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Key Points Ofatumumab with glucocorticoid therapy for cGVHD resulted in 62.5% ORR at 6 months and 53% FFS at 12 months.Safety was observed with ofatumumab plus glucocorticoid for initial therapy., Visual Abstract, Standard initial therapy of chronic graft vs. host disease (cGVHD) with glucocorticoids results in suboptimal response. Safety and feasibility of therapy with ofatumumab (1000 mg IV on days 0 and 14) and prednisone (1 mg/kg/day) was previously established in our phase I trial (n = 12). We now report the mature results of the phase II expansion of the trial (n = 38). The overall NIH severity of cGVHD was moderate (63%) or severe (37%) with 74% of all patients affected by the overlap subtype of cGVHD and 82% by prior acute cGVHD. The observed 6 month clinician-reported and 2014 NIH-defined overall response rates (ORR = complete + partial response [CR/PR]) of 62.5% (1-sided lower 90% confidence interval=51.5%) were not superior to pre-specified historic benchmark of 60%. Post-hoc comparison of 6 month NIH response suggested benefit compared to more contemporaneous NIH-based benchmark of 48.6% with frontline sirolimus/prednisone (CTN 0801 trial). Baseline cGVHD features (organ involvement, severity, initial immune suppression agents) were not significantly associated with 6-month ORR. The median time to initiation of second-line therapy was 5.4 months (range 0.9-15.1 months). Failure-free survival (FFS) was 64.2% (95% CI 46.5-77.4%) at 6 months and 53.1% (95% CI 35.8-67.7%) at 12 months, whereas FFS with CR/PR at 12 months of 33.5% exceeded a benchmark of 15% in post-hoc analysis, and was associated with greater success in steroid discontinuation by 24 months (odds ratio 8 (95% CI 1.21-52.7). This single-arm phase II trial demonstrated acceptable safety and potential efficacy of the upfront use of ofatumumab in combination with prednisone in cGVHD. This trial was registered at www.clinicaltrials.gov as #NCT01680965.

Post-transplantation cyclophosphamide (PTCy) is being increasingly used for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic cell transplantation (allo-HCT) across various donor types. However, immune reconstitution and infection incidence after PTCy-based versus conventional GVHD prophylaxis has not been well studied. We evaluated the infection density and immune reconstitution (ie, absolute CD4+ T cell, CD8+ T cell, natural killer cell, and B cell counts) at 3 months, 6 months, and 1 year post-HCT in 583 consecutive adult patients undergoing allo-HCT with myeloablative (n = 223) or reduced-intensity (n = 360) conditioning between 2012 and 2018. Haploidentical (haplo; n = 75) and 8/8 HLA-matched unrelated (MUD; n = 08) donor types were included. GVHD prophylaxis was PTCy-based in all haplo (n = 75) and in 38 MUD allo-HCT recipients, whereas tacrolimus/methotrexate (Tac/MTX) was used in 89 and Tac/Sirolimus (Tac/Sir) was used in 381 MUD allo-HCT recipients. Clinical outcomes, including infections, nonrelapse mortality (NRM), relapse, and overall survival (OS), were compared across the 4 treatment groups. The recovery of absolute total CD4+ T-cell count was significantly lower in the haplo-PTCy and MUD-PTCy groups compared with the Tac/MTX and Tac/Sir groups throughout 1 year post-allo-HCT (P = .025). In contrast, CD19+ B-cell counts at 6 months and thereafter were higher in the haplo-PTCy and MUD-PTCy groups compared with the Tac/MTX and Tac/Sir groups (P

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy for myelodysplastic syndromes (MDS), although it is infrequently offered to older patients. The relative benefits of HCT over non-HCT therapy in older patients with higher-risk MDS have not been defined. METHODS We conducted a multicenter biologic assignment trial comparing reduced-intensity HCT to hypomethylating therapy or best supportive care in subjects 50-75 years of age with intermediate-2 or high-risk de novo MDS. The primary outcome was overall survival probability at 3 years. Between January 2014 and November 2018, we enrolled 384 subjects at 34 centers. Subjects were assigned to the Donor or No-Donor arms according to the availability of a matched donor within 90 days of study registration. RESULTS The median follow-up time for surviving subjects was 34.2 months (range: 2.3-38 months) in the Donor arm and 26.9 months (range: 2.4-37.2 months) in the No-Donor arm. In an intention-to-treat analysis, the adjusted overall survival rate at 3 years in the Donor arm was 47.9% (95% CI, 41.3 to 54.1) compared with 26.6% (95% CI, 18.4 to 35.6) in the No-Donor arm ( P = .0001) with an absolute difference of 21.3% (95% CI, 10.2 to 31.8). Leukemia-free survival at 3 years was greater in the Donor arm (35.8%; 95% CI, 29.8 to 41.8) compared with the No-Donor arm (20.6%; 95% CI, 13.3 to 29.1; P = .003). The survival benefit was seen across all subgroups examined. CONCLUSION We observed a significant survival advantage in older subjects with higher-risk MDS who have a matched donor identified and underwent reduced-intensity HCT, when compared with those without a donor. HCT should be included as an integral part of MDS management plans in fit older adults with higher-risk MDS.

Immunomodulatory properties of histone deacetylase inhibitors represent a reasonable approach for acute graft-versus-host disease (aGVHD) prevention. We report a phase 2 trial evaluating panobinostat (PANO) administered over 26 weeks, starting on day −5 (5 mg orally 3 times a week) with tacrolimus initiated on day −3 plus sirolimus on day −1, with a median patient age of 58 years (range, 19-72 years) (n = 38). Donor source consisted of HLA 8/8–matched donors, related (n = 13) or unrelated (n = 25), using granulocyte colony-stimulating factor–stimulated peripheral blood stem cells. Myeloablative (n = 18) or reduced-intensity (n = 20) conditioning regimens were used for patients with acute myeloid leukemia (n = 17), myelodysplastic syndrome (n = 13), or other malignancies (n = 8). The cumulative incidence of aGVHD II-IV by day 100 was 18.4% (90% confidence interval [CI], 9.4% to 29.9%). Cumulative incidence of chronic GVHD at 1 year was 31.6% (90% CI, 19.5% to 44.3%). Adverse events related to PANO were thrombocytopenia (n = 5), leukopenia (n = 6), gastrointestinal toxicity (n = 3), rash (n = 4), renal failure/peripheral edema (n = 1), and periorbital edema (n = 1). At 1 year, overall survival was 89.5% (90% CI, 81.6% to 98.0%), relapse-free survival was 78.9% (90% CI, 68.8% to 90.6%), nonrelapse mortality was 2.6% (90% CI, 0.3% to 9.9%), and GVHD relapse-free survival was 60.5% (90% CI, 48.8% to 75.1%). PANO hits histone 3 as early as day 15 in CD8, CD4 and T regs. In conclusion, PANO combination met the primary study end point for aGVHD prevention and warrants further testing. This trial was registered at www.clinicaltrials.gov as #NCT02588339.

Background Fatigue is a prominent quality of life concern among recipients of hematopoietic cell transplantation (HCT). Purpose The present study investigated whether objectively measured sleep efficiency and sedentary behavior are related to greater reports of fatigue. Methods Eighty-two allogeneic HCT recipients who were 1–5 years post-transplant and returning for a follow-up visit participated (age M = 56, 52% female, 56% leukemia). They wore an actigraph assessing sleep efficiency and sedentary behavior for one week and completed an electronic log assessing fatigue each evening during the same period. Results Twenty-six percent of patients reported clinically meaningful fatigue. On average, fatigue was mild (M = 2.5 on 0–10 scale, SD = 2.0), sleep was disturbed (sleep efficiency M = 78.9%, SD = 8.9), and patients spent the majority of time in sedentary (M = 55.4%, SD = 10.2) or light (M = 35.9%, SD = 8.6) activity. Multilevel model analysis of between-person differences indicated that patients who experienced less efficient sleep the previous evening provided greater evening reports of average fatigue, b = –0.06, 95% CI (–0.11, –0.01). Similarly, within-person analyses indicated that when patients experienced less efficient sleep the previous evening or were more sedentary as compared to their average, they provided greater evening reports of average fatigue, b = –0.02, 95% CI (–0.05, –0.004); b = 4.46, 95% CI (1.95, 6.97), respectively. Conclusions Findings demonstrate that poor sleep and daily sedentary behavior are related to evening reports of fatigue and should be considered modifiable targets for intervention.

Purpose:One of the challenges of adoptive T-cell therapy is the development of immune-mediated toxicities including cytokine release syndrome (CRS) and neurotoxicity (NT). We aimed to identify factors that place patients at high risk of severe toxicity or treatment-related death in a cohort of 75 patients with large B-cell lymphoma treated with a standard of care CD19 targeted CAR T-cell product (axicabtagene ciloleucel).Experimental Design:Serum cytokine and catecholamine levels were measured prior to lymphodepleting chemotherapy, on the day of CAR T infusion and daily thereafter while patients remained hospitalized. Tumor biopsies were taken within 1 month prior to CAR T infusion for evaluation of gene expression.Results:We identified an association between pretreatment levels of IL6 and life-threatening CRS and NT. Because the risk of toxicity was related to pretreatment factors, we hypothesized that the tumor microenvironment (TME) may influence CAR T-cell toxicity. In pretreatment patient tumor biopsies, gene expression of myeloid markers was associated with higher toxicity.Conclusions:These results suggest that a proinflammatory state and an unfavorable TME preemptively put patients at risk for toxicity after CAR T-cell therapy. Tailoring toxicity management strategies to patient risk may reduce morbidity and mortality.

BACKGROUND Quantification of skeletal muscle using computed tomography (CT) is accessible using cancer patients' standard oncologic images. Reduced muscle mass may be related to reduced respiratory muscle strength; however, the impact of this on lung functional parameters is not characterized in adult allogeneic haematopoietic stem cell transplant (alloHCT) recipients. METHODS A consecutive retrospective series (n = 296) of patients who had alloHCT at a comprehensive cancer centre between March 2005 and April 2015 were included. Pre-transplant CT scans were used to quantify skeletal muscle and adipose tissue at the fourth thoracic (T4) and/or third lumbar (L3) level. Tumour and patient characteristics were recorded, including forced expiratory volume in 1 second (FEV1 ) by spirometry. Regression models were created to characterize predictive relationships. RESULTS A total of 296 patients (♂n = 161; ♀n = 135) were included, all of whom had chest CT as part of standard care; a subset of these (n = 215, 72.6%) also had abdominal CT. Diagnoses were non-Hodgkins lymphoma (n = 165), acute myeloid leukaemia (n = 66), Hodgkin's disease (n = 14), acute lymphocytic leukaemia (n = 14), myelodysplastic syndromes (n = 18), and other (n = 19). In multivariable linear regression adjusted for sex (P

There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P < .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P < .001). Long-term relapse was lower with FM (HR = 0.65, P < .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.

