR score was also associated with NK cell reconstitution post-HCT. KIR-KIRL interactions as reflected by the w-KIR and IM-KIR scores influence both relapse risk and survival in recipients of HLA-matched URD HCT with hematologic malignancies.

Unrelated Donor KIR B/X Genotype Reduces Relapse and Improves Progression-Free Survival after HLA-Matched Allogeneic Transplantation for Relapsed/Refractory Non-Hodgkin Lymphoma

▪While allogeneic donor hematopoietic cell transplantation (HCT) can cure non-Hodgkin lymphoma (NHL) by inducing a graft-versus-lymphoma effect, 10-35% of patients experience progression or relapse. We investigated whether the genotype of allogeneic donor natural killer (NK) cell killer immunoglobulin-like receptors (KIR) impacts the survival of lymphoma patients. The importance of KIR genetics in unrelated donor (URD) HCT has been demonstrated in AML where donors with favorable KIR gene content reduced the risk of relapse by 30%. Because the consequence of donor KIR genotype in NHL is unknown, we evaluated its effect on transplant outcome in 614 adults with NHL (28% follicular lymphoma, 16% diffuse large B cell lymphoma, 17% mantle cell lymphoma, 37% other) who underwent T cell replete URD HCT between 1990-2009 with outcomes reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Donor samples from the NMDP/CIBMTR Repository were genotyped (15 KIR genes) by MALDI-TOF mass spectroscopy. KIR haplotypes (A/A or B/x) were determined by presence/absence of individual KIR genes. Multivariate regression models were used to test the associations between donor KIR genotype and clinical outcome. The median patient age was 50 years (range 19-72), 93% were Caucasians and 62% had chemosensitive lymphoma. Most (60%) were >1.5 years from diagnosis; 41% received myeloablative preparative regimens and 61% received peripheral blood derived grafts. Most transplants were 10/10 matched for HLA alleles (n=396), the remainder 9/10 matched (n=158) or ≤8/10 matched (n=60). The frequencies of KIR genotypes in donors reflected the Caucasian population: 70% (n=428) were KIR B/x and 30% (n=180) were KIR A/A. Patients receiving 10/10 HLA-matched grafts (65%) experienced significantly lower relapse at 5 years when donors were KIR B/x genotype (n=281; 26% [95%CI 21-32%]) compared to KIR A/A genotype (n=115; 37% [95% CI 27-46%] ;p=0.05; Figure left) leading to improved progression-free survival (PFS) (35% [95% 26-44] vs. 22% [95%CI 11-35%]; p=0.02; Figure right). After adjusting for significant clinical variables, KIRB/x donors conferred significant protection against relapse (RR 0.63 [95%CI 0.43-0.92]; p=0.02) and improved PFS (RR 0.71 [95% CI 0.55-0.91]; p=0.008) compared to KIR A/A donors. The relapse protection and improved survival associated with KIR B/x donors was highly significant in the 10/10 HLA matched cohort (n=396) but not in the HLA-mismatched transplants (n=218; PFS RR 1.21 [95%CI 0.86-1.7]; Relapse RR 1.49 [0.87-2.55], p=NS for both). Importantly, the use of KIR B/x donors was associated with improved clinical outcomes for patients after both myeloablative and reduced intensity conditioning. Donor KIR genotype had no effect on rates of acute graft-versus-host disease (HR 1.05; p=0.86), and treatment related mortality at 1 year was similar for both groups (28% [B/x] and 30% [A/A]). In multivariate analysis of the entire cohort, other factors adversely impacting PFS included chemoresistant lymphoma (HR 1.52; p=0.03), disease other than follicular lymphoma (HR 1.34; p=0.0001) and <1.5 years interval from diagnosis to HCT (HR 1.35; p=0.003). Our results demonstrate that donors with KIR B/x genotypes, whose NK cells express more activating KIR, are associated with decreased relapse and improved survival after 10/10 HLA-matched URD HCT for NHL. The results suggest that NK cells may contribute to graft-versus-lymphoma effects and support the consideration of KIR genotyping with HLA typing into URD search criteria for patients with NHL. [Display omitted] DisclosuresMiller:Coronado: Speakers Bureau; BioSciences: Membership on an entity’s Board of Directors or advisory committees; SAB: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau.

