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: Key Points Carfilzomib 56 mg/m2 provided a high overall response rate with a remarkable duration of response in patients with R/RMM. Nonhematologic grade 3/4 AEs likely related to carfilzomib treatment included hypertension and heart failure.

Description: Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is the only curative treatment for myelodysplastic syndrome (MDS). Relapse, infections and graft-versus-host disease (GvHD) are the main causes of treatment failure. We compared the outcomes of patients receiving T cell depleted (TCD) grafts at Memorial Sloan-Kettering Cancer Center (MSKCC) with patients receiving unmodified grafts at MD Anderson Cancer Center (MDACC) for advanced MDS (RAEB-1 and 2). Adult patients transplanted between 2001 -2012 were included in this retrospective analysis. All recipients of TCD grafts (N=60) received myeloablative conditioning (MAC) and antithymocyte globulin (ATG) to prevent graft rejection. None of them received post-transplant GvHD prophylaxis. Of the 129 recipients of unmodified grafts, 87 received MAC and 42 reduced intensity conditioning (RIC); GvHD prophylaxis consisted of tacrolimus and mini-dose methotrexate in the majority of patients (N=113). ATG was given to all matched unrelated donor (MUD) recipients. Patients in the unmodified group had more therapy-related MDS (MDS-t), very poor risk cytogenetics by IPSS-R at diagnosis and bone marrow (BM) blast count 〉5% at transplant. Only the TCD group had mismatched donors (Table 1). Univariate analysis identified a lower incidence of grade II-IV acute GvHD in the TCD group with 100-day cumulative incidence (CI) of 13.3% vs. 34.1% in the unmodified group (p=0.031). There was no difference in grade III-IV acute GvHD with a 10% CI in both groups at day-100 (p=0.546). The incidence of chronic GvHD was lower in the TCD group with a CI at 3-yrs of 3.4% vs. 44.3% in the unmodified group (p 〈 0.001). The non-relapse mortality (NRM) in both groups was similar. CIs at day 100, 1yr, and 3 yrs in the TCD group were 8.3%, 20.2% and 32.7% vs. 12.4%, 22.5% and 28.1% in the unmodified group (p=0.628). Relapse was lower in the TCD group, with CI at 1 and 3 yrs of 8.5% and 15.5%, vs. 31.0% and 39.4% in the unmodified group (p=0.002). Since the unmodified recipients had worse disease characteristics, further analyses in patients with good/intermediate risk cytogenetic showed that the relapse incidence was similar between these subgroups, with 3-yr CIs of 7.9% in TCD vs. 18% in unmodified group (p=0.185). The most common causes of death in the TCD group were infections (32%) and relapse (28%), while in the unmodified group it was relapse (55%), GVHD (20%) and infections (13%). Considering the differences in disease characteristics between the groups, multivariate regression models were performed for relapse-free survival (RFS) and overall survival (OS) adjusting for MDS-t, high-risk cytogenetics at diagnosis and high blast count at HSCT. No significant differences were observed between the groups for RFS (HR=1.44, p=0.128) and OS (HR= 1.35, p=0.236) (Table 2). High-risk cytogenetics at diagnosis (very poor risk) was the only significant prognostic factor for RFS (HR=5.32, p

Description: Keywords Allogeneic transplantation; endothelial damage; biomarkers. Background Endothelial damage is associated with severe complications and increased risk of death after allogeneic hematopoietic cell transplantation (AlloHCT). The recently developed Endothelial Activation and Stress Index (EASIX) is a prognostic tool that uses clinical lab values and has been shown to predict non-relapse mortality (NRM) and overall survival (OS) at onset of acute graft versus host disease (aGVHD) in reduced intensity (RIC) alloHCT (Luft, Lancet Haematol 2017). We hypothesized that EASIX may be valuable for more broadly predicting aGVHD, NRM and OS after AlloHCT, beyond time of onset of aGVHD. Design We evaluated 152 adult patients who received an unmodified RIC AlloHCT from a related or unrelated donor with uniform GVHD prophylaxis of sirolimus/tacrolimus and low-dose MTX for treatment of lymphoid malignancies, between April 2008 and May 2017. The EASIX formula (LDH*Creatinine/platelet counts) was calculated at multiple timepoints (pre-HCT, day 30, day 100, onset TMA and aGVHD). For all EASIX assessments post-HCT, a landmark analysis was conducted at the given timepoint A log transformation using base 2 (log2) was applied to all EASIX variables to reduce skew. A one-unit increase in