Abstract: HLA-haploidentical hematopoietic cell transplantation (Haplo-HCT) using posttransplantation cyclophosphamide (PT-Cy) has improved donor availability. However, a matched sibling donor (MSD) is still considered the optimal donor. Using the Center for International Blood and Marrow Transplant Research database, we compared outcomes after Haplo-HCT vs MSD in patients with acute myeloid leukemia (AML) in first complete remission (CR1). Data from 1205 adult CR1 AML patients (2008-2015) were analyzed. A total of 336 patients underwent PT-Cy–based Haplo-HCT and 869 underwent MSD using calcineurin inhibitor–based graft-versus-host disease (GVHD) prophylaxis. The Haplo-HCT group included more reduced-intensity conditioning (65% vs 30%) and bone marrow grafts (62% vs 7%), consistent with current practice. In multivariable analysis, Haplo-HCT and MSD groups were not different with regard to overall survival (P = .15), leukemia-free survival (P = .50), nonrelapse mortality (P = .16), relapse (P = .90), or grade II-IV acute GVHD (P = .98). However, the Haplo-HCT group had a significantly lower rate of chronic GVHD (hazard ratio, 0.38; 95% confidence interval, 0.30-0.48; P & lt; .001). Results of subgroup analyses by conditioning intensity and graft source suggested that the reduced incidence of chronic GVHD in Haplo-HCT is not limited to a specific graft source or conditioning intensity. Center effect and minimal residual disease–donor type interaction were not predictors of outcome. Our results indicate a lower rate of chronic GVHD after PT-Cy–based Haplo-HCT vs MSD using calcineurin inhibitor–based GVHD prophylaxis, but similar other outcomes, in patients with AML in CR1. Haplo-HCT is a viable alternative to MSD in these patients.

Abstract: Introduction: Plasmablastic lymphoma (PBL) is a rare and aggressive lymphoma, with an immunophenotype of a terminally differentiated B-lymphocyte. It is more likely to occur in HIV-positive individuals, commonly involves oral sites, and is associated with EBV infection. However, in recent years, there have been several case reports suggesting the changing epidemiology of PBL affecting HIV-negative patients and increasingly involving non-oral sites. In order to investigate the epidemiology of PBL we conducted a retrospective analysis of all consecutive patients diagnosed with PBL at Montefiore Medical Center between Jan 1997 and May 2014. Patient demographics, tumor location and pathological characteristics, laboratory data, treatment received, and survival data were recorded. Results: A total of 16 patients (8 males, 8 females) with PBL were identified. Median age of all patients was 55.5 years (IQR, 37.3- 62.0), 10/16 (62.5%) patients were HIV positive (median age, 39.5; median CD4, 151.5) and 6/16 (37.5%) were HIV negative, including one post renal transplant patient. Most of the patients had extra-oral involvement 11/16 (68.8%) with the commonest extra-oral site being the GI tract. Half of the patients were Ann Arbor Stage III or IV and the median LDH was only mildly increased at 256 (IQR, 200.5-431.5) despite these tumors having a high Ki67. All tumors were CD20 negative and positive for CD138. EBV encoded small RNA (EBER) was positive in 13/16 patients (81.3%) and was more sensitivie than the EBV latent membrane protein 1 which was positive in only 68.8% of patients suggesting EBV infection. HHV-8 was negative in 12/16 (75%) patients. Only half of the patients (62.6%) had evidence of free light chain restriction (Kappa-restricted, 43.8%, Lambda-restricted, 18.8%). Data on Ki67 was available in 12/16 patients, and 8/12 patients had a Ki67 of 〉 =90%. 4/12 (33.3%) patients had a Ki67 = 〈 50%. Most of the patients received chemotherapy (75%), of which, 7/12 (58.3%) patients received combination chemotherapy with EPOCH. 3/12 (25%) received consolidation with autologous stem cell transplantation. The median overall survival calculated as the number of months from diagnosis to last follow up or date of death was 17 months (0-54). It is of note that 3/16 patients were initially diagnosed with solitary extramedullary plasmacytoma (SEP)/plasmacytoid neoplasm, and the disease course led to revision of the diagnosis to PBL. Conclusion: This is an important study highlighting the epidemiological changes in PBL, an aggressive B cell neoplasm, which is not limited to the HIV-positive population, nor to oral sites. In fact, more than half of our patients with PBL presented with tumors involving extra-oral sites. These tumors were CD 20 negative, and CD 138 positive, and the majority were EBER positive and HHV8 negative. A low Ki67 does not rule out the diagnosis of PBL. Distinction of PBL from SEP may be challenging and the aggressive clinical course of the former may occasionally be the only pointer to the diagnosis. Overall prognosis remains poor and new approaches are warranted in the management of this disease. Disclosures No relevant conflicts of interest to declare.

