ALBERT

Description: Rationale: Allogeneic hematopoietic stem cell transplantation (HSCT) remains the most effective therapy for patients with acute myeloid leukemia (AML). The graft-versus-leukemia effect (GVL), mediated by the engrafted T lymphocytes targeting leukemic cells, is thought to play an important role in affecting the overall outcome of patients with AML. Umbilical cord blood (UCB) has emerged as an alternative and effective source of hematopoietic stem cells in high risk patients. We previously reported the hematopoietic reconstitution and clinical outcomes in 45 patients undergoing haplo-cord transplant, a novel approach which combines haploidentical and cord blood grafts to avoid delayed hematopoietic recovery after cord blood transplant (Liu H,et al. Blood. 2011;118(24):6438-45). However, very little is known about immune reconstitution of cord blood cells and whether the emerging immune repertoire correlates with clinical outcome. The great majority of T cell receptors in T lymphocytes are heterodimers of alpha (TCRA) and beta (TCRB) subunits. Somatic recombination combining the VJ (alpha) and VDJ (beta) segments results in an astronomical functional diversity and complexity of TCR receptors, and makes the characterization of their functions a tremendously complex process. To obtain insights into the T-cell repertoire, we have utilized next-generation sequencing (NGS) technology to comprehensively characterize T-cell kinetics and diversity following haplo-cord transplantation. Methods: We evaluated the emerging T-cell repertoire in 10 patients (pts) with high-risk AML enrolled on a clinical trial of haplo-cord transplantation at the University of Chicago. The median age of the pts was 57 years old (range: 26-67) and 3 pts had active disease at the time of transplant. The median UCB dose was 1.6x107 TNC/kg with HLA cord matching of 4/6 in 3 pts and 5/6 or 6/6 in 7 pts. The median overall and disease free survival were 2.4 and 2.2 years, respectively. cDNA was generated from mRNA isolated from peripheral blood mononuclear cells prior to and at sequential time points 30, 100, 180 and 365 days post haplo-cord transplant were sequenced the samples with Ion Personal Genome Machine (PGM) Sequencer and a 400-bp reading kit. We analyzed the sequences by applying a recently developed algorithm in order to determine the VJ and VDJ combinations and CDR3 sequences. Chimerism was determined by microsatellite sequences of DNA of donor and recipient cells. Diversity was calculated for each of TCRA and TCRB using the inverse Simpson’s index. Results: Several clones found in pre-treatment samples obtained from recipients before transplant persisted at low frequency on days 100 and 365 post-transplant suggesting that these clones have evaded the immuno-suppressive conditioning regimens. In order to correlate the diversity of TCRs with the percentage of cord cells in patients’ blood at different time points, we dichotomized patients into cord present (〉5%) and cord absent (≤5%) groups, based on the cord blood percentage in blood on day 30 post haplo-cord transplant and correlated it with diversity on day 100. We found that TCRs of pts with 〉5% cord cells on day 30 post haplo-cord transplant were significantly more diverse (TCRA; P=0.008) and (TCRB; P=0.01) (Fig.1) on day 100 compared to TCRs in patients with 90% cord cells on day 100 post-transplant. Therefore, we examined the correlation between diversity calculated on day 100 and percentage of persisting haplo-identical cells on the same day. We found,, the diversity of TCRB of pts with persistence of 〉10% haplo-identical cells were 15.05 compared with 72.95 for those with 10% and