We conducted a prospective study of adult allogeneic hematopoietic cell transplantation (HCT) recipients to assess pre- and post-HCT physical function. Baseline measurements included a wrist actigraphy, a 6 min walk test (6MWT), an international physical activity questionnaire (IPAQ), and a Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) as well as serial post-HCT assessments of 6MWT, IPAQ, and FACT-BMT. Forty-seven patients were evaluable for functionality assessments, with a median follow-up of 54.5 months for surviving recipients. No patients demonstrated vigorous or very vigorous activity at any time during monitoring by wrist actigraphy; patients spent a median of 6 h daily sedentary. Self-reported activity via the IPAQ showed 36%, 43%, and 21% of subjects reporting light, moderate, and vigorous activity prior to HCT, respectively. Post-HCT 6MWTs on day +30 demonstrated the greatest association with subsequent survival and non-relapse mortality. A decline in 6MWT distance over time also demonstrated worsened overall survival. This study shows the feasibility of fitness assessments and the ability to risk stratify for subsequent mortality, particularly using the 6MWT on the day +30 single time point assessment and change scores from baseline to day +30 post HCT. These pilot findings suggest important targets for future study.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment option for patients with acute lymphoblastic leukemia (ALL). Both total body irradiation (TBI)-based and chemotherapy only-based myeloablative transplantation conditioning regimens have been applied, but the optimal regimen remains unclear. We performed a systematic review to assess the efficacy of TBI-based versus chemotherapy only-based myeloablative conditioning regimens. We searched PubMed, Embase, and Cochrane databases and meeting abstracts for all studies comparing TBI-based and chemotherapy only-based conditioning regimens in patients who underwent allo-HCT for ALL. Two authors independently reviewed all studies for inclusion and extracted data related to overall survival (OS), progression-free survival (PFS), nonrelapse mortality (NRM), relapse, and acute and chronic graft-versus-host disease (GVHD). Eight studies were included in the final analysis. The overall methodological quality of the included studies was optimal. TBI-based regimens showed evidence of benefit compared with chemotherapy only-based conditioning regimens in terms of relapse (relative risk [RR], 0.82; 95% confidence interval [CI], 0.72 to 0.94; 6 studies, 5091 patients), OS (hazard ratio [HR], 0.76; 95% CI, 0.64 to 0.89; 7 studies, 4727 patients), and PFS (HR, 0.74; 95% CI, 0.63 to 0.85; 7 studies, 4727 patients). The TBI-based regimen did not increase the likelihood of grade II-IV acute GVHD (RR, 1.12; 95% CI, 0.92 to 1.36; 5 studies, 4996 patients) or chronic GVHD (RR, 1.10; 95% CI, 1.00 to 1.21; 5 studies, 4490 patients), or NRM (RR, 0.94; 95% CI, 0.69 to 1.28; 6 studies, 4522 patients). However, TBI-based regimens were associated with an increased risk of grade III-IV acute GVHD (RR, 1.29; 95% CI, 1.01 to 1.63; 3 studies, 3675 patients). A subgroup comparison of patients age ≥16 years showed similar results. This systematic review represents evidence supporting the use of TBI-based conditioning regimen in patients undergoing allo-HCT for ALL who are candidates for myeloablative conditioning, as it offers better OS, PFS, and less relapse with acceptable NRM.

Background: Physical function prior to allogeneic hematopoietic cell transplant (HCT) is associated with survival and may be associated with patient physical activity (PA). Tools to evaluate PA prior to HCT are scarce. We aimed to evaluate the impact of easily obtained patient-report of PA prior to HCT on survival. Methods: HCT recipients between January 1, 2011 and July 5, 2018 and who completed an International Physical Activity Questionnaire Short Form were included. This patient survey captures self-reported activities over the preceding week to determine PA level. Results: We report a retrospective study of 587 adult (age ≥18) HCT recipients. The median age for the cohort was 57.9 years (range 19.9–76.1) with 149 patients (25.4%) age ≥65. Younger patients reported higher PA (low, median age 59.7 years; moderate, 56.1; high, 55.7; p < 0.001). High activity level was reported by males (66.7%; p < 0.001). Patients with low PA had HCT-comorbidity index (HCT-CI) ≥ 3 (68.1%, p = 0.002). When controlling for HCT-CI and disease risk index, higher PA was associated with improved overall survival (HR 0.954, 95% CI 0.921–0.988, p = 0.009). After adjusting for HCT-CI, higher PA was associated with reduced non-relapse mortality (NRM) (HR 0.931, 95% CI 0.891–0.972, p = 0.0013). Subgroup analysis in adults age ≥65 years also found that PA was lower in this population and associated with NRM mortality (HR 0.95, 95% CI 0.90–0.99, p = 0.041). Conclusion: Patient-reported PA is a predictor of post-HCT survival. Future studies to validate incorporation of self-report tools to better predict patient-related adverse risk are warranted.

The introduction of posttransplant cyclophosphamide (PTCy) made performing allogeneic hematopoietic cell transplantation (HCT) from HLA haplotype–incompatible donors possible. In a setting of PTCy and tacrolimus/mycophenolate mofetil (MMF) as a graft-versus-host disease (GVHD) prophylaxis, a peripheral blood (PB) graft source as compared with bone marrow reduces the relapse rate but increases acute GVHD (aGVHD) and chronic GVHD (cGVHD). This phase 2 trial assessed sirolimus and MMF efficacy following PTCy as a GVHD prophylaxis after PB haploidentical HCT (haplo-HCT). With 32 evaluable patients (≥18 years) enrolled, this study had 90% power to demonstrate a reduction in 100-day grade II-IV aGVHD to 20% from the historical benchmark of 40% after haplo-HCT using PTCy/tacrolimus/MMF. At a median follow-up of 16.1 months, the primary end point of the trial was met with a day-100 grade II-IV aGVHD cumulative incidence of 18.8% (95% confidence interval [CI], 7.5% to 34.0%). There were no graft-failure events and the 1-year probability of National Institutes of Health (NIH) moderate/severe cGVHD was 18.8% (95% CI, 7.4% to 34.0%), nonrelapse mortality was 18.8% (95% CI, 7.4% to 34.0%), relapse was 22.2% (95% CI, 9.6% to 38.2%), disease-free survival was 59.0% (95% CI, 44.1% to 79.0%), GVHD-free relapse-free survival was 49.6% (95% CI, 34.9% to 70.5%), and overall survival was 71.7% (95% CI, 57.7% to 89.2%) for the entire cohort. These data demonstrate that GVHD prophylaxis with sirolimus/MMF following PTCy effectively prevents grade II-IV aGVHD after PB haplo-HCT, warranting prospective comparison of sirolimus vs tacrolimus in combination with MMF following PTCy as GVHD prophylaxis after PB HCT. This trial was registered at www.clinicaltrials.gov as #NCT03018223.

Optimal conditioning chemotherapy for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remains uncertain. Myeloablative regimens such as fludarabine/busulfan are favored over reduced-intensity fludarabine/melphalan (Flu/Mel); however, it is not known if Flu/Mel is inferior. We analyzed hematopoietic cell transplantation recipients with AML and MDS who received fludarabine with once-daily intravenous busulfan targeted to either area under the curve (AUC) 5300 µM*L/min (Flu/Bu 5300) (

Background Mutations in the tumor suppressor gene TP53 are found in up to 20% of patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Allogeneic hematopoietic SCT remains the only potentially curative therapy however outcomes remain poor, with a 1-year relapse-free survival (RFS) of ~30% and median overall survival (OS) of ~8 months. Prior data on post-SCT maintenance therapies, including AZA, have failed to demonstrate improved post-SCT outcomes. Eprenetapopt, a small molecule p53 stabilizer, targets cellular redox balance resulting in tumor cell apoptosis and ferroptosis as well as immune modulation of the tumor microenvironment. Pre-clinical data demonstrates synergistic myeloid cell cytotoxicity in vitro and in vivo AML burden reduction when eprenetapopt is combined with AZA. Additionally, the known tolerability of this combination in AML/MDS patients makes it an attractive maintenance strategy. Methods This is a multi-center, open label, Phase II clinical trial to assess the safety and efficacy of eprenetapopt in combination with AZA as maintenance therapy after SCT for patients with TP53 mutant AML and MDS. Patients with MDS and AML with a known TP53 mutation were prescreened prior to SCT and protocol eligibility was confirmed post-SCT. Treatment consisted of up to 12 cycles of eprenetapopt 3.7 g/day Days 1-4 with AZA 36 mg/m 2/day IV/SC on Days 1-5 every 28 days. The primary objectives of this study are to assess RFS and the safety and tolerability of the combination. Additional endpoints include OS, time to progression (TTP), non-relapse mortality (NRM) and cumulative incidence of acute and chronic graft-versus-host disease (GVHD). Results The study enrolled a total of 33 patients (19 MDS, 14 AML) for active therapy. Demographics across all patients included median age 65 years (range: 40-74), 64% males, and Karnofsky performance status of ≥ 80 in 79%. The majority (76%) received a reduced intensity conditioning regimen. At initial diagnosis, 97% (32) had TP53 mutations, 9% (3) had >1 TP53 mutation, 82% (27) had complex cytogenetics (>=3), 45% (15) had chromosome (chr) 17, 76% (25) had chr 5, and 45% (15) had chr 7 abnormalities. Among 25 patients with available molecular data from a pre-SCT sample, 22 (88%) patients had a residual detectable TP53 gene mutation, 8 (36%) had > 1 TP53 mutation, and 9 (36%) patients had non-TP53 gene mutations: ASXL1 (2 ), JAK2 (4), DNMT3A (3), IDH2 (2), IDH1 (2), NRAS (1) and SF3B1 (1). As of the data cutoff date of 22 June 2021, patients completed a median of 7 cycles (1,12) of study treatment with 6 patients (18.2%) remaining on study treatment. The primary reasons for study treatment discontinuation among 27 patients, were completion of 12 cycles of treatment (9) and disease relapse (9). With median duration of RFS follow up of 413 days the median RFS was 368 days [95% CI (233-not evaluable)] and the 1-year RFS was 58%. With median duration of OS follow up of 429 days the median OS was 586 days [95% CI (369-not evaluable)] and 1-year OS 79%. All-grade treatment emergent adverse events (TEAEs) occurring in ≥20% of patients included nausea (61%), platelet count decreased (49%), vomiting (46%), anemia, dizziness, and white blood cell count decreased (39% each), fatigue (36%), diarrhea and tremor (33% each), cough, neutrophil count decreased, pruritus, and pyrexia (24% each), abdominal pain, constipation, decreased appetite, headache and hypocalcemia (21% each). Grade ≥3 TEAEs in ≥10% of patients were platelet count decreased (36%), white blood cell count decreased (33%), anemia (27%), neutrophil count decreased (24%), thrombocytopenia and hypertension (12% each). SAEs in ≥2 patients were pyrexia (12%), febrile neutropenia and dyspnea (6% each). Two patients (6%) experienced TEAEs leading to discontinuation of study treatment. Acute and chronic GVHD events of any grade were reported in 12% and 30% of patients, respectively. Conclusions Post-SCT maintenance therapy with eprenetapopt in combination with AZA was safe and tolerable with favorable results in patients with TP53 mutant MDS and AML, with 9 patients completing 12 cycles of therapy at the data cutoff date and the majority of reported TEAEs comprising known complications of high-risk MDS and AML patients in the post-SCT period. In addition, the observed RFS and OS data are highly encouraging compared to the historical outcomes for this high-risk group of patients with unmet medical need. Disclosures Mishra: Novartis: Research Funding. DeZern: Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees. Byrne: Karyopharm: Research Funding. Chen: Gamida: Consultancy; Incyte: Consultancy. Gallacher: Aprea Therapeutics: Current Employment, Current equity holder in publicly-traded company. Wennborg: Aprea Therapeutics: Current Employment, Current equity holder in publicly-traded company. Kaylor Hickman: Aprea Therapeutics: Current Employment, Current equity holder in publicly-traded company. Attar: Aprea Therapeutics: Current Employment, Current equity holder in publicly-traded company. Fernandez: Incyte: Honoraria. OffLabel Disclosure: The presentations includes the use of experimental agent eprenetapopt (APR-246) and the agent azacitidine in the post-transplant maintenance setting.