Abstract: Background: Carfilzomib and Bendamustine are currently FDA approved for therapy of relapsed refractory multiple myeloma (MM). Bendamustine, in addition to interference with DNA replication, it can induce inhibition of mitotic checkpoints, inefficient DNA repair, and initiation of a p53-dependent DNA-damaging stress response leading to apoptosis of tumor cells (1). It has previously shown significant activity in relapsed myeloma (2). Carfilzomib is a second generation, irreversible proteasome inhibitor has demonstrated promising activity in first line therapy (3,4). we hypothesized that combining them will yield an effective induction regimen in the newly diagnosed MM. Study design: Inclusion criteria included newly diagnosed MM with measurable disease, age ≥18, ECOG PS 0-2, adequate renal (creatinine clearance 〉 30 mL/min), cardiac and hepatic function. Carfilzomib was given IV on days 1, 2, 8, 9, 15, 16. All patients received 20 mg/m2 on days 1 and 2 of cycle 1, after which their dose was escalated to one of the following levels: 27, 36, 45, or 56 mg/m2. Bendamustine IVPB on days 1, 2, at 70 (dose levels 1 and 2) or 90 mg/m2 (dose levels 3-5). Dexamethasone 20 mg PO or IV D 1, 2, 8, 9, 15, 16, 22, 23. Each cycle of therapy was 28 days, and a total of 8 cycles was given. Stem cell harvest was done after 4 cycles and eligible patients proceeded to ASCT after 8 cycles. Maintenance was recommended - either carfilzomib (36mg/m2 D 1,2, 15, 16 of a 28-day cycle for 2 years, or investigator's choice. Primary objective was to determine the recommended phase 2 dose (RP2D) and additional objectives assessed efficacy and safety. Results: Between February 2014 and May 2018, 20 patients with newly diagnosed MM pts were accrued onto study (5 pts in phase I and 15 in phase II). Median age was 65 (range 48-74), and 14 (70%) patients were male. 7 (35%) were of Hispanic ethnicity. 3 patients (15%) were R-ISS stage 3, and 1 (5%) had high-risk cytogenetics. We did not observe any DLTs with our study treatment and established the RP2D as: carfilzomib 56 mg/m2, bendamustine 90 mg/m2 and dexamethasone 20 mg on the dosing schedule given above. The most common and severe toxicities were hematologic. Grade 3/4 hematologic toxicities were lymphocytopenia in 90% of patients, neutropenia 40%, anemia 20% and thrombocytopenia 20%. Notable non-hematologic toxicities were grade 3/4 infection in 20% of patients (typically upper respiratory and pneumonia), grade 1/2 acute kidney injury in 45% of patients, and grade 1/2 diarrhea in 40% of patients. No treatment emergent hypertension or heart failure were noted. 1 patient died while on study, from septic shock due to pneumonia 7 weeks after completion of induction. The regimen was highly effective, with an ORR of 100%. Best responses were: 2 (11%) PR, 5 VGPR (26%), and 12 CR (63%) (Figure 2). Among the CRs, 4 were MRD-positive, 5 were MRD-negative, and 3 did not have MRD testing. With a median follow-up of 28 months (range 11-71), 2 patients have progressed - 1 with del(17p) at 19 months after diagnosis, and the other with standard cytogenetic risk disease at 56 months. 2 patients have died - the patient with del(17p) from refractory myeloma at 37 months after diagnosis, and the other from septic shock as discussed above. Median PFS was 56 months, and median OS has not been reached. Conclusion: Carfilzomib, Bendamustine and Dexamethasone is safe and highly effective for newly diagnosed transplant eligible MM and should be further explored in a larger prospective trial for this patient population. References: 1. Leoni LM, Hartley JA. Mechanism of action: the unique pattern of bendamustine-induced cytotoxicity. Seminars in hematology 2011;48 Suppl 1:S12-23. 2. Lentzsch S, O'Sullivan A, Kennedy RC, et al. Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study. Blood 2012;119:4608-13. 3. Dimopoulos MA, Goldschmidt H, Niesvizky R, et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. The Lancet Oncology 2017;18:1327-37. 4. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 2012;120:1801-9. Disclosures Bhutani: Sanofi: Membership on an entity's Board of Directors or advisory committees. Assal:Incyte corporation: Consultancy, Research Funding; boston biomedical: Consultancy. Lentzsch:Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy; Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy. OffLabel Disclosure: Carfilzomib, Bendamustine and Dexamethasone for newly diagnosed multiple myeloma.