Description: Background: Disease relapse remains the primary cause of mortality following allogeneic hematopoietic cell transplantation (alloHCT). One important mechanism of disease relapse in this setting is failure of the graft-versus-tumor (GvT) effect, and the PD-1/PD-L1 axis may diminish GvT after alloSCT. We hypothesized that PD-1/PD-L1 interactions prevent donor-derived T cells from eliminating malignant cells expressing minor histocompatibility antigens, and that blocking PD-1/PD-L1 interactions with the anti-PD-1 antibody, pembrolizumab (pem), might restore GvT and induce clinical responses in patients (pts) with relapsed hematologic malignancies following alloHCT. However, PD-1 blockade therapy has been associated with severe graft-versus-host disease (GVHD) in murine models, and GVHD has been reported in humans treated with anti-PD-1 therapy after alloHCT. Thus, we developed a prospective clinical study to test the tolerability and preliminary efficacy of pembrolizumab in patients with relapsed leukemia/lymphoma after alloSCT. Methods: Pts with AML, MDS, or B cell lymphomas with biopsy-proven recurrence after alloSCT were eligible, as long as no active acute GVHD 〉 grade 1 or chronic GVHD was present. Pts were treated with pem 200 mg IV q3 weeks for up to 2 years, provided that neither intolerable side-effects nor disease progression occurred. Pem could be delayed for treatment-limiting toxicities (TLT), defined as immune-related adverse events (irAEs) not meeting criteria for a dose-limiting toxicity (DLT). DLT was defined as the development of grade 3 or 4 acute GVHD/irAE, any unexpected grade 〉 2 toxicity related to pem, or development of 〉 grade 2 vital organ dysfunction secondary to an irAE within 90 days of pem initiation. A two-stage mini-max design was chosen, with an early stopping rule for DLT after the first 11 patients were enrolled. Results: 11 pts (7 male, 4 female), mean age 49.5 yrs (range, 27-62 yrs) have been enrolled. 8 pts had AML and 3 had lymphoma (DLBCL - 2, cHL - 1). 6 pts had matched-related donors (MRD) and 5 pts had haploidentical/umbilical cord blood (haplo-cord) donors. Pts with MRD were conditioned with fludarabine, melphalan, and alemtuzumab, or fludarabine and busulfan. Pts with haplo-cord donors were conditioned with fludarabine, melphalan, and ATG. 5 pts had prior acute GVHD. Pts relapsed following alloHCT at a median of 453 days (range, 101-1021 days). A median of 2 cycles of pembrolizumab (range, 1-8) was administered. 3 pts are receiving ongoing treatment. 3 pts experienced a DLT due to an irAE (grade 3-4 pneumonitis 2 pts; grade 3 hyperthyroidism 1 pt), all of which occurred after 1-2 cycles of pem, and resolved after pem discontinuation and corticosteroid treatment. 1 pt experienced a TLT (grade 2 rash), but resumed pem treatment. Among all pts, irAEs of any grade occurred in 7 pts. 7 pts were evaluable for response. 3 pts (2 AML, 1 DLBCL) experienced progressive disease (PD), 2 pts (AML) had stable disease (SD), and 2 pts achieved CR (DLBCL, cHL). 1 pt with AML (myeloid sarcoma) in whom pem was discontinued for PD by PET/CT imaging had a concurrent tumor biopsy that revealed marked T cell infiltration and PD-L1 expression on a significant fraction of malignant myeloid cells, suggestive of possible inflammatory "pseudo-progression". 1 pt in CR developed therapy-related AML unrelated to pem. Notably, both patients with CR following pem had PD-L1 gene-amplified lymphomas by FISH, and diffuse PD-L1 protein expression on pre-treatment biopsies. Currently, 4 pts have died, all due to disease progression, and 7 are alive. A total of 26 patients are expected to be enrolled. Conclusions: Treatment with pem in the post-alloHCT disease relapse setting is feasible, but can induce early and severe irAEs, requiring vigilant monitoring. To date, objective responses were seen in 2/3 lymphoma patients treated with pem. In AML, pem may be less effective, where a best response of SD was observed in 2 pts, and possible "pseudo-progression" in a patient with myeloid sarcoma. This study continues to accrue pts, and correlative analyses are underway. To our knowledge, these are the first prospective data of PD-1 blockade therapy in the post-alloHCT setting. Disclosures Kline: iTeos: Research Funding; Merck: Honoraria, Research Funding. Liu:BMS: Research Funding. Curran:Merck: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Smith:BMS: Consultancy; Portola: Honoraria. Bishop:Juneau Therapeutics: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; United Healthcare: Employment; Novartis Pharmaceuticals Corporation: Speakers Bureau.

