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Background Myelofibrosis (MF) is a myeloproliferative neoplasm that commonly harbors acquired somatic gene mutations in JAK2, CALR, or MPL. In the Phase 3 COMFORT-1 trial, which enrolled 309 patients (pts) with JAK inhibitor-naïve MF, ruxolitinib (RUX) showed spleen volume reduction of ≥35% (SVR35) and an improvement of 50% or more in the total symptom score (TSS50) in 42% and 46%, respectively compared to placebo. Activity has been shown with the combination of selinexor (SEL) plus RUX in preclinical studies. Methods XPORT-MF-034 is an open-label, Phase 1/2 study (NCT04562389) to evaluate the safety and efficacy of SEL plus RUX in treatment-naïve MF pts. SEL is evaluated at 2 dose levels, 40mg and 60mg once-weekly plus twice daily RUX in 28-day cycles. For nausea, all pts receive prophylaxis with a 5-HT3 antagonist prior to each SEL dose and as needed. Primary endpoints are to determine maximum tolerated dose, recommended Phase 2 dose (RP2D), and safety. Secondary endpoints include spleen and symptom response, and hemoglobin stabilization and improvement. The efficacy population for spleen and symptom evaluable pts included those who had a spleen assessment or at least one symptom score available, respectively, at baseline and the W12 or W24 timepoint. Results As of Oct 21, 2022, 24 pts have received at least one dose of 40mg or 60mg weekly SEL with RUX twice daily as per standard of care. Median age was 64 years old (range 44-77) and 11 pts had primary MF, 6 had post-ET MF, and 7 had post-PV MF. DIPSS risk category was int-1, int-2, and high risk for 7, 11, and 6, respectively. The median daily dose of ruxolitinib received was 20 mg. In efficacy evaluable pts, 63% (12/19) and 92% (11/12) achieved SVR35 at W12 and W24, and 83% (10/12) and 67% (4/6) achieved TSS50 at W12 and W24. Among the 11 pts who had a baseline hemoglobin level Conclusions To date, in pts with treatment-naïve MF, the novel combination of SEL and RUX has been reasonably well-tolerated with a generally manageable safety profile and has shown encouraging activity in spleen and symptom responses, in addition to hemoglobin stabilization. Updated safety and efficacy, including symptom data amongst those pts non evaluable for TSS50 at the time of the Oct data cutoff, as well as RP2D, will be available for presentation at AACR 2023. Citation Format: Haris Ali, Ashwin Kishtagari, Keri Maher, Sanjay Mohan, Karen Ansaldo, Xulong Wang, Kamal Chamoun, Josef T. Prchal, Srinivas K. Tantravahi. A Phase 1, open-label, dose-escalation study of selinexor plus ruxolitinib in patients with treatment-naïve myelofibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT261.

Patients with higher-risk myelodysplastic syndromes (MDS) refractory to hypomethylating agents (HMAs) have limited therapeutic options and an expected overall survival (OS) of 3–5 months. Eltanexor is an investigational oral selective inhibitor of nuclear export with low central nervous system penetrance and an acceptable tolerability profile. Preclinical studies suggest that myeloid malignancies are sensitive to nuclear export inhibition. Eltanexor exhibited efficacy in hematologic models, supporting exploration in a clinical trial. This phase 1/2 study (NCT02649790) assessed single-agent activity of eltanexor in patients with higher-risk MDS and 5–19% myeloblasts. Two starting doses of eltanexor were evaluated: 20 mg (n = 15), 10 mg (n = 5), both administered on days 1–5 each week of a 28-day cycle. Twenty patients with primary HMA-refractory MDS, with a median age of 77 years (range 62–89), and a median of two prior treatment regimens (range 1–4) were enrolled. Of these, 15 were evaluated for efficacy and 20 for safety. The overall response rate (ORR) was 53.3%, with seven patients (46.7%) achieving marrow complete remission (mCR) and one additional patient achieving hematologic improvement (HI). In the 10 mg group, three patients (60%) reached mCR and two (40%) stable disease (SD), while for 20 mg, four patients (40%) had mCR and two (20%) SD. A total of three patients (20%) had HI and became transfusion independent ≥ 8 weeks. Median OS for the efficacy-evaluable patients (n = 15) was 9.86 months (7.98, NE). Overall, the most frequently reported treatment-related adverse events were nausea (45%), diarrhea (35%), decreased appetite (35%), fatigue and neutropenia (both 30%). Single-agent oral eltanexor was active, safe, and well tolerated in patients with higher-risk, primary HMA-refractory MDS.

Patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL) have a poor prognosis and a median overall survival of less than 6 months. Outcomes and responses were evaluated in 134 patients with DLBCL administered selinexor. Our findings demonstrate that selinexor treatment in DLBCL patients can safely induce durable responses and improve outcomes regardless of prior treatments and refractory status. Background: Despite a number of treatment options, patients with diffuse large B-cell lymphoma (DLBCL) whose disease has become refractory to treatment have a poor prognosis. Selinexor is a novel, oral drug that is approved to treat patients with relapsed/refractory DLBCL. In this post hoc analysis of the SADAL study, a multinational, open-label study, we evaluated subpopulations to determine if response to single agent selinexor is impacted by number of lines of prior treatment, autologous stem cell transplant (ASCT), response to first and most recent therapies, and time to progressive disease. Patients: Patients (n = 134) with DLBCL after 2-5 prior therapies were enrolled in SADAL and received 60mg selinexor twice weekly. Results: The median overall survival was 9.0 months and median progression free survival was 2.6 months. Patients who had the best overall response rate (ORR) and disease control rate were those who had prior ASCT (42.5% and 50.0%) or responded to last line of therapy (35.9% and 43.5%). Patients with primary refractory DLBCL also showed responses (ORR 21.8%). Adverse events between subgroups were similar to the overall study population, the most common being thrombocytopenia (29.1%), fatigue (7.5%), and nausea (6.0%). Conclusion: Regardless of prior therapy and disease refractory status, selinexor treatment demonstrated results consistent with its novel mechanism of action and lack of cross-resistance. Thus, single agent oral selinexor can induce deep, durable, and tolerable responses in patients with DLBCL who have recurrent disease after several chemoimmunotherapy combination regimens. (C) 2021 Published by Elsevier Inc.

The phase 2b, open-label, multicenter SADAL study evaluated single agent oral selinexor, a selective inhibitor of nuclear export (SINE) compound, in patients with diffuse large B cell lymphoma (DLBCL) after >= 2 lines of systemic therapy. Similar activity was observed in GCB- and non-GCB DLBCL with a trend to higher response rates in DLBCL transformed from follicular lymphoma. Lower response rates were observed in double expressor DLBCL; higher response rates were observed in patients with baseline hemoglobin >= 10 g/dL and normal levels of C-MYC or BCL-2 expression (51%). Overall, strong single agent activity with selinexor were observed in patients with relapsed/refractory DLBCL.Background: The SADAL study evaluated oral selinexor in patients with relapsed and/or refractory diffuse large B-cell lymphoma (DLBCL) after at least 2 prior lines of systemic therapy. In this post-hoc analysis, we analyzed the outcomes of the SADAL study by DLBCL subtype to determine the effects of DLBCL subtypes on efficacy and tolerability of selinexor. Patients and Methods: Data from 134 patients in SADAL were analyzed by DLBCL subtypes for overall response rate (ORR), overall survival (OS), duration of treatment response, progression-free survival, and adverse events rate. Results: ORR in the entire cohort was 29.1%, and similar in patients with germinal center (GCB) versus non-GCB DLBCL (31.7% vs. 24.2%, P = 0.45); transformed DLBCL showed a trend towards higher ORR than de novo DLBCL: 38.7% vs. 26.2% (P = 0.23). Despite similar prior treatment regimens and baseline characteristics, patients with DLBCL and normal C-MYC/BCL-2 protein expression levels had a significantly higher ORR (46.2% vs.14.8%, P = 0.012) and significantly longer OS (medians 13.7 vs. 5.1 months, hazard ratio 0.43 [95% CI, 0.23-0.77], P = 0.004) as compared with those whose DLBCL had C-MYC and BCL-2 overexpression. Among patients who had normal expression levels of either C-MYC or BCL-2 and baseline hemoglobin levels >= 10g/dL, ORR was 51.5% (n = 47), with median OS of 15.5 months and median PFS of 4.6 months. Similar rates of adverse events were noted in all subgroups. Conclusions: Overall, single agent oral selinexor showed strong responses in patients with limited treatment alternatives regardless of germinal center B-cell type or disease origin. (C) 2021 Elsevier Inc. All rights reserved.

There is limited data on the outcomes of autologous hematopoietic cell transplantation (auto-HCT) in myeloma patients, 75 or older. We retrospectively analyzed all myeloma patients (n = 72)...

Although bortezomib and rituximab have synergistic activity in patients with lymphoma, and can both attenuate graft-versus-host disease (GVHD), the drugs have not been used together in patients undergoing allogeneic stem-cell transplantation (alloSCT). In this phase 1/2 trial, we assessed the safety and activity of bortezomib added to the rituximab (R) plus BEAM (carmustine, etoposide, cytarabine, melphalan) regimen in patients with relapsed lymphoma undergoing alloSCT. Primary GVHD prophylaxis consisted of tacrolimus and methotrexate. Bortezomib (1 – 1.3 mg/m(2) per dose) was administered intravenously on days −13, −6, −1, and +2. We performed inverse probability weighting analysis to compare GVHD and survival results to a historical control group that received R-BEAM without bortezomib. Thirty-nine patients were assessable for toxic effects and response. The median age was 54 years. The most common diagnosis was diffuse large B-cell lymphoma (41%). Twenty-two patients (56%) and 17 patients (44%) received their transplants from matched related and unrelated matched donors, respectively. The maximum tolerated bortezomib dose was 1 mg/m(2). The weighted cumulative incidences of grade II-IV and grade III or IV acute GVHD were 50% and 34%, respectively; these incidences and survival rates were not significantly different from those of the control group. Median survival has not been reached in patients age ≤50 years and who had a long follow-up time of 60.7 months. The R-BEAM regimen has a survival benefit in lymphoma patients age ≤50 years undergoing alloSCT. The addition of bortezomib has no impact on survival or incidence of GVHD.

