ALBERT

Description: Introduction: Allogeneic hematopoietic stem cell transplantation (Allo-HCT) is the only curative treatment for myelodysplastic syndrome (MDS). The portion of patients referred for transplant and the proportion who are subsequently transplanted is unknown. Aim: Tostudy the frequency of allo-HCT in pts with MDS and identify factors associated with transplant referral and barriers to transplant. Methods: Pts were included if they were under the age of 75 and seen at our center by a leukemia physician between 2008-2015 and within 6 months of MDS diagnosis. Pts were eligible for allo-HCT if they did not have major organ dysfunction, i.e. left ventricular ejection fraction 2mg/dL, FEV1

Description: The addition of alemtuzumab to conditioning may decrease the incidence of graft versus host disease (GVHD) after unrelated donor (URD) allogeneic hematopoietic cell transplantation (alloHCT) but may also contribute to impaired pathogen immunity due to donor lymphocyte depletion. We identified and graded infections occurring within 6 months after URD alloHCT in 78 individuals treated either with (N=40) or without (N=38) alemtuzumab during alloHCT for hematologic cancers. Conditioning included fludarabine (120 mg/m2 total) and cyclophosphamide (4,800 mg/m2 total) over 4 days with either alemtuzumab (100 mg total days -8 to -4) followed by cyclosporine (AC) or with tacrolimus, methotrexate, and sirolimus (TMS) based GVHD prophylaxis. Both groups received a filgrastim mobilized peripheral blood graft from an 8/8 or 7/8 HLA-matched unrelated donor and received GVHD prophylaxis for 180 days. Filgrastim was administered post HCT until neutrophil recovery. Infections were graded according to Cordonnier et al. (Transplantation 2006). Only proven/probable pulmonary fungal episodes by EORT/MSG criteria were included. Infection prophylaxis during the study period included trimethoprim/sulfamethoxazole BID thrice weekly after HCT engraftment and daily acyclovir or valacyclovir. Fungal prophylaxis was fluconazole until day 100 or either micafungin or voriconazole in persons receiving 1+ week of 〉1 mg/kg/d prednisone or equivalent. Ceftazidime was administered to persons with neutrophil count

Description: Abstract 3476 The development of reduced intensity conditioning (RIC) regimens has increased the use of allogeneic hematopoietic stem cell transplantation (alloHSCT) in patients with chronic lymphocytic leukemia (CLL). Despite decreased rates of transplant related mortality, RIC regimens confer slower rates of donor engraftment and increased relapse post-transplant. It has been reported that faster rates of conversion to donor chimerism after RIC alloHSCT result in lower rates of CLL relapse1. We hypothesized that systematic targeted host T-lymphocyte depletion (TLD) to a target level by serial administration of standard chemotherapy prior to RIC alloHSCT will result in more rapid donor engraftment and full donor chimerism, thereby enhancing graft versus leukemia activity. We evaluated the effects of TLD on host CD4 lymphocyte depletion, disease response, and toxicity as well as donor engraftment, non-relapse mortality, and disease control in 27 patients undergoing RIC alloHSCT for CLL from 1999 to 2010. All patients underwent TLD receiving 1–3 cycles of EPOCH-F±R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, fludarabine ± rituximab) prior to RIC (fludarabine/cyclophosphamide) and matched-related (N=17) or unrelated (N=10) donor transplantation followed by calcineurin inhibitor-based GVHD prophylaxis. The number of cycles administered (max of three cycles) was titrated to achieve an absolute CD4 count ≤ 100 cells/μL prior to RIC. The median number of EPOCH-F±R cycles given was 2. The median CD3+, CD4+, and CD8+ lymphocyte counts at baseline were 819, 443, and 269 cells/μL, respectively. The median CD3+, CD4+ and CD8+ lymphocyte counts after TLD were 124, 97, and 52 cells/μL, respectively. The overall response rate to EPOCH-F±R was 50% (9% CR, 41% PR), including 44% of patients who were refractory to their last treatment. The incidence of grade 3 and 4 non-hematologic toxicity with TLD was 72% and 32%, respectively. No