Background: Patients with TP53 MUT MDS/AML experience poor clinical outcomes with high rates of disease recurrence and short overall survival (OS). Characterization of these individuals' post-HCT mortality is uniquely challenging due to competing risks from disease relapse and treatment toxicity. Transplant registries contain high-level outcomes data, however, there is a lack of detailed data in molecularly defined subsets of diease. This analysis was undertaken to bridge this gap. Methods: Allogeneic HCT recipients between 1/2014 and 12/2018 were retrospectively studied. Key inclusion criteria were TP53 MUT by NGS or deletion of chromosome 17/17p by FISH/cytogenetics. The primary outcome of non-relapse mortality (NRM) was defined as death from any cause other than disease with relapse as competing risk. Secondary outcomes for this analysis were OS, cumulative incidence of relapse (CIR), and relapse free survival (RFS). Relapse was defined as relapse/progression with NRM as competing risk. Results: 384 TP53 MUT MDS/AML patients were analyzed. 55% of patients were transplanted for AML, 41% received myeloablative conditioning (MAC), 39% had secondary MDS/AML, and 26% received prior chemo and/or radiation therapy (XRT). Median time from HCT to last follow-up was 321 days (range 8-2,385 days). Mutational data was available in 264 patients and cytogenetic data was available in 368 patients; 78% of patients had a complex karyotype (CK), 82% had TP53 missense mutations, and 74% had bi-allelic targeting of the TP53 gene. The incidence of all-grade acute and chronic GVHD (cGVHD) was 52% and 31%, respectively. One and 2 year OS was 48.5% and 30.9%, respectively. Estimated CIR at 1 and 2 years was 49% and 54.9%, respectively. The 1 year NRM was 13.7% and 2 year NRM was 18.1%. In multivariate analysis (MVA), there was no association between NRM and the clinical, molecular, or genetic features of TP53 MUT MDS/AML. HCT diagnosis of MDS (HR: 0.67, 95% CI: 0.46-0.97, p: 0.036), mono-allelic TP53 MUT (HR: 0.6, 95% CI: 0.39-0.94, p: 0.023), achievement of full donor PB chimerism (HR: 0.33, 95% CI: 0.14-0.85, p: 0.022), BM chimerism (HR: 0.33, 95% CI: 0.18-0.60, p: 0.003), and cGVHD (HR: 0.35, 95% CI: 0.23-0.51, p: In subgroup analysis, history of chemo and/or XRT increased NRM in AML (HR: 4.24, 95% CI: 1.35-13.39, p: 0.014). Pre-HCT TP53 MUT persistence by NGS (HR: 3.59, 95% CI: 1.43-9, p: 0.007) predicted for post-HCT relapse whereas pre-HCT CR (HR: 2.93, 95% CI: 1.54-5.59, p: 0.001) and full donor BM chimerism (HR: 0.14, 95% CI: 0.05-0.38, p: No significant NRM associations were identified in MDS. CK (HR: 5.04, 95% CI: 1.95-13.01, p: Conclusions: From this large multi-institutional cohort of TP53 MUT myeloid neoplasms, we report a low NRM rate, likely due to high rates of post-HCT relapse/progression. These data demonstrate associations between bi-allelic TP53m/CK and post-HCT outcomes. Our work highlights the importance donor chimerism after HCT and provides new understanding of the importance of chronic GVHD in TP53 MUT MDS/AML. Figure 1 Figure 1. Disclosures Byrne: Karyopharm: Research Funding. Logan: Amgen, Pfizer, AbbVie: Consultancy; Pharmacyclics, Astellas, Jazz, Kite, Kadmon, Autolus, Amphivena: Research Funding. Lee: CareDx: Membership on an entity's Board of Directors or advisory committees; Kadmon: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Fresensius Kabi: Consultancy; Jazz,: Consultancy; Incyte: Research Funding. Goodman: Seattle Genetics: Consultancy, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria. Gill: Interius Biotherapeutics: Current holder of stock options in a privately-held company, Research Funding; Novartis: Other: licensed intellectual property, Research Funding; Carisma Therapeutics: Current holder of stock options in a privately-held company, Research Funding. Jimenez: Takeda: Research Funding; AbbVie: Research Funding. Metheny: Pharmacosmos: Honoraria; Incyte: Speakers Bureau. Bhatnagar: Pfizer: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Cell Therapeutics: Honoraria, Research Funding; Kite: Honoraria; Karyopharm: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Research Funding. Hamilton: Syndax: Membership on an entity's Board of Directors or advisory committees; Equilium: Membership on an entity's Board of Directors or advisory committees. Mishra: Novartis: Research Funding. Savona: BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding.

Background: Recent advances in the treatment of myelodysplastic syndrome (MDS) have improved patient survival and quality of life (QOL), while reducing transfusion burden. However, allogeneic hematopoietic cell transplantation (HCT), widely used in younger MDS patients, remains the only curative therapy for MDS. While transplantation outcomes among selected older patients with MDS are similar to younger patients with MDS, early transplantation for older patients is infrequently offered since the relative benefits of HCT over non-HCT therapy in have not been well defined in this patient group. We conducted a multi-center, biologic assignment trial in older individuals with high risk MDS to define the benefit of HCT over non-HCT therapy. Methods: The study was a multicenter, biologic assignment trial in subjects aged 50-75 with higher risk de novo MDS (IPSS Intermediate-2 (Int-2) or High) who were candidates for reduced-intensity conditioning (RIC) allogeneic HCT, comparing outcomes of those with a suitable 8/8 HLA-matched donor to those without a donor. The trial was conducted by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 1102, NCT02016781). Eligible subjects were enrolled prior to a formal donor search, and before or after MDS treatment was initiated. Biological assignment to the Donor or No Donor arm was based on high-resolution HLA typing of eligible family members and a search of the unrelated donor registries. Subjects were initially assigned to the No Donor arm and re-assigned to the Donor arm when a suitable donor was identified. Subjects who died or whose 90-day donor search ended without identifying a suitable donor remained in the No Donor arm. Subjects in the Donor arm were expected to undergo RIC HCT within 6 months of enrollment. Subjects underwent RIC HCT or non-HCT therapy according to institutional standards. The primary analysis compared three-year overall survival (OS) between arms using adjusted survival estimates to account for the potential bias resulting from biological assignment. The sample size was selected to provide at least 80% power to detect a difference of 15% in 3-year OS. Between January 2014 and November 2018, 384 subjects (Donor n=260, No Donor n=124) were enrolled at 34 centers. The study arms were well balanced for age, gender, KPS, IPSS risk, MDS disease duration and responsiveness to hypomethylating therapy (Table). The median follow-up time for surviving patients was 34.2 months (range: 2.3-38 months) in the Donor arm and 26.9 months (range: 2.4-37.2 months) in the No Donor arm. Results: In an intent-to-treat analysis, adjusted OS at 3 years from study enrollment in the Donor arm was 47.9% (95% CI: 41.3%-54.1%) compared with 26.6% (95% CI: 18.4%-35.6%) in the No Donor arm (p=0.0001, absolute difference 21.3%, 95% CI: 10.2%-31.8%)(Figure). A sensitivity analysis excluding subjects assigned to the No Donor arm who died or withdrew prior to the end of the 90-day search window showed no effect on outcome (Adjusted OS: 48.0% vs. 28.1%, p=0.0004). Leukemia-free survival (LFS) at 3 years was greater in the Donor arm (35.8%, 95% CI: 29.8%-41.8%) compared with the No Donor arm (20.6%, 95% CI: 13.3%-29.1%, p=0.003), with no changes in the sensitivity analysis. An OS and LFS benefit was seen across all subgroups tested (Figure). There were no clinically significant differences in QOL between Donor and No Donor arms as measured by the FACT-G, the MOS-SF36 Physical and Mental Component Scores and the EQ-5D utility score at all time points. The overall non-compliance rate for the trial was 26.3%. Reasons for non-compliance included the use of myeloablative conditioning or failure to proceed to RIC transplant in the Donor arm, and the use of alternative donors in the No Donor arm. In an as-treated analysis, comparison of the HCT and No HCT arms demonstrated a significant advantage in 3-year OS (47.4% vs. 16.0%, p Conclusions: We observed a significant OS advantage in older patients with Int-2 and High IPSS risk de novo MDS who are RIC HCT candidates and have an HLA-matched donor, when compared with those without a donor. The benefit of having a matched donor was seen across subgroups, including those who were of Medicare age (>65) and below. HCT should be offered to all individuals between the ages of 50-75 with Int-2 and High IPSS risk MDS in whom a suitable donor can be identified. Table Disclosures Nakamura: Magenta Therapeutics: Other: Advisory board meeting; Kyowa-Kirin: Other: Support on a meeting presentation; Alexion: Other: Support on a meeting presentation; Merck: Other: advisory board meeting; NapaJen Pharma: Consultancy; Kadmon Corporation: Other: Advisory board meeting; Celgene: Other: Support on seminar; Viracor: Consultancy. Scott:Alexion, Incyte, Novartis, Regeneron: Consultancy; Agios, BMS: Honoraria; BMS, Novartis: Research Funding. Oran:ASTEX: Research Funding; Celgene: Consultancy; Arog Pharmaceuticals: Research Funding. Maziarz:Novartis, Incyte, CRISPR Therapeutics, Artiva Biotherapeutics, and AlloVir: Consultancy; Novartis and Athersys: Other: DSMB participant; Athersys: Patents & Royalties; Incyte, Kite, BMS/Celgene, PACT Pharma, Orca BioSystems, and Omeros: Honoraria; Novartis and Juno: Research Funding. McGuirk:Allo Vir: Consultancy, Honoraria, Research Funding; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; Bellicum Pharmaceutical: Research Funding; Astellas: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding; Kite Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Juno Therapeutics: Consultancy, Honoraria, Research Funding. Sekeres:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cutler:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kadmon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medsenic: Consultancy, Membership on an entity's Board of Directors or advisory committees; Generon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mesoblast: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Background Post-transplant cyclophosphamide (PTCY) is being increasingly used for graft-versus-host disease (GVHD) prophylaxis after hematopoietic cell transplantation (HCT) across various donor types. However, immune reconstitution after PTCY-based vs. conventional GVHD prophylaxis has not been well studied. Methods We evaluated the pace of immune reconstitution (CD4+ T-cell, CD8+ T-cell, NK-cell and B-cell) at 3 months, 6 months and 1 year post-HCT in 583 adult patients receiving myeloablative (n=223) or reduced intensity conditioning (n=360) HCT (2012-2018). Haploidentical (Haplo; n=75) and 8/8 HLA-matched unrelated (MUD, n=508) donor types were included. GVHD prophylaxis was PTCY-based in 75 Haplo and 38 MUD (MUD-PTCY) HCT, while tacrolimus/methotrexate (TAC/MTX) was used in 89 and TAC/Sirolimus (TAC/SIR) in 381 MUD HCT. Clinical outcomes including viral infections, non-relapse mortality (NRM) and overall survival (OS) were compared across all four treatment groups. Results The recovery of absolute total CD4+ T-cell count after Haplo-PTCY and MUD-PTCY was significantly lower compared to MUD TAC/MTX or MUD TAC/SIR throughout 1 year of HCT (Figure). In contrast, CD19+ B-cell recovery at 6 months and thereafter was more rapid after Haplo-PTCY and MUD-PTCY HCT in comparison to MUD TAC/MTX and MUD TAC/SIR. In subgroup analysis compared to MUD TAC/MTX HCT, total CD8+ T-cell or NK-cell recovery was not significantly different after Haplo-PTCY or MUD-PTCY HCT. However, patients receiving MUD TAC/SIR vs. MUD TAC/MTX had significantly slower reconstitution of total CD8+ T-cells up to 6 months and CD19+ B-cells at 1 year of HCT, but no significant differences in CD4+ T-cell or NK-cell recovery. The distribution of recipient CMV serostatus was similar in all four groups: 72% in Haplo-PTCY, 62 % in MUD-PTCY HCT, 68% in MUD TAC/MTX and 63% in MUD TAC/SIR (p=0.11). Cumulative incidence of CMV reactivation/infection at 1-year of HCT was higher in patients receiving Haplo-PTCY (39.6%) or MUD TAC-MTX (37.7%) compared to those receiving MUD-PTCY (27.0%) or MUD TAC/SIR (22.8%; p Conclusion Our data demonstrate that the pattern of immune reconstitution after HCT is different after PTCY-based vs. conventional GVHD prophylaxis with delayed total CD4+ T-cell but more rapid B-cell recovery after PTCY-based GVHD prophylaxis. The rates of CMV and EBV viral infections were different across the donor types. However, these differences had no significant influence on NRM or survival after HCT.