BACKGROUND The combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has proven to be the most effective therapy for patients with acute promyelocytic leukemia (APL). The majority of the morbidity and mortality from APL therapy occur during the induction phase. The objective of the current study was to identify the risk factors associated with transfer to the intensive care unit (ICU) and endotracheal intubation during induction therapy in patients with APL. METHODS The authors analyzed the clinical characteristics of 187 patients with newly diagnosed APL who were treated with ATRA and ATO with or without gemtuzumab ozogamicin. The authors documented the percentage change in body weight from baseline to the maximum recorded weight during induction or to the day of ICU transfer. RESULTS A total of 18 patients (10%) who initiated therapy with ATRA and ATO on a regular hospital floor required transfer to the ICU after a median of 12 days of induction therapy. The median volume of transfusions was 4350 mL (range, 60-30,750 mL). The volume of transfusions was the main factor associated with the risk of ICU transfer (odds ratio, 4.1; P

Patients with RR DLBCL who have received ≥ 2 lines of therapy have limited treatment options and an expected overall survival (OS) of < 6 months. The SADAL study evaluated single-agent oral selinexor in patients with RR DLBCL and demonstrated an overall response rate (ORR) of 29.1% with median duration of response (DOR) of 9.3 months. The analyses described here evaluated a number of subpopulations in order to understand how response correlates with survival outcomes in order to identify patients who could most optimally benefit from selinexor treatment. Median age was 67 years; 44.8% of patients were ≥ 70 years of age. The median OS was 9.0 months (95% CI 6.2, 13.7) at a median follow-up of 14.8 months. The median OS was not reached in patients with a CR or PR, while patients who did not respond have a median OS of 4.9 months (p < 0.0001). Patients < 70 years had an OS of 11.1 months compared with 7.8 months in patients ≥ 70 years. Among patients with or without prior ASCT, the median OS was 10.9 and 7.8 months, respectively. Among patients with disease refractory to the most recent DLBCL treatment regimen, the median OS was 7.0 months compared with 11.1 months for disease not refractory to the most recent treatment. In a patient population in which survival is expected to be < 6 months, treatment with single-agent oral selinexor was associated with a median survival of 9 months. Increased median OS observed in patients responding to selinexor was consistent across subgroups regardless of age, prior ASCT therapy, or refractory status. Randomized studies of selinexor in combination with a variety of other anti-DLBCL agents are planned. This trial was registered at ClinicalTrials.gov (NCT02227251) on August 28, 2014. https://clinicaltrials.gov/ct2/show/NCT02227251., SCOPUS: le.j, info:eu-repo/semantics/published

7060 Background: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by unregulated, clonal proliferation of a hematopoietic stem cells in the bone marrow and is commonly associated with gene mutations in JAK2, CALR, or MPL. Front-line therapy may include the JAK1/2 inhibitor ruxolitinib (RUX), resulting in spleen volume reductions and improvement in MF-related symptoms. Despite the therapeutic effect of RUX, most patients (pts) eventually progress and thus novel combinations are required to increase responses and delay progression. Selinexor (SEL) is an oral selective inhibitor of nuclear export (SINE) compound, specifically inhibiting exportin-1 (XPO1), and currently approved for treatment of multiple myeloma and diffuse large B-cell lymphoma. Significant activity of SEL in combination with RUX has been shown in preclinical studies, and SEL monotherapy in MF refractory to JAK inhibitors demonstrated robust clinical activity and a tolerable safety profile (NCT03627403). Here, we present the initial results of a phase 1 dose escalation study of the combination SEL and RUX in treatment-naïve MF. Methods: The ongoing multicenter, open-label, Phase 1/2 study (NCT04562389) is evaluating the efficacy and safety of SEL plus RUX in JAKi-naïve MF pts. Two dose levels of SEL were evaluated, 40mg and 60mg once-weekly (QW) plus RUX twice daily (BID) as per label in 28-day cycles, using a 3+3 design. All pts received 5-HT3 antagonist for nausea prophylaxis. Primary objectives include safety, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and preliminary efficacy. Secondary objectives include spleen, symptom, and anemia response, and OS. Results: As of 31 Jan 2022, 10 pts have been dosed in 2 dose levels (40mg (n = 3), and 60mg (n = 7) SEL QW plus RUX). RUX starting dose was 20 mg in 8 pts, 15 mg in one patient and 10 mg in one patient. The median age was 64 (range 45-76). Seven pts had primary MF and 3 had post-ET MF. DIPSS risk category was int-1 (n = 4), int-2 (n = 4) and high risk (n = 2). No dose limiting toxicities have been reported at either dose levels of SEL. One patient required dose interruption due to dizziness and later discontinued treatment due to new onset of atrial fibrillation and pulmonary hypertension (unrelated to SEL and RUX) after 5 months of therapy. All other pts remain on study. There was no grade 3 neutropenia or thrombocytopenia observed. Hemoglobin level was maintained without any significant worsening. The most common treatment-emergent adverse event was low grade nausea (30%). All pts experienced improvement in their white blood cell count. Four of the first 5 evaluable pts demonstrated ≥35% spleen volume reduction at week 12. Conclusions: The combination of SEL and RUX has been well-tolerated and with a manageable side effect profile. No dose limiting toxicities were observed in pts with treatment-naïve MF in cohort 1 of once weekly oral SEL 40 and 60 mg with RUX. Clinical trial information: NCT04562389.