patients failed to engraft. The median days to full donor peripheral blood lymphoid and myeloid chimerism were 28 (14-60) and 21 (14-180), respectively. Development of full lymphoid chimerism by day 14 (first evaluation point) versus day 28 or greater trended towards association with development of acute GVHD (90% vs. 35%, P=0.014) but not chronic GVHD (50% vs. 41%, P=0.71). Achievement of full lymphoid chimerism on day 14 as compared to day 28 or greater trended towards association with decreased CLL cells identified in the bone marrow by multicolor flow cytometry at day 100 (median 0% vs. 8.5%, P=0.016) but was not associated with (P=0.077) improved overall survival (OS). There was no association between rates of development of full myeloid chimerism and acute or chronic GVHD or disease control. The rates of acute (grade 2–4) and chronic GVHD were 52% and 44%, respectively. Non-relapse related mortality at one and two years was 21% and 30%, respectively. The rate of complete remission was 54% and the rate of minimal residual disease negativity after transplantation as assessed by multicolor flow cytometry was 55%. The incidence of disease progression after transplant was 33%. The three year event-free and OS probabilities were 56% and 57%, respectively. The median OS was 5.99 years (95% CI, 2.11-NR). In summary, the use of TLD resulted in a high rate of early donor engraftement after RIC alloHSCT in patients with CLL. Rapid donor engraftment was associated with better disease control and occurence of acute GVHD, but it did not appear to alter overall survival. These data suggest that methods resulting in faster donor chimerism may improve CLL control after RIC alloHSCT. Separation of antileukemic effects from severe GVHD remain a challenge. 1. Brown JR et al. Biol Blood Marrow Transplant. 2006 Oct;12(10):1056-64. Table 1: Patient characteristics at study entry N 27 Median age (range) 56 (37–71) Number male 21 (78%) Rai stage 3/4 16 (59%) Poor risk cytogenetics1 (n=25) 12 (44%) Bulky disease ≥5 cm (n=25) 6 (24%) ≥4 Prior regimens 16 (59%) Refractory to last regimen 14 (52%) Median time from diagnosis to HSCT (range) 58 m (17–205) Sorror comorbidity score2     0-2 20 (74%)     3+ 7 (26%) 1. Defined by deletion of 17p or 11q. 2. Sorror et al. Blood 2005;106:2912-2919. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: CB transplantation (CBT) after intermediate intensity conditioning is a less toxic alternative to CBT after high dose myeloablation. However, determinants of progression-free survival (PFS) and the impact of the pre-transplant revised Disease Risk Index (rDRI) and age-adjusted Hematopoietic Cell Transplant Co-morbidity Index (aaHCT-CI) are not established. Methods: We evaluated 2-year PFS in double-unit CBT (dCBT) recipients with hematologic malignancies who were conditioned with a myeloablative but intermediate intensity regimen of cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, thiotepa 5-10 mg/kg, 400 cGy of TBI with cyclosporine-A/mycophenolate mofetil and no ATG. Eligible patients for this analysis included first allograft recipients aged 〈 70 years with acute leukemia, MDS, MPD (all 〈 10% blasts pre-transplant), B-cell NHL or HL. Patients were scored by the rDRI (with FLT-3 positivity categorized as high risk) and aaHCT-CI. PFS was estimated using the Kaplan-Meier method, while Cox proportional hazards regression models were used to assess the association between patient and graft characteristics and PFS. Results: Patients [n = 100, median age 51 years (range 19-70) and median weight 78 kg (32-139) had AML (38 CR1,17 CR2, 1 refractory), ALL (13 CR1, 2 CR2, 1 CR3), MDS (10, blasts ranging 1-10%), MPD (5), B-cell NHL (11 DLBCL or indolent) or HL (2). The rDRI distribution was 6 (6%) low, 55 (55%) intermediate, 34 (34%) high, and 5 (5%) very high whereas the median aaHCT-CI was 3 (range 0-9). The median infused CD34+ cell doses of the larger and smaller units were 1.17 (range 0.35-3.72) and 0.68 (range 0.17-2.18) x 105/kg, respectively, whereas the median 8 allele HLA-match was 5/8 (range 2-8/8). In 42/100 (42%) patients the dCBT grafts were supplemented by CD34+ cell selected haplo-identical peripheral