BACKGROUND: Outcomes of patients with acute promyelocytic leukemia (APL) have improved; however, a number of patients, particularly those with high-risk APL, still relapse despite all-trans-retinoic acid (ATRA) and arsenic-based therapies. We present single institution outcomes of autologous (auto) and allogenic (allo) hematopoietic cell transplantation (HCT) in patients with relapsed APL. PATIENTS AND METHODS: We retrospectively reviewed outcomes in patients with relapsed APL who underwent either auto- or allo- HCT at Moffitt Cancer Center from 1990 to 2018 utilizing the clinical data obtained from BMT Research & Analysis Information Network (BRAIN). Survival data were analyzed using Kaplan-Meier estimates. RESULTS: Autologous HCT Cohort: A total of 15 received auto-HCT with a median age at HCT of 39 (range, 21-60) years. Disease status at HCT were first complete remission (CR1) in 5 (33%) and CR2 in 10 (67%). Majority of patients (13/15, 87%) received busulfan/cyclophosphamide (Bu/Cy) conditioning and remaining (2/15, 13%) Bu/Cy/etoposide. All (n=15) patients received peripheral blood (PB) stem cell grafts. Median time to neutrophil engraftment was 11 (range, 10-14) days and platelet recovery was 14 (range 9-44) days. The median progression-free survival (PFS) for auto HCT was 12.9 (95% confidence interval (CI): 1.2-24.8) months. With a median follow up of 45.1 months for surviving patients, overall survival (OS) for auto HCT was 12.9 (95%CI: 0-27.8) years. At the time analysis, 8 patients were relapse-free. Allogeneic HCT Cohort: A total of 10 patients received allo HCT with a median age of 46 (range, 22-56) years at HCT. Disease status at allo HCT was CR2 in 2, CR3 in 6, and two had refractory disease. Two patients had prior auto HCT. Donor type was HLA-identical sibling=5; one antigen-mismatched sibling=1; HLA-matched unrelated donor=3; related haploidentical=1. Seven patients received peripheral blood graft and 3 received bone marrow graft. Conditioning regimen intensity was myeloablative in 7 (fludarabine/busulfan +/- anti-thymocyte globulin=3; Bu/Cy=3; cyclophosphamide/total body irradiation=1), and reduced intensity in 3 (fludarabine/melphalan=2; fludarabine/cyclophosphamide/total body irradiation=1). Seven patients received tacrolimus-based graft-versus-host disease (GVHD) prophylaxis. Median time of neutrophil engraftment was 15 (range, 12-22) days, and platelet engraftment was 22 (range, 15-28) days. The median PFS for allo HCT was 11.9 (95%CI: 2.1-21.6) months. With a median follow up of 48.2 months for surviving patients, median OS for allo HCT was 12.4 (95%CI: 4.8-19.9) months. At the time of analysis 4 patients were relapse-free. CONCLUSIONS: In our single center analysis, auto HCT for APL resulted in a durable remission and prolonged survival. Outcomes after allo HCT were suboptimal primarily due to their heavily pretreated condition and chemotherapy resistant disease. Further research on novel conditioning regimen and relapse prevention is needed to improve the outcomes of allo HCT in APL. Figure Disclosures Lancet: Jazz Pharmaceuticals: Consultancy; Agios Pharmaceuticals: Consultancy; Daiichi-Sankyo: Consultancy; Pfizer: Consultancy. Sweet:Pfizer: Consultancy; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Stemline: Consultancy; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Komrokji:JAZZ: Speakers Bureau; Novartis: Speakers Bureau; Agios: Consultancy; JAZZ: Consultancy; Incyte: Consultancy; pfizer: Consultancy; DSI: Consultancy; celgene: Consultancy. Bejanyan:Kiadis Pharma: Other: advisory board. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nishihori:Novartis: Research Funding; Karyopharm: Research Funding.

Background Additional tools for risk-stratification of chronic graft vs. host disease (cGVHD) may enhance the established NIH consensus-based severity score. Radiographic body composition metrics arising from standardly performed CT-scans have previously shown significant association with treatment complications in other cancer populations. We aimed to characterize skeletal muscle (SM) and adiposity in cGVHD patients to discern potential association with subsequent mortality. Methods A consecutive retrospective series of patients who underwent allogeneic hematopoietic cell transplantation (HCT) at our center from 2005-2016 and had the following criteria were evaluated: 1) diagnosis of either non-Hodgkin (NHL) or Hodgkin Lymphoma (HL) to enrich for available CT, and 2) had a history of cGVHD. Skeletal muscle index (SMI) and fat index (FI) were quantified on CT imaging at the 3rd lumbar (L3) and 4th thoracic (T4) vertebra. SM Hounsfield units (HU) were obtained to evaluate SM density. Cut points for SMI and FI were done via gender specific optimal stratification. Results A total of n=115 patients met the inclusion criteria for this analysis. The median age was 52 (range 22-69), and patients were predominantly male (n=71, 62%) and diagnosed with NHL (n=110, 96%). Onset cGVHD NIH overall severity was mild in N=56 (49%), moderate in 44 (38%), and severe in 15 (13%). When considering all body composition parameters, high L3 fat index (FI) at D100 was associated with worsened OS (HR 2.83, 95% CI 1.30, 6.12, p=0.008), but SMI and SM HU were not associated with OS (p=NS). In multivariate analysis, high L3 FI was independently associated with increased mortality (HR 2.29, 95% CI 1.03-5.1, p=0.043) (Table 1), while SMI and HU were not (p=NS). In secondary analysis, we quantified the change in body composition in evaluable patients (n=72). Cachexia development was observed from pre- to post-HCT (median % weight change -5.5 [-50.1-13.3]. The majority of patients had decline in both FI and SMI (Figure 1). These changes were also seen in CT chest with high correlation between SMI and FI when comparing CT abdomen chest r=0.854 and r=0.798 respectively. Conclusions Increased FI is associated with worsened overall survival in cGVHD patients, while SMI and HU are not. These findings suggest that low skeletal muscle mass alone does not predict for poor outcomes in cGVHD as previously described in other cancers. Body composition analysis in a larger cGVHD cohort is needed to confirm these findings and examine risk-stratification within NIH severity groups.

Systemic glucocorticoids remain the standard treatment for gastrointestinal (GI) acute graft-versus-host disease (aGVHD) despite their toxicity and incomplete efficacy. Controlled trials have tested poorly absorbable steroids as adjuncts with systemic glucocorticoids, but only small case series have reported treatment with poorly absorbed beclomethasone dipropionate (BDP) and budesonide (BUD) alone. Our team has adopted the practice of administering BDP or BDP+BUD without systemic glucocorticoids as first-line therapy for isolated upper GI (UGI) aGVHD. We report results in 76 patients treated with BDP alone and in 81 patients treated with BDP+BUD, with allocation by physician choice. Almost all patients received peripheral blood stem cells (92%) from a fully HLA-matched related or unrelated donor (80%) after myeloablative conditioning (76%) for acute leukemia (49%), myelodysplastic syndrome (17%), non-Hodgkin lymphoma (14%), or another hematopoietic disorders (20%). After 28 days of treatment with BDP, 46% of the patients had a complete response (CR) and 10% had a partial response (PR); after 200 days, 61 (80%) patients were alive, 34% maintained a CR, and 3% maintained a PR, whereas 53% required additional immunosuppression (IS). After 28 days of treatment with BDP+BUD, 67% had a CR and 10% a PR; after 200 days, 74 (91%) patients were alive, 46% maintained a CR, and 2% maintained a PR, whereas 43% required additional IS. Among the entire cohort of 157 patients, 66 (42%) were treated successfully without systemic glucocorticoids. This study reports the efficacy of poorly absorbable steroids alone for patients with isolated UGI aGVHD. Prospective trials should test for the potential advantages of BDP and BUD use over systemic glucocorticoids.

BACKGROUND: European LeukemiaNet (ELN) 2017 risk stratification by genetics is prognostic of outcomes in patients with acute myeloid leukemia (AML). However, the prognostic impact of the 2017 ELN genetic risk stratification after allogeneic hematopoietic cell transplantation (alloHCT) is not well established. OBJECTIVE: We examined the effect of 2017 ELN genetic risk stratification on alloHCT outcomes of AML. METHODS: We included 500 adult (≥18 years) AML patients in first (n=370) or second (n=130) complete remission receiving alloHCT from 2005 to 2016. Patients were classified into favorable (12%), intermediate (57%), and adverse (32%) 2017 ELN risk groups. The Cox proportional hazard model was used to conduct the multivariable analyses of leukemia-free survival (LFS) and overall survival (OS). Relapse and non-relapse mortality were analyzed by the Fine-Gray regression model. RESULTS: OS at 2 years was 72% in the favorable vs. 60% in the intermediate vs. 45% in the adverse risk groups (p

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for patients with myelodysplastic syndrome (MDS). Because MDS predominantly affects an older population, age-associated comorbidities can preclude patients from cure. HSCT is associated with the risk of morbidity and mortality; however, with safer conditioning regimens and improved supportive care, eligible patients with an appropriately matched donor can receive this therapy without exclusion by older age alone. We discuss the role of improved MDS prognostic scoring systems and molecular testing for selection for HSCT, and review the pre-HSCT tolerability assessment required for this advanced aged population.

Introduction: Previous studies have demonstrated that allogeneic haploidentical (haplo) peripheral blood stem cell transplantation (PBSCT) with post-transplant cyclophosphamide (PTCy) yields improved progression free survival (PFS) when compared to haplo bone marrow transplant (BMT) with PTCy, attributable to lower relapse without an increase in non-relapse mortality (NRM) (Bashey, et al. JCO. 2017). However, haplo PBSCT results in higher rates of graft-versus-host disease (GVHD) which may negate these benefits in older patients who are more susceptible to transplant related toxicity. Thus, evaluation of the outcomes of haplo PBSCT with PTCy in older patients is warranted. Methods: We retrospectively evaluated 121 adult patients with hematologic malignancies treated at the Moffitt Cancer Center with allogeneic T-cell replete PBSCT from a haplo donor followed by PTCy-based GVHD prophylaxis. Data were extracted from the Moffitt BMT Research & Analysis Information Network (BRAIN) database. Myeloablative (n=70, 58%) and reduced intensity (n=51, 42%) conditioning regimens were included. Transplant related outcomes were compared between two age groups: 60 years (n=55). Associations with transplant related survival outcomes were assessed using univariate and multivariate Cox proportional hazard survival models. Fine and Gray regression models were used to assess associations of transplant related endpoints with competing risks. Kaplan-Meier curves and cumulative incidence function curves were also plotted. Results: The median age at the time of transplant was 42 years (range: 20-59) for the younger group and 66 years (range: 61-75) for the older group. The median follow-up was 17 months (range: 2-53) for the entire cohort. Younger patients were more likely to receive myeloablative conditioning (83% versus 27%, p Neutrophil engraftment (>500/uL) by day 30 did not differ significantly between the younger and older group (98% versus 93%, p=0.26). However, the median time to neutrophil engraftment was faster in the younger group versus the older group (16 versus 21 days, p20,000/uL) by day 90 was achieved in 92% in the younger group versus 76% in the older group (p=0.03). The time to platelet engraftment was faster in the younger group: 28 days versus 36 days (p=0.006). At day 100, the cumulative incidence (CuI) of grade II-IV acute GVHD in younger patients was 42% (95% CI 29-61%) and for older patients was 35% (95% CI 22-55%, p=0.82). The CuI for grade III-IV acute GVHD for the younger and the older groups were 8% (95% CI 4-25%) and 15% (95% CI 7-38%, p=0.23), respectively. At 2 years, the CuI of chronic GVHD was 67% (95% CI 55-82%) for younger patients versus 56% (95% CI 38-82%) for older patients (p=0.20). NRM for the younger group and the older group, respectively, was 6% (95% CI 2-16%) versus 19% (95% CI 11-34%) at 100 days and 14% (95% CI 6-30%) versus 22% (95% CI 13-37%) at 2 years (p=0.17). The CuI of relapse at 2 years was not significantly different between the two age groups, with the younger recipients having a CuI of 42% (95% CI 20-60%) and the older group 31% (95% CI 17-56%, p=0.70). The 2-year DFS was similar between the younger and older group, respectively: 51% (95% CI 36-66%) and 53% (95% CI 37-70%, p=0.72). Similarly 2-year overall survival (OS) for the younger group was 59% (95% CI 44-74%), while the older group was 66% (95% CI 52-80%, p=0.92). In multivariate analysis, NRM was superior in the younger group (HR=0.31, 95% 0.12-0.82, p=0.02). Otherwise, age was not associated with engraftment, risk of acute or chronic GVHD, relapse, DFS, or OS. Conclusion: Our results demonstrate that outcomes following allogeneic haplo PBSCT with PTCy in patients >60 years approximate outcomes in patients Disclosures Khimani: Bristol Myers Squibb-Moffitt-Alliance: Research Funding. Nishihori:Novartis: Other: Research support to institution; Karyopharm: Other: Research support to institution. Pidala:Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Johnson and Johnson: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; BMS: Research Funding. Bejanyan:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees.

