Abstract: Background MHC class I chain-related gene A (MICA) is a polymorphic ligand of the natural killer (NKG2D) receptor on immune effector cells. The activating NKG2D receptor controls immune responses by regulating NK cells, NKT cells and γδ-T cells. Dimorphisms at sequence position 129 of the MICA gene confers varying levels of binding affinity to NKG2D receptor. MICA previously has been associated with post-allogeneic hematopoietic cell transplantation (alloHCT) outcomes including graft-versus-host-disease (GvHD), infection, and relapse. However, it is unclear how MICA interacts with cytogenetic and somatic mutations in regards to these outcomes in acute myeloid leukemia (AML). Methods We conducted a single center, retrospective analysis of adult AML patients in first or second complete remission (CR1, CR2), who underwent T-cell replete matched related or unrelated donor alloHCT. Analysis was limited to those who had MICA data available for donors and recipients. In addition to cytogenetic risk group stratification by European LeukemiaNet criteria (Döhner H, et al, Blood 2016), a subset of patients had a 36-gene somatic mutation panel assessed prior to alloHCT by next-generation sequencing. Dimorphisms at the MICA-129 position have previously been categorized as weaker (valine/valine: V/V), heterozygous (methionine/valine: M/V), or stronger (methionine/methionine: M/M) receptor binding affinity. Fine and Gray or Cox regression was used to identify the association of MICA and outcomes with results as hazard ratios (HR) and 95% confidence intervals (CI). Results From 2000 - 2017, 131 AML patients were identified meeting inclusion criteria. Median age at transplant was 54 years (18-74), with 98% Caucasian. Disease status at transplant included 78% CR1 and 22% CR2. Cytogenetic risk stratification showed 13% of patients as favorable, 56% as intermediate, and 31% as adverse-risk. The five most common somatic mutations were FLT3 (15%), NPM1 (14%), DNMT3A (11%), TET2 (7%), and NRAS (6%). 60% of patients had a related donor. A myeloablative transplant was performed in 84% of patients and 53% had a bone marrow graft source. The most common conditioning regimen used was busulfan/cyclophosphamide (52%). 12% of patients were MICA mismatched with their donor. The distribution of donor MICA-129 polymorphisms were 41% V/V, 53% M/V, and 6% M/M. In univariable analysis, donor-recipient MICA mismatch tended to be associated with a lower risk of infection (HR 0.49, CI 0.23-1.02, P=0.06) and grade 2-4 acute GvHD (HR 0.25, CI 0.06-1.04, P=0.06) but was not associated with other post-transplant outcomes. In multivariable analysis, donor MICA-129 V/V was associated with a higher risk of non-relapse mortality (NRM) (HR 2.02, CI 1.01-4.05, P=0.047) (Figure 1) along with increasing patient age at transplant (HR 1.46, CI 1.10-1.93, p=0.008) and the presence of a TET2 mutation (HR 6.00, CI 1.77-20.3, P=0.004). There were no differences between the V/V and the M/V+M/M cohorts regarding somatic mutational status, cytogenetics and other pre-transplant characteristics and post-transplant outcomes. With a median follow-up of 65 months for both cohorts, 45% vs. 49% of patients remain alive, respectively. The most common causes of death between the V/V and the M/V+M/M cohorts was relapse (38% vs. 62%) and infection (31% vs. 8%), respectively. Conclusion While previous studies have demonstrated associations of somatic mutations and cytogenetics with survival outcomes after alloHCT for AML, we observed mutations in TET2 and the V/V donor MICA-129 polymorphism to be independently prognostic for NRM. Mechanistic studies may be considered to assess for possible interactions of TET2 mutations with NK cell alloreactivity. The weaker binding affinity to the NKG2D receptor by the V/V phenotype may diminish immune responses against pathogens that subsequently contribute to higher NRM. These observations may have implications for enhancing patient risk stratification prior to transplant and optimizing donor selection. Future investigation with larger cohorts interrogating pre-transplant AML somatic mutations with MICA polymorphisms on post-transplant outcomes may further elucidate which subsets of patients may benefit most from transplant. Disclosures Nazha: MEI: Consultancy. Mukherjee:Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; BioPharm Communications: Consultancy; Bristol Myers Squib: Honoraria, Speakers Bureau; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; LEK Consulting: Consultancy, Honoraria; Aplastic Anemia & MDS International Foundation in Joint Partnership with Cleveland Clinic Taussig Cancer Institute: Honoraria. Advani:Amgen: Research Funding; Pfizer: Honoraria, Research Funding; Glycomimetics: Consultancy; Novartis: Consultancy. Carraway:Novartis: Speakers Bureau; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Speakers Bureau; FibroGen: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Speakers Bureau. Gerds:Apexx Oncology: Consultancy; Celgene: Consultancy; Incyte: Consultancy; CTI Biopharma: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy. Majhail:Incyte: Honoraria; Anthem, Inc.: Consultancy; Atara: Honoraria.