Description: Background: Myeloproliferative neoplasms (MPNs) that progress to an accelerated phase (AP) or blast phase (BP) have poor outcomes with a median survival of 3 to 5 months. Approximately 20% of MPN-BP patients have a pathogenic mutation in IDH1 or IDH2. Ivosidenib and enasidenib, inhibitors of the IDH1 and IDH2 mutant enzymes respectively, provide a new treatment approach for high-risk IDH-mutated acute myeloid leukemia (AML). There are limited clinical trial data and real-world experience with IDH inhibitors in MPN-AP/BP. We hypothesized that patients with IDH-mutated MPN-AP/BP may benefit from IDH inhibitor therapy. We performed a single institution retrospective analysis of patients with AML arising from a prior chronic myeloid neoplasm treated with an IDH inhibitor and evaluated outcomes of the MPN-AP/BP patients. Methods: Retrospective chart review was done to identify patients with IDH1/2-mutated MPN AP/BP, AML arising from myelodysplastic syndrome (MDS-AML), or AML arising from CMML (CMML-AML), that were treated with ivosidenib or enasidenib from 1/1/2009-5/14/2019. Response was assessed using both the 2003 International Working Group AML (2003 IWG AML) criteria and 2017 European LeukemiaNet (ELN) criteria. For the MPN-AP/BP patients, response was also assessed using the 2012 Post-MPN AML Consortium (2012 MPN-BP) criteria (Mascarenhas et al. Leuk Res 2012). Overall survival from initiation of IDH inhibitor therapy and adverse event data were collected. Results: There were 96 patients with IDH1 or IDH2 mutations identified by analysis of Next Generation Sequencing (NGS) data. 15 of these patients underwent treatment with an IDH inhibitor and had an antecedent chronic myeloid neoplasm: 7 MPN-BP, 1 MPN-AP, 5 MDS-AML, and 2 CMML-AML. Median age was 69 years old with a median Charlson Comorbidity Index of 6. ELN risk criteria could be assessed in 13/15 patients; of those, 54% were adverse-risk. 13 IDH2 mutated patients received enasidenib as monotherapy (n=12) or combined with azacitidine (n=1). 2 IDH1-mutated patients received ivosidenib as monotherapy (n=1) or combined with azacitidine (n=1). Of the 8 MPN-AP/BP patients, 6 received IDH inhibitor therapy in the front-line setting. Of the 7 patients with MDS-AML or CMML-AML, only 2 patients received IDH inhibitor therapy in the frontline setting. The overall response rate (ORR) to IDH inhibitor therapy for the 15 patients was 40% using both the 2003 IWG AML criteria and the 2017 ELN criteria. In the 8 patients with MPN-AP/BP, the ORR was 37.5% using both the 2003 IWG AML response criteria and the 2017 ELN criteria and was 75% when using the 2012 MPN-BP response criteria (Table 1). Median overall survival was not reached for the 3 MPN-BP patients reclassified as responders using 2012 MPN-BP criteria with median follow-up at time of data lock being 431 days (range, 67-1218+). Median duration of IDH inhibitor therapy in the whole 15 patient cohort was 126 days (range, 14-1218+) and 258 days (14-1218+) for MPN-BP patients. Median follow-up at time of data lock was 151 days for all patients and 272 days for MPN-BP patients. Within the MPN-AP/BP cohort, 3 are still on therapy at this time, 2 had stopped due to progression of disease, and 3 had stopped due to an adverse event or clinical deterioration (Figure 1). Median overall survival for all patients after initiation of IDH inhibitor therapy was 235 days (Figure 2). Median survival for patients with MPN-AP/BP (n=8) was not reached compared to 193 days for the 7 patients with MDS-AML or CMML-AML. The incidence of Grade 3 or greater adverse events was similar to the known AE profile of these agents. NGS analysis at time of progression to AML/accelerated phase identified JAK2 and SRSF2 mutations as the most frequent co-mutations (Table 2). Conclusions: Treatment with IDH inhibitor therapy in IDH-mutated MPN-AP/BP patients holds promise as a means of inducing durable responses that extend beyond historical survival data for MPN-BP. In addition, utilization of the 2012 MPN-BP criteria to assess response in this patient population can provide better insight into the benefit of this treatment strategy. Our single institutional experience merits confirmation in a larger group of patients with IDH1/2-mutated MPN-AP/BP. Disclosures Liu: Agios: Honoraria; Novartis: Other: PI of clinical trial; Arog: Other: PI of clinical trial; Karyopharm: Research Funding; BMS: Research Funding. Thirman:Celgene: Consultancy; Pharmacyclics: Research