Haploidentical hematopoietic cell transplantation (haplo-HCT) with post-transplant cyclophosphamide (PTCy) is increasingly offered as a curative treatment for patients with hematological malignancies. In a recent registry study (Bashey et al. JCO 2017), peripheral blood (PB) as a graft source compared to bone marrow reduced the risk of relapse but increased acute and chronic GVHD after haplo-HCT with PTCy in combination with calcineurin inhibitor (CNI) and mycophenolate mofetil (MMF). In this phase II trial we aimed to assess the efficacy of Sirolimus (Sir) in combination with PTCy and MMF as a CNI-free GVHD prophylaxis after PB haplo-HCT (NCT03018223). The primary end point was the cumulative incidence of grade II-IV acute GVHD at day 100 after HCT. With 32 evaluable patients enrolled, the study had a 90% power (α = 0.1) to demonstrate a reduction in 100-day grade II-IV acute GVHD from the historical benchmark of 40% (haplo-HCT and PTCy/Tac/MMF) to 20%. Sir was administrated from days +5 to +90 at target level of 8-14 ng/ml, followed by taper by day +180 in the absence of acute GVHD. A total of 32 patients with hematological malignancies were treated on trial 2/2017- 8/2018. The median age at HCT was 50 years (range, 23-75) and 59% of patients were racial/ethnic minorities. AML (50.0%) was the most common indication for HCT. The majority (66%) received myeloablative Fludarabine (Flu) and Busulfan (AUC of 5300), while 34% received non-myeloablative Flu/Cy/TBI 200 cGy. There were no graft failure events and the median time of neutrophil engraftment was 17 days (range, 12 - 30). With a median follow-up of 15.4 months, the primary endpoint was met with day 100 grade II-IV acute GVHD cumulative incidence of 18.8% (95% CI 7.5 - 34.0; grade III-IV = 9.4%). The cumulative incidence of 1-year NIH moderate/severe chronic GVHD was 20.0% (95% CI 7.9-36.0) (Figure). Only 3 patients required systemic glucocorticoids for chronic GVHD therapy. At last follow up, all immunosuppression was successfully discontinued in 43% (n=12) of all surviving study patients. The 1-year probability of non-relapse mortality was 19.7% (95% CI 7.8 - 35.5), relapse was 23.7% (95% CI 10.2 - 40.4), disease-free survival was 56.6% (95% CI 41.3 - 77.7) and overall survival was 70.2% (95% CI 55.5 - 88.6) for the entire cohort. These data demonstrate that PTCy/Sir/MMF GVHD prophylaxis effectively prevents grade II-IV acute GVHD after PB haplo-HCT and results in successful hematopoietic engraftment. Furthermore, the initial chronic GVHD, relapse and survival outcomes appear favorable. These findings warrant prospective comparison of PTCy/Sir/MMF with PTCy/Tac/MMF after PB haplo-HCT.

Introduction Mycophenolate mofetil (MMF) dose/kg can influence clinical outcomes of allogeneic hematopoietic cell transplantation (HCT) including acute graft-versus-host disease (GVHD) (Harnicar BBMT 2015; Bejanyan BBMT 2018). When used for GVHD prophylaxis in conjunction with post-transplant cyclophosphamide (PTCy), MMF is generally dosed at 15 mg/kg three times daily (capped at a maximum of 3 g/day) and combined with either tacrolimus or sirolimus. Thus, many adults receive the maximum dose and a variable dose/kg of MMF. Objectives We sought to investigate the impact of MMF dose/kg on clinical outcomes of HCT in the setting of PTCy-based GVHD prophylaxis, where the effect of MMF dose/kg is unknown. Methods Included are 112 consecutive adult patients with hematologic malignancies who received myeloablative (n=70) or reduced intensity (n=42) HCT at the Moffitt Cancer Center between 2012-2018 with T-cell replete peripheral blood stem cells (n=94) or bone marrow (n=18). GVHD prophylaxis consisted of PTCy/MMF and either tacrolimus (n=57) or sirolimus (n=55). MMF dose relative to patient actual body weight (mg/kg/day), was stratified by tertiles into low ( 40 mg/kg/day, n=36). Results The median age at transplant was 57.8 (range: 21-75) years. Median follow-up was 12 months (range: 0.3-39). Donors were haploidentical related (n=74), mismatched unrelated (n=26), and matched related/unrelated (n=12). MMF dose groups had similar characteristics, except the low dose group having a higher proportion of males (p Conclusion In patients receiving PTCy based GVHD prophylaxis, MMF dose/kg had no significant effect on GVHD. However, lower MMF dose/kg was associated with worse DFS. This study suggests that

Disease Risk Index (DRI) and Hematopoietic Cell Transplant Comorbidity Index (HCT-CI) are independently validated and powerful pretransplant prognostic tools for overall survival (OS) of patients receiving allogeneic HCT (alloHCT) for hematological malignancies. Here we examined the prognostic significance of the DRI in conjunction with HCT-CI on OS among 341 elderly patients (≥60 years old) with AML (n=214) and MDS (n=127) who received alloHCT from 2005 to 2016. The median age at alloHCT for all patients was 66 (range, 60-76) years: 42% were age 60-64, 43% age 65-69 and 15% age ≥70. DRI classified patients as low/intermediate risk (LR/IR DRI, 63%) or high/very high risk (HR DRI, 37%). Nearly half of the patients had many comorbidities (HCT-CI ≥3) and 30% of all patients had lower Karnofsky Performance Status score (KPS Our findings suggest that most elderly patients with AML and MDS benefit from potentially curative alloHCT. Survival was worse for patients with combined high risk DRI and many comorbidities (HR DRI+ HCTCI ≥3). Thus, combining DRI and HCT-CI can serve as an effective pre-HCT tool to prognosticate survival after alloHCT. Age alone should not be a limiting factor in transplant decision making in otherwise eligible patients with AML and MDS.

Introduction One of the main complications of adoptive T cell therapy (ACT) is the en-masse activation of tumor-reactive T cells leading to adverse events. These are classified as cytokine release syndrome (CRS) and CAR T Related Encephalopathy Syndrome (CRES). Here, we report the results of cytokine analysis using a point of care (POC) device to predict immune-related toxicities in patients with relapsed/refractory (R/R) DLBCL treated with axicabtagene ciloleucel (axi-cel). Methods Patients with R/R DLBCL treated with commercial axi-cel were included in this study. To select which cytokines to monitor, we retrospectively analyzed 38 serum cytokines in a cohort of 53 patients with R/R B-ALL who were treated with 19-28z CAR T cells. We observed several cytokines which were significantly elevated in patients with CRS and/or CRES requiring treatment (Figure 1a). Based on this analysis and results of published studies, eight serum proteins were selected, including IL-1b, IL-2, IL-6, IL-15, IFNg, TNFa, and angiopoietin-1 &2 (ANG1/ANG2). We monitored these proteins using a POC device that allows for rapid daily monitoring with a turnaround time of two hours. CRS and CRES were prospectively graded using revised Lee criteria and the CARTOX group respectively. Results A total of 20 patients with R/R DLBCL treated with commercial axi-cel were identified. Median age 64 years (range 43-73). Grades 1-3 CRS were observed in 45%, 40% and 5% of patients respectively. There were no observed grade 0 or grade 4 CRS. There were two patients (10%) who died in the setting of severe toxicity. Patients with grade 5 CRS had higher levels of IL-6 and angiopoietin 2/angiopoietin 1 ratio at day one, which correlated with severity of toxicity r=0.52 (p= 0.039) and r=0.53 (p=0.033) respectively (Fig. 1b). Patients with high grades CRS had elevated levels of IL-15 at day seven (r=0.83, p=0.006). The majority of patients (55%) had grades 1-2 CRES. There were no significant correlations between serum cytokine levels and CRES. Conclusion In this analysis of 20 patients, we observed a correlation between severe CRS and elevated serum cytokine levels of IL-6 and ANG2/ANG1 ratio at day one suggesting that these biomarkers may be utilized to predict severe toxicity in patients treated with ACT. While this study is limited by small sample size, our observations correlate with previously published biomarkers data in patients enrolled in clinical trials. In select cases, monitoring of cytokines using the POC device provided clinical insight that wasn't evident from standard biomarkers. For example, one patient who developed delayed CRS had high serum levels of IL-6 but did not have elevated levels of CRP (Fig.1c). We continue to enroll patients to validate cytokines as predictive biomarkers with the goal of informing the development of preventative strategies to mitigate CAR T cell therapy immune related adverse events.

Effective pharmacological strategies employed in allogeneic hematopoietic cell transplantation should prevent serious chronic graft-versus-host disease and facilitate donor-recipient immune tolerance. Based on demonstrated pro-tolerogenic activity, sirolimus (rapamycin) is an agent with promise to achieve these goals. In a long-term follow-up analysis of a randomized phase II trial comparing sirolimus/tacrolimus versus methotrexate/tacrolimus for graft-versus-host disease prevention in matched sibling or unrelated donor transplant, we examined the impact of prolonged sirolimus administration (≥ 1 year post-transplant). Median follow-up time for surviving patients at time of this analysis was 41 months (range 27-60) for sirolimus/tacrolimus and 49 months (range 29-63) for methotrexate/tacrolimus. Sirolimus/tacrolimus patients had significantly lower National Institutes of Health Consensus moderate-severe chronic graft-versus-host disease (34% vs. 65%; P=0.004) and late acute graft-versus-host disease (20% vs. 43%; P=0.04). While sirolimus/tacrolimus patients had lower prednisone exposure and earlier discontinuation of tacrolimus (median time to tacrolimus discontinuation 368 days vs. 821 days; P=0.002), there was no significant difference in complete immune suppression discontinuation (60-month estimate: 43% vs. 31%; P=0.78). Prolonged sirolimus administration represents a viable approach to mitigate risk for moderate-severe chronic and late acute graft-versus-host disease. Further study of determinants of successful immune suppression discontinuation is needed.

Glucocorticoids for primary therapy of acute GVHD have limited responses. A phase I/II trial tested 4 weeks of deacetylase inhibitor panobinostat started within 48 h of glucocorticoids (1 mg/kg/day prednisone or equivalent) as primary treatment for patients with either classic acute GVHD (n = 16) or acute GVHD overlapping with chronic (n = 6). Four patients received 2.5 mg/m(2) IV three times a week (TIW). Subsequent to discontinuation of IV panobinostat, patients received oral doses (PO). Two patients treated with 10 mg TIW (PO level 1) had progressive GVHD, after which patients were treated with 5 mg TIW (PO level −1; n = 16); 31/41 adverse events were possibly related, including thrombocytopenia (n = 13), leukopenia (n = 7), hypercholesterolemia (n = 3), hypertriglyceridemia (n = 5), anemia (n = 1), fatigue (n = 1), and hepatobiliary disorder (n = 1). GVHD responses were complete (n = 12) or partial (n = 3), with 1 progression at PO level −1. T-regulatory cells increased at day 8, CD4/CD8 and monocytes exhibited enhanced H3 acetylation, and CD4 or CD8 numbers remained unchanged with a decreased interleukin 12p40 plasma level. Panobinostat in combination with prednisone is safe and warrants further testing in GVHD.

Sirolimus (SIR)/tacrolimus (TAC) is an alternative to methotrexate (MTX)/TAC. However, rational selection among these GvHD prophylaxis approaches to optimize survival of individual patients is not possible based on current evidence. We compared SIR/TAC (n = 293) to MTX/TAC (n = 414). The primary objective was to identify unique predictors of overall survival (OS). Secondary objective was to compare acute and chronic GvHD, relapse, non-relapse mortality, thrombotic microangiopathy (TMA), hepatic veno-occlusive disease (VOD/SOS), and acute kidney injury. Day 100 grades II–IV acute GvHD was significantly reduced in SIR/TAC vs MTX/TAC group (63 vs 73%, P = 0.02). An interaction between GvHD prophylaxis groups and comorbidity index (hematopoietic cell transplantation (HCT)-CI) significantly impacted OS. Patients with HCT-CI ⩾ 4 had significantly worse OS with MTX/TAC (HR 1.86, 95% CI 1.14–3.04, P = 0.01) while no such effect was seen for SIR/TAC (HR 0.78, 95% CI 0.48–1.26, P = 0.31). Other end points did not significantly differ between groups except TMA and VOD/SOS were increased in the SIR/TAC group, but excess death from these complications was not observed. We conclude, GvHD prophylaxis approach of SIR/TAC is associated with reduced grades II–IV acute GvHD, comparable toxicity profile to MTX/TAC, and improved OS among patients with HCT-CI ⩾ 4.

