ALBERT

Description: 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

Description: Background: Disease relapse following allogeneic stem-cell transplantation remains unacceptably high and there is an urgent need for new therapies that decrease relapse rates and improve survival post-transplant. Natural killer (NK) cells have potent antitumor effects, particularly those expended with mb-IL21 from peripheral blood. Preliminary data from a phase-1 dose-escalation study of up to 1x108 NK cells/Kg/dose and multiple dosing yielded promising results and a favorable safety profile (Ciurea SO.Blood.2017;130:18657). This report presents long-term follow-up from a phase-1/2 clinical trial in patients with high-risk myeloid malignancies (AML/MDS/CML) (clinicaltrials.gov NCT01904136) and a comparison with CIBMTR controls. Methods: Patients received conditioning with fludarabine 160 mg/m2, melphalan 140 mg/m2 and 2GyTBI, post-transplant cyclophosphamide-based GVHD prophylaxis and bone marrow graft from a haploidentical donor. Ex vivo expanded NK cells were generated from peripheral blood mononuclear cells of the same donor with a K562 feeder cells expressing mb-IL21 and 41BB and infused fresh on Day-2, and cryopreserved on Day+7 and +28 (up to Day+90). 1x108/Kg/dose was chosen for the phase 2 trial. An independent matched-pair analysis was done using controls from the CIBMTR database stratified by conditioning intensity. Results: 24/26 patients treated to date were evaluable (one short follow-up and one excluded as ineligible). 80% (19/24) of patients received all 3 doses of NK cells. The median age was 45 years (range 18-59), median follow-up was 43.6 months (range 15.1-60.9). Thirteen patients (54%) were females. 5 patients had donor-specific anti-HLA antibodies (DSA). The median HCT-CI was 2 (range 0-8), 12 patients (50%) had HCT-CI〉3. 17 patients (72%) had AML/MDS and 7 (28%) advanced CML. Of AML/MDS patients, 10 (59%) had high-risk cytogenetics, 7 (41%) had measurable residual disease, 9 (53%) had intermediate/adverse-risk ELN2017 and 5 (29.4%) had primary induction failure. No infusion reactions or significant adverse events were observed to date. All patients (100%) achieved engraftment after a median of 19 days (range 14-42). The cumulative incidence (CI) of grade 2-4 aGVHD was 29.2% at Day100 and 41.7% at 1-year post-transplant. Only one patient developed severe grade 3-4 aGVHD and one patient had extensive cGVHD. Only one patient relapsed (a patient with DSA who did not receive desensitization prior to transplantation), 1-year CI of relapse was 5.9%. The CI of TRM at 1-year for patients without DSA was 21%. The median overall survival and progression-free survival (PFS) were not reached. The 1-year and 3-year PFS for all patients and patients without DSA was 70.8% and 66.1%, and 79% and 72.9% for patients without DSA, respectively (Figure 1). One-year and 3-years GRFS for all patients and patients without DSA was 70.8% and 66.1%, and 79% and 72.9%, respectively. An independent matched-pair analysis (at least 1:1) was conducted by CIBMTR after the first 18 patients treated on study in 07/2018 with RIC (N=57) or MAC (N=61) controls. The relapse was 1/18 vs 25/57 for RIC (p=0.037) and 15/61 for MAC (p=0.07), while the 1-year PFS was 82% vs 49% for RIC and 64% for MAC (p=0.21) (Figure 1). Updated results of this analysis will be presented at the meeting. Conclusions: Results from this long-term follow-up analysis confirm very low relapse rate and excellent GRFS after haploSCT for patients treated with high-doses of NK cells expanded with mbIL21 stimulation. A prospective multi-center phase 2 BMTCTN study will evaluate the safetly and efficacy of high doses of NK cells for the prevention of relapse in patents with AML/MDS receiving haploSCT. Figure 1 Disclosures Ciurea: Miltenyi: Research Funding; Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder; MolMed: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees. Bashir:Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; StemLine: Research Funding; Acrotech: Research Funding; Celgene: Research Funding; Imbrium: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Pasquini:Novartis: Research Funding; Kite Pharmaceuticals: Research Funding; BMS: Research Funding; Medigene: Consultancy; Amgen: Consultancy; Pfizer: Consultancy. Lee:Kiadis Pharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

