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Donor Killer Cell Immunoglobulin-Like Receptor Genotype Does Not Improve Graft-versus-Leukemia Responses in Chronic Lymphocytic Leukemia after Unrelated Donor Transplant: A Center for International Blood and Marrow Transplant Research Analysis.

ABSTRACT: Allogeneic hematopoietic cell transplantation (alloHCT) remains the sole curative therapy for patients with chronic lymphocytic leukemia (CLL), leading to 40% to 45% long-term survival. The impact of donor killer immunoglobulin-like receptor (KIR) genotype on outcomes of unrelated donor (URD) alloHCT for CLL is unknown. We examined 573 adult URD CLL recipient pairs. KIR genotype (presence/absence) was determined for each donor, and comprehensive modeling of interactions with recipient HLA class I loci (KIR ligands) was used to evaluate their effect on relapse and survival. Recipients had a median age of 56 years, and most were not in remission (65%). Both 8/8 HLA-matched (81%) or 7/8 HLA matched grafts (19%) were studied. Factors associated with improved overall survival (OS) were reduced-intensity conditioning (hazard ratio [HR] of death, .76) and good performance status (HR, .46), whereas alloHCT in nonremission (HR, 1.96) and mismatched donors (HR, 2.01) increased mortality. No models demonstrated a relationship between donor KIR genotype and transplant outcomes. Cox regression models comparing donors with A/A versus B/x KIR haplotypes and those with KIR gene content scores of 0 versus 1 versus ?2 yielded similar rates of nonrelapse mortality, relapse, acute graft-versus-host disease (GVHD), and chronic GVHD and the same progression-free survival and OS. Relapse risk was not different for grafts from donors with KIR3DL1 transplanted into HLA C1/1 versus C2 recipients. This large analysis failed to demonstrate an association between URD KIR genotype and transplant outcome for patients with CLL, and thus KIR genotyping should not be used as a donor selection criterion in this setting.

SUBMITTER: Bachanova V

PROVIDER: S-EPMC6511301 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Donor Killer Cell Immunoglobulin-Like Receptor Genotype Does Not Improve Graft-versus-Leukemia Responses in Chronic Lymphocytic Leukemia after Unrelated Donor Transplant: A Center for International Blood and Marrow Transplant Research Analysis.

Bachanova Veronika V Weisdorf Daniel J DJ Wang Tao T Marsh Steven G E SGE Cereb Nezih N Haagenson Michael D MD Spellman Stephen R SR Lee Stephanie J SJ Guethlein Lisbeth A LA Parham Peter P Miller Jeffrey S JS Cooley Sarah A SA

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 20181227 5

Allogeneic hematopoietic cell transplantation (alloHCT) remains the sole curative therapy for patients with chronic lymphocytic leukemia (CLL), leading to 40% to 45% long-term survival. The impact of donor killer immunoglobulin-like receptor (KIR) genotype on outcomes of unrelated donor (URD) alloHCT for CLL is unknown. We examined 573 adult URD CLL recipient pairs. KIR genotype (presence/absence) was determined for each donor, and comprehensive modeling of interactions with recipient HLA class ...[more]