Background Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy characterized by neoplastic cells that are positive for CD123, CD4, BDCA2, and TCL1 and aberrant expression of CD56. Historically, patients with BPDCN have an unfavorable prognosis and the optimal treatment is not established due to lack of prospective data. Case report In this report we describe a patient with Felty’s syndrome and myelodysplastic syndrome (MDS) in whom a population of aberrant plasmacytoid dendritic cells emerged while on treatment with decitabine. Approximately 4 months later he transformed to leukemic BPDCN with skin and eye manifestations. Cytogenetic analysis showed diploid karyotype and molecular analysis showed mutations in KRAS, NOTCH1, and RUNX1 genes. He was treated with CD123-targeted therapy and had significant response in his marrow, skin, eyes, and functional status after one cycle. Conclusion The case demonstrates that minimal transformative disease of BPDCN may be detectable in patients with MDS well before fulminant progression. Early detection of emerging leukemic clones may allow for alternative monitoring and treatment considerations.

Background: Selinexor is an oral, small molecule, selective inhibitor of nuclear export (SINE) compound that specifically blocks the karyopherin protein exportin 1 (XPO1, CRM1). In an shRNA library screen, we discovered that the survival of JAK2V167F mutant HEL cells is dependent on XPO1-mediated nuclear-cytoplasmic transport. Selinexor selectively suppressed primary myelofibrosis (MF) cells as compared with normal progenitor cells and induced hematologic responses in an MPN mouse model. Methods: An open label, prospective, investigator-initiated single center study is ongoing in adults with primary or secondary MF with resistance or intolerance to JAK inhibitor (JAKi) therapy with platelets > 30 K/μL and neutrophils > 500/μL. Selinexor was given orally once a week. Spleen volume was assessed by MRI at week 12 and week 24. The study was amended to include additional MRIs every 12 weeks in the year 1 and 24 weeks in the year 2. Primary end point is spleen response, defined as ≥ 35% spleen volume reduction (SVR) by MRI or CT, where applicable) at week 24. Bone marrow was evaluated at baseline and at week 24. The projected sample size of 24 will provide 83% power to reject a response rate of 15% and allow for up to a 25% dropout rate. We provide an interim report after completing 50% enrollment. Results: Between May 2019 and February 2021, 12 patients (pts) were enrolled. JAK2, CALR and MPL mutations were present in 7 (58.3%), 4 (33.3%) and 1 (8.3%) pts respectively. Eight pts (66.6%) had at least one high molecular risk mutation at baseline (Table 1). Median duration of prior JAKi therapy was 22 months (0.5 to 96 months) and 11 out of 12 were refractory to ruxolitinib at study enrollment. Median baseline spleen volume was 1454 cm 3(range 835 to 5792). Selinexor starting dose was 80 mg weekly in the first 6 pts and 60 mg for subsequent pts. At data cutoff, median duration of selinexor therapy was 36 weeks (range 11-114 weeks). One pt was not response evaluable and died due to liver abscess at week 12 (unrelated). One pt discontinued selinexor at week 18 due to grade 3 fatigue and was not evaluable for the primary end point. Of the 11 pts who had week 12 MRI or CT, 6 showed ≥ 10% SVR, 3 showed ≥ 25% SVR and 1 pt had early progression (Figure 1). At week 24, 5/9 (56%) pts had ≥ 25% SVR and 2/9 (22%) had ≥ 35% SVR (Figure 1). In 9 pts who had ≥24 weeks of selinexor, SVR ≥ 25% and ≥ 35% occurred at any point during study treatment in 4 (44%) and 3 (33%) pts, respectively. Two pts were red cell transfusion dependent at baseline; 1 became transfusion independent after 36 weeks of treatment, has not required transfusion for 49 weeks and remains on study treatment to date (114 weeks). Six pts (50%) discontinued selinexor. Reasons for treatment discontinuation are death in 1 pt, progressive disease in 1 pt, alternative treatment in 2 pts, and toxicity in 2 pts. Ten pts required dose reduction due to fatigue (1pt), anemia (1 pt), thrombocytopenia (2 pts), abdominal pain (1pt) and weight loss (5 pts). The most common treatment related adverse event was weight loss (grade 2 in 4 pts and grade 3 in 1 pt). This was manageable with treatment interruption and dose reduction, except in one pt who discontinued selinexor. As yet no changes in reticulin fibrosis MF grade were observed among 9 patients who received at least 24 weeks of treatment. Conclusions: Once weekly, oral selinexor showed single agent activity with sustained spleen responses in pts with JAKi refractory MF. Long-term administration of selinexor was well tolerated over time in MF pts. Correlatives studies including circulating inflammatory cytokine levels and mutant allele burden, as well as clonality studies by X-chromosome inactivation studies in woman, are underway and will be presented. Figure 1 Figure 1. Disclosures Tantravahi: BMS: Research Funding; Novartis: Research Funding; CTI BioPharma: Research Funding; Abbvie Inc.: Research Funding; Karyopharm Therapeutics Inc.: Consultancy, Honoraria, Research Funding. Patel: Stemline: Research Funding; Genentech: Research Funding; Roche: Research Funding. Chamoun: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm: Current Employment. George: Celgene: Consultancy; Bristol Meyers Squibb: Consultancy; Incyte Corporation: Consultancy; Blueprint Medicines: Consultancy. Deininger: Fusion Pharma, Medscape, DisperSol: Consultancy; SPARC, DisperSol, Leukemia & Lymphoma Society: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Novartis: Consultancy, Research Funding; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Research Funding.