Abstract: Background Cytomegalovirus (CMV) is a common infectious complication after allogeneic hematopoietic cell transplantation (alloHCT). Efforts to enhance immune reconstitution post-transplant have been pursued to help facilitate clearance of such infections. Assessment of natural killer (NK) cell allo-reactivity with investigation of killer cell immunoglobulin-like receptors has been reported to be associated with protection from CMV infection after alloHCT (Davis ZB et al, BBMT 2015). In addition, the activating NKG2D receptor controls immune responses by regulating NK cells, NKT cells and γδ-T cells. MHC class I chain-related gene A (MICA) is a polymorphic ligand of the NKG2D receptor on these immune effector cells. Given the potential benefit of NK cell allo-reactivity for protection from CMV infection after alloHCT we hypothesized that MICA polymorphisms may influence CMV infection rates after such transplants. Methods We conducted a single center, retrospective analysis of allogeneic HCTs for adults with hematologic malignancies in which MICA data were available for donors and recipients. Analysis was restricted to patients with T-cell replete HLA-8/8 matched related or unrelated donor. Fine and Gray regression was used to identify risk factors for CMV infection. The first episode of graft-versus-host-disease (GVHD) was analyzed relative to CMV as a time-dependent covariate. An analysis was performed examining dimorphisms at the MICA-129 position, which previously has been categorized as weaker (valine/valine: V/V), heterozygous (methionine/valine: M/V), or stronger (methionine/methionine: M/M) receptor binding affinity. Results From 2000-2016, 423 alloHCT patients were identified who had MICA data. Diagnoses included 197 AML, 82 MDS, 34 ALL, 34 NHL, 22 CML, 12 CMML, 9 CLL, 9 myelofibrosis, 9 plasma cell myeloma, 9 other leukemias, and 6 Hodgkin lymphoma. High, intermediate, and low co-morbidity index was seen in 42%, 33%, and 25% of patients, respectively. Median age at transplant was 52 years (range, 18-76), with 95% Caucasian. A myeloablative transplant was performed in 80% of patients and 52% had a bone marrow graft source. CMV infection occurred in 141 (33%) of patients at a median time of 46 days post-transplant (range, 0-609 days) with 29 (21%) occurring within 30 days, 108 (77%) within 100 days and 33 (23%) after day 100. Thirty-three (8%) patients were MICA mismatched with their donor. Donor MICA-129 dimorphisms included 203 (48%) V/V, 190 (45%) M/V and 30 (7%) M/M. Baseline donor(d)/recipient(r) CMV serostatus for V/V vs. M/V + M/M cohorts were 25% vs. 28% for d+/r+, 11% vs 9% for d+/r-, 39% vs. 37% for d-/r+, and 25% vs. 26% for d-/r- (P=0.75). In univariate analysis, MICA mismatch was associated with a higher risk of CMV (HR 1.64, CI 1.00-2.69, P=0.049), and V/V donor MICA-129 dimorphism with a marginally higher risk of CMV (HR 1.32, CI 0.85-1.83, P=0.10). In multivariable analysis, MICA mismatch was not associated with CMV infection (HR 1.38, CI 0.83-2.29, P=0.22) while V/V donor MICA-129 dimorphism was associated (HR 1.40, CI 1.00-1.96, P=0.05) (Figure 1). Other significant variables in multivariable analysis were year of transplant (HR 0.95, CI 0.92-0.99 P=0.01), non-Caucasian race (HR 2.15, CI 1.18-3.91, P=0.01), high-risk disease (HR 1.62, CI 1.13-2.32 P=0.008), baseline CMV serostatus (HR 7.51, CI 3.76-15.0, P & lt;0.001 for d+/r+, HR 7.73, CI 3.90-15.3, P & lt;0.001 for d-/r+, both relative to d-/r-), and development of GVHD prior to CMV (HR 2.02, CI 1.37-2.96, P & lt;0.001). There was no association of MICA mismatch with acute (HR 1.05, CI 0.66-1.68, P=0.83) or chronic (HR 0.94, CI 0.51-1.76, P=0.85) GVHD. As compared to the V/M+M/M cohort, patients with V/V donors had a longer interval from diagnosis to transplant (median 8.2 vs 6.2 months, P=0.036) and more often received myeloablative conditioning (P=0.030). Conclusion We conclude that the donor MICA-129 V/V dimorphism with weak NKG2D receptor binding affinity is associated with increased risk of CMV infection after alloHCT. The presence of at least one M residue encoding allele may confer enhanced NK cell anti-viral reactivity. These observations potentially may have implications in optimizing donor selection. Further investigation of MICA may also help better predict which patients are at higher risk of CMV infection in order to consider intervening sooner with CMV specific therapy or more rapid tapering of immunosuppression. Figure 1 Figure 1. Disclosures Gerds: CTI BioPharma: Consultancy; Incyte: Consultancy. Majhail: Sanofi: Honoraria; Anthem, Inc.: Consultancy.