Description: The significance of conditioning regimen intensity on the outcomes of T-cell replete HLA-haploidentical transplants is not known. This study compared outcomes of commonly used myeloablative (MAC) to reduced intensity (RIC) conditioning regimens in 1325 such transplants (AML; n=818; ALL; n=286 and MDS; n=221) in the US between 2008 and 2016. The median age of the study population was 54 years (18 - 70). Most patients (80%) with AML and ALL were in first or subsequent remission; 83% of those with MDS had refractory anemia with excess blasts at transplantation. Fifty-one percent of patients with AML and ALL had intermediate disease risk index (DRI). In contrast, 50% of patients with MDS had high or very high DRI. Patients received MAC (n=526; 40%) or RIC (n=799; 60%) transplant conditioning regimens and a uniform graft-versus-host disease (GVHD) prophylaxis: post-transplant cyclophosphamide, calcineurin inhibitor and mycophenolate. Approximately 50% of patients reported a HCT-CI score of 0-2 in MAC and RIC groups. Sixty-six percent of MAC and 42% of RIC recipients received peripheral blood grafts. Total body irradiation (TBI) + fludarabine (TBI/Flu; 33%) and busulfan with cyclophosphamide with/without Flu (Bu/Cy ± Flu; 36%) were the predominant MAC regimens. Other MAC regimens included TBI/Cy or other agents (10%), Flu/Bu4 (13%), melphalan (140 mg/m2) + Flu ± thiotepa (Flu/Mel ± TT; 9%). TBI (200cGy)/Cy/Flu (84%) was the predominant RIC regimen. Other RIC regimens included TBI 200cGy + Bu or Mel + Flu (7%), Flu/Bu2 (1%) and Flu/Mel (100mg/m2) ± TT (5mg/kg) (8%). The primary endpoint was disease-free survival (relapse or death). Cox regression models were built to study the effect of conditioning regimens on transplant outcomes after adjusting for other factors significantly associated with outcomes. Differences in transplant-outcomes were observed between ages 18-54 years and 55-70 years. The effect of age was further tested within the 18-54 and 55-70 age groups and there were no differences in outcome. In patients aged 18-54 years (n=689), 55% received MAC and 54% received RIC regimens. In patients aged 55-70 years (n=636), 22% received MAC and 78% received RIC regimens. Table 1 shows the effect (hazard ratio; HR) of conditioning regimen intensity in the two age groups adjusted for HCT-CI, recipient CMV serostatus, disease, DRI and graft type and the 2-year probabilities for the outcomes of interest. In patients aged 18-54 years who were equally likely to receive MAC or RIC regimens, relapse risks were higher after RIC regimens that resulted in lower disease-free survival. There were no differences in non-relapse mortality (NRM) or overall survival by conditioning regimen intensity. In patients aged 55-70 years who were more likely to receive RIC regimen, NRM was lower after RIC but without an advantage for relapse, disease-free or overall survival. Figure 1A and 1B show the 2-year probability of disease-free survival by conditioning regimen intensity in patients aged 18-54 and 55-70 years, respectively. Consistent with the main analysis, a subset analysis limited to AML also confirmed higher relapse (HR 1.43, p=0.03) and lower disease-free survival (HR 1.38, p=0.02) after RIC regimens in patients aged 18-54 years but not in patients aged 55-70 years. Acute GVHD (HR 1.01, p=0.94) and chronic GVHD (HR 0.82, p=0.14) did not differ by conditioning regimen intensity. Table 2 compares the effect of TBI- and non-TBI containing MAC and RIC regimens adjusted for age, HCT-CI, recipient CMV serostatus, disease, DRI and graft type. NRM risks were higher after RIC non-TBI compared to RIC TBI regimens. The predominant RIC non-TBI regimen was Flu/Mel (100mg/m2) ± TT (5mg/kg). In conclusion, a MAC regimen offers higher disease-free survival for those aged 18-54 years and can tolerate MAC regimens. For patients who are unable to tolerate MAC regimens, regardless of their age, TBI200 cGy/Cy/Flu is preferred to Flu/Mel ± TT to minimize NRM risks. Disclosures Shah: Juno Pharmaceuticals: Honoraria; Lentigen Technology: Research Funding; Exelexis: Equity Ownership; Geron: Equity Ownership; Miltenyi: Other: Travel funding, Research Funding; Oncosec: Equity Ownership. Brunstein:Gamidacell: Research Funding. Champlin:Otsuka: Research Funding; Sanofi: Research Funding. Hamadani:Celgene Corporation: Consultancy; Merck: Research Funding; Janssen: Consultancy; ADC Therapeutics: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Cellerant: Consultancy; Takeda: Research Funding; Ostuka: Research Funding; MedImmune: Consultancy, Research Funding. McGuirk:Gamida Cell: Research Funding; Kite Pharma: Honoraria, Other: travel accommodations, expenses, speaker ; Fresenius Biotech: Research Funding; Pluristem Ltd: Research Funding; Bellicum Pharmaceuticals: Research Funding; Astellas Pharma: Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Other: speaker, Research Funding. Vasu:Boehringer Ingelheim Inc: Membership on an entity's Board of Directors or advisory committees. Waller:Pharmacyclics: Other: Travel Expenses, EHA, Research Funding; Cambium Medical Technologies: Consultancy, Equity Ownership; Celldex: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kalytera: Consultancy.

Description: T cell-replete haploidentical donor transplants (HAPLO-HCT) using post-transplant cyclophosphamide for control of alloreactivity is now being increasingly utilized. HAPLO-HCTs were originally performed using BM grafts. However, recently, a few single center studies have reported good outcomes using G-CSF mobilized PBSC grafts for HAPLO-HCT. No prospective randomized comparisons of BM to PBSC grafts for HAPLO-HCT have been performed. Therefore, we analyzed outcomes for 687 adults (496 BM, 191 PBSC) who received HAPLO-HCT for hematologic malignancies using post-transplant cyclophosphamide + mycophenolate + calcineurin inhibitor for GVHD prophylaxis between 2009 and 2014 in the United States. The primary outcome was overall survival. The characteristics of recipients of BM and PBSC were similar except BM recipients were older, more likely to have a performance score ≥90, HCT-CI index ≤2, be CMV seronegative, have a lymphoid malignancy and receive reduced-intensity conditioning. Most PBSC transplants occurred between 2012 and 2014. The median follow-up was 35 and 20 months for recipients of BM and PBSC grafts, respectively. Cox regression models were built to study the effect of graft type adjusted for other significant factors on overall mortality, non-relapse mortality, relapse and graft-versus-host disease (GVHD) and outcomes censored at 2-years to accommodate differential follow-up between treatment groups (Table 1). After adjusting for age, CMV serostatus, disease risk index (disease type/disease status for myeloid and lymphoid malignancy and cytogenetic risk for acute leukemia and myelodysplastic syndrome) and transplant conditioning regimen there were no significant differences in risks for overall mortality (HR 1.00, p= 0.98; 2-year overall survival: 54% and 57%) or non-relapse mortality (HR 0.92, p=0.74; 2-year non-relapse mortality: 17% and 16%) after transplantation of BM compared to PBSC, respectively. However, relapse risks were higher after transplantation of BM compared to PBSC (HR 1.49, p=0.009; 2-year relapse: 45% and 28%). Subset analyses explored the effect of graft type separately for myeloablative and reduced intensity conditioning regimen adjusting for age, CMV serostatus and disease risk index. Consistent with the main analysis there were no differences in overall or non-relapse mortality risks and relapse risks were higher with BM compared to PBSC with myeloablative regimens (Table 1). Although this may in part be explained by lower chronic GVHD risks with transplantation of BM grafts, chronic GVHD was not significantly predictive of relapse risk when modeled as a time-dependent covariate (HR= 0.73, p=0.49). Grade II-IV acute GVHD risks (HR 0.45, p