Abstract: Whether a complication of gynecologic surgeries or a peripartum event, ovarian vein thrombosis (OVT) remains poorly understood, with no consensus regarding its importance or treatment. In an effort to better understand the significance of OVT, we investigated the incidence, clinical features, predisposing factors, future thrombotic complications, and therapeutic patterns of this condition. Methods : We collected cases of OVT in adult women encountered over the 10 years. Data mining software was used to search the text of imaging reports for the terms ovarian or gonadal located within 5 words of the terms thrombus, thrombosis or thrombosed. Records were reviewed to confirm diagnosis and collect demographic data, presentation and features of OVT at baseline, past medical and surgical history, and future venous thromboembolism (VTE) events. Follow up period was defined as date of last EMR entry. All chart review were conducted by study authors and discrepancies reviewed by at least two authors. Data were analyzed using Chi-squared, t-testing for unpaired samples, and ANOVA. Results : 223 cases of confirmed OVT were identified and included in the analysis. Average follow-up time was 1163 (±977) days. The majority of cases were identified on computed tomography (CT) imaging (n=219). Mean age was 55 years (range 20 - 89 years). History of VTE was noted in 22 patients, diabetes in 44 patients and cancer in 134 patients, 64.3% of which were gynecologic. In a majority of patients, OVT was associated with a history of abdominal surgery; 60.5% of these were gynecologic procedures and 83.7% of those included a hysterectomy. Only 36.6% were noted to have otherwise unexplained abdominal pain. Chemotherapy was administered to 99 (44.4%) patients, 57 (57.6%) of which developed OVT during chemotherapy. Taxol was used in 61 patients (61.6%); 43 (70.5%) of which developed OVT during Taxol therapy. The incidence of right (R) or left (L) OVT was similar (44.6% vs. 41.4% respectively) with a high percentage of bilateral (B) thrombi (14%). Peripartum state was associated with an increase in ROVT (60.0% versus 43.1%, p=0.033); cancer patients had a higher incidence of LOVT and BOVT compared to non-cancer patients (46.6% and 18.8% vs. 33.7% and 6.7% respectively, p=0.0005). Gynecologic surgery was also associated with an increase in LOVT and B OVT (44.0% and 18.7% versus 37.5% and 6.8% p=0.007). Our cohort experienced 26 (11.7%) recurrent VTE events, 20 DVTs and 6 PEs (Table 1). Average time to recurrence was 393.5 (±400) days. Past VTE was associated with a higher risk of future DVT but not PE (22.0% and 0%, p=0.046 for VTE). No recurrent VTE events were noted in the peripartum group, however this did not reach statistical significance (p=0.089). Even when peripartum patients were excluded, LOVT and BOVT were associated with a higher VTE recurrence rate than ROVT (16.3% and 19.4%, p=0.01). Patients with cancer tended to have a higher VTE recurrence rate than non-cancer patients, but this did not reach statistical significance (14.2% versus 7.9%, p=0.15). However, recurrence was associated with greater mortality (p=0.002). Anticoagulation was initiated at the time of OVT diagnosis in only 21 (9.4%) patients, with 4 VTE recurrent events. Conclusion: This is the largest OVT study to date. We demonstrate that OVT can occur within either ovarian vein, but occurs predominantly on the right in peripartum patients. We show increased recurrent events in our cohort and an association of recurrence with mortality, which argues against a benign' nature of OVT in post-hysterectomy patients. We were not able to detect increased VTE recurrence in cancer patients, in the peripartum, in diabetics, or in patients with a history of VTE. Anticoagulation initiated at the time of OVT was not associated with decreased recurrence rates but this may be due to selection bias. This study provides evidence that a prospective study of patients is needed to determine the utility of therapy for OVT. Table 1 Subgroup analysis of the risk of future thrombotic events Variable (N) Recurrent VTE N (%) P Value Total (223) 26 (11.7%) Peripartum (20) 0 (0%) 0.089 Cancer (134) 19 (14.2%) 0.15 History of VTE (22) 5 (22.7%) 0.088 Laterality BOVT (31) 6 (19.4%) 0.07 LOVT (92) 15 (16.3%) ROVT (99) 5 (5.1%) Extension Present (17) 3 (17.6%) 0.42 Absent (206) 23 (11.2%) During chemotherapy (57) 9 (15.8) 0.65 Anticoagulated for OVT (21) 4 (19.0) 0.27 Disclosures No relevant conflicts of interest to declare.