Abstract 5079: Adjudicating complex phenotypes for use in GWAS: A study of transplant-related mortality (TRM) after unrelated donor hematopoietic cell transplantation (URD-HCT)

Abstract As a first step in a 2-phase GWAS of TRM in patients with acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) after URD-HCT, a consensus panel (CP), composed of BMT physicians and epidemiologists, reviewed all cause-specific deaths (CSDs) reported by 151 US transplant centers (TC) from 2000-11. Agreement measures, statistics and models were used to compared CP and TC CSD and the factors impacting the determination of CSDs. Less affected by prevalence and marginal probabilities than Cohen's K, Gwet's Agreement Coefficient (AC1) measured the agreement between TC and CP CSD and the 95% confidence intervals were generated by bootstrapping the conditional distributions of the CSDs. For each CSD (disease, graft versus host (GvHD), infection, organ failure, other) we determined the proportion of agreement (PA) between the TC and CP and the Bias Index (BI, the proportion of cases the CP moved into or out of a CSD category). Logistic and log-linear models identified factors significantly associated with TC/CP odds of agreement and dependencies between covariates and TC/CP CSD, respectively. The discovery cohort (c1) includes 2609 10/10 HLA matched URD-HCT patients from 2000-8, reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) by TCs. The validation cohort (c2) includes 920 10/10 or 8/8 HLA matched URD-HCT patients from 2000-11. The CP adjudicated CSDs in c1 using in-person meetings and teleconferences over 1 year; c2 cases were reviewed during a 2-day in-person meeting. A total of 1116 (c1) and 388 patients (c2) died ≤1-yr post-URD-HCT. External and internal validity showed &amp;gt;96% agreement. The AC1 statistic was .751 (.726, .801) and .658 (.567, .682), for c1 and c2 respectively. The PA for GvHD was 12% lower in c2 than c1 but the proportion of GvHD cases was higher in c2; these same differences were also seen for organ failure CSD. BI showed the rate of movement between CSDs was almost identical in both cohorts. In c1, TC and CP were &amp;gt;2 fold less likely to agree on CSD for both ALL and MDS (p&amp;lt;.05) when URD-HCT was in the early 2000s. The log-linear models also showed c1 cohort effects, as well as dependencies in both cohorts between age and TC CSD and CP CSD and disease status (early/advanced). The cohort effect and age dependencies with TC CSD in c1 were not present when a systematic review of cases by the CP was performed. In c2 the TC CSD did not show evidence of a cohort effect; however a greater understanding of the lower AC1 in c2 vs. c1 was gained through use of PA. In both cohorts the BI and log-linear models show consistency in CSDs as determined by the CP. Our work illustrates that CPs are a worthwhile part of genomic studies of complex multi-factorial phenotypes, and the use of agreement statistics and dependency models is imperative to monitor CP phenotype reliability and understand data structure for subsequent analyses. Citation Format: Lara Sucheston-Campbell, Theresa Hahn, Leah Preus, Kenan Onel, Xiaochun Zhu, Song Liu, Li Yan, Alyssa Clay, David Tritchler, Marcelo Pasquini, Philip McCarthy. Adjudicating complex phenotypes for use in GWAS: A study of transplant-related mortality (TRM) after unrelated donor hematopoietic cell transplantation (URD-HCT). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5079. doi:10.1158/1538-7445.AM2014-5079

Polymorphism in the Interleukin‐7 Receptor‐alpha and Outcome after Allogeneic Hematopoietic Cell Transplantation with Matched Unrelated Donor