blood stem cells. The cumulative incidence of day 45 neutrophil engraftment was 97% whereas day 100 grade II-IV and III-IV aGVHD were 69% and 15%, respectively, and 1-year chronic GVHD was 6%. Day 180 TRM was 17% and 2-year relapse incidence was 11%. With a median survivor follow-up of 27 months (range 5-91), the 2-year PFS was 66% (95%CI: 56-75). Kaplan-Meier estimates and univariate and multivariate analyses of 2-year PFS by relevant patient and graft variables are shown (Table and Figures). Dividing patients into low-intermediate vs high-very-high rDRI and aaHCT-CI 0-2, 3 and 〉 4 revealed high aaHCT-CI was associated with worse PFS whereas older age alone and high-very high rDRI were not. The adverse effect of high aaHCT-CI was mediated by an increased risk of TRM early post-transplant. Conclusions: dCBT with intermediate intensity conditioning (Cy/Flu/Thio/TBI 400) is effective in adult patients with high-risk malignancies. Notably, pre-transplant rDRI was not associated with PFS suggesting this therapy is associated with a robust graft-versus-malignancy effect. High aaHCT-CI, however, adversely impacted PFS. These findings support the use of intermediate intensity dCBT in patients with high risk disease without concurrent high aaHCT-CI, and, as with adult donor allografts, new treatment strategies are required for patients with a significant co-morbidity burden. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Giralt: JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding. Scaradavou:National Cord Blood Program- New York Blood Center: Employment.

Description: Abstract 1349 Background: Clinical and translational studies suggest that allogeneic hematopoietic cell transplantation (alloHCT) may induce production of anti-tumor antibodies in the recipient after transplantation. We hypothesized that this phenomenon can serve as a platform for the generation of novel therapeutic monoclonal antibodies (mAbs). An important step to this goal is the identification of targeted antigens with defined ability to support antibody induced cell death. To address this challenge, we developed a chronic lymphocytic leukemia (CLL) membrane protein display system capable of discovering cell surface proteins targeted by serum antibodies and applied this tool to post-alloHCT patient samples. Methods: Total and mRNA was purified from peripheral blood mononuclear cells from six untreated CLL patients and used to generate cDNA. The patient cDNA was pooled, cloned into the retroviral vector pBMN, and expressed in the murine T-cell line Bw 5147 (Bw-CLL-Lib). Enrichment of Bw-CLL-Lib cells displaying membrane proteins of interest was performed via fluorescence activated cell sorting. The unselected Bw-CLL-Lib pool was blocked with recombinant human Fc followed by staining with 1:200 diluted post-alloHCT patient sera and by secondary staining with pooled Alexa Fluor 647 labeled goat-anti-human-lambda and -anti-kappa light chain specific antibodies. Bw-CLL-Lib cells positively binding to serum antibodies were collected and re-grown in culture to 1×106 cells. A second round of enrichment was performed, after which the Bw-CLL-Lib cells were placed in limiting dilution culture. Individual clones were screened for serum reactivity and the retroviral inserts in reactive Bw-CLL-Lib clones were rescued via PCR and sequenced. Proteins of interest were re-expressed in Bw 5147 cells and used to confirm reactivity of the patient serum with specific cell surface proteins. Results: The Bw-CLL-Lib cell pool was screened separately with serum from ten patients with CLL post unrelated donor alloHCT. Serum from three patients enriched positively binding Bw-CLL-Lib clones. Thus far, we have successfully identified serum antibodies to a membrane proximal epitope on a therapeutically relevant CLL cell surface protein. Conclusions: Here we demonstrate a methodology for identifying targets of anti-tumor antibodies in serum from patients after alloHCT. This technique yields a high degree of successful identification of antibody reactivity with cell surface proteins in post alloHCT serum samples. When combined with post-alloHCT antibody Fab phage display (Baskar et al., Blood 114, 4494–4502, 2009) this methodology forms a complete drug and target discovery platform for the generation of tumor specific mAbs derived from alloHCT patients. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: Ex-vivo CD34+ selected allogeneic hematopoietic cell transplantation (alloHCT) after myeloablative conditioning (MAC) has been successfully utilized in the treatment of hematologic malignancies, with high rates of survival and a reduced incidence of graft-vs-host disease (GVHD). However, as MAC is associated with higher toxicity than reduced intensity conditioning (RIC), a comprehensive evaluation of toxicities and the effect on survival and non-relapse mortality (NRM) within the first year (yr) after myeloablative allo-HCT is necessary. Methods: Toxicities (≥ grade 3 by CTCAE 4.0) were retrospectively collected on 200 pts within the 1st yr of alloHCT (CD34+ selection with the ClinicMACS® CD34 Reagent System) after MAC from 2006-2012. Individual toxicities were organized into 91 toxicity categories and further into 17 organ-based groups. One toxicity per group per specified time period was used for statistical analyses. Overall survival (OS) and NRM were calculated using Kaplan Meier methods, and Cox regression was used for univariate analysis of risk of toxicities and survival outcomes across patient and treatment characteristics. Results: 200 pts (median age 57, range 19 -73) were included in the study. Indications for HCT were AML/ALL/MDS (n=144, 72%), multiple myeloma (n=30, 15%), other (n=26, 13%). Donors were MRD or MMRD (n=77, 38%), MUD (n=78, 39%) or MMUD (n=45, 23%). Median HCT-comorbidity index (HCT-CI) score was 2 (0-10). MAC was chemotherapy (n=144, 72%) or total body irradiation (TBI, n=56, 28%) based. The follow up period for surviving pts was 12 months. At day 100, 23 pts (11.5%) experienced grade 2-4 acute GVHD, while 6 pts (3%) developed grade 3-4 acute GVHD. The 5 most common grade 〉 3 toxicities, with associated cumulative incidences by day 365, were infection (0.91, 95% CI 0.86-0.94), metabolic (0.91, 0.86-0.94), hematologic (0.87, 0.81-0.91), oral/ gastrointestinal (GI) (0.66, 0.59-0.72), and pulmonary (0.24, 0.18-0.30). At 1 year post alloHCT, OS and progression-free survival (PFS) for the cohort were 75% and 67%, respectively (Fig 1A). The median number of toxicities at day 100 was 6. Pts experiencing 〉6 toxicities at day 100 had the same 1yr OS as pts with 〈 6 toxicities (80%, p=0.92). NRM was 17% at 1 yr (Fig 1B). Univariate analysis of risk factors identified associations with common toxicities occurring in the 1st yr. While no specific factors increased the risk of infection, age and male gender were associated with a decreased risk [HR 0.98 (0.97-1.0), p=0.02, HR 0.6 (0.47-0.78), p=0.002 respectively]. Patients with a high absolute lymphocyte count (ALC) [HR 0.41 (0.26 to 0.63), p= 2500 [HR 3.46 (1.9 to 6.32), p= target [HR 2.79 (1.32 to 5.91), p= 3 [2.45 (1.08 to 5.57), p=0.01] increased the risk of death and NRM [HR 3.09 (1.33 to 7.18), p=0.001, HR 3 (1.03 to 8.7), p=0.02] respectively. Factors such as age, male gender, male donor, disease type, URD, CMV+ donor, TBI, palifermin use, and albumin levels did not impact OS or NRM. Table 1 summarizes individual toxicity groups associated with OS and NRM. Conclusion: In the 1st yr after MAC alloHCT, pts experienced grade 〉 3 hematologic, metabolic, infectious, GI and hepatic complications, which would be expected with MAC. This is consistent with BMT-CTN data indicating CD34+ grafts with MAC seem to be associated with similar 〉3 toxicities as unmanipulated grafts. Further toxicity may be related to methotrexate and calcineurin inhibitors used in conventional transplants. The pts in this analysis still exhibited high OS and PFS with a low rate of acute GVHD. This analysis can contribute to identifying toxicities and methods to mitigate them through patient selection and post alloHCT management. These results are also highly relevant to the ongoing prospective exploration of CD34+ selection in pts with hematologic malignancies in the BMT-CTN 1301 randomized phase 3 trial. Disclosures No relevant conflicts of interest to declare.