Funding; Merck: Research Funding; TG Therapeutics: Research Funding; Up to Date: Honoraria; Gilead: Research Funding; Janssen: Consultancy; Astra Zeneca: Consultancy; Roche/Genentech: Consultancy; AbbVie: Consultancy, Research Funding. Artz:Miltenyi: Research Funding. Larson:Celgene: Consultancy; Agios: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials. Stock:Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria; Research to Practice: Honoraria. Segal:Astra Zeneca: Consultancy; Merck: Consultancy; BMS: Consultancy, Research Funding; AbbVie: Research Funding. Odenike:Agios: Research Funding; CTI/Baxalta: Research Funding; Gilead Sciences: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Oncotherapy: Research Funding; Astex Pharmaceuticals: Research Funding; Astra Zeneca: Research Funding; Janssen Oncology: Research Funding; NS Pharma: Research Funding. OffLabel Disclosure: We discuss the use of the IDH inhibitors ivosidenib and enasidenib in treatment of advanced-phase Ph-negative myeloproliferative neoplasms. Ivosidenib is currently approved for use in the frontline setting in IDH1-mutated AML patients 〉75 years old or with comorbidities precluding the use of intensive induction therapy. Ivosidenib is also approved in the relapsed/refractory setting for IDH1-mutated AML. Enasidenib is approved in the relapsed/refractory setting for IDH2-mutated AML.

Description: Abstract 3978 It has been demonstrated that MEK/MAPK and PI3K/Akt are constitutively activated in the majority of AML cases and that their aberrant expression is associated with a poor prognosis. Targeted inhibition of either the MEK/MAPK or the PI3K/Akt pathway alone has only demonstrated mild to modest clinical activity, possibly due to feedback activation of compensatory pathways. Thus, preclinical studies have recently turned to targeted inhibition of both of these pathways simultaneously. In the current study, the efficacy of the combination of two orally available inhibitors to MEK (AZD6244, Astra Zeneca) and PI3K/mTOR (NVP-BEZ235, Novartis) was evaluated in AML cell lines and in primary AML patient samples. In MV 4;11 AML cells (harboring both the MLL re-arrangement and FLT3 internal tandem mutation), AZD6244 or BEZ235 alone moderately decreased viable cell numbers by 30–40% as measured by the MTS assay, a colorimetric assay for cellular growth and survival, but the combination of these two had a dramatic additive effect with a decrease of viable cell numbers by 70–80%. Similar effects were observed in AML cell lines with different cytogenetic and molecular abnormalities including THP-1 [t (6;11)], HL-60, KG-1 [del(5q)], and Kasumi-1 [t(8;21)]. Similar results were also obtained in leukemia cells from 3 patients with AML with different recurring cytogenetic abnormalities. Apoptotic cell death was determined by detection of

Description: Abstract 3921 Autologous stem cell transplantation (ASCT) is an effective treatment strategy for Mantle Cell Lymphoma (MCL) that has been shown to improve disease free survival. However, data from recent trials suggest that the presence of minimal residual disease (MRD) contributes to relapse following current intensive treatment strategies, including ASCT. Thus, we sought to test a highly selective approach to eradication of MRD in stem cell collections from MCL patients using targeted small peptides that disrupt the aberrant cyclin/CDKs interactions that are involved in the pathogenesis of MCL. In the current study, the efficacy of a mimetic peptide to the CDK inhibitor p16INK4a to eliminate MRD was tested. Using (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) cell viability assays, we demonstrated that a transducible TAT-p16 mimetic peptide was able to induce cell death in the MCL cell line, Jeko-1, in a dose and time-dependent fashion (see Figure). A TAT-p16 mimetic was able to induce cell death in approximately 60% of Jeko-1 cells after 4 hours of incubation, and approximately 80% of Jeko-1 cells at 24 hours. In contrast, the same dose of TAT-p16 mimetic had no effect on cell survival when it was incubated with CD34+ rich apheresis samples from healthy donors. Furthermore, CFU-GM, BFU-E colony assays showed that there was no toxicity of the TAT-p16 mimetic when compared to untreated cells or cells treated with a control, scrambled TAT-p16 peptide. TAT-p16 mimetic did not impair erythroblast differentiation but induced mild apoptotic cell death in the erythroblast cells. The strategy was further tested using a CD34+ enriched