PMID: 30594542

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Project description:Natural killer (NK) cell determinants predict relapse-free survival after allogeneic hematopoietic cell transplantation (HCT) for acute myelogenous leukemia, and previous studies have shown a beneficial graft-versus-leukemia effect in patients with juvenile myelomonocytic leukemia (JMML). However, whether NK cell determinants predict protection against relapse for JMML patients undergoing HCT is unknown. Therefore, we investigated NK cell-related donor and recipient immunogenetics as determinants of HCT outcomes in patients with JMML. Patients with JMML (age 0 to <19 years) who underwent a first allogeneic HCT from an unrelated donor between 2000 and 2017 and had available donor samples from the Center for International Blood and Marrow Transplant Research Repository were included. Donor killer immunoglobulin receptor (KIR) typing was performed on pre-HCT samples. The primary endpoint was disease-free survival (DFS); secondary endpoints included relapse, grade II-IV acute graft versus-host-disease (aGVHD), chronic GVHD (cGVHD), GVHD-free relapse-free survival, transplantation-related mortality, and overall survival (OS). Donor KIR models tested included KIR genotype (AA versus Bx), B content (0-1 versus ≥2), centromeric and telomeric region score (AA versus AB versus BB), B content score (best, better, or neutral), composite score (2 versus 3 versus 4), activating KIR content, and the presence of KIR2DS4. Ligand-ligand and KIR-ligand mismatch effects on outcomes were analyzed in HLA-mismatched donors (≤7/8; n = 74) only. Univariate analyses were performed for primary and secondary outcomes of interest, with a P value <.05 considered significant. One hundred sixty-five patients (113 males), with a median follow-up of 85 months (range, 6 to 216 months) met the study criteria. Of these, 111 underwent an unrelated donor HCT and 54 underwent a UCB HCT. Almost all (n = 161; 98%) received a myeloablative conditioning regimen. After exclusion of recipients of reduced-intensity/nonmyeloablative conditioning regimens and ex vivo T cell-depleted grafts (n = 8), there were 42 AA donors and 115 Bx donors, respectively. Three-year DFS, OS, relapse, and GRFS for the entire cohort were 58% (95% confidence interval [CI], 50% to 66%), 67% (95% CI, 59% to 74%), 26% (95% CI, 19% to 33%), and 27% (95% CI, 19% to 35%), respectively. The cumulative incidence of grade II-IV aGVHD at 100 days was 36% (95% CI, 27% to 44%), and that of cGVHD at 1 year was 23% (95% CI, 17% to 30%). There were no differences between AA donors and Bx donors for any recipient survival outcomes. The risk of grade II-IV aGVHD was lower in patients with donors with a B content score of ≥2 (hazard ratio [HR], 0.46; 95% CI, 0.26 to 0.83; P = .01), an activating KIR content score of >3 (HR, 0.52; 95% CI, 0.29 to 0.95; P = .032), centromeric A/B score (HR, 0.57; 95% CI, 033 to 0.98; P = .041), and telomeric A/B score (HR, 0.58; 95% CI, 0.34 to 1.00; P = .048). To our knowledge, this is the first study analyzing the association of NK cell determinants and outcomes in JMML HCT recipients. This study identifies potential benefits of donor KIR-B genotypes in reducing aGVHD. Our findings warrant further study of the role of NK cells in enhancing the graft-versus-leukemia effect via recognition of JMML blasts.

Project description:PurposeHematopoietic cell transplantation (HCT) is curative for hematologic disorders, but outcomes are historically inferior when using HLA-mismatched donors. Despite unrelated donor registries listing > 38 million volunteers, 25%-80% of US patients lack an HLA-matched unrelated donor, with significant disparity across ethnic groups. We hypothesized that HCT with a mismatched unrelated donor (MMUD) using post-transplant cyclophosphamide (PTCy), a novel strategy successful in overcoming genetic disparity using mismatched related donors, would be feasible and increase access to HCT.Patients and methodsWe performed a prospective phase II study of MMUD bone marrow HCT with PTCy for patients with hematologic malignancies. The primary end point was 1-year overall survival (OS), hypothesized to be 65% or better. 80 patients enrolled at 11 US transplant centers (December 2016-March 2019). Following myeloablative or reduced-intensity conditioning-based HCT, patients received PTCy on days +3, +4, with sirolimus and mycophenolate mofetil starting on day +5. We compared outcomes to Center for International Blood and Marrow Transplant Research contemporary controls receiving PTCy.ResultsNotably, 48% of patients enrolled were ethnic minorities. 39% of pairs were matched for 4-6 out of 8 HLA alleles. The primary end point was met, with 1-year OS of 76% (90% CI, 67.3 to 83.3) in the entire cohort, and 72% and 79% in the myeloablative and reduced-intensity conditioning strata, respectively. Secondary end points related to engraftment and graft-versus-host-disease were reached. Multivariate analysis comparing the study group with other mismatched HCT controls found no significant differences in OS.ConclusionOur prospective study demonstrates the feasibility and effectiveness of HCT with an MMUD in the setting of PTCy. Remarkably, nearly half of the study participants belonged to an ethnic minority population, suggesting this approach may significantly expand access to HCT.

Dataset Information

Donor Killer Cell Immunoglobulin-Like Receptor Genotype Does Not Improve Graft-versus-Leukemia Responses in Chronic Lymphocytic Leukemia after Unrelated Donor Transplant: A Center for International Blood and Marrow Transplant Research Analysis.

Publications

Donor Killer Cell Immunoglobulin-Like Receptor Genotype Does Not Improve Graft-versus-Leukemia Responses in Chronic Lymphocytic Leukemia after Unrelated Donor Transplant: A Center for International Blood and Marrow Transplant Research Analysis.

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