Background Next-generation sequencing has identified somatic mutations that are prognostic of cancer. Patients and Methods We evaluated the incidence and prognostic significance of somatic mutations in 89 myelodysplastic syndrome (MDS) patients who received an allogeneic hematopoietic cell transplantation. Next-generation sequencing was performed on paraffin embedded bone marrow, which was obtained at a median of 31 days before initiating the preparative regimen. Results The 3 most common subtypes of MDS were refractory anemia with excess blasts (RAEB)-1 (35%), RAEB-2 (29%), and refractory cytopenia with multilineage dysplasia (18%). Most patients (91%) received a myeloablative regimen of fludarabine with intravenous busulfan. Somatic mutations (> 0) were identified in 39 (44%) of analyzed samples. The 6 most commonly identified gene mutations were ASXL1 (8%), DNMT3A (8%), RUNX1 (7%), KRAS (6%), IDH2 (4%), and TP53 (4%). The low incidence of mutations in our study sample might be explained by tissue source and stringent variant-calling methodology. Moreover, we speculate that the low incidence of mutations might, perhaps, also be explained by previous azacitidine treatment in 82% of cases. Multivariate analysis identified TP53 (hazard ratio [HR], 3.82; 95% confidence interval [CI], 1.12-13.09; P = .03) and IDH2 mutations (HR, 4.74; 95% CI, 1.33-16.91; P = .02) as predictors of inferior 3-year overall survival. Conclusion This study furthers implementation of clinical genomics in MDS and identifies TP53 and IDH2 as targets for pre- or post-transplant therapy.

Background: Tumor protein 53 (TP53), located on the short arm of chromosome 17, is an important tumor suppressor gene responsible for critical regulatory functions. There is existing controversy regarding the role of allogeneic stem cell transplantation (allo-SCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) harboring a TP53 mutation. While most studies report increased relapse and poor survival after allo-SCT with TP53 mutated AML or MDS, (Bajar et al., JCO 2014; Lindsley et al., 2017) others found no influence of TP53 mutation on allo-SCT outcomes (Aldoss et al., 2017). Notably, previous studies have predominantly evaluated the prognostic impact of TP53 mutation at the time of diagnosis and not serially in response to treatment. In this study, we aim to clarify the prognostic impact of TP53 mutation clearance prior to allo-SCT in patients with TP53 mutated AML or MDS. Methods: Data was obtained and analyzed on MDS or AML patients who received allo-SCT at the Moffitt Cancer Center (2013-2018) and had presence of TP53 at least once after diagnosis and prior to allo-SCT. TP53 clearance was defined by last next-generation sequencing (NGS) test prior to allo-SCT demonstrating no TP53 mutation with a variant allele frequency (VAF) greater than 5%. We utilized clinical data captured by BMT Research and Analysis Information Network (BRAIN). Univariate and multivariate analyses were conducted using log-rank and Cox regression, respectively. Kaplan-Meier analysis with log-rank test was used to estimate relapse free survival (RFS) and median overall survival (OS) from the time of allo-SCT. Cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were performed as defined by the Fine and Gray model. Results: We identified 47 patients (29 males/18 females) with TP53 mutation prior to allo-SCT with primary diagnosis of AML (55.3%) or MDS (44.7%) (Table 1). The median follow-up was 25.4 months with 2-year OS of 32.8% for the entire cohort. The median age at diagnosis was similar between TP53-cleared and TP53-persistent groups with 68% of the patients >= 60 years at the time of allo-SCT. Only 26% (n=12) had clearance of their TP53 mutation prior to allo-SCT. The majority of the patients had complex cytogenetics at diagnosis (85%) with deletion 5q being the most common coexisting aberration (75% in TP53-cleared and 68.6% in TP53-persistent, p=NS). Patients with TP53 clearance received hypomethylating agent (HMA) as frontline treatment more frequently compared to those with persistent TP53 (66.7% vs. 45.7%, p=NS). They also had fewer lines of therapy (83.3% with 1 line vs. 62.9%, p=NS), and a higher rate of complete response prior to allo-SCT (83.3% vs. 57.1%, p=NS). Amongst patients receiving HMA as frontline therapy (n=24), we observed significantly better survival in TP53-cleared patients compared to those with persisted TP53 (median OS of 21.73 months vs. 6.44 months, p=0.042) (Figure 1). Myeloablative conditioning (MAC) regimen was used in 33.3% of TP53-cleared in comparison to 42.9% in TP53-persistent cohort (p=NS). Median OS was 21.7 months for patients with clearance of TP53 vs. 8.1 months for those with persistent TP53 at allo-SCT; although it did not meet statistical significance (p=0.106). MAC compared to reduced intensity conditioning (RIC) regimen resulted in significantly worse RFS (HR 2.06, 95% CI 1.04-4.12, p=0.040) and OS (HR 2.70, 95% CI 1.30-5.60, p=0.008). Conditioning intensity was the only factor that significantly influenced RFS and OS outcomes (Table 2). When repeating these analyses separately on the TP53-cleared and TP53-persistent groups, only the latter remained significant for conditioning (MAC, univariate OS: HR 2.6, 95% CI 1.14-5.92, p=0.023). Conclusions: TP53 clearance at the time of allo-SCT is predictive of better outcomes in patients who had frontline HMA therapy. For patients with persistent TP53 at the time of allo-SCT, those received MAC experienced worse outcomes compared to RIC in this cohort. The OS at 2-year for TP53-persistent patients is over 30% suggesting even these patients can potentially benefit from transplantation. Disclosures Talati: Celgene: Honoraria; Agios: Honoraria; Pfizer: Honoraria; Astellas: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Sallman:Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Research Funding; Incyte: Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau. Bejanyan:Kiadis Pharma: Other: advisory board. Kuykendall:Celgene: Honoraria; Incyte: Honoraria, Speakers Bureau; Janssen: Consultancy; Abbvie: Honoraria. Padron:Incyte: Research Funding. Komrokji:Incyte: Consultancy; Agios: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau; celgene: Consultancy; DSI: Consultancy; pfizer: Consultancy. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy. Sweet:Incyte: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Stemline: Consultancy; Pfizer: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees.

INTRODUCTION: Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic cell transplant (HCT) resulting in significant morbidity and mortality. The combination of tacrolimus and sirolimus (TAC/SIR) has emerged as a GVHD prophylaxis platform preferred by many institutions given its association with rapid engraftment and acceptable transplant-related toxicity. However, overlapping toxicities between the two drugs can lead to intolerance and premature discontinuation in some patients. There is limited literature describing outcomes and subsequent management of such patients. The goal of this study is to investigate the clinical outcomes of patients becoming intolerant to the combination of TAC/SIR prophylaxis. METHODS: We retrospectively evaluated consecutive adult patients (n=100) at the Moffitt Cancer Center who received allogeneic HCT with TAC/SIR for GVHD prophylaxis in 2018. TAC/SIR intolerance was defined as discontinuation due to the toxicity of either TAC or SIR before post-transplant day 100. Survival analyses were estimated from the time of transplant with the Kaplan-Meier method and compared using the log-rank test. Patients intolerant of this prophylaxis regimen were compared to patients who completed >100 days of therapy, using Mann-Whitney U test for continuous variables and Pearson Chi-square tests for categorical variables. All statistical analyses were performed using SPSS v25 and NCSS v11. RESULTS: Demographics and clinical characteristics of all patients are summarized in Table 1A. TAC/SIR intolerance occurred in 25% (24 discontinued TAC, 1 discontinued SIR) of patients at a median duration of therapy of 19 days (range 4-92). The most common TAC/SIR toxicity (Table 1B) was acute kidney injury (AKI, n=11, 44%), followed by thrombotic microangiopathy (TMA, n=3, 12%). Baseline metabolic and clinical variables including creatinine, liver function, and conditioning intensity were not predictive of TAC-SIR intolerance. At a median follow-up of 10 months, the median overall survival (OS) for patients intolerant of TAC/SIR was 10 months versus was not reached for the patients without intolerance (HR 5.42; 95% CI 1.71-17.14; p CONCLUSIONS: Outcomes for patients completing over 100 days of TAC/SIR for GVHD prophylaxis following allogeneic HCT are favorable. However, early intolerance of TAC/SIR GVHD prophylaxis occurred in 25% of allogeneic HCT in 2018 alone and predicted a poor prognosis with increased NRM and overall mortality, largely from drug-related toxicities. Notably, premature discontinuation of TAC/SIR did not contribute to higher subsequent risks of GVHD. Strategies to mitigate the risks of TAC/SIR toxicity are warranted. Future studies are also needed to identify the optimal GVHD prophylactic regimen for patients after TAC/SIR intolerance. Disclosures Nishihori: Novartis: Research Funding; Karyopharm: Research Funding. Bejanyan:Kiadis Pharma: Other: advisory board.

Introduction: Higher infused total nucleated cell dose (TNC) in allogeneic bone marrow transplant (BMT) with post-transplant cyclophosphamide (PTCy) resulted in improved overall survival (OS) in a recent report (McCurdy, et al. BBMT. 2018). As many centers prefer peripheral blood stem cell grafts (PBSCT) with PTCy, the optimal cell dose with this platform requires elucidation. Methods: We retrospectively evaluated 144 consecutive adult patients with hematologic malignancies treated at the Moffitt Cancer Center between 2012-2018 with allogeneic T-cell replete PBSCT followed by PTCy-based graft-versus-host disease (GVHD) prophylaxis. Data were extracted from the Moffitt BMT Research & Analysis Information Network (BRAIN) database. Both myeloablative (n=87) and reduced intensity (n=57) conditioning regimens were included. For analyses, CD34+ cell dose was stratified into low (10x106/kg). TNC was stratified as higher or lower than the median. CD3+ T cell dose was evaluated as a continuous, linear variable. Associations with transplant related survival outcomes were assessed using univariate and multivariate Cox proportional hazard survival models. Fine and Gray regression models were used to assess associations of transplant related endpoints with competing risks. Kaplan Meier curves and cumulative incidence function curves were also plotted. RESULTS: The median follow-up for the entire cohort was 24 months. The median age at PBSCT was 58 (range: 21-76) years. Donors were haploidentical (n=72, 50%), matched unrelated (n=39, 27%), matched related (n=18, 13%), and mismatched unrelated (n=15, 10%). Median CD34+ cell dose was 8.12 x 106/kg (range: 2.27 - 22.4 x 106/kg). Stratified CD34+ dose was low for 16 patients (11.1%), intermediate for 93 patients (64.6%), and high for 35 patients (24.3%). Median CD3+ dose was 2.89 x 108 (range: 2.33 x 105 - 6.54 x 108/kg). Median TNC was 9.66 x 108/kg (range: 3.82 x 108 - 1.04 x 109/kg). Overall, successful neutrophil engraftment by day 30 was achieved in 94% (95% CI 91-98%) and platelet engraftment (>20,000/mL) by day 100 in 87% (95% CI 81-93%) of all patients. The likelihood of neutrophil recovery was similar in the high and low CD34+ cell groups, while it was higher for the intermediate CD34+ cell group (HR=1.52, 95% CI 1.0-2.2; p=0.03). Platelet recovery was similar in the intermediate and high CD34+ cell groups, but significantly lower in low CD34+ cell group (HR=0.38, 95% CI 0.2-0.8; p=0.01). CuI of grade II-IV acute GVHD at day 100 was 39% (95% CI 32-48%) and of grade III-IV acute GVHD was 10% (95% CI 6-17%). CuI of chronic GVHD at 2 years was 50% (95% CI 41-59%). The CD34+ cell dose had no significant impact on either acute or chronic GVHD. Nonrelapse mortality (NRM) at 1 year was 19% (95% CI 13-27%). By CD34+ cell dose, the rates of NRM for low, intermediate, and high dose were 46% (95% CI 25-85%), 15% (95% CI 10-25%), and 15% (95% CI 7-34%), respectively (p=0.002). Relapse rate was 30% at 2 years with no differences across dose levels. Progression free survival (PFS) probability at 2 years was 47% (95% CI 39-57%) for the entire group, 0% (95% CI 0%) for the CD34+ low group, 53% (95% CI 42-65%) for the intermediate group and 51% (95% CI 35-73%) for the high dose group (p=0.0003). Two-year OS for the entire group was 57% (95% CI 49-67%), and was inferior in the low group (0%, 95% CI 0%) with no difference between the intermediate (61%, 95% CI 50-73%) and high (67%, 95% CI 52-87%) CD34+ cell dose groups (p=0.0002). In multivariable modeling, the low CD34+ cell dose group was associated with worse NRM (HR=4.1, 95% CI 1.2-14.5, p=0.03), PFS (HR=2.9, 95% CI 1.3-6.5, p=0.01), and OS (HR=3.2, 95% CI 1.4-7.6, p=0.01) compared with the high group, while there were no differences between the high and intermediate groups. Increasing CD3+ dose was also associated with improved NRM (HR=0.8, 95% CI 0.69-0.97, p=0.02), PFS (HR=0.7, 95% CI 0.5-0.9, p=0.02), and OS (HR=0.7, 95% CI 0.5-0.9, p=0.004). TNC had no impact on survival outcomes. CONCLUSION: In patients receiving allogeneic PBSCT with PTCy, CD34+ cell doses below 5 x 106 cells/kg yielded inferior OS and PFS, attributable to higher NRM. Doses of 5-10 x 106 cells/kg and >10 x 106 cells/kg resulted in comparable outcomes. Higher CD3+ dose/kg was also associated with improved survival outcomes. Overall, this study supports targeting a CD34+ dose of >5 x 106 cells/kg for allogeneic PBSCT with PTCy. Disclosures Nishihori: Novartis: Research Funding; Karyopharm: Research Funding. Bejanyan:Kiadis Pharma: Other: advisory board.