Description: Introduction Allogeneic hematopoietic cell transplantation (HCT) remains the sole curative therapy for patients with juvenile myelomonocytic leukemia (JMML) leading to a 5-year disease-free survival of ~50%. Whether donor NK cell determinants (e.g., KIR mismatch, KIR A/B genotype) correlate with relapse and survival are unknown. We previously demonstrated that JMML stem cells, defined as Lin-CD34+CD38-, express ligands for NKG2D, NKp30, and NKp44 at levels equal or greater than AML stem cells and that colony-forming units were significantly reduced following incubation of JMML cells with NK cells. Based on these observations we hypothesized that NK cell-dependent mechanisms are a major component of protection from JMML relapse after HCT, and specifically that determinants of greater donor NK cell function (e.g. KIR Bx donors or KIR ligand mismatch) are associated with reduced relapse. We therefore investigated NK cell-related donor and recipient immunogenetics as determinants for outcomes in children transplanted for JMML. Methods: Patients (0 to 〈 19 years) who received a first allogenic HCT from an alternative donor between 2000 to 2017 and had available donor samples from the Center for International Blood and Marrow Transplant Research (CIBMTR) repository were included in the study. Donor KIR typing was performed on pre-HCT samples and results were correlated with clinical data extracted from the CIBMTR database. The primary endpoint was disease free survival (DFS); secondary endpoints included relapse rate (REL), acute graft versus host disease (aGVHD), chronic graft versus host disease (cGVHD), GVHD relapse free survival (GRFS) and overall survival (OS). Patient and transplant related variables included age (〈 2 years vs ≥ 2 years), sex, race, performance score (〈 90 vs 〉90), disease status, graft type (bone marrow, peripheral blood, and cord blood), HLA matching (8/8 vs others), conditioning intensity (myeloablative vs others), use of serotherapy, GVHD prophylaxis (calcineurin inhibitor (CNI)+ methotrexate (Mtx) ± others vs others) and year of HCT (2000-2007 vs 2008-2017). KIR models tested included KIR genotype (AA vs Bx), Donor KIR B content (0-1 vs ≥ 2), centromeric and telomeric region score (AA vs AB vs BB), donor KIR B content score (best, better, neutral), KIR composite score (2 vs 3 vs 4), activating KIR content, presence of activating KIR DS4, ligand-ligand (L-L) mismatch, KIR ligand (KIR-L) mismatch, and missing ligand. Proportional hazards were checked for all covariates in every model. Univariate analysis was performed for primary and secondary outcomes of interest. Covariates with overall p-value 〈 0.05 and pairwise comparisons with p-value 〈 0.05 were considered significant. L-L and KIR-L mismatch effects were studied for all outcomes in a subgroup of HLA-mismatched donors (high resolution match

Description: Post transplant cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis has allowed haploidentical (Haplo) transplantation to be performed with results similar to that after matched unrelated donor (MUD) transplantation with traditional prophylaxis. The relative value of transplantation with MUD versus Haplo donors when both groups receive PTCy/calcineurin inhibitor/mycophenolate containing GVHD prophylaxis is not known. We compared outcomes after 2036 Haplo and 284 MUD transplantations with PTCy GVHD prophylaxis for acute leukemia or myelodysplastic syndrome in adults between 2011 and 2018. Cox regression models were built to compare outcomes between donor types. Recipients of myeloablative and reduced intensity regimens were analyzed separately. Among recipients of reduced intensity regimens, 2-year graft failure (3% versus 11%), acute grade II-IV GVHD (HR 0.70, p=0.022), acute grade III-IV GVHD (HR 0.41, p=0.016) and non-relapse mortality (HR 0.43, p=0.0008) were lower after MUD compared to Haplo transplantation. Consequently, disease-free (HR 0.74, p=0.008; 55% versus 41%) and overall survival (HR 0.65, p=0.001; 67% versus 54%) were higher after MUD compared to Haplo transplants. Among recipients of myeloablative regimens, day-100 platelet recovery (95% versus 88%) was higher and grade III-IV acute (HR 0.39, p=0.07) and chronic GVHD (HR 0.66, p=0.05) were lower after MUD compared to Haplo transplantation. There were no differences in graft failure, relapse, non-relapse mortality, disease-free and overall survival between donor types with myeloablative conditioning regimens. These data extend and confirm the importance of donor-recipient HLA matching for allogeneic transplantation. A MUD is the preferred donor, especially for transplantations with reduced intensity conditioning regimens.