Description: Older patients are at increased risk for complications and death following allogeneic hematopoietic cell transplantation (allo-HCT). Traditional transplant-specific prognostic indices such as hematopoietic cell transplant comorbidity index (HCT-CI) may not capture all underlying geriatric vulnerabilities, and in-depth evaluation by a geriatrician prior to transplant may not always be available. We hypothesize that routine pre-transplant assessments by interdisciplinary clinical providers including advanced practice providers, nursing staff, physical therapists, occupational therapists, and dietitians, as well as common laboratory tests, may uncover additional geriatric deficits. Using an institutional database and the electronic medical records of 406 adults age 60 years and older (range 60-78.7) who underwent first allo-HCT for hematological malignancies from 2010 to 2016, we examined the prevalence and the prognostic impact of pre-transplant geriatric deficits identified by interdisciplinary clinical providers including geriatric domains of functional activity, cognition, medication, nutrition, and mobility (Table 1), and by routine laboratory tests. With a median follow-up of 39 months for survivors, the 3-year probability of overall survival (OS) and progression-free survival was 47% (95% CI 42-53) and 40% (95% CI 35-45), respectively. The 2-year cumulative incidence of non-relapse mortality (NRM) was 26% (95% CI 22-29). Among pre-transplant geriatric and laboratory variables, we found that impairment in instrumental activities of daily living (IADL) and pre-transplant ferritin level ≥1200 was independently associated with increased NRM and inferior OS. In the multivariate analysis, HCT-CI ≥3, IADL impairment, ferritin level ≥1200, and Karnofsky Performance Scale (KPS)

Description: Introduction : Myeloablative conditioned (MAC) allogeneic hematopoietic cell transplantation (alloHCT) with ex-vivo CD34+ selection results in favorable disease control and lower incidence of graft-versus-host disease (GVHD) without the need for pharmacologic immunosuppression. However, detailed analyses of post-HCT toxicities with this platform are limited. We compiled all high-grade toxicities in long-term survivors of ex-vivo CD34+ selected alloHCT with the goal of identifying areas of potential toxicity mitigation by improved patient (pt) selection and post-HCT management. Methods: We retrospectively collected all grade ≥ 3 adverse events by CTCAE v.4.0 of 131 adults who underwent a MAC alloHCT with ex-vivo CD34+ selection (CliniMACS® CD34 Reagent System) as GVHD prophylaxis between 2006 - 2012 and who were alive without relapse/progression at 1 year. Individual toxicities were organized into 17 organ-based groups and 1 toxicity per group per specified time period after the 1-year landmark was used for statistical analyses. Cox regression was used to compare the risk of toxicities across pt and treatment characteristics, overall survival (OS) and non-relapse mortality (NRM). Results: We included 97 pts with AML/ALL/MDS (74%), 15 pts with multiple myeloma (11%), and 19 pts with other histologies (15%). Median age was 54 (19-72), and 46 pts were ≥ 60 years old. MAC was chemotherapy- and total body irradiation-based in 71% and 29% of pts, respectively. Median HCT-Comorbidity Index (HCT-CI) was 2 (0-10). Allografts were HLA MRD or MMRD in 52 pts (40%) and MUD in 53 (40%) or MMUD in 26 (20%). The overall incidence of grade 2-4 acute GVHD at day 100 was 10%, and only 4 of 13 pts had grade 3-4 GVHD. The incidence of grade 2-4 late acute GVHD was 14%. Median follow-up of survivors was 36 months post-landmark. During the study period, 29 pts died: 9 (7%) of relapsed disease and 20 (15%) of NRM (Figure 1). At 4 years, OS and progression-free survival (PFS) for the cohort were 77% and 70%, respectively (Figure 2A). A