Background: Patients with higher-risk myelodysplastic syndrome (MDS) refractory to hypomethylating agents (HMAs) have limited therapeutic options and poor prognosis with a median overall survival (mOS) of 4-6 months. Lack of response to HMA therapy, advanced age at relapse, male sex, bone marrow blasts >5% and high risk disease classification by International Prognostic Scoring System (IPSS) confer worse outcomes. Eltanexor is a second-generation, oral, selective inhibitor of nuclear export (SINE) compound with markedly reduced brain penetration relative to selinexor in preclinical models. This is believed to result in attenuation of centrally mediated anorexia, weight loss, and nausea, allowing for more frequent dosing. Early results from a phase 1/2 study of eltanexor in patients with higher-risk HMA-refractory MDS demonstrated marrow complete responses (mCRs), hematologic improvement (HI) and stable disease (SD); side effects were primarily low-grade, dose-dependent, and reversible (Lee EHA 2021). Here we provide an update on baseline characteristics, blast reduction in mCR patients, extent of transfusion independence and additional subgroup analyses. Methods: This phase 1/2 study (NCT02649790) evaluated oral eltanexor monotherapy in patients with high-risk or intermediate-2 by IPSS and 5%-19% myeloblasts. Of 20 patients enrolled, 15 patients were evaluable for efficacy and constitute the population studied in this analysis; 5 patients were non evaluable for efficacy due to trial discontinuation prior to response assessment. Two doses of eltanexor were evaluated: 10 mg (n=5) or 20 mg (n=10) each given qd 5 days per week. Results: Amongst the 15 efficacy evaluable patients, there were 8 males, median age 76 years (range 62-89), 10.0% (range 7-18%) median bone marrow blasts at enrollment, and with a median of two prior regimens (range 1-4). All patients primary HMA-refractory MDS; 9 patients (60%) with high risk and 5 (33%) with intermediate-2 per IPSS, 1 with intermediate-1 per IPSS. Similarly, using the global MD Anderson Cancer Center risk prognosis model, 14 patients (93%) had intermediate-2 or high-risk MDS. The overall response rate (mCR+HI) was 53% including 47% mCRs. Additionally, 5 patients (33%) had SD. Median blast reduction in the 7 patients with mCR was 78.6% (range 55.6%, 85.7%). Four patients had hematologic improvement (HI) including 2 patients with tri-lineage HI. Of the 7 patients who achieved mCR, 4 had significant reduction in transfusion requirements with 3 of these patients achieving complete transfusion independence for 5-10 cycles. In the 10-mg cohort (n=5), all patients derived clinical benefit with 3 patients reaching mCR and 2 patients with SD. In the 20-mg cohort (n=10), 4 patients had mCR and 3 had SD. Median overall survival for all efficacy evaluable patients was 9.86 months. OS for patients who reached mCR (n=7) was significantly longer than for patients who did not reach mCR (n=8): median 11.86 vs 8.67 months (hazard ratio [HR]=0.27, p=0.05), and significantly longer than OS for patients with PD (n=3, mOS=3.15 months, HR=0.23, p=0.04). Notably, mCR was seen in the 3 patients treated with >2 prior therapies and/or with secondary MDS: 1 patient with secondary MDS and 4 prior therapies; 1 with secondary MDS and one prior therapy; and 1 with de novo MDS and 3 prior therapies). Conclusions: Single-agent oral eltanexor was active in patients with higher-risk, primary HMA-refractory MDS including those with secondary MDS or with >2 lines of prior therapy. Patients with mCR had significantly longer mOS than patients without mCR and had median blast reduction of 78.6%. Further evaluation of eltanexor in MDS as a single agent and in combination with other agents is ongoing. Disclosures Lee: Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pin Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mohan: Astex: Research Funding; Incyte: Research Funding. Knupp: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Chamoun: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Karasik: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Bai: Abbvie: Current equity holder in publicly-traded company; Takeda: Current Employment, Current equity holder in publicly-traded company; Karyopharm Therapeutics Inc.: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Ingalls: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Yang: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Kauffman: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shacham: Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Bhatnagar: Astellas: Honoraria; Cell Therapeutics: Honoraria, Research Funding; Celgene: Honoraria; Pfizer: Honoraria; Kite: Honoraria; Karyopharm Therapeutics Inc.: Honoraria, Research Funding; Novartis: Honoraria; Sumitomo Dainippon Pharma: Research Funding.