Abstract: Background While allogeneic hematopoietic cell transplantation (alloHCT) can be curative for patients with acute myeloid leukemia (AML), relapse remains a significant challenge. Previous work has suggested that disease status at time of transplant and cytogenetics are important predictors of relapse. However, it is unclear if common somatic mutations or dimorphisms of MHC class I chain-related gene A (MICA), a ligand of the natural killer (NKG2D) receptor on immune effector cells that helps mediate NK cell alloreactivity, also contribute. Moreover, the mechanisms of early relapse are an area of ongoing investigation. We assessed risk factors for relapse within 6 and 12 months after alloHCT. Methods We conducted a single center, retrospective analysis of adults with AML who underwent a first alloHCT. Analysis was restricted to patients with T-cell replete HLA-8/8 matched related or unrelated donor. In addition to cytogenetic risk group stratification by European LeukemiaNet criteria (Döhner H, et al, Blood 2016), a subset of patients had a 36-gene somatic mutation panel assessed prior to alloHCT by next-generation sequencing. Dimorphisms at the MICA-129 position have previously been categorized as weaker (valine/valine: V/V), heterozygous (methionine/valine: M/V), or stronger (methionine/methionine: M/M) receptor binding affinity. Risk factors for early relapse were assessed with Fine and Gray competing risk regression with results as hazard ratios (HR) and 95% confidence intervals (CI). Results From 2000 - 2017, 319 adult AML patients were identified meeting inclusion criteria. Median age at transplant was 51 years (range, 18-74), with 95% Caucasian. The distribution of low, intermediate, and high HCT-CI scores was 28%, 28%, and 44%, respectively. 75% of patients were transplanted ≤12 months from diagnosis. Disease status at transplant included 48% in first complete remission (CR1), 19% in second CR (CR2), 33% in third CR or relapsed/refractory or untreated (collectively, 〈 CR2). By cytogenetic risk stratification, 13% of patients had favorable, 58% had intermediate, and 29% had adverse-risk cytogenetics. The four most common somatic mutations were FLT3 (12%), NPM1 (10%), DNMT3A (7%), and TET2 (6%). MICA mismatch was present in 10% of patients. The distribution of donor MICA-129 dimorphisms were 44% V/V, 51% M/V, and 5% M/M. 56% of patients had a related donor. A myeloablative transplant was performed in 88% of patients and 63% had a BM graft source. Conditioning with busulfan/cyclophosphamide was used in 56% of patients. In univariable analysis, non-Caucasian race, disease status 〈 CR2, and adverse cytogenetics were risk factors for relapse within 6 months; all but race were also risk factors for relapse within 12 months. None of the somatic mutations assessed, MICA mismatch, nor dimorphisms at the MICA-129 position were identified as risk factors for early relapse. In multivariable analysis, relative to CR1, patients in 〈 CR2 was a risk factor for relapse within 6 months (HR 2.21, CI 1.28-3.82, P=0.005) and 12 months (HR 2.23, CI 1.39-3.58, P 〈 0.001), while patients in CR2 also had higher risk of relapse within 12 months relative to CR1 (HR 2.02, CI 1.10-3.70, P=0.024) (Figures 1A, 1B). In addition, adverse-risk cytogenetics were a risk factor for relapse within 6 months (HR 3.96, CI 1.33-11.8, P=0.013) and 12 months (HR 3.58, CI 1.67-7.68 P=0.001) (Figures 2A, 2B). Relapse incidence estimates (CI) at 6 months were 16% (11-22) CR1, 15% (7-25) CR2, and 33% (24-42) 〈 CR2; estimates were 10% (3-22) for favorable, 17% (12-23) intermediate, and 31 % (22-41) adverse-risk cytogenetics. Relapse incidence estimates at 12 months were 21% (15-28) CR1, 30% (19-41) CR2, and 42% (33-52) 〈 CR2; estimates were 21% (10-36) for favorable, 21% (15-27) intermediate, and 47% (36-57) adverse-risk cytogenetics. Conclusion Relapse after alloHCT for AML remains a challenge. In our study, the strongest risk factors for early relapse after alloHCT remains absence of CR1 disease status at transplant and adverse-risk cytogenetics. We observed no prognostic effect of somatic mutations nor MICA dimorphisms prior to transplant on 6 or 12-month relapse post-transplant. Further interrogation of pre-transplant or post-transplant persistence of somatic mutations in a larger series may better risk stratify subjects who may benefit from more intensive or innovative approaches to prevent post-transplant relapse. Disclosures Nazha: MEI: Consultancy. Advani:Amgen: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Consultancy; Glycomimetics: Consultancy. Carraway:Novartis: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; FibroGen: Consultancy; Jazz: Speakers Bureau; Agios: Consultancy, Speakers Bureau. Gerds:Celgene: Consultancy; Apexx Oncology: Consultancy; Incyte: Consultancy; CTI Biopharma: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Majhail:Atara: Honoraria; Incyte: Honoraria; Anthem, Inc.: Consultancy.