Interleukin-7 (IL-7) is essential for T cell development in the thymus and maintenance of peripheral T cells. The α-chain of the IL-7R is polymorphic with the existence of SNPs that give rise to non-synonymous amino acid substitutions. We previously found an association between donor genotypes and increased treatment-related mortality (TRM) (rs1494555G) and acute graft versus host disease (aGvHD) (rs1494555G and rs1494558T) after hematopoietic cell transplantation (HCT). Some studies have confirmed an association between rs6897932C and multiple sclerosis. In this study, we evaluated the prognostic significance of IL-7Rα SNP genotypes in 590-recipient/donor pairs that received HLA-matched unrelated donor HCT for haematological malignancies. Consistent with the primary studies, the rs1494555GG and rs1494558TT genotypes of the donor were associated with aGvHD and chronic GvHD in the univariate analysis. The Tallele of rs6897932 was suggestive of an association with increased frequency of relapse by univariate analysis (P=0.017) and multivariate analysis (P=0.015). In conclusion, this study provides further evidence of a role of the IL-7 pathway and IL-7Rα SNPs in HCT.

Impact of In Vivo T-Cell Depletion on Outcome of Reduced Intensity Conditioning (RIC) Hematopoietic Cell Transplantation (HCT) for Hematologic Malignanciesimpact of In Vivo T-Cell Depletion on Outcome of Reduced Intensity Conditioning (RIC) Hematopoietic Cell Transplantation (HCT) for Hematologic Malignancies

AbstractAbstract 2305HCT using RIC regimens has increased steadily over the past decade. In vivo administration of anti-T cell antibodies, such as alemtuzumab and anti-thymocyte globulin (ATG) preparations, is often employed to promote engraftment and limit graft-versus-host disease (GVHD). While these antibodies might reduce the severity and incidence of GVHD, they may also blunt the allo-immune graft-versus-tumor effect of HCT. Transplant outcomes after in vivo T-cell depletion (n=584 ATG; n=213 alemtuzumab) were compared to those after T-cell replete (n=879) RIC transplants for myeloid and lymphoid malignancies. Patients were aged 21–69 yrs and transplanted from 2000–2007. Median follow-up of patients is 3 years. Conditioning regimens consisted of an alkylating agent (melphalan, busulfan, or cyclophosphamide) with fludarabine. 792 patients (47%) received allografts from a HLA-matched sibling, 650 (39%) from an 8/8 and 234 (14%) from a 7/8 HLA-matched unrelated donor. In vivo T-cell depletion was used for 35% of matched sibling HCT, 57% of 8/8 and 64% of 7/8 HLA matched unrelated donor HCT. Results of multivariable analysis adjusted for age, disease and disease stage, donor, year of transplant, conditioning regimen, and GVHD prophylaxis are shown in Table below. Grade 2–4 acute GVHD was lower with alemtuzumab containing regimens (20%) than ATG containing (41%) or T replete (42%) regimens. Chronic GVHD occurred in 27% of recipients of alemtuzumab, 43% of ATG, and 57% of T replete regimens, respectively. Compared to T-cell replete regimens, relapse risks were higher with ATG and alemtuzumab containing regimens (38%, 49% and 51%, respectively) and non-relapse mortality, higher with ATG containing regimens only. Treatment failure (relapse or death) was higher with both ATG and alemtuzumab containing regimens compared to T replete regimens. Overall mortality was highest with ATG containing regimens. These observations are independent of disease, disease status and donor type including 7/8 HLA-matched HCT. The 3-year probabilities of disease-free survival (DFS) were 25%, 30% and 39% with ATG-containing, alemtuzumab-containing and T-cell replete regimens, respectively. Corresponding probabilities for overall survival were 38%, 50% and 46%. There were no differences in disease-free and overall survival at 3-years by ATG source or dose. The incidence of EBV-PTLD was higher with alemtuzumab and ATG containing compared to T-cell replete regimens (2% vs. 2% vs. 0.2%). These results suggest in-vivo T-cell depletion with RIC regimens containing an alkylating agent and fludarabine significantly lowers DFS despite lower GVHD. The routine use of in-vivo T-cell depletion in this setting warrants a cautious approach in the absence of a prospective randomized trial.Alemtuzumab vs. T-cell repleteATG vs. T-cell repleteAlemtuzumab vs. ATGHazard ratio, p-valueHazard ratio, p-valueHazard ratio, p-valueGrade 2-4 acute GVHD0.33, p<0.00010.88, p=0.120.38, p<0.001Grade 3-4 acute GVHD0.42, p<0.00010.86, p=0.200.48, p=0.001Chronic GVHD0.34, p<0.00010.69, p<0.00010.49, p<0.0001Non-relapse mortality1.04, p=0.851.34, p=0.010.78, p=0.19Relapse1.54, p=0.00011.53, p<0.00011.01, p=0.94Treatment failure1.40, p=0.00031.46, p<0.00010.96, p=0.67Overall mortality1.09, p=0.461.25, p=0.0020.87, p=0.22 Disclosures:No relevant conflicts of interest to declare.