Abstract: Introduction: Sickle cell disease (SCD) affects 300,000 annual births globally, and about 100,000 individuals in the United States. Allogeneic hematopoietic stem cell transplant (HSCT) remains the only cure. HSCT risks necessitate a risk-benefit analysis in each case. Excellent long-term overall survival (OS) of 91-95% has been described with matched-sibling (SIB) HSCT, but fewer than 15% of SCD patients have a SIB donor. Matched unrelated donor (MUD) availability is limited for ethnic groups afflicted with SCD. Alternative donor HSCT from mismatched unrelated donors (MMUD) or haploidentical donors improves donor availability but increases toxicity and risk of graft failure. SCD-induced organ damage is another limitation to HSCT. In this study, we review our experience with HSCT for SCD and demonstrate that most patients can receive a curative HSCT despite lack of SIB donor and presence of significant co-morbidities. Methods: All adult SCD patients who received HSCT at our center since 2014 were included. Patients had at least 2 hospitalizations per year for pain crises despite hydroxyurea compliance and evidence of end-organ damage. Patients with a SIB donor (n=6) received conditioning with alemtuzumab and 3Gy TBI (per Hsieh et al, 2009). Patients with MUD/MMUD (n=4) or haploidentical (n=1) donors received conditioning with alemtuzumab, fludarabine, melphalan, and a CD34+ selected graft with CD3+ cell add back on an ongoing clinical trial for non-malignant hematologic diseases. One patient s/p kidney transplant and liver failure requiring TIPS procedure was conditioned with alemtuzumab and 4Gy TBI, received a 10/10 MUD graft, and given post-HSCT cyclophosphamide (50 mg/kg d+3) along with sirolimus continuation as GVHD prophylaxis. GVHD prophylaxis otherwise consisted of sirolimus (n=10) and tacrolimus (n=1). All patients received a G-CSF mobilized peripheral blood stem cell (PBSC) graft and underwent RBC exchange to achieve Hgb S 〈 30%. Results: Twelve patients are included in this analysis. Median age was 28.7 (18.5 - 44.2) years with 6 males and 6 females. Median follow up was 13.6 months (range 1.4 - 51.3). Two patients had stage V renal disease with one patient on active dialysis. Two patient were s/p kidney transplant with one patient awaiting a 2nd kidney transplant. Median CD34 cell dose in SIB and MUD/MMUD HSCT was 14.8 and 8.5 x 10e6 CD34/kg respectively. Median T cell add back in CD34-selected M/MMUD recipients was 2.5 x 10e5 CD3/kg. No G-CSF was used. All patient engrafted with no cases of graft failure or treatment related mortality (TRM). Median time to neutrophil engraftment for SIB and M/MMUD recipients was 24.5 and 19 days respectively. Median time to platelet engraftment was 19 days for M/MMUD recipients and 2 of 6 SIB recipients required only 1 platelet transfusion each. The patient s/p kidney allograft and TIPS for liver failure engrafted neutrophils and platelets on day +22 and +26 respectively. All patients are alive and free of SCD. Available chimerism analysis at 6 months (n=8) shows median myeloid chimerism to be the same in SIB and M/MMUD recipients (99.7%) where median T Cell chimerism was 35% and 65% for SIB and M/MMUD recipients respectively. Chimerism at 1 year shows stable myeloid engraftment and median T cell chimerism of 61.5% for SIB recipients. Two cases of PRES were noted after HSCT, one in a patient on tacrolimus after which the CD34-selected protocol was modified to include sirolimus as GVHD prophylaxis. Another case of PRES was noted on sirolimus which was switched to prednisone and mycophenolate mofetil. Two patients discontinued sirolimus due to myalgias and were switched to tacrolimus on days +44 and +58 with resolution of symptoms. Acute/Late acute GVHD occurred in 4 patients. Three cases were noted in patients treated on the CD34-selected protocol; two MMUD (Grade III and Grade I) and one haploidentical (Grade III) graft recipients. One case of late acute liver GVHD, evident in elevation of liver enzymes and alkaline phosphatase with evidence of hepatitis on biopsy, occurred in a SIB recipient (Grade I). All cases responded to corticosteroid therapy. Conclusion: SCD patients with or without a SIB donor can be offered a curative HSCT that is safe without TRM. SCD patients with severe SCD-related organ damage can also be offered HSCT however further research is warranted to identify optimal conditioning and GVHD prophylaxis regimens for these patients. Disclosures Reshef: Kite Pharma: Consultancy; Atara Biotherapeutics: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda Pharmaceuticals: Consultancy; Pfizer: Consultancy; Incyte: Consultancy.