apheresis sample collected from a patient with MCL with documented MRD who had been treated on a clinical trial of ASCT for MCL. Using Real-time quantitative PCR for IgH and BCL1 gene rearrangements, we demonstrated that the TAT-p16 mimetic was able to reduce MRD level by 40% compared with the scrambled TAT-p16 peptide. These data suggest that the use of a peptide-mimetic to p16 selectively and effectively can reduce MRD in MCL cells and in an apheresis (stem cell) sample from a patient with MCL. Treatment with the peptide allowed differentiation of CD34+ progenitor cells. A combinational approach using additional targeted cell cycle regulatory peptides that block p21CIP1/WAF1 and cyclin D2 is being explored to optimize the efficacy of this purging technique. Thus, this novel strategy may be an effective, selective and non-toxic method for eradication of MRD in MCL. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 496 HCT may provide long-term disease control for patients (pts) with relapsed and/or refractory acute leukemias (AL) and advanced myelodysplastic syndromes (MDS). Active disease burden at HCT is associated with high relapse rates and poor long-term outcomes. We hypothesized tolerable intensification would be achieved safely by clofarabine cytoreduction followed by HCT conditioning at the nadir and would result in improved outcomes. We performed a prospective study (3/08 – 9/10) to examine the feasibility and efficacy of clofarabine (Clo) cytoreduction prior to HCT for relapsed or refractory AL and MDS with 〉 5% marrow blasts. Clo was administered at 30mg/m2/day IV over 2 hours for 5 consecutive days. On Day 12 post Clo initiation, a bone marrow (BM) biopsy determined cytoreduction, followed by HCT conditioning by day 21 post-Clo. Our primary endpoint was to assess the proportion of pts who achieved effective cytoreduction, defined as BM cellularity

Description: Background: Selinexor, an exportin 1 (XPO1) inhibitor, has demonstrated anti-leukemic effect as a single agent. There are also data demonstrating synergistic killing of leukemia cells with the combination of selinexor with anthracyclines and/or DNA damaging agents. The HiDAC/Mito combination is an effective induction regimen for relapsed/refractory (R/R) AML patients with a reported overall response rate (ORR) of 55% at our institution. We hypothesize that adding selinexor to HiDAC/Mito is feasible and has synergistic anti-leukemic effects. Methods: We performed a phase I dose escalation trial with cohort expansion in patients with AML that combined increasing doses of selinexor with age-adjusted HiDAC/Mito (NCT02573363). The primary endpoint was to determine the maximum tolerated dose of selinexor when given in combination with HiDAC/Mito. Selinexor was given orally on days 2, 4, 9, and 11 during the induction phase of the study. HiDAC (1.5 to 3 gm/m2 depending on age, IV over 3 hours) followed immediately by Mito (20 to 30 mg/m2 IV over 1 hour) was administered on day 1 and 5. Initial selinexor dose was 60mg (~35mg/m2) followed by a dose escalation to a target level of 80mg (~50mg/m2). Patients who entered remission proceeded to stem cell transplantation (SCT) or consolidation chemotherapy with HiDAC/selinexor followed by maintenance therapy with weekly selinexor alone for up to one year. Dose limiting toxicity (DLT) was defined as any grade 3 or greater non-hematologic toxicity, except transient (56 days in the absence of disease. Once a dose level was declared tolerable, more patients could be enrolled at that level to provide additional safety, tolerability, and efficacy data. Results: As of July 2016, 12 patients had enrolled. Selinexor dose levels were 60mg (n=3) and 80mg (n=9). Median age = 61 (range 44 - 74). De novo AML = 5 (42%); secondary AML = 3 (25%), R/R AML = 4 (33%). Eight (67%) patients were previously untreated, 1 (8%) was beyond the first relapse, and 3 (25%) had primary refractory disease. Prior therapies included combination cytarabine with anthracycline, HiDAC, decitabine, and clinical trial agents. Molecular/genetic subgroup profiles by European Leukemia Net (ELN) criteria included favorable = 1 (8%), intermediate I = 5 (42%), intermediate II = 1 (8%), and adverse = 5 (42%). Only 10 patients are evaluable for safety and efficacy at the time of analysis. Myelosuppression was the most common side effect and was universal. Median and average times to count recovery for responding patients from day 1 were 38 and 47 days, respectively. Febrile neutropenia was observed in 8 patients (80%), compared to our historical experience of 64% for HiDAC/Mito alone. Other significant adverse events included line-associated thromboses (n=3), cardiac toxicity (n=3), cerebellar toxicity (n=1), arm cellulitis (n=1), and syncope (n=1). No DLTs were observed. 