HCT-CI ≥ 3 was associated with poorer OS [HR 2.5 (95% CI: 0.9-6.6), p=0.036] and higher NRM [HR 5.3 (1.2-23.1), p=0.004]. The most common toxicities occurring 1-year post-HCT (N=285) were: infectious (24%), hematologic (20%), metabolic (17%), hepatic (8%), cardiovascular (6%), pulmonary (4%), and other (20%). The median number of toxicities within the first year was 7. Pts with 〉 7 toxicities within the first year had a 4-year OS of 67% versus 86% [HR 3.2 (1.4-7.2), p=0.006] (Figure 2B) and higher NRM [HR 4.8 (1.6 to 14.4)], p=0.005. Having 〉 7 toxicities within the first year correlated with more hematologic [HR 2.77 (1.5-5.2)], p=0.001, infectious [HR 3.6 (1.7-7.4)], p=0.001 and metabolic [HR 3.4 (1.5-7.6)], p=0.004 toxicities. Table 1 shows the toxicity groups whose development was associated with poorer OS and higher NRM. Grade 2-4 GVHD in the first year was associated with worse OS [HR 3.5 (1.7-7.3), p=0.001] and higher NRM [HR 5.9 (2.4-14.3), p= 1000 ng/mL increased the risk of NRM [HR 3.6 (1.3-10.3), p=0.032], whereas albumin 〉 4.0 reduced the risk of NRM [HR 0.4 (0.2-0.9), p=0.03]. Pre-HCT absolute lymphocyte count (ALC) 〉 0.5 K/mcL was associated with improved OS [HR 0.3 (0.1-0.7), p=0.004], decreased risk of NRM [HR 0.3 (0.1-0.8), p=0.015] and a reduced risk of hematologic [HR 0.3 (0.14-0.6), p=0.001], infectious [HR 0.4 (0.2-0.9), p=0.023] and metabolic [HR 0.4 (0.14-0.96), p=0.04] toxicities. Age, gender, disease, HLA match, MAC type, CMV status, busulfan dose, and use of Palifermin were not associated with the risk of toxicities, OS or NRM. Conclusions: One-year survivors of ex-vivo CD34+ selected MAC alloHCT have excellent OS and a toxicity burden comparable to unmanipulated MAC alloHCT based on BMT CTN data. The number and type of toxicities in the first year, HCT-CI, and development of GVHD predict for higher NRM and poorer OS. Pre-HCT ALC and albumin are biomarkers for less toxicity, lower NRM, and improved OS and may contribute to previously validated pre-HCT prognostic tools. These analyses have identified areas of potential investigation to further mitigate post-HCT toxicity and reduce NRM. Moreover, these data may serve as a guide for health providers of pts enrolled on the pivotal Phase III BMT-CTN 1301 PROGRESS II trial of calcineurin inhibitor-free interventions for GVHD prevention. Disclosures No relevant conflicts of interest to declare.

Description: Donor natural killer (NK) cells impart a potent anti-leukemia effect after allogeneic hematopoietic cell transplantation (allo HCT). The killer Ig-like receptors (KIR) play a central role in modulating NK effector function. Chief among them, the inhibitory KIR3DL1 exhibits a high degree of allelic polymorphism. We previously demonstrated that highly expressed KIR3DL1 alleles (KIR3DL1 allele groups *001 and *002) bind preferentially to HLA-Bw4 with I80 to confer a high degree of inhibitory signaling. Similarly, poorly expressed KIR3DL1 alleles (KIR3DL1 allele groups *005 and *007) bind to HLA-Bw4 with T80 to confer a strong inhibitory signal. In a retrospective cohort of 299 patients undergoing allo HCT for AML, we demonstrated that these highly inhibitory donor KIR3DL1/recipient HLA-Bw combinations (KIR3DL1-HIGH) resulted in a greater incidence of recipient relapse when compared to other donor/recipient KIR3DL1/HLA-Bw pairings with low or absent inhibitory signal (KIR3DL1-LOW/NO). (Giglio F et al, ASH Annual Meeting Abstracts, 2012) Here, we evaluated whether it was feasible to prospectively type and use KIR3DL1 allotypes in unrelated allo HCT donor selection, and whether this intervention would result in improved outcomes in patients undergoing transplant for AML and MDS. We performed PCR-SSP based intermediate resolution KIR3DL1 allele typing on all unrelated adult donors evaluated for patients with MDS and AML at our center from 