Abstract: Introduction: The only cure for sickle cell disease (SCD) is allogeneic hematopoietic stem cell transplant (HSCT) although autologous HSCT of genetically engineered hematopoietic stem cells is promising. Lack of suitable matched related donors (MRD) is a major limitation driving interest in improving outcomes using unrelated donors. While excellent outcomes are achieved with non-myeloablative MRD HSCT in adults (Hsieh et al, 2009 and 2014), results from matched unrelated donor (MUD) HSCT have been limited by excessive graft versus host disease (GVHD) and treatment-related mortality (Shenoy et al, 2016). Here we present updated follow up of our institutional experience using MUD and mismatched unrelated donors (MMUD) in comparison to patients with MRD. Methods: Eligibility for HSCT included frequent pain crises requiring hospitalization and evidence of end-organ damage. Non-myeloablative conditioning with alemtuzumab and 3 Gy total body irradiation (TBI) was used for MRD HSCT (n=7), whereas patients without an MRD were transplanted using MUD, MMUD or haploidentical grafts (n=6) on a previously reported institutional protocol after conditioning with alemtuzumab (54 mg/m2), fludarabine (180 mg/m2), and melphalan (140 mg/m2), using a CD34+ selected graft with CD3+ cell add back. MRD recipients received sirolimus as GVHD prophylaxis. Non-MRD recipients initially received tacrolimus as GVHD prophylaxis (n=1) but subsequently received sirolimus (n=5) due to the first patient developing posterior reversible encephalopathy syndrome (PRES). All grafts were G-CSF mobilized peripheral blood grafts and all patients underwent RBC exchange to achieve Hgb S 〈 30%. Data is reported using n (%) or median (range) and Wilcoxon rank-sum test was used for continuous variables. Results: Median follow up is 21.7 months (range 4.7 - 63.4). Median age for MRD recipients was 28.7 (21.4 - 35.5) years and 22.8 (18.5 - 34.6) for non-MRD recipients. Of note, the MRD group included one patient with a renal allograft from the same donor and another with stage V renal disease awaiting a kidney transplant. All patients where homozygous for hemoglobin S except one who had hemoglobin Sβo -thalassemia in the MRD group, and another heterozygous for hemoglobin S and C in the non-MRD group. Patients in the MRD group received unmanipulated grafts with a median of 14 (6.2 - 16.9) x 10E6 CD34+ cells/kg. Non-MRD recipients received CD34 - selected grafts with a median of 7.8 (4.1 - 15.1) x 10E6 CD34+ cells/kg with 2.2 x 10E5 (0.1 - 2.5) CD3+ cells add back. No growth factors were used post-transplant. All patient engrafted with no cases of graft failure. Median time to engraftment was significantly longer for the MRD group at 25 (22 - 30) vs 19 (13 - 21) days, p=0.003. Two patients in the MRD group developed acute/late acute GVHD (2 grade II), and 3 patients in the non-MRD group (1 grade II, 2 grade III), 2 of which developed in while switching immune suppression due to PRES. All GVHD cases were steroid responsive and resolved. Three patients in the non-MRD group developed PRES and none in the MRD group. There were no cases of treatment related mortality and all patients are alive and free of SCD. As both groups received alemtuzumab, and the non-MRD group received a CD34-selected graft, we examined lymphocyte subset reconstitution at day 100 and 1 year post-HSCT. The most striking difference was in median CD8+ T cell counts at day +100 which were lower in the non-MRD group approaching significance [101 (43 - 2995) vs 6.5 (3 - 2233) cells/uL, p=0.055, for the MRD and non-MRD respectively]. CD8+ T-cell counts were not significantly different at 1 year [402 (184 - 1066) vs 774 (143 - 1002) cells/uL, p 〈 0.99]. Results from other lymphocyte subsets including CD4+ T-cells, NK cells and B cells are shown in table 1 and were not significantly different between the 2 groups. Of note, early donor T-cell chimerism at D100 was not significantly different between MRD and non-MRD groups [27.0 (18.0 - 50.0) % vs 37.5 (3.0 - 80.0) %, p=0.83] whereas at 1-year, MRD group donor T cell chimerism was significantly lower [53.5 (17.0 - 65.0) % vs 82.7 (69 - 90), p=0.01]. Conclusion: We demonstrate excellent outcomes with 100% survival and no graft rejection following matched and mismatched unrelated donor HSCT for adult patients with