Description: An HLA-matched sibling has been considered the optimal donor for allogeneic hematopoietic cell transplantation (HSCT). However, several potential transplant recipients may have a haploidentical sibling or an offspring who may also serve as donors. In this study, we sought to determine the optimal alternative related donor (haploidentical sibling or an offspring) as compared to an HLA-matched sibling. The primary objective was comparison of chronic graft-versus-host disease (GVHD). Secondary outcomes included acute GVHD, non-relapse mortality (NRM), relapse, treatment failure (relapse or death, inverse of relapse-free survival) and overall mortality. The study population included 4540 donor-recipient pairs (n=218 haploidentical sibling; n=218 offspring; n=4104 HLA-matched sibling) with acute myeloid (n=3617) and acute lymphoblastic (n=923) leukemia transplanted in 2008 to 2015. There were few offspring (n=87) who donated to patients aged 18-54 years and haploidentical siblings (n=61) who donated to patients aged 55-76 years and were excluded from the analysis. Post-transplant cyclophosphamide (PT-Cy) with calcineurin inhibitor (CNI) and mycophenolate was used for GVHD prophylaxis for all haploidentical HSCTs. HLA-matched siblings received CNI-containing GVHD prophylaxis; CNI with methotrexate was the predominant prophylaxis regimen. Patient age was correlated with donor age and donor-recipient relationship. Bone marrow was the predominant graft for haploidentical HSCTs (64%) and peripheral blood (89%) for HLA-matched sibling HSCTs. Younger patients (age 18-54 years) of were more likely to receive reduced intensity conditioning regimens for haploidentical HSCTs compared to HLA-matched sibling HSCTs (22%). Among older patients, conditioning regimen intensity did not differ by donor type. Exploratory analysis confirmed differences in survival by patient age. Therefore, based on differences in survival by patient age, two age groups were created: 18 - 54 years and 55 - 76 years and within each patient age group, donor-recipient relationship and its effect on transplant outcomes were tested using Cox regression models. In addition to the standard Cox regression model, we also performed a matched-pair analysis. Recipients of haploidentical HSCT (cases; n=436) were matched to HLA-matched siblings (controls; n=1707) on age, disease and disease risk index. 88% of patients aged 18-54 years were matched to 4 controls and 96% of patients aged 55-76 years were matched to 4 controls. The median difference in age between cases and controls were 0.08 (range 0-9.9) years for patients aged 18-54 years and 0.05 (0 - 9.5) years for patients aged 55-76 years. The results of multivariate Cox regression and matched-pair analysis are shown in Tables 1, 2. Among patients aged 18-54 years, chronic GVHD risks were lower after haploidentical sibling compared to HLA-matched sibling HSCT. There were no differences in acute GVHD, NRM, relapse, treatment failure or overall mortality. Among patients aged 55-76 years, acute and chronic GVHD risks were lower after offspring compared to HLA-matched sibling HSCT. But risks for NRM, treatment failure and overall mortality were higher after offspring compared to HLA-matched sibling HSCT. The 2-year probabilities of overall survival, adjusted for disease risk index and sex are shown in Figure 1. In summary, chronic GVHD rates were lower after haploidentical HSCT with PT-Cy containing GVHD prophylaxis regimens compared to HLA-matched sibling HSCT for all patients. Whether this can be attributed solely to the GVHD prophylaxis regimen or in part attributed to use of peripheral blood grafts for HLA-matched sibling HSCT must be