2013 to present as previously described. (Boudreau J et al, PLoS One, 2014) KIR3DL1 status was provided to the treating physicians, who made the final donor selection. A total of 941 prospective allo HCT donors underwent high resolution HLA typing and KIR3DL1 allotyping for 252 patients (median per patient = 4, range 1-12). Among all donors evaluated, 27% were found to be KIR3DL1-HIGH when considering the respective recipient HLA-Bw. Having multiple donors evaluated improved the likelihood of avoiding a KIR3DL1-HIGH donor: Among recipients with one donor evaluated, 27% had only KIR3DL1-HIGH donors available compared to 12% in recipients with 2-3 donors evaluated and 4% for recipients with 〉3 donors evaluated (P 〈 0.0001). Among all evaluated patients, 41% had both KIR3DL1-HIGH and KIR3DL1-LOW/NO donors available, indicating a potential selection based on KIR3DL1 was possible. Among 252 patients evaluated, 115 proceeded to allo HCT (48 with MDS, 67 with AML). The median age at transplant was 62 years (range 3.6-78). Donors were HLA matched in 105 transplants and were single loci mismatched in 10 transplants. Conditioning was myeloablative in 73 (11 with total body irradiation). GVHD prophylaxis was with ex vivo CD34+ selection in 65 patients and with tacrolimus/methotrexate in the remaining patients. The median follow-up in transplanted patients was 13.1 months (range 0.5-43.3 months). On univariate analysis, the 2-year disease-free survival was 64% (95% confidence interval: 54-76%) in those with KIR3DL1-LOW/NO donors versus 39% (22-68%) in recipients with KIR3DL1-HIGH donors (P = 0.05). The incidence of relapse was similar but favored patients with KIR3DL1-LOW/NO donors (26% [15-37%] versus 35% [13-57%], P = 0.5). 2-year overall survival was similar between those with KIR3DL1-LOW/NO versus KIR3DL1-HIGH donors (75% [65-86%] versus 69% [52-91%], P = 0.43). The time from the initiation of a formalized donor search to transplant did not differ between recipients with KIR3DL1-LOW/NO versus KIR3DL1-HIGH donors (median 81 v. 83 days, respectively, P = 0.97). Recipients with KIR3DL1-LOW/NO donors were CIBMTR Transplant Risk Score low = 53, intermediate = 6, and high = 33; whereas recipients of KIR3DL1-HIGH donors were low = 17, intermediate = 2, and high = 4 (P = 0.15). These results indicate that disease severity and transplant urgency did not influence whether a KIR3DL1-LOW/NO donor was able to be selected. In summary, these prospective data on 115 patients from a single center support improved outcomes in patients with AML and MDS undergoing unrelated donor allo HCT using a donor with low or absent KIR3DL1 inhibition. A multi-center, prospective study to evaluate the prospective use of HLA and KIR genotype based selection of URDs for patients undergoing allo HCT for AML is underway (NCT02450708). Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Kernan: Gentium: Research Funding; The National Cancer Institute of the National Institutes of Health: Research Funding.

Description: Introduction: Systemic evaluation of toxicities after allogeneic hematopoietic stem cell transplantation (allo-HCT) has been limited. Ex vivo CD 34+ selection prior to allo-HCT reduces GVHD without increasing relapse, but is usually done in the context of myeloablative conditioning. Comprehensive collection of toxicities is particularly important in older patients (pts) who usually receive a reduced intensity conditioning. Aim: To identify toxicity patterns in older pts and their association with overall survival (OS) and non-relapse mortality (NRM). Methods: A retrospective analysis was performed at Memorial Sloan Kettering Cancer Center (MSKCC) including 200 pts who underwent CD34+ selection allo-HCT using the ClinicMACS® system between 2006-2012. All grade 3-5 toxicities by CTCAE v4.0 were collected and compared between pts ≥ 60 or