severe SCD. Larger cohorts are needed to confirm these results and further delineate the impact of T-cell subset reconstitution on early-post transplant complications. Disclosures Assal: Incyte corporation: Consultancy, Research Funding; boston biomedical: Consultancy. Bhatia:BMS: Consultancy; Vertex Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Bhutani:Sanofi: Membership on an entity's Board of Directors or advisory committees. Lentzsch:Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy; Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy. Reshef:Magenta: Consultancy; Kite: Consultancy, Research Funding; Atara: Consultancy, Research Funding; Pfizer: Consultancy; BMS: Consultancy; Pharmacyclics: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Celgene: Research Funding; Shire: Research Funding.

Abstract: Introduction: Hematopoietic stem cell transplantation (HSCT) is associated with severe intestinal microbiota injury as a consequence of broad spectrum antibiotics, mucosal damage from conditioning, and dietary changes. Intestinal dysbiosis has been correlated with adverse outcomes post-transplant. We aimed to characterize and compare the patterns of microbiota injury that occur post autologous and allogeneic transplant. We characterized the specific risk factors associated with decreased microbial diversity in HSCT, and defined specific bacterial taxa that are enriched or depleted in patients based on the type of transplant and various other risk factors Methods: Stool samples from 35 patients (pts) undergoing HSCT were collected immediately pre-conditioning, at day 14, 28, and 100 post-transplant. 17 pts underwent an autologous (auto-) and 18 pts underwent an allogeneic transplant (allo-HSCT). The stool microbiome was characterized by sequencing of the V3V4 16s rRNA region; a- and b-diversity were determined and differential abundance analysis of OTUs was performed using DESeq2. Results: In the auto-HSCT cohort 70% of pts had plasma cell dyscrasia, and 24% had non-Hodgkin lymphoma. 83% of pts in the allo-HSCT cohort had a myeloid neoplasm, and 17% had a T cell neoplasm. 33% of pts undergoing allo-HSCT developed grade 2-4 GVHD within 100 days and 56% developed GVHD within 6 months. The pre-transplant intestinal microbiome α-diversity was significantly higher in pts undergoing auto-HSCT compared to allo-HSCT (Fig 1). The etiology for this was likely multifactorial. More pts in the allo-HSCT cohort had received antibiotics within 30 days prior to transplant, compared to the auto-HSCT cohort (56% vs 18%). Pts in the allo-HSCT cohort had a higher proportion of VRE or MDR Gram-negative bacteria on screening cultures (44% vs 29%), which may be associated with domination of certain species. In both the allo- and auto-HSCT cohorts, the α-diversity significantly decreased at days 14 and 28, but recovered to pre-transplant levels by day 100. Pts in the auto-HSCT cohort displayed faster recovery kinetics, and had a significantly higher α-diversity at day 28 compared to the allo-HSCT cohort (Fig 1). The microbiome recovery in the auto-HSCT cohort was consistent across the whole group and was characterized by a much smaller variance compared to the allo-HSCT cohort. This may reflect lower total antibiotic exposure in the auto-HSCT cohort (Fig 2). Other factors specific to the allo-HSCT cohort were the occurrence of GVHD and the use of TBI, both of which were associated with decrease in α-diversity in our population (Fig 3). Of note, Faecalibacterium prausnitzii was found to have a 〉 20 log reduction in both the auto and allo-HSCT cohorts. It is a commensal gut bacterium, and its depletion has previously been reported in inflammatory bowel disease. There is very limited data on this bacterium in the peri-transplant setting. It has an anti-inflammatory effect on the intestinal microenvironment through production of butyrate, inhibition of NF-kB, upregulation of regulatory T cell production, and release of metabolites that enhance intestinal barrier function (Lopez-Siles et al, ISME 2017). Transplantation of F. prausnitzii has been shown to decrease inflammation in mice models of colitis (Sokol 2009). We then evaluated the association between microbiota injury and GVHD. α-diversity was significantly decreased at day 14 and day 28 in pts who developed GVHD within 100 days. In