Pharmacodynamics of mycophenolate mofetil after nonmyeloablative conditioning and unrelated donor hematopoietic cell transplantation

The immunosuppressive drug mycophenolate mofetil (MMF) is used after nonmyeloablative hematopoietic cell transplantation (HCT); however, limited pharmacodynamic data are available. We evaluated plasma concentrations of mycophenolic acid (MPA), the active metabolite of MMF, and outcomes in 85 patients with hematologic malignancies conditioned with fludarabine and 2 Gy total body irradiation followed by HLA-matched unrelated-donor HCT and postgrafting cyclosporine and MMF. The first 38 patients received MMF 15 mg/kg twice daily; the next 47 patients received MMF 3 times daily. MPA pharmacokinetics were determined on days 7 and 21. Comparing the twice-daily and 3-times-daily MMF groups, the mean total MPA concentration steady state (Css) was 1.9 and 3.1 microg/mL; the unbound Css was 18 and 36 ng/mL, respectively (P < .001). Sixteen patients with a total MPA Css less than 3 microg/mL had low (< 50%) donor T-cell chimerism (P = .03), and 6 patients with MPA Css less than 2.5 microg/mL had graft rejection. An elevated unbound Css was associated with cytomegalovirus reactivation (P = .03). There were no significant associations between MPA pharmacokinetics and acute graft-versus-host disease (GVHD) or relapse. We conclude that increased MPA Css's predicted higher degrees of donor T-cell chimerism after unrelated donor nonmyeloablative HCT and suggest that targeting MPA Css's greater than 2.5 microg/mL could prevent graft rejection.

HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies

AbstractA hematopoietic cell transplantation (HCT) approach was developed for elderly or ill patients with hematologic malignancies that employed nonmyeloablative conditioning to avoid common regimen-related toxicities and relied on graft-versus-tumor effects for control of malignancy. Eighty-nine patients, median age 53 years, were given fludarabine (90 mg/m2) and 2 Gy total body irradiation. Marrow (n = 18) or granulocyte colony-stimulating factor (G-CSF)–stimulated peripheral blood mononuclear cells (G-PBMCs; n = 71) were transplanted from unrelated donors matched for human leukocyte antigen A (HLA-A), -B, -C antigens and -DRB1 and -DQB1 alleles. Postgrafting immunosuppression included mycophenolate mofetil and cyclosporine. Donor T-cell chimerism was higher for G-PBMCs compared with marrow recipients. Durable engraftment was observed in 85% of G-PBMCs and 56% of marrow recipients. Cumulative probabilities of grade II, III, and IV acute graft-versus-host disease (GVHD) were 42%, 8%, and 2%, respectively. Nonrelapse mortality at day 100 and at 1 year was 11% and 16%, respectively. One-year overall survivals and progression-free survivals were 52% and 38%, respectively. G-PBMC recipients had improved survival (57% vs 33%) and progression-free survival (44% vs 17%) compared with marrow recipients. HLA-matched unrelated donor HCT after nonmyeloablative conditioning is feasible in patients ineligible for conventional HCT. G-PBMCs conferred higher donor T-cell chimerism, greater durable engraftment, and better progression-free and overall survivals compared with marrow.