30 and 60-day induction mortality was 10% (1 patient with R/R AML died from progressive disease). Ten patients are evaluable for response: complete remission (CR) = 4 (40%), CR with incomplete count recovery (CRi) = 1 (10%), partial remission (PR) = 1 (10%), and treatment failure (TF) = 4 (40%). Thus, the ORR is 60%. Of those who responded, 2 patients proceeded to consolidation, 1 underwent allo-SCT, and 3 are in preparation for allo-SCT. No response was achieved in patients with R/R AML. Bone marrow samples from screening and day 12 of treatment were used for biomarker analysis in three CR patients. A marked reduction in KI67, MYC, FLT3, KIT, and DNA damage response proteins was observed in the remaining tumor cells in the post-treatment samples. Staining for P53 showed an increase in nuclear staining intensity, which is consistent with the known effect of selinexor on tumor cells. Conclusions: The selinexor/HiDAC/Mito regimen is feasible and tolerable at selinexor doses up to 80mg/day or ~50 mg/m2/day twice weekly. It yields an ORR of 60% based on currently available data. The recommended phase II dose is 80mg of selinexor. Additional molecular correlative studies are evaluating patients' marrow and blood samples for markers that predict response and relapse. Disclosures Odenike: Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI/Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Algeta Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Suneisis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Stock:Sigma-Tau: Honoraria, Research Funding; ADC Therapeutics: Honoraria; Gilead Sciences: Honoraria; Amgen: Honoraria; Royalties for a chapter in Up to Date: Patents & Royalties. Liu:Karyopharm: Research Funding; BMS: Research Funding.

Description: Background:Treatment options are limited for patients (pts) with hematologic malignancies who relapse after allogeneic stem cell transplantation (allo-SCT). We hypothesized that checkpoint inhibitors may offer a novel approach for maintaining remission after allo-SCT. Data from pre-clinical studies have suggested a potential role for PD-1/PD-L1 inhibitors in acute myeloid leukemia (AML) (Zhang et al., Blood 2009), so it is possible that immunomodulation with checkpoint inhibitors could stimulate the donor anti-leukemia immune response and prevent disease relapse. However, the safety of checkpoint blockade early after allografting remains to be established. Methods:We conducted a pilot study to assess the tolerability and efficacy of Nivolumab, a PD-1 inhibitor, as maintenance therapy after allo-SCT (NCT02985554). Pts were eligible if they were post allo-SCT without evidence of relapse or active graft-vs-host disease (GVHD) or history of prior greater than stage I skin acute GVHD. Nivolumab was to be administered intravenously at 1mg/kg every 2 weeks for 4 doses followed by dosing every 12 weeks. Treatment started 4 weeks after routine immunosuppression was discontinued until 2 years after the transplant. The primary objective was to determine the tolerability of Nivolumab on this schedule. Secondary objectives were evaluation of adverse events, relapse, and overall survival. Results:Four pts were enrolled from December 2017 through November 2018. (Table 1)All pts experienced immune-related adverse events (irAE) from Nivolumab, and 2 (50%) pts experienced serious adverse events. (Table 2)One pt developed grade (G) 4 neutropenia soon after the first dose. (Figure 1)The absolute neutrophil count nadired at 20 cells/µL, at which point pegfilgrastim was administered. An interim bone marrow biopsy (BMBx) confirmed no evidence of relapsed disease. Full neutrophil recovery occurred approximately 3 months after the initial dose, and no subsequent toxicities occurred. Another pt developed G3 autoimmune encephalopathy concurrently with G2 transaminitis and G2 thrombocytopenia after one dose of Nivolumab. (Figure 2)Intravenous methylprednisolone (1mg/kg daily for 3 days) and immunoglobulin (2g/kg in 4 divided doses) were administered, followed by a 7-week steroid taper with full resolution of symptoms. Relapsed disease was ruled out by a BMBx. A third pt developed G2 skin rash approximately 10 days after