studied further in a setting in which PT-Cy containing GVHD prophylaxis is used for HLA-matched sibling HSCT. Despite lower chronic GVHD with haploidentical sibling donor HSCT with PT-Cy, NRM and overall survival did not differ by donor type for patients aged 18-54 years. However, for patients aged 55 - 76 years, despite lower chronic GVHD with offspring donor HSCT with PT-Cy, NRM was higher and overall survival was lower compared to HLA-matched sibling HSCT. Definitive proof of these findings would require a prospective randomized trial. Disclosures Ciceri: GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding. Mohty: Sanofi: Honoraria, Speakers Bureau.

Description: Introduction: Allogeneic hematopoietic cell transplantation (HCT) is curative for myelofibrosis (MF). However, prognosis post HCT is variable. Identifying subsets of patients who can greatly benefit from HCT is important for clinical decision-making and patient counseling. The Dynamic International Prognostic Scoring System (DIPSS) score includes cytogenetic abnormalities provides important prognostic information. Here, we used high-resolution single nucleotide polymorphism (SNP) arrays to characterize chromosomal aberrations in pre-HCT blood samples from patients with MF and evaluated their added value in patient risk stratification for post HCT survival. Methods: We used the Illumina Global Screening Array to detect somatic copy number alterations (SCNAs) sized ≥2Mb (by calculating the log2 R ratio and B allele frequency and leveraging haplotype information) in pre-HCT blood samples (collected 2-4 weeks prior to HCT conditioning regimen administration) from 923 MF patients who underwent HCT between 2000-2016. Clinical data and blood samples were obtained from the Center for International Blood and Marrow Transplant Research. We used Kaplan-Meier survival analysis and multivariable Cox regression to evaluate the prognostic significance of observed SCNAs on survival after HCT. Results: Median age at HCT was 58 years (range=0.7-76). About 58% were males (N=536), 85% received unrelated donor HCT (N=787), 90% received peripheral blood stem cell grafts (N=826), 47% (N=429) received myeloablative conditioning (MAC), 34% (N=312) received HCT within 1 year from diagnosis, and 537 patients (58%) had known DIPSS score at HCT (47% of them were intermediate II or high). A high frequency of SCNAs were noted in MF (N=623; 67.5%), most commonly on chromosome (chr) 9p (N=224, 24%), chr13q (N=104, 11%), and chr20q (N=102, 11%) (Figure 1). Aberrations noted on chromosomal regions harboring the known MF genes (MPL, DNMT3A, TET2, EZH2, JAK2, SRSF2, CALR, ASXL1, U2AF1) accounted for 28% of all detected (40% of the patients), including JAK2 (9p24.1, N=253, 27%), MPL (1p34.2, N=30, 3.3%) and CALR (19p13.13, N=23, 2.5%). Multivariable models including all MF genes (adjusted for DIPSS score, KPS, year of HCT, hemoglobin count, splenectomy, age, sex, time from diagnosis to HCT, and stratified on CMV match, graft type and conditioning regimen) showed an association between SCNAs on TET2 or SRSF2 regions and poor survival (HR for TET2 =2.40, 95% CI=1.33-4.32, p=0.004; and HR for SRSF2= 2.22, 95% CI=1.26-3.89, p=0.006). TET2 region aberrations were associated with an increased risk of transplant-related mortality (TRM) (HR=2.97, 95% CI=1.53-5.78, p=0.001), worse disease-free survival (DFS; HR=2.22, 95% CI=1.33-3.69, p=0.002), but not the risk of relapse (p=0.12). SRSF2 region aberrations were associated with DFS (HR=1.94, 95% CI=1.11-3.37, p=0.02); no statistically significant association was noted with the risk of relapse (p=0.07) or TRM (p=0.44). These associations were predominant in patients receiving reduced intensity (RIC) or non-myeloablative regimens (Figure 2). Further univariate analyses focusing on all frequently affected chromosomes (affecting ≥10 patients) showed poor OS with SCNAs on chr17p (log-rank p