Background A cytokine release syndrome (CRS) or neurotoxicity described as a chimeric antigen receptor (CAR) T Related Encephalopathy Syndrome (CRES) is one of the main complications while CD19 CAR T has been successful in relapsed/refractory (R/R) B cell malignancies. CRS and/or CRES have been associated with standard biomarkers such as CRP and ferritin but also with cytokines. We report the results of cytokine analysis using a point of care (POC) device to predict immune-related toxicities in patients with R/R DLBCL treated with axicabtagene ciloleucel (axi-cel). Methods Patients treated with commercial axi-cel in Moffitt Cancer Center were included in this study. Serum samples were collected prior to lymphodepleting chemotherapy at baseline and then during hospitalization. Based on 38 serum cytokineś analysis in B-cell acute lymphoblastic leukemia patients treated with 19-28z CAR T and results of published studies, 8 serum proteins were selected to monitor. CRS and CRES were prospectively graded by Lee criteria and CARTOX respectively. Results 41 patients were identified. Median age was 64 years old (76% male). Non-severe (grade 0-2) and severe (grade 3-5) CRS were observed in 93% and 7% respectively while non-severe and severe CRES were observed in 71% and 29% respectively. 2 patients died in the setting of severe toxicity. Baseline CRP, ferritin, IL-6 levels were significantly elevated in the patients who developed severe CRS and/or CRES. Baseline angiopoietin-2/angipoietin-1 ratio (ANG-2/1) was also correlated with severe CRES. In select cases, monitoring of cytokines provided clinical insight that wasnt evident from standard biomarkers. Conclusions We observed correlations between severe toxicities and elevated serum cytokine levels of baseline IL-6 and ANG-2/1 suggesting that these biomarkers may be utilized to predict severe toxicity in patients treated with CAR T. Monitoring of cytokines using a POC device is feasible and would be useful clinically.

CONTEXT: Quality of life is increasingly recognized as an important outcome of cancer treatment. Previous studies have examined clinical predictors of quality of life, but with the increasing prevalence of wearable sensors that monitor sleep and activity patterns, further investigation into whether these behaviors are predictive of post-treatment quality of life is now feasible. Among patients receiving aggressive cancer treatment such as hematopoietic cell transplantation (HCT), analysis of circadian rhythms (24-hour patterns of sleep and activity) via wearable sensors is limited. OBJECTIVE: Evaluate the relationship between overall quality of life and circadian rhythms in patients receiving allogeneic HCT. METHODS: Patients wore an ActiGraph GT3X (Pensacola, FL) activity monitor for at least 72 hours prior to the initiation of conditioning chemotherapy and transplantation, and completed a quality of life (FACT-G) assessment. Quality of life assessments were also completed 1, 3, and 6 months after HCT. RESULTS: Patients (n=45, M age=55) were mostly male (66%) with a total FACT-G score of 80.96 (SD=16.05) pre-HCT. Mixed models revealed robust cross-sectional associations between overall quality of life and multiple circadian rhythmicity parameters, including durations of high physical activity, overall circadian rhythmicity, and earlier starts of daily activity (ps

European LeukemiaNet (ELN) 2017 updated prognostic system for acute myeloid leukemia (AML), which incorporates both cytogenetic and molecular risks, stratifying patients into 3 distinct genetic risk groups: favorable, intermediate and adverse. While most patients in favorable risk group can be cured with chemotherapy alone, the majority of patients in intermediate and adverse genetic risk groups are considered for curative allogeneic hematopoietic stem cell transplantation (alloHCT). However, the impact of ELN 2017 risk classification on survival of AML patients after alloHCT remains unclear. We examined the prognostic significance of ELN 2017 classification on 503 AML patients in first or second complete remission (373 CR1/ 130 CR2) receiving alloHCT at Moffitt Cancer Center) from 2005-2016. Patients were classified into favorable (n=58, 11.6%), intermediate (n=284, 56.8%) and adverse (n=158, 31.6%) ELN risk groups. The median age at alloHCT for the entire cohort was 55 years (range, 18-76 years) and 29% of all patients had many comorbidities (HCT ≥3) at transplant. Disease risk index (DRI) was low in 38 (7.6%), intermediate in 393 (78.6%) and high in 69 (13.8%) patients, and 22% (n=109) of all patients had secondary AML. Myeloablative conditioning was used in 77% (n=389) of patients, while 23% (n=114) received reduced-intensity conditioning regimen. HLA-matched unrelated donor (47%) was the most commonly used donor type, followed by matched related (27.7%) and mismatched donors (n=75, 9.8%). For the entire cohort, 2-year overall survival (OS) was 56% (52-60%) and leukemia-free survival (LFS) was 51% (47-55%). Patients with CR1 and CR2 status at alloHCT had similar OS (58% vs. 53%, p=0.17). We identified that ELN 2017 genetic risk is prognostic of OS after alloHCT in patients with AML: 72% (61-84%) in favorable risk vs. 60% (54-66%) in intermediate risk vs. 45% (38-53%) in adverse risk groups (p Our findings highlight the prognostic impact of ELN 2017 genetic risk on survival of AML patients undergoing alloHCT in CR1/CR2. Patients in the adverse risk group had higher risk of relapse and worse survival. Thus, ELN 2017 prognostic system can help identify AML patients in CR1/CR2 who can benefit from clinical trials offering relapse reduction strategies in order to improve their survival.

Background Precise quantification of skeletal muscle using computed tomography is accessible using cancer patients' standard oncologic images. Reduced muscle mass (i.e. sarcopenia) has been related to mortality, treatment complications and QOL and reduced respiratory muscle strength, however these associations are not well characterized in adult alloHSCT recipients. Methods A consecutive retrospective series (n=296) patients who had allogeneic BMT at a comprehensive Center between 01/2016 and 12/2017. Pre-transplant CT scans were used to quantify skeletal muscle and adipose tissue at the 3rd lumbar (L3) and/or 4th thoracic (T4) vertebra. Tumor and patient characteristics were recorded, including FEV1 by spirometry. Sarcopenia was defined according to Prado et al. (PMID:18539529) Results 296 patients (male n=161; female n=135) were included, all of whom had thoracic-CT; a subset of these (n=195) also had lumbar-CT. Diagnoses were NHL (n=172), AML (n=66) HD (n=14), ALL (n=14), MDS (n=18) and other (MM, MPN, CML; n=12). Patients had increased BMI (male= 28.7 kg/m2, female=26.5 kg/m2), with many patients (♂64.7%; ♀57.0%) meeting criteria for sarcopenia. Rates of sarcopenia were higher (p Men and women were more muscular at T4 than L3. L3 and T4 skeletal muscle areas were moderately correlated (r2 =0.33- 0.47), as were L3 and T4 muscle radiodensities (r2 =0.58-0.63) and subcutaneous fat areas (r2 =0.69- 0.71), (p In multivariable linear regression, independent predictors of muscularity (i.e. T4 muscle index) were age (p=0.005), sex (p=0.000), BMI (p=0.000) and HCT-CI (p=0.057). Disease severity (Armand DRI) (p=0.131) was not significantly associated with T4 muscle index. Similar conclusions were obtained for L3 muscle index. In multivariable linear regression adjusted for sex (p=0.000), age (p=0.000) and HCT-CI (p=0.000) and both T4 muscle index (b 0.252 [95%CI 0.126;0.412] p=0.000) and T4 muscle radiodensity (b 0.165 [95%CI 0.110;0.630] p=0.006) were independently associated with FEV1; Armand DRI (p=0.712) and KPS (p=0.991) were not associated with FEV1. Similar conclusions were obtained when muscle index and radiodensity at L3 were considered. Discussion and Conclusion Lumbar or thoracic CT images are useful for body composition assessment in this population, and reveal high rates of sarcopenia, similar to those reported in very elderly patients. Reduced muscle mass and radiodensity associate with impaired FEV1. More muscular patients were male, younger, of high BMI and had fewer comorbidities.

The International Prognostic Scoring System (IPSS) was recently revised (IPSS-R) under the auspices of the MDS Foundation as a collaborative international effort to refine its prognostic power. Our purpose was to externally validate this new risk model using a large single-institution cohort, determine its prognostic power in patients receiving active treatment, and explore its utility in guiding therapeutic decisions. Data were collected retrospectively from our myelodysplastic syndrome (MDS) database and verified by chart review. Of the data available for 1,088 patients, 152 (14%), 353 (32%), 237 (22%), 190 (18%), and 156 (14%) patients were classified as very low, low, intermediate, high, and very high risk, respectively, with median overall survival (OS) of 90 (95%CI 71–109), 54 (95%CI 50–59), 34 (95%CI 26–43), 21 (95%CI 17–25), and 13 months (95%CI 11–15), respectively (P