the first dose of Nivolumab. Skin biopsy demonstrated drug hypersensitivity reaction vs GVHD, and the pt was treated with a 3-week prednisone course (starting at 1mg/kg followed by a taper). A mild flare recurred 2 weeks later, which was treated with topical steroids only. However, Nivolumab was not resumed. The fourth pt developed G2 elevated TSH approximately 2 months into therapy and after 4 doses of Nivolumab. Thyroid hormone replacement was initiated with subsequent symptom improvement and normalization of TSH over a 4-month period. As a result of these unexpected severe toxicities, the study was closed to further enrollment, and further Nivolumab administration ceased. Thus far, one pt (#1) relapsed after a total remission duration of 530 days; the remission duration after starting Nivolumab was 318 days. One pt has mild chronic skin GVHD. All 4 patients remain alive with a median overall survival of 2.3 years (range, 1.9-4.7). Conclusions:Even at low doses, the use of Nivolumab as maintenance therapy in the post allo-SCT setting was not tolerable at the current dosing and schedule due to an unexpected number of high grade irAEs. Additional studies of dose and timing after allo-SCT are needed to improve safety and tolerability, in conjunction with correlative studies to better understand the immunomodulatory processes in the post-transplant setting. Disclosures Kline: Merck: Honoraria; Merck: Research Funding. Stock:Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria; Research to Practice: Honoraria. Artz:Miltenyi: Research Funding. Larson:Agios: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials; Celgene: Consultancy. Riedell:Novartis: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Speakers Bureau; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau. Bishop:CRISPR Therapeutics: 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, Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Liu:Arog: Other: PI of clinical trial; BMS: Research Funding; Agios: Honoraria; Novartis: Other: PI of clinical trial; Karyopharm: Research Funding. OffLabel Disclosure: Nivolumab used as maintenance therapy in the post-transplant setting

Description: Background: Selinexor, an exportin 1 (CRM1/XPO1) inhibitor, has demonstrated anti-leukemic effects as a single agent and in combination with anthracyclines and DNA damaging agents. HiDAC/Mito is an effective induction regimen for patients with relapsed/refractory (R/R) AML and has a reported overall response rate (ORR) of 55% at our institution. We hypothesized that adding selinexor to HiDAC/Mito would be feasible and have synergistic anti-leukemic effects. Early results of the trial were previously reported (Wang et al., J Hematol Oncol, 2018), and here we present more mature data on survival and relapse. Methods: We performed a phase 1 dose escalation trial with cohort expansion in patients with AML. This study tested increasing doses of selinexor combined with age-adjusted HiDAC/Mito (NCT02573363). The primary endpoint was to determine the maximum tolerated dose of the regimen. Selinexor was given orally on days 2, 4, 9, and 11 during the induction phase. HiDAC (1.5 to 3 g/m2 depending on age, IV over 3 hours) followed immediately by Mito (20 to 30 mg/m2 IV over 1 hour) was administered on day 1 and 5. Initial selinexor dose was 60mg (~35mg/m2) followed by a dose escalation to a target level of 80mg (~50mg/m2). Patients who entered remission proceeded to stem cell transplantation (SCT) or consolidation chemotherapy with HiDAC/selinexor followed by maintenance therapy with weekly selinexor alone for up to one year. Dose limiting toxicity (DLT) were only evaluated during dose escalation and was defined as any grade 3 or greater non-hematologic toxicity, except transient (56 days in the absence of disease. Once a dose level was declared tolerable, more patients could be enrolled at that level to provide additional safety, tolerability, and efficacy data. Results: The study enrolled a total of 28 patients from October 2015 to October 2017. Selinexor dose levels were 60mg (n=3) and 80mg (n=25). Median age = 61 (range 37 - 76). De novo AML = 15 (54%); secondary AML = 12 (43%), and therapy-related AML = 1 (3%). Of these, 13 patients had R/R disease (6 primary refractory, 6 in first relapse, 1 in second relapse). Fifteen (54%) patients were previously untreated. Molecular/genetic subgroup profiles by European Leukemia Net 2010 criteria included favorable = 6 (21%), intermediate I = 9 (32%), intermediate II = 5 (18%), and adverse = 8 (29%). No DLTs were observed in dose escalation. Myelosuppression was universal. Median time to count recovery (ANC 〉1.0 x 109/L, platelet count 〉100 x 109/L for the 16 responding patients was 46 days. Febrile neutropenia occurred in 21 (75%) patients. Common selinexor-related adverse effects included diarrhea (32%), electrolyte disturbances (32%), bacteremia (32%), anorexia (29%), nausea/vomiting (29%), fatigue (25%), and acute kidney injury (25%). One patient from the expansion cohort died from hemorrhagic stroke prior to completing induction. The ORR was 64% (18/28 pts): complete remission (CR) = 46% (13 pts), CR with incomplete count recovery (CRi) = 14% (4 pts), partial remission (PR) = 4% (1 pt), and treatment failure (TF) = 36% (9 pts). ORR was 87% (9 CR, 3 CRi, 1 PR, 2 TF) for newly diagnosed pts and 38% (4 CR, 1 CRi, 8 TF)) for R/R pts. Of the responders, 6 proceeded to consolidation without allo-SCT, 10 eventually underwent allo-SCT, and 2 relapsed prior to either. The 10 non-responding patients proceeded to another line of therapy, and 3 eventually underwent allo-SCT. Eleven (40%) patients are alive with a median observation period of 13 months (range 8 days to 34 months). The median relapse free survival (RFS) and overall survival (OS) was 11 and 16 months, respectively. The 1-year PFS and OS was 44% and 61%, respectively. Median OS was 9 months for non-responders and 19 months for responders (HR 1.8, 95% CI 0.6 - 5.7, p=0.2); 1-year OS rates were 50% vs 67%, respectively. One CR patient completed consolidation and maintenance without allo-SCT remains in remission 33 months later. Conclusions: The selinexor/HiDAC/Mito regimen is feasible and tolerable at selinexor doses up to 80mg/day or ~50 mg/m2/day twice weekly. This regimen yields an ORR of 64% based on currently available data. We had previously reported molecular correlatives demonstrating the effect of selinexor. The recommended phase 2 dose is 80mg of selinexor. Figure. Figure. Disclosures Larson: Ariad/Takeda: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Odenike:Agios: Research Funding; Astex: Research Funding; Dava Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI/Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncotherapy Science: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; NS Pharma: Research Funding; Celgene: Research Funding; Gilead Sciences: Research Funding; ABBVIE: Honoraria, Research Funding; Janssen: Research Funding. Bishop:United Healthcare: Employment; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juneau Therapeutics: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Novartis Pharmaceuticals Corporation: Speakers Bureau. Curran:Merck: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Liu:BMS: Research Funding.

Description: Background: Survival in patients (pts) with relapsed/refractory (R/R) acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS) is dismal. Treatment options are limited; however, a proportion of these individuals can be rescued by allogeneic stem cell transplantation (allo-SCT). Historically, allo-SCT, especially for R/R myeloid diseases, has used myeloablative regimens and no T-cell depletion (TCD) to maximize graft-versus-leukemia effect, often restricting this approach to younger and fit pts with matched donors. The aim of this study was to investigate outcomes of in vivo T-cell depleted stem cell transplantation (TCD-SCT) in a high-risk AML and MDS population. Methods: We performed a retrospective analysis of 141 patients with R/R AML (n=108)/high risk MDS (RAEB or CMML, n=33) who received TCD-SCT at our center from 2002-2015. Median age was 55 years (18-71) with 37 (26%) pts older than 60. Patients underwent in vivo TCD with alemtuzumab or ATG and 117 (88%) received reduced-intensity conditioning (RIC). Alemtuzumab was generally given as 100 mg total divided over 5 days whereas rabbit ATG dosing included days -1, - 3, -5 (+/- on day -7). Alemtuzumab usually partnered with matched related (n=65; 46%) or unrelated (n=53; 38%) peripheral blood stem cell (PBSC) grafts whereas ATG mostly was a component of umbilical cord grafts combined with a CD34 selected haploidentical donor (haplo-cord) (n=23; 16%). Prognostic factors such as age, HCT-CI, CIBMTR score (Duval 2010), revised disease risk index (R-DRI), donor type and pre-transplant disease status were analyzed. Multivariate cox regression models were considered from forward selection for factors with a p value