Description: Introduction: Post-transplant cyclophosphamide (PT-Cy) in HLA-haploidentical hematopoietic cell transplantation (Haplo-HCT) results in acceptable engraftment and graft-versus-host disease (GVHD). Results of BMT CTN 1203 that compared matched unrelated donor (MUD) HCT with PT-Cy containing to calcineurin inhibitor (CNI) containing GVHD prophylaxis following reduced intensity conditioning, showed better 1-year GVHD free relapse free survival with PT-Cy. The relative value of a MUD versus a Haplo donor in the context of PT-Cy is not known. In this study we compared outcomes after Haplo- and MUD HCT with PT-Cy containing GVHD prophylaxis. Methods: Eligible patients were aged 〉18 years and received haplo-HCT or MUD HCT for AML, ALL and MDS in the US from 2011-2018. Patients received myeloablative (n=1001) or reduced intensity (n=1398) regimens and were analyzed separately. All recipients of haplo-HCT and reduced intensity conditioning MUD HCT received PT-Cy + CNI + mycophenolate mofetil (MMF) for GVHD prophylaxis. Among recipients of myeloablative conditioning MUD HCT, 55% received PT-Cy + CNI + MMF and 45%, PT-Cy + CNI. Cox regression models were built to compare outcomes between donor types. As PT-Cy containing GVHD prophylaxis for myeloablative conditioning MUD HCT is recent; therefore, outcomes were censored at 1-year. A p-value ≤0.01 was considered significant. Results: Myeloablative conditioning regimen: Age at transplant, sex, performance score, co-morbidity and CMV serostatus did not differ between recipients of haplo- and MUD HCT. Haplo-HCT recipients were less likely to be Caucasian (69% vs. 91%). They were also more likely to have AML (55% vs. 47) and less likely to have MDS (13% vs. 31%). Disease risk index did not differ between treatment groups. The predominant conditioning regimen for haplo-HCT was total body irradiation (TBI) + fludarabine (44%) for Haplo-HCT and for MUD HCT, fludarabine + busulfan ± thiotepa (59%). Engraftment rates did not differ between groups. Results of multivariate analyses are shown in Table 1. Compared to Haplo-HCT, grade II-IV acute GVHD risk was higher after MUD-HCT with PT-Cy + CNI GVHD prophylaxis. There were no differences in grade III-IV acute or chronic GVHD risk between treatment groups. Non-relapse mortality, relapse, disease-free and overall survival did not differ between treatment groups. Reduced intensity conditioning regimen: Age at transplant, sex, performance score, co-morbidity and CMV serostatus did not differ between recipients of haplo- and MUD HCT. Haplo-HCT recipients were less likely to be Caucasian (72% vs. 95%). Haplo-HCT recipients were less likely to have MDS (19% vs. 24%). Disease risk index did not differ between treatment groups. The predominant conditioning regimen was TBI 200 cGy + fludarabine + cyclophosphamide (88%) for Haplo-HCT and for MUD HCT, TBI 200 cGy + fludarabine + cyclophosphamide (37%) and fludarabine + melphalan (33%). Engraftment rates did not differ between groups. Results of multivariate analyses are shown in Table 2. Compared to Haplo-HCT acute and chronic GVHD risks did not differ between treatment groups. However, non-relapse mortality was lower after MUD-HCT which led to higher disease-free and overall survival. Conclusion: In patients who received myeloablative conditioning and PT-Cy + CNI + MMF GVHD prophylaxis, haploidentical related and matched unrelated donors are comparable. However, in patients who received less intense conditioning