Introduction: One of the main complications of adoptive T cell therapy (ACT) is the en-masse activation of tumor-reactive T cells inducing a large release of cytokines followed by activation of other immune cells leading to adverse events. These are classified as a cytokine release syndrome (CRS) or neurotoxicity described as a CAR T Related Encephalopathy Syndrome (CRES). Several biomarkers have been associated with CRS and/or neurotoxicity such as LDH, ferritin and CRP. Cytokines have also been associated with CRS and and/or CRES, but present approaches rely on retrospective study of collected biomarkers. Here, we report the results of cytokine analysis using a point of care (POC) device to predict immune-related toxicities in patients with relapsed/refractory (R/R)DLBCL treated with axicabtagene ciloleucel (axi-cel). Methods: Patients with R/R DLBCL treated with commercial axi-cel were included in this study. Baseline serum samples were collected prior to lymphodepleting chemotherapy and then daily during hospitalization. To select which cytokines to monitor, we retrospectively analyzed 38 serum cytokines in a cohort of 53 patients with R/R B cell acute lymphoblastic leukemia (B-ALL) who were treated with 19-28z CAR T cells. The patients were divided into those requiring treatment with tocilizumab and/or steroids versus those who did not require treatment. We observed several cytokines, including IL-2, IL-6, IL-15 and IFNg, which were significantly elevated in patients with CRS and/or CRES requiring treatment (Figure 1a). Based on this analysis and results of published studies, eight serum proteins were selected in our study including IL-1b, IL-2, IL-6, IL-15, IFNg, TNFa, and angiopoietin-1 &2. We monitored these proteins using a POC device that allows for rapid daily monitoring with a turnaround time of two hours. We established that the results from the POC device strongly correlate with a current gold standard device(Luminex), which has a typical two day turn around time. CRS and CRES were prospectively graded using revised Lee criteria (Lee et al Blood 2014) and the CARTOX group (Neelapu et al. NRCO 2017) respectively by an experienced clinical team and confirmed by chart review retrospectively. Results: A total of 20 patients with R/R DLBCL treated with commercial axi-cel were identified. Median age 64 years ( range 43-73) with 80% male.In our cohort, grades 1-3 CRS were observed in 45%, 40% and 5% respectively. There were no observed grade 0 or grade 4 CRS. There were two patients (10%) who died in the setting of severe toxicity. Patients with grade 5 CRS had higher levels of IL-6 and angiopoietin 2/angiopoietin 1 ratio at day one, which correlated with severity of toxicity r=0.52 (p= 0.039) , and r=0.53 (p=0.033) respectively (Fig. 1b). Furthermore, patients with high grades CRS had elevated levels of IL-15 at day seven (r=0.83, p=0.006). The majority of patients (55%) had grade 1-2 CRES.There were no significant correlations between serum cytokine levels and CRES or between those who required tocilizumab/steroids vs. those who did not, likely due to the small sample size. In select cases, daily monitoring of cytokines using the POC device provided clinical insight that wasn't evident from standard biomarkers. For example, one patient who developed delayed CRS had high serum levels of IL-6 but did not have elevated levels of CRP(Fig.1c). Discussion: In this analysis of 20 patients, we observed a correlation between severe CRS and elevated serum cytokine levels of IL-6 and angiopoietin 2/angiopoietin 1 ratio at day one suggesting that these biomarkers may be utilized to predict severe toxicity in patients treated with ACT. While this study is limited by small sample size, our observations correlate with previously published biomarkers data in patients enrolled in clinical trials. To our knowledge this is the first reported cytokine data using commercial axi-cel. Monitoring of cytokines using a POC device is feasible and will be useful clinically. High risk patients may be identified early and help guide intervention in real time, for example day one elevated IL-6 levels might inform earlier use of tocilizumab. We continue to enroll patients to validate cytokines as predictive biomarkers with the goal of informing the development of preventative strategies to mitigate CAR T cell therapy immune related adverse events. Disclosures Locke: Cellular BioMedicine Group Inc.: Consultancy; Kite Pharma: Other: Scientific Advisor; Novartis Pharmaceuticals: Other: Scientific Advisor. Brentjens:Juno Therapeutics, a Celgene Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Park:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Kite Pharma: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Shire: Consultancy. Davila:Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees.

We hypothesized that tobacco usage is an independent prognostic factor in patients with myelodysplastic syndromes (MDS). To evaluate the impact of tobacco usage in this population, we identified patients diagnosed with MDS in our Center’s MDS database and reviewed individual charts retrospectively. Of the 767 MDS patients identified, 743 patients (97%) had a known tobacco usage history. Given that the majority of tobacco users were smokers, we stratified patients as having never smoked (never-smoker group) versus current or former smokers (ever-smoker group). Greater than 60% of ever-smokers were risk stratified as having low or intermediate-1 (int-1) risk at diagnosis based on the International Prognostic Scoring System for MDS. In patients with lower-risk MDS, we found that ever-smokers had an increased proportion of poor-risk karyotypes (8.8%) compared with never-smokers (2.4%) (P = 0.003). The adverse effect of smoking was greatest in the low-risk and int-1-risk groups, where median overall survival was 69 months (95% CI 42–96) in never-smokers versus 48 months (95% CI 41–55) in ever-smokers (P = 0.006). The median overall survival for never-smokers, former smokers, and current smokers was 69 months (95% CI 42–96), 50 months (95% CI 43–57), and 38 months (95% CI 23–53), respectively, in patients risk stratified as lower-risk MDS (P = 0.01). Our findings suggest that tobacco usage negatively impacts overall survival in patients with lower-risk MDS.

s / Biol Blood Marrow Transplant 21 (2015) S322eS354 S344 Teresa Field , Linda Kelley , Mohamed Kharfan-Dabaja , Frederick L. Locke , Asmita Mishra , Michael L. Nieder , Taiga Nishihori , Jose-Leonel Ochoa-Bayona , Lia Elena Perez , Marcie L. Riches , Claudio Anasetti . 1 Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; 2 Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL Standard primary therapy for chronic graft vs. host disease (GVHD) is incompletely effective. Based on biologic insights implicating pathogenic B cells, we conducted a phase I-II trial examining the combination of standard ( 1mg/kg/day prednisone) glucocorticoid therapy with ofatumumab, a humanized anti-CD20 monoclonal antibody, for primary chronic GVHD therapy (NCT01680965). We here report the results of the phase I trial. Patients age 18 with NIH Consensus moderate-severe chronic GVHD newly requiring 1mg/kg/day prednisone were treated at three escalating dose levels (300mg, 700mg, and 1,000mg) of IV ofatumumab on day 1 and 14 of initial glucocorticoid therapy. Dose-limiting toxicity (DLT) was defined by the following: grade 4 infusion reactions, related grade 4 constitutional symptoms, related grade 3 organ toxicities, and grade 4 neutropenia lasting >14 days. Secondary endpoints included: adverse events, infectious complications, clinical response to therapy including reduction in prednisone dose, and serial measures of lymphocyte subsets and immunoglobulins. A total of 12 patients (median age 54, range 25-72) were treated (dose level 1: n1⁄43; level 2: n1⁄43; level 3: n1⁄46). At enrollment, overall chronic GVHD was moderate (n1⁄47) or severe (n1⁄45), with diverse organ involvement (skin: n1⁄48; mouth: n1⁄48; eye: n1⁄48; lung: n1⁄44; GI: n1⁄43; liver: n1⁄45; genital: n1⁄42; joint/fascia: n1⁄45), and both overlap (n1⁄47) and classic (n1⁄45) sub-types were represented. KPS was 80% in 11/12, median platelet count was 164 (range 92287), and median bilirubin 0.6 (range 0.2-0.9). Infusion of ofatumumab was well tolerated: Two infusion reactions (grades 2 and 3) occurred, resolved with supportive care, and all patients completed d1 and 14 infusions. No DLT was observed. From the total number of adverse events (n1⁄427), possibly related AE (n1⁄43) included grade 1 fatigue, grade 1 transaminitis, and grade 3 hand/foot cramping. Infectious complications were expected, and there were no cases of hepatitis B reactivation or progressive multifocal leukoencephalopathy (PML). At 3 months after therapy initiation, overall clinical response among evaluable patients was CR (n1⁄41), PR (n1⁄47), or SD (n1⁄41), and responses were sustained at 6 months (including one conversion from PR to CR). Encouraging reduction in prednisone dose was observed at 3 (median 89%, range 57-100%) and 6 months (median 93%, range 71-100%). Therapy produced significant B-lymphopenia (figure). Ofatumumab in combination with prednisone is safe, and phase II examination of efficacy is ongoing.

We prospectively evaluated the allogeneic hematopoietic cell transplantation (HCT) outcomes in high-risk myelodysplastic syndrome (MDS) patients who received pretransplantation 5-azacitidine. Twenty-five patients evaluated for allogeneic HCT consult and considered medically eligible for a donor search were enrolled. Azacitidine was administered at 75 mg/m2 for 5 to 7 days every 4 weeks until a suitable donor was found. A median of 3 (range, 0 to 6) cycles of 5-azacitidine were administered. Preallogeneic HCT responses to 5-azacitidine, based on the International Working Group criteria, were 48% partial response, 33% stable disease, and 19% progressive disease. Four patients did not proceed to allogeneic HCT. Twenty-one patients, a median age of 55 (range, 25 to 67) years, received allogeneic HCT after myeloablative pharmacokinetically targeted i.v. busulfan and fludarabine conditioning regimen. Donors were either HLA-matched related or unrelated, except for 1 mismatch unrelated donor. With a median follow-up of 30 months, 1-year relapse-free and overall survivals were 52% (95% confidence interval [CI], 30% to 71%) and 62% (95% CI, 38% to 79%), respectively. Preallogeneic HCT 5-azacitidine administration was well tolerated and provided reasonable disease control before allogeneic HCT. (Registered at ClinicalTrials.gov as NCT00660400).

Introduction: Fludarabine (Flu)-based conditioning regimens, combined with either melphalan (Mel) or intravenous busulfan (Bu), are often utilized in patients undergoing allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). While recent data supports that a myeloablative conditioning (MAC) strategy improves survival in patients who are able to tolerate this approach, the optimal regimen for patients elderly or unfit for MAC remains unclear. A single-center retrospective analysis was performed to evaluate outcomes in patients with AML or MDS deemed eligible only for reduced intensity regimens. Methods: Patients with AML and MDS who underwent peripheral blood mobilized allogeneic HCT at a single institution between January 2008 and December 2014 were identified. Of those, patients who received conditioning with either once-daily Bu (75-95 mg/m2) targeted to an area under the curve of 3500 µM*L/min and Flu 160 mg/m2 (Flu/Bu 3500) or Mel 140 mg/m2 plus Flu 120-160 mg/m2 (Flu/Mel) were evaluated and compared. All disease statuses (complete remission (CR), second CR, or with active disease) at time of HCT were included. Regimen toxicities, cumulative incidences of acute and chronic graft-versus-host disease (GVHD), non-relapse mortality (NRM), cumulative incidence of relapse (CIR), progression free survival (PFS), and overall survival (OS) were evaluated. Results: We identified 150 consecutive patients who received Flu/Bu 3500 (n=81) or Flu/Mel (n=69). Regimens were selected at physicians' discretion. The median ages for Flu/Bu 3500 and Flu/Mel were similar (66.9 (range, 48.2-75.9) and 65.8 (40.9-75.2) (p=0.14)). No differences were detected between the two groups with regard to recipient and donor gender, primary disease, donor type, recipient and donor cytomegalovirus (CMV) status, and Karnofsky performance status. Additionally, there were no differences between either groups in disease specific prognostic variables such as Disease Risk Index (Armand et al.), blast percentage at time of HCT, International Prognostic Scoring System (IPSS) and revised IPSS scoring in MDS patients, or AML cytogenetics at time of HCT. Patients receiving Flu/Mel had higher HCT-specific comorbidity index (HCT-CI, >3) when compared to Flu/Bu 3500 prior to transplantation (66.7% versus 46.9%, p=0.02). OS was similar between both arms (p=0.1) as was NRM (Hazard ratio (HR) 0.61 (CI, 0.34 - 1.1, p=0.1)) and PFS, HR 1.26 (CI, 0.83 - 1.94, p=0.2). However, CIR at 2 years post-allograft was significantly higher in the Flu/Bu 3500 arm, HR 2.54 (CI, 1.4 - 4.6, p=0.002) in comparison to Flu/Mel regimen (Figure 1). There was no difference detected in the cumulative incidences of either grades 2-4 acute GVHD, HR 1.00 (CI, 0.66 - 1.55, p=1.0), or grades 3-4 acute GVHD, HR 0.66 (CI, 0.27 - 1.57, p=0.3) between either conditioning regimen. The cumulative incidence of chronic GVHD was also similar, HR 1.27 (CI, 0.84 - 1.92, p=0.2). With regard to toxicity, diarrhea occurred more frequently in the Flu/Mel arm (p=0.0003) in the first 20 days following transplant. However, in the same period, mucositis occurred more frequently in the Flu/Bu 3500 arm (p=0.005). No differences were noted between the arms when assessing incidence of sinusoidal obstructive syndrome, diffuse alveolar hemorrhage, or thrombotic microangiopathy up to 90 days. Amongst patients receiving Flu/Mel, the most common cause of death was pneumonia or pulmonary failure (n=7) whereas the most common cause of death in the Flu/Bu 3500 arm was disease related (n=31). Conclusion: Flu/Mel resulted in a lower CIR at 2 years post-HCT compared to patients receiving Flu/Bu 3500 conditioning. Regarding toxicity, Flu/Mel produced more diarrhea but significantly less mucositis in comparison to Flu/Bu 3500; otherwise toxicity was comparable. Though there were no differences in OS and NRM between the two conditioning regimens, we speculate that the impact of the higher HCT-CI in the Flu/Mel arm may have contributed negatively to the lack of benefit in NRM and OS. Disclosures Locke: Kite: Membership on an entity's Board of Directors or advisory committees. Nishihori:Signal Genetics: Research Funding; Novartis: Research Funding. Fernandez:Chimerix: Honoraria; Otsuka: Honoraria; Sanofi: Speakers Bureau.