log2 EASIX is associated with a doubling (one-fold increase) of EASIX on the original scale. Kaplan-Meier, cumulative incidence, and cox modeling (cause specific for NRM and aGVHD) were used to evaluate EASIX as it relates to outcomes of interest. Relapse and death or relapse were considered competing risks for NRM and aGVHD respectively. Results The median age at transplant was 54 years (range 23-78), 70% were males, a majority had non-Hodgkin lymphoma (68%), and most had sensitive disease at time of HCT (CR=56%; PR=33%). All patients, except two, received peripheral blood stem cells. Sixty-three patients had an HLA-identical related donor, while the remaining 89 had an unrelated donor transplant (HLA-matched in 75 patients, and HLA-mismatched in 14 patients). HCT-CI was 0 in 49 patients, 1-2 in 41 and ≥ 3 in 62 patients. With a median follow-up in surviving patients of 5.4 years (range, 0.8-10), the 1 and 3 years OS rate was 84.2% (95% CI, 77.3-89.1) and 67.9% (95% CI, 59.6-74.8), respectively. The NRM rate at 1 and 3 years was 7.9% (95% CI, 4.3-12.9) and 16.4% (95% CI, 10.9-22.8), respectively. The 1-year cumulative incidences of grades 1-4, 2-4 and 3-4 aGVHD were 56.6% (95% CI, 48.3-64.1), 42.1% (95% CI, 34.2-49.8) and 7.9% (95% CI, 4.3-12.9), respectively. Post-HCT thrombotic microangiopathy was only observed in 13 patients, representing too few events for EASIX analysis. As expected, HCT-CI was significantly associated with both OS and NRM. Pre-HCT EASIX was significantly associated with increased NRM (HR=1.60 [95% CI, 1.15-2.23], p=0.005) and aGVHD grade 1-4 and 2-4 (HR=1.33 [95% CI, 1.08-1.64], p=0.006 and HR=1.39 [95% CI, 1.10-1.75], p=0.005; respectively), but not OS or grade 3-4 aGVHD (Table 1). EASIX at day 30 and day 100 was significantly associated with both OS and NRM (Figures 1-4). Furthermore, confirming the results of Luft, EASIX calculated at onset of any grade aGVHD was significantly associated with OS (HR=1.34 [1.10-1.63], p=0.004) and NRM (HR=1.47 1.11-1.94], p=0.007). Finally, there was no correlation between HCT-CI and EASIX score. Conclusions We conclude that the EASIX formula, calculated at various timepoints pre and post AlloHCT, is significantly associated with NRM and OS. Pre-HCT EASIX also predicts risk of aGVHD, confirming prior results, EASIX at onset of acute GVHD is a predictor of NRM and OS in adult recipients RIC AlloHCT. EASIX provides an independent and easily accessible tool to predict important AlloHCT outcomes that can be used in addition to HCT-CI to better risk stratify patients. Disclosures Sauter: Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Perales:Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Merck: Other: Personal fees; Takeda: Other: Personal fees; Abbvie: Other: Personal fees; Novartis: Other: Personal fees.

Description: Background Acute graft-versus-host disease (aGVHD) is common after double-unit cord blood transplantation (CBT) with an incidence of grade II-IV aGVHD as high as 55% by day 180 in patients transplanted without ATG. aGVHD is associated with increased morbidity and transplant-related mortality (TRM). Mycophenolate mofetil (MMF) combined with a calcineurin-inhibitor is commonly used to prevent GVHD after CBT. However, unlike the 1 gram (gm) every 8 hours dosing that is now standard in adult donor allografts, MMF dosing in CBT has traditionally been every 12 hours. Our center has increased MMF dose from 1 gm every 12 (q12) to 1 gm every 8 (q8) hours in an effort to reduce severe aGVHD after double-unit CBT. However, the efficacy of this intervention is not established and a theoretical concern is that intensified MMF dosing could result in an increased risk of delayed engraftment or graft failure. Methods We evaluated 171 double-unit CBT recipients (median age 39 years, range 0.9-71) transplanted with either myeloablative (MA, n = 133) or non-myeloablative (NMA, n = 38) conditioning for high-risk hematologic malignancies between 10/2005 and 4/2013. CB units were 4-6/6 HLA-A, -B antigen, -DRB1 allele matched to the recipient (16 6/6, 171 5/6, 155 4/6). All patients received GVHD prophylaxis with intravenous calcineurin-inhibitor (predominantly CSA) and MMF from day -3 without ATG. Prior to 9/2009, 80 patients (47%) received MMF 1 gm IV q12 (and those 12 years and ≥50 kg (or 15 mg/kg/dose if 〉12 years but

Description: Key Points ST2 is independently associated with aGVHD after day 28 in cord blood transplantation recipients. High ST2 levels predict for increased TRM in cord blood transplantation recipients.