regimens, disease free and overall survival was higher after MUD HCT compared to Haplo-HCT. Disclosures Arora: Fate Therapeutics: Consultancy; Pharmacyclics: Research Funding; Kadmon: Research Funding; Syndax: Research Funding. Al Malki:Neximmune: Consultancy; Jazz Pharmacuticals, Inc: Consultancy; Rigel Pharma: Consultancy. Brunstein:Magenta: Research Funding; Gamida: Research Funding; Astex: Research Funding; AlloVir: Other: Advisory board. Grunwald:Merck: Consultancy; Agios: Consultancy; Abbvie: Consultancy; Agios: Consultancy; Celgene: Consultancy; Incyte: Consultancy, Research Funding; Premier: Consultancy; Amgen: Consultancy; Amgen: Consultancy; Merck: Consultancy; Cardinal Health: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Cardinal Health: Consultancy; Merck: Consultancy; Cardinal Health: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Abbvie: Consultancy; Incyte: Consultancy, Research Funding; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Premier: Consultancy; Trovagene: Consultancy; Astellas: Consultancy; Astellas: Consultancy; Premier: Consultancy; Trovagene: Consultancy; Trovagene: Consultancy; Genentech/Roche: Research Funding; Janssen: Research Funding; Genentech/Roche: Research Funding; Genentech/Roche: Research Funding; Forma Therapeutics: Research Funding; Merck: Research Funding; Janssen: Research Funding; Forma Therapeutics: Research Funding; Forma Therapeutics: Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Pfizer: Consultancy. Kekre:Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. McGuirk:Juno Therapeutics: Consultancy, Honoraria, Research Funding; Allo Vir: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding; Kite Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pluristem Ltd: Research Funding; Gamida Cell: Research Funding; Bellicum Pharmaceutical: Research Funding. Mehta:CSL Behring: Research Funding; Incyte: Research Funding; Kadmon: Research Funding. Modi:MorphoSys: Membership on an entity's Board of Directors or advisory committees. Reshef:Gilead: Consultancy, Honoraria, Other: Travel support, Research Funding; Immatics: Research Funding; Celgene: Consultancy; Takeda: Research Funding; Monsanto: Consultancy; Incyte: Research Funding; Shire: Research Funding; Novartis: Honoraria; Pharmacyclics: Research Funding; Magenta: Consultancy; Bristol-Myers Squibb: Research Funding; Kiadis: Research Funding; Bluebird: Research Funding; Atara: Consultancy, Research Funding. Schroeder:Partners Therapeutics: Other; Gilead Sciences Inc: Other; Pfizer: Other; Genentech Inc: Research Funding; Incyte Corporation: Other: served on advisory boards and received honoraria or consultant fees, Research Funding; Novo Nordisk: Other; Merck: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; GSK: Other; FlatIron Inc: Other; Dova Pharmaceuticals: Other; Astellas: Other; Janssen: Research Funding; Genzyme Sanofi: Other: served on advisory boards and received honoraria or consultant fees, Research Funding; PBD Incorporated: Research Funding; Celgene: Research Funding; Amgen: Other: served on advisory boards and received honoraria or consultant fees, Research Funding; Seattle Genetics: Research Funding; Fortis: Research Funding; Cellect Inc: Research Funding. Soiffer:alexion: Consultancy; Rheos Therapeutics: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; VOR Biopharma: Consultancy; Gilead: Consultancy; Be the Match/ National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees; Precision Bioscience: Consultancy; Mana Therapeutics: Consultancy; Cugene: Consultancy; Juno: Membership on an entity's Board of Directors or advisory committees. Waller:Verastem Oncology, Inc: Consultancy, Research Funding.