Introduction: Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) that blocks XPO1, forcing the nuclear retention and re-activation of tumor suppressor proteins including p53, p73, FOXO, I□B and Rb. The phase 2b SADAL study included 134 patients with relapsed or refractory DLBCL with single agent oral selinexor twice weekly. The overall response rate (ORR) was 29.1%, median duration of response (DOR) was 9.3 months and the median overall survival (OS) was 9 months. Based on these data, selinexor was recently approved by the US FDA for the treatment of relapsed or refractory DLBCL, de novo or transformed from follicular lymphoma. Patients with DLBCL tend to be older (over the age of 65) and have a number of comorbidities, which limits the use of aggressive and multi-agent combination therapies. We performed post-hoc analyses of the SADAL study to determine the effects of age on the efficacy and safety of selinexor in this population. Methods: The SADAL study is multi-center, open-label Phase 2b study that enrolled patients with DLBCL previously treated with 2-5 lines of therapy. Patients may have progressed post-stem cell therapy (SCT) or were not candidates for SCT. In this study, 60 mg of selinexor was administered twice weekly until disease progression. The primary endpoint was ORR, and other endpoints included DOR, OS, and safety assessments. For the current analysis, outcomes were assessed in patients Results: Of the 134 patients enrolled in the study, 52 (39%) were 65 (3.8% vs. 11.0%). Conclusions: Patients with relapsed/refractory DLBCL who were ≥65 years had a similar clinical benefit to those Disclosures Schuster: Amgen, Abbvie, Gilead, Takeda, Celgene, Pharmacyclics, Astellas, Verastem, Merck, Novartis, Takeda, Genentech,, Seattle Genetics: Other: Personal Fees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Canales:Janssen: Honoraria; Roche: Speakers Bureau; Gilead: Honoraria; Sandoz: Honoraria; Janssen: Speakers Bureau; Sandoz: Speakers Bureau; Roche: Speakers Bureau; Novartis: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Sandoz: Honoraria; Roche: Honoraria; Takeda: Speakers Bureau; Novartis: Honoraria; Sandoz: Speakers Bureau; iQone: Honoraria; Karyopharm: Honoraria; Takeda: Speakers Bureau; Roche: Honoraria; Janssen: Speakers Bureau. Westin:Genentech: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Curis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; 47: Research Funding; Amgen: Consultancy; Janssen: Consultancy, Research Funding. Zijlstra:Roche: Research Funding. Follows:Karyopharm, Roche, Abbvie, Astrazeneca, Janssen, BMS: Membership on an entity's Board of Directors or advisory committees. Karmali:Takeda: Research Funding; Karyopharm: Honoraria; AstraZeneca: Speakers Bureau; BeiGene: Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Kalakonda:Verastem, Gilead, Celgene, Roche: Research Funding; Gilead, Janssen, Karyopharm: Honoraria. Goy:Constellation: Research Funding; Regional Cancer Care Associates/OMI: Current Employment; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Infinity: Research Funding; Karyopharm: Research Funding; PracticeUpdate Oncology: Consultancy; MD Anderson: Research Funding; AbbVie: Research Funding; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; Xcenda: Consultancy; Infinity Verastem: Research Funding; RCCA/OMI: Current Employment; Morphosys: Research Funding; Genentech/Roche: Research Funding; Hackensack UMC and University of Nebraska: Research Funding; Bayer: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; CALBG: Research Funding. Casasnovas:Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Abbvie: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Thieblemont:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Bristol-Myers Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Hospira: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Honoraria; Bayer: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Cavallo:Gilead: Other: Speaker Fee; Takeda, Janssen: Membership on an entity's Board of Directors or advisory committees. Hill:Pharmacyclics: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding. Tilly:BMS: Honoraria. Jaeger:Novartis: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Karyopharm: Honoraria; CDR Life AG: Consultancy, Research Funding; Miltenyi: Consultancy, Honoraria; F. Hoffmann-La Roche: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria. Gurion:JC Health CARE: Consultancy, Honoraria; Medison: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Takeda Pharmaceuticals: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Caimi:Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding; Genentech: Research Funding. Martin:Janssen: Consultancy; Regeneron: Consultancy; Teneobio: Consultancy; Celgene: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Karyopharm: Consultancy, Research Funding. Davies:Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Roche, Celgene, Kite Pharma, Acerta, Karyopharma, Regeneron, Incyte: Consultancy; Roche, Acerta Pharma, AstraZeneca, Celgene, Gilead, ADC Therapeutics, Gilead: Research Funding; Celegene, Roche, Kite Pharma, Celegene: Honoraria. Smith:TG Therapeutics: Consultancy, Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; FortySeven: Research Funding; Karyopharm: Consultancy, Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy; Janssen: Consultancy. Collins:Amgen: Research Funding; Pfizer: Honoraria; Celgene: Research Funding; Celleron: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau. Salles:Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Novartis: Consultancy, Honoraria, Other; MorphoSys: Consultancy, Honoraria, Other; Debiopharm: Consultancy; Genmab: Consultancy; Karyopharm: Consultancy; Amgen: Honoraria, Other: Participation in educational events; Kite: Consultancy, Honoraria, Other; Epizyme: Consultancy; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Takeda: Consultancy, Honoraria, Other; Bristol Myers Squibb: Consultancy, Other; Autolus: Consultancy; Gilead: Consultancy, Honoraria, Other: Participation in educational events; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Celgene: Consultancy, Honoraria, Other: Participation in educational events. Ma:Karyopharm: Current Employment, Current equity holder in private company. Corona:Karyopharm: Current Employment. Saint-Martin:Karyopharm: Current Employment. Joshi:Karyopharm Therapeutics Inc: Consultancy. Chamoun:Karyopharm: Current Employment. Wang:Curis: Ended employment in the past 24 months; Karyopharm: Current Employment. Shah:Karyopharm: Current Employment, Current equity holder in publicly-traded company. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

Introduction: Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) that blocks XPO1, forcing the nuclear retention and re-activation of tumor suppressor proteins including p53, p73, FOXO, IkB and Rb. The phase 2b SADAL study included 134 patients with relapsed or refractory DLBCL with single agent oral selinexor twice weekly. The overall response rate (ORR) was 29.1%, median duration of response (DOR) was 9.3 months and the median overall survival (OS) was 9 months. Based on these data, selinexor was recently approved by the US FDA for the treatment of relapsed or refractory DLBCL, de novo or transformed from follicular lymphoma. Patients with DLBCL tend to have a number of comorbidities, including poor renal function, which can require a reduction in the dose of intensive chemotherapy as well as lenalidomide, leading to inferior outcomes. Selinexor is not metabolized nor cleared by the kidneys and has been demonstrated to be safe and active in patients with myeloma and renal dysfunction. We performed post-hoc analyses of the SADAL study to determine the efficacy and safety among patients stratified by renal function at baseline. Methods: The SADAL study is multi-center, open-label Phase 2b study that enrolled patients with DLBCL previously treated with 2-5 lines of therapy. Patients may have progressed post-stem cell therapy (SCT) or were not candidates for SCT. In this study, 60 mg of selinexor was administered twice weekly until disease progression. The primary endpoint was ORR, and other endpoints included DOR, OS, and safety assessments. For the current analysis, outcomes were assessed according to baseline renal function as estimated by the Cockroft-Gault formula for creatinine clearance (CrCl). Groups included those with reduced (CrCl ≤60 mL/min) and normal (CrCl >60 mL/min) renal function. Results: Of 134 patients, 37 (28%) had a reduced baseline CrCl (≤60 mL/min) while 97 (72%) had CrCl >60 mL/min. The median age of patients with reduced CrCl was 74 years with 70% ≥70 years, while the median for those with normal CrCl was 65 years, with 35% ≥70 years. De novo and transformed DLBCL showed similar renal function levels: 78% and 22% with reduced CrCl and 76% and 24% with normal CrCl. Of patients with reduced CrCl, the DLBCL subtype was 41% GCB and 57% non-GCB compared to 50% and 46% in patients with normal CrCl. The group of patients with reduced CrCl had baseline ECOG performance status of 2 in 16% vs 11% in those with normal CrCl. Treatment with selinexor demonstrated a similar ORR in patients with a baseline reduced CrCl (29.7%) versus normal CrCl (28.9%). A complete response (CR) was observed in 8 (21.6%) patients with reduced and 10 (10.3%) patients with normal CrCl. The median duration of response (DOR) in patients who had reduced CrCl was 23.0 months compared to 9.2 months in patients with normal CrCl. The median progression-free survival (PFS) was 3.5 months (95% CI 1.7, 24.8) and 2.3 months (95% CI 1.9, 3.7) and overall survival was 7.8 months and 9.1 months in patients with reduced CrCl and those with normal CrCl. The most common grade ≥3 treatment-related AEs for patients with reduced versus normal CrCl were thrombocytopenia (45.9% vs. 38.1%), nausea (5.4% vs. 6.2%), and fatigue (8.1% vs. 11.3%). There was no clinically significant