Description: Background: Hepatic SOS is a serious complication after allogeneic HSCT. It has been reported elsewhere that in the period between 1979-2007, the overall mean incidence of hepatic SOS was 13.7% (95%CI:13-15). While prophylactic procedures are widely used, there is no uniform consensus on the optimal strategy for the prevention of this disease. Low dose UFH have been used but its benefit in the prevention of SOS and the potential associated risk of serious bleeding complications have not been fully established. Methods: We evaluated 730 adult allograft recipients transplanted 01/2003-12/2013 for hematologic malignancies [401 (55%) acute leukemia/ MDS, 235 (32%) lymphoma, 64 (9%) multiple myeloma, 30 (4%) CML/myeloproliferative disorder]. The majority received myeloablative conditioning (n = 466, 65%) with either total body irradiation-based (n = 243) or busulfan-based (n = 233), followed by non-myeloablative conditioning (n = 143, 19%) and reduced intensity (RIC) (n = 111, 15%). Approximately half of the patients had T-cell depleted (TCD) grafts (402, 55%). All patients had SOS prophylaxis with low dose heparin 100 units/kg given as continuous IV over 24 hours from admission to day +21 or engraftment. Prior allogeneic HSCT, non-malignant or refractory disease, dual prophylaxis with UFH/ursodiol or therapeutic anticoagulation at the time of allograft admission were all excluded. Results: The median age was 51 (range 21-65) years, and 415 (56%) were male. During the 10 year study period only 15 patients developed hepatic SOS with a day 100 incidence of 2% (95%CI:1-3). When evaluated by conditioning intensity, myeloablative and reduced intensity conditioning recipients had a day 100 incidence of 3% (95%CI:2-4) (Figure) whereas none of the NMA recipients developed SOS. Univariate analysis showed that age, HLA-match, previous hepatitis B or C exposure did not influence SOS development (Table). There was a significantly higher incidence of hepatic SOS in recipients of unmodified (3%) versus TCD grafts (1%), p= 0.025. The median time to SOS onset was 29 days (range 5-57). Six patients received supportive care only whereas 9 had defibrotide therapy. Of those, 7 patients developed severe SOS resulting in multi-organ failure (5 supportive care, 2 defibrotide). Four of 15 patients diagnosed with hepatic SOS are alive at last follow up (7 deaths attributed to SOS). Bleeding complications occurred in 26/730 patients (4%) of which only 4 (0.5%) patients had significant grade 3-4 bleeding. The day 100 grade II-IV and III-IV acute liver GVHD is 2% (95%CI:1-3) and 0.5% (95%CI:0.2-1), respectively. The incidence of day 100 TRM was 9% (95%CI:7-11) for the entire cohort of patients. Conclusion: To our knowledge, this is the largest analysis evaluating the use of low dose UFH for the prevention of hepatic SOS. We demonstrated that UFH prophylaxis is associated with a low incidence of hepatic SOS, is well tolerated, and severe bleeding complications are uncommon. Low dose UFH may be consider as a strategy for the prevention of hepatic SOS in selected patients. Further prospective studies comparing UFH to other hepatic SOS prophylaxis methods are warranted. Table. Univariate analysis of variables potentially associated with day 100 SOS. Variable (95% CI) p-value Age (years) 0.745 〈 40 2% (1-6) ≥ 40 2% (1-3) HLA-match 0.857 8/8 2% (1-4) ≤ 7/8 2% (1-5) Graft 0.025 TCD 1% (0.3-2) Unmodified 3% (2-6) Conditioning regimen 0.054 Myeloablative/RIC 3% (2-4) Non-Myeloablative 0 (NA) Myeloblative conditioning type 0.353 Busulfan-based 2% (1-5) TBI-based 3% (2-6) Hepatitis B & C Serologies 0.089 Negative 2% (1-3) Positive 8% (0.4-30) Figure 1. Figure 1. Disclosures Bhatt: Spectrum: Consultancy. Off Label Use: Use of low dose unfractionated heparin for the prevention of hepatic SOS. van den Brink:Boehringer Ingelheim: Consultancy, Other: Advisory board attendee; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria; Merck: Honoraria; Tobira Therapeutics: Other: Advisory board attendee. Giralt:TAKEDA: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding.