Abstract: Although outcomes after allogeneic hematopoietic cell transplantation (alloHCT) for AML have improved, this has mainly been attributed to a reduction in transplant-related mortality rather than reduced leukemia relapse. NK cell alloreactivity is regulated by inhibitory and activating signals mediated through cell-surface receptors including the killer immunoglobulin-like receptors (KIRs). Group A and B KIR haplotypes have distinct centromeric (Cen) and telomeric (Tel) gene-content motifs and donor Cen group B KIR haplotypes have been reported to be associated with decreased relapse and improved survival in AML patients undergoing unrelated donor alloHCT. We hypothesized that donor KIR genotype may also be predictive of outcomes after matched related donor (MRD) alloHCT. We evaluated 93 AML patients in CR1/CR2 who underwent T-cell replete alloHCT using HLA- matched related donors at our institution from 1/2000-3/2013. Sixty-six had myeloablative conditioning (MAC) that that was busulfan/cyclophosphamide-based and 27 had reduced-intensity conditioning (RIC) with fludarabine/total body irradiation or busulfan/fludarabine. Donors were KIR genotyped to assign haplotypes A/A vs. B/X and the distinctive Cen and Tel gene-content motifs of group A and B KIR haplotypes according to the presence or absence of one or more B haplotype-defining KIR genes. KIR B–content score for each KIR genotype was defined as the number of Cen and Tel gene-content motifs containing B haplotype–defining genes (range, 0-4). As compared to those with haplotypes B/X (n=40; B content scores of 1-4) those with haplotype A/A (n=25; B content score of 0) undergoing MAC had significantly lower 100-day, 6-, 12- and 24-month non-relapse mortality (NRM) (8% vs. 0%, 13% vs. 0%, 15% vs. 0%, 25% vs. 0%, respectively, Figure 1) which was confirmed on multivariable analysis (HR 9.19, p=0.03). There were no differences between these groups regarding patient and transplant-related characteristics, or for acute or chronic GVHD, relapse, or survival. The causes of death in the group with haplotypes B/X were most commonly attributed to infection and then GVHD. However, within the group with B/X haplotypes, the B motif content score (1-4) was not associated with significant differences in NRM (HR 0.79, p=0.56). No difference in outcomes was observed for those undergoing RIC. The number of donor activating KIR genes (2SD1, 2DS2, 2DS3, 2DS4, 2DS5, and 3DS1) was then assessed. As compared to those with 3-6 activating KIR genes (n=20) those with 0-2 (n=41) undergoing MAC had significantly lower 100-day, 6-, 12- and 24-month non-relapse mortality (NRM) (15% vs. 0%, 15% vs. 5%, 15% vs. 5%, 29% vs. 8%, respectively, Figure 2) which was confirmed on multivariable analysis (HR 4.07, p=0.01). There were no differences in other post-transplant outcomes when comparing these groups or when considering those undergoing RIC. An increase of 1 donor activating KIR also was highly associated with NRM (HR 1.37, p=0.008). Overall, these results suggest that in the MRD MAC alloHCT setting donor KIR genotype may be predictive of increased NRM risk, particularly for those with B/X haplotypes and greater numbers donor activating KIRs. No comparable effects were observed in the RIC setting. Future strategies to further enhance immune reconstitution post-transplant may be appropriate to pursue for these higher risk patients. These results may have potential implications to improve donor selection for those AML patients with multiple HLA-matched related donors and need to be validated in larger cohorts. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.