differential abundance analysis of samples from pts who developed acute GVHD within 6 months, there was a 〉 20 log reduction in the Bifidobacterium, Blautia, and Eubacterium Dolichum. Decrease in Blautia has previously been associated with increased GVHD related mortality. Bifidobacterium and Eubacterium Dolichum have not been reported in association with GVHD in humans before. All three bacterial taxa reported here are involved in production of short chain fatty acids, which may provide a common protective mechanism. In summary, this study showed that pts undergoing autologous transplant have a healthier pre-transplant microbial diversity, and that microbiota injury heals quicker after transplant. We have identified TBI as a risk factor for microbiome injury, which has not been previously studied in the context of HSCT. We also identify previously unreported bacterial taxa whose depletion is strongly associated with GVHD. Disclosures Assal: Incyte corporation: Consultancy, Research Funding; boston biomedical: Consultancy. Uhlemann:Merk: Research Funding; GSK: Research Funding; Allergan: Research Funding. Reshef:Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Atara: Consultancy, Research Funding; Magenta: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy, Research Funding; Celgene: Research Funding; Incyte: Consultancy, Research Funding; Shire: Research Funding; BMS: Consultancy.

Abstract: Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment of chronic myeloid leukemia (CML). Optimal conditioning intensity for allo-HCT for CML in the era of tyrosine kinase inhibitors (TKIs) is unknown. Using the Center for International Blood and Marrow Transplant Research database, we sought to determine whether reduced-intensity/nonmyeloablative conditioning (RIC) allo-HCT and myeloablative conditioning (MAC) result in similar outcomes in CML patients. We evaluated 1395 CML allo-HCT recipients between the ages of 18 and 60 years. The disease status at transplant was divided into the following categories: chronic phase 1, chronic phase 2 or greater, and accelerated phase. Patients in blast phase at transplant and alternative donor transplants were excluded. The primary outcome was overall survival (OS) after allo-HCT. MAC (n = 1204) and RIC allo-HCT recipients (n = 191) from 2007 to 2014 were included. Patient, disease, and transplantation characteristics were similar, with a few exceptions. Multivariable analysis showed no significant difference in OS between MAC and RIC groups. In addition, leukemia-free survival and nonrelapse mortality did not differ significantly between the 2 groups. Compared with MAC, the RIC group had a higher risk of early relapse after allo-HCT (hazard ratio [HR], 1.85; P = .001). The cumulative incidence of chronic graft-versus-host disease (cGVHD) was lower with RIC than with MAC (HR, 0.77; P = .02). RIC provides similar survival and lower cGVHD compared with MAC and therefore may be a reasonable alternative to MAC for CML patients in the TKI era.

Abstract: 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 & lt; .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 & lt; .001). Long-term relapse was lower with FM (HR = 0.65, P & lt; .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.

Abstract: Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes in patients with acute myeloid leukemia (AML). We evaluated 8709 patients with AML from the CIBMTR database, and after selection and manual curation of the cytogenetics data, 3779 patients in first complete remission were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis detected an increased risk of relapse for patients with KMT2A-rearranged or adverse-risk AML as compared to those with intermediate-risk disease (hazards ratio [HR], 1.27; P = .01; HR, 1.71; P & lt; .001, respectively). Leukemia-free survival was similar for patients with KMT2A rearrangement or adverse risk (HR, 1.26; P = .002, and HR, 1.47; P & lt; .001), as was overall survival (HR, 1.32; P & lt; .001, and HR, 1.45; P & lt; .001). No differences in outcome were detected when patients were stratified by KMT2A fusion partner. This study is the largest conducted to date on post-HCT outcomes in AML, with manually curated cytogenetics used for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A-rearranged and adverse-risk disease.