Description: Background: A variety of next-generation sequencing methods have been used to investigate the genomic landscape of primary lymphoma patient samples, including whole-genome, whole-exome, and RNA sequencing. In diffuse large B cell lymphoma (DLBCL), sequencing studies identified numerous genomic alterations (GAs) of potential clinical relevance, but the distribution and frequency of GAs have not been precisely determined. Discrepancies in existing data likely arise from variability in types of specimens examined, sequencing technologies employed, and depth of coverage utilized to identify GAs. In this study, we performed comprehensive DNA/RNA sequencing of genes known to be important across the spectrum of hematologic malignancies in order to determine the nature and prevalence of GAs with potential diagnostic, prognostic, or therapeutic implications in a cohort of 112 well-annotated clinical DLBCL cases. Methods: We performed hybridization capture of 405 cancer-related genes and 31 genes commonly rearranged in cancer (FoundationOne Heme) and 265 frequently rearranged genes for RNA-seq applied to ³50ng of DNA and sequenced to high, uniform coverage. Genomic alterations, including short variants (small indels and base substitutions), rearrangements, and copy number alterations, were determined. All captured libraries were sequenced to high depth (Illumina HiSeq), averaging 〉500x for DNA and 〉20,000,000 total pairs for RNA, to enable the sensitive and specific detection of GAs. Significant non-synonomous variants were identified as mutations from the COSMIC database, amplifications of established oncogenes, or homozygous deletions and/or clear loss-of-function mutations of known tumor suppressors. Results: GAs with diagnostic, prognostic, or therapeutic relevance were identified in 96% of cases, with a median of 5 (range 0 to 12) alterations per sample. Figure 1 shows the frequencies of different GAs. De novo DLBCL tended to exhibit fewer GAs (median 4) than relapsed/refractory (median 6) or transformed disease (median 6) (p=0.179; Wilcoxon rank sum). Compared with reported frequencies ranging from 5 to 44%, we detected alterations in CREBBP/EP300 in 21% of cases, with CREBBP mutations preferentially found in germinal-center B cell-like (GCB) compared to non-GCB DLBCL (26% vs. 8%; p=0.02; Pearson's chi-squared). Although previously described only in Burkitt lymphoma, we identified mutations in ID3 (L70P, P98R, Q100P) and TCF3 (N551K) in GCB-phenotype DLBCL cases with aggressive pathologic features and no MYC expression by IHC. Additional novel findings included alterations of genes involved in cellular metabolism in 18% of cases, including one IDH2 R172M mutation and two cases with SDHA L649fs* truncating mutations. We also identified several mutations more commonly found in solid tumors and leukemias, including BRAF V600E and KRAS G13D. With respect to genomic rearrangements, combined DNA/RNA capture and sequencing detected translocations/fusions in MYC, BCL2, and BCL6, which were concordant with cytogenetics/FISH analysis. We also identified rearrangements involving TBXL1XR1-P63, NOTCH2, SOCS1, and ETV6. Copy number alterations were detected in 26 different genes, including amplifications of CD274/PDCD1LG2 (PD-L1/PD-L2) (n=4) that were restricted to non-GCB cases. Alterations in TP53 were more frequently observed in transformed (42%) and relapsed/refractory (26%) compared to de novo DLBCL (12%; p=0.007; Pearson's chi-squared). TP53 mutations predicted for lack of response to chemotherapy, with chemo-refractory disease occurring in 48% of TP53-mutant patients compared to 10% of patients with intact TP53 (p=0.0004; Fisher's exact). Truncating mutations or deletions of RB1, albeit rare (5% of cases), were the most significant negative prognostic factor and were associated with therapeutic resistance and poor overall survival. Conclusions: Our results demonstrate the utility of comprehensive combined DNA/RNA next-generation sequencing as a promising method to identify clinically relevant GAs in clinical lymphoma specimens. This streamlined approach has the potential to combine multiple molecular and cytogenetic tests into a single platform. Future efforts will be directed at incorporating this approach both retrospectively and prospectively into clinical trials to identify predictive biomarkers to guide therapeutic decisions. Figure 1 Figure 1. Disclosures Intlekofer: Foundation Medicine, Inc: Consultancy. Levine:Foundation Medicine, Inc: Consultancy. Zelenetz:Foundation Medicine, Inc: Consultancy. Dogan:Foundation Medicine, Inc: Consultancy. Palomba:Foundation Medicine, Inc: Consultancy. van den Brink:Foundation Medicine, Inc: Consultancy. Brennan:Foundation Medicine, Inc: Employment. Young:Foundation Medicine, Inc: Employment. He:Foundation Medicine: Employment. Nahas:Foundation Medicine, Inc: Employment. Yelensky:Foundation Medicine, Inc: Employment. Otto:Foundation Medicine, Inc: Employment. Lipson:Foundation Medicine, Inc: Employment. Stephens:Foundation Medicine, Inc: Employment. Miller:Foundation Medicine, Inc: Employment. Younes:Foundation Medicine, Inc: Consultancy.

Description: Background The efficacy and toxicity of induction regimens for acute lymphoblastic leukemia (ALL) are affected by numerous patient and regimen specific variables including age, performance status, cytogenetics, comorbidities, and the selection and dosing of chemotherapeutic agents. Notably, the incidence of leukemia and the ability to achieve remission have been shown to be affected by obesity.1,2 Although there is a lack of data in obese adults with ALL, previous studies have confirmed the poor prognostic implications of obesity in pediatric patients.3 Current practice with regard to chemotherapy dosing in obese patients is dependent on the American Society of Clinical Oncology (ASCO) guidelines, which recommend that chemotherapy should be dosed on actual body weight, regardless of obesity status.4 With the lack of data in obese adults with ALL, it has been postulated that empirically reducing chemotherapy doses may worsen their prognosis. This provided the rationale for this investigation into the effect of obesity on the efficacy and toxicity of induction chemotherapy in adults with ALL. Methods The primary objective of this study was to evaluate complete remission (CR) rate to initial induction chemotherapy of obese patients (defined as actual body weight (ABW) 〉 130% of ideal body weight (IBW)), compared to that of non-obese patients. Secondary objectives included overall survival (OS), relapse free survival (RFS), time to platelet and absolute neutrophil count (ANC) recovery, and grade 3/4 non-hematologic toxicities as graded by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). OS and RFS were estimated by the Kaplan-Meier method, with differences across groups accessed via the logrank test. The incidence of CR was estimated by the cumulative incidence method for competing risks, with differences across groups accessed via Gray's test. Death was considered a competing risk for CR. This retrospective chart review included patients with ALL who received initial induction chemotherapy between January 1, 2003, and December 31, 2013, at Memorial Sloan Kettering Cancer Center (MSKCC). Patients included were 〉 18 years old, newly diagnosed with ALL who were chemotherapy-naïve for treatment of ALL. Results Seventy-two patients were identified during the specified period with a median age at diagnosis for all patients of 46 years (18-86). Patients were primarily excluded as chemotherapy was initiated prior to establishing care with MSKCC. A majority of patients received multi-agent chemotherapy with ALL2, L-20, NY-II, ECOG2993, and CALGB 10403 with a smaller subset of patients of older age or poor performance status treated with vincristine and steroids. Twenty-three patients were identified as being obese with a median of 154% of their IBW. The median % of IBW among the non-obese patients (49 patients) was 115%. All patients received chemotherapy based on body surface area (BSA) calculated on total body weight. All patients in the obese group and 96% of non-obese patients experienced at least one grade 3 or 4 non-hematologic toxicity. Time to ANC recovery (26 days vs. 31 days, for obese and non-obese patients respectively) and platelet recovery (29 days vs. 35 days, respectively) were not different between groups. There was no difference in the cumulative incidence of CR among obese and non-obese patients (p=0.477), with a 1 year incidence of 96% in both groups. RFS was similar among obese and non-obese patients (p=0.203, 36.4% and 52.9% respectively at 3 years). Similarly, there was no significant difference in OS between obese and non-obese patients (p=0.161, 45.5% and 57.1% respectively at 3 years). Univariate analyses demonstrated that there was no significant effect of intensity of regimen utilized or baseline cytogenetics on relapse free survival or overall survival. Conclusion The findings of this retrospective chart review are consistent with current ASCO guidelines for dosing in obese patients. As there were no differences noted in efficacy or safety between obese and non-obese patients in our study, it remains appropriate to continue dosing obese patients based on actual body weight. Further prospective evaluations are necessary to confirm these findings. References Pulte et al. PloS ONE 2014; 9: e85554. Castillo JJ et al. Leuk Res 2012; 36:868-875. Butturini AM et al. Journ Clin Onc 2007; 25(15):2063-2069. Griggs JJ et al. J Clin Oncol 2012; 30(13): 1553-61. 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.