increase in treatment-related serious adverse events (21.6% vs. 20.6%) and adverse events leading to discontinuation (10.8% vs. 7.2%) in patients with reduced or normal CrCl, respectively. Conclusions: Selinexor showed similar anti-DLBCL activity and tolerability in patients with relapsed/refractory DLBCL with a reduced renal function (CrCl Disclosures Schuster: Amgen, Abbvie, Gilead, Takeda, Celgene, Pharmacyclics, Astellas, Verastem, Merck, Novartis, Takeda, Genentech,, Seattle Genetics: Other: Personal Fees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Canales:Novartis: Honoraria; Janssen: Honoraria; Novartis: Honoraria; iQone: Honoraria; Sandoz: Speakers Bureau; Karyopharm: Honoraria; Janssen: Speakers Bureau; Janssen: Honoraria; Roche: Speakers Bureau; Takeda: Speakers Bureau; Janssen: Speakers Bureau; Roche: Speakers Bureau; Sandoz: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Honoraria; Roche: Honoraria; Sandoz: Honoraria; Sandoz: Honoraria; Gilead: Honoraria; Roche: Honoraria; Karyopharm: Honoraria. Westin:Novartis: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; Amgen: Consultancy; 47: Research Funding. Zijlstra:Roche: Research Funding. Follows:Karyopharm, Roche, Abbvie, Astrazeneca, Janssen, BMS: Membership on an entity's Board of Directors or advisory committees. Karmali:Takeda: Research Funding; AstraZeneca: Speakers Bureau; Karyopharm: Honoraria; BeiGene: Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Kalakonda:Gilead, Janssen, Karyopharm: Honoraria; Verastem, Gilead, Celgene, Roche: Research Funding. Goy:AbbVie: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; MD Anderson: Research Funding; Xcenda: Consultancy; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; Regional Cancer Care Associates/OMI: Current Employment; Bayer: Research Funding; PracticeUpdate Oncology: Consultancy; RCCA/OMI: Current Employment; Morphosys: Research Funding; Karyopharm: Research Funding; Genentech/Roche: Research Funding; Constellation: Research Funding; CALBG: Research Funding; Infinity Verastem: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Hackensack UMC and University of Nebraska: Research Funding; Infinity: Research Funding. Casasnovas:Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding; Abbvie: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Thieblemont:Cellectis: Speakers Bureau; Roche, Amgen, Kyte Gilead, Celgene, Abbvie, Novartis, Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche, Hospita: Research Funding. Cavallo:Takeda, Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Other: Speaker Fee. Hill:Celgene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Takeda: Research Funding. Tilly:BMS: Honoraria. Jaeger:Novartis: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Honoraria; AbbVie: Honoraria; F. Hoffmann-La Roche: Honoraria, Research Funding; Miltenyi: Consultancy, Honoraria; CDR Life AG: Consultancy, Research Funding. Gurion:JC Health CARE: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda Pharmaceuticals: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Medison: Consultancy, Honoraria. Caimi:Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding; Genentech: Research Funding. Martin:Kite: Consultancy; Morphosys: Consultancy; I-MAB: Consultancy; Janssen: Consultancy; Sandoz: Consultancy; Regeneron: Consultancy; Incyte: Consultancy; Karyopharm: Consultancy, Research Funding; Teneobio: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Cellectar: Consultancy; Beigene: Consultancy. Davies:Roche, Acerta Pharma, AstraZeneca, Celgene, Gilead, ADC Therapeutics, Gilead: Research Funding; Roche, Celgene, Kite Pharma, Acerta, Karyopharma, Regeneron, Incyte: Consultancy; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celegene, Roche, Kite Pharma, Celegene: Honoraria. Smith:TG Therapeutics: Consultancy, Research Funding; Janssen: Consultancy; Celgene: Consultancy, Research Funding; BMS: Consultancy; Karyopharm: Consultancy, Research Funding; FortySeven: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding. Collins:BeiGene: Consultancy; MSD: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; ADC Therapeutics: Consultancy, Honoraria; Celleron: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Speakers Bureau; Celgene: Research Funding; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; Amgen: Research Funding. Salles:Epizyme: Consultancy; Gilead: Consultancy, Honoraria, Other: Participation in educational events; Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Kite: Consultancy, Honoraria, Other; Debiopharm: Consultancy; Celgene: Consultancy, Honoraria, Other: Participation in educational events; Karyopharm: Consultancy; Genmab: Consultancy; Amgen: Honoraria, Other: Participation in educational events; Autolus: Consultancy; MorphoSys: Consultancy, Honoraria, Other; Novartis: Consultancy, Honoraria, Other; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Bristol Myers Squibb: Consultancy, Other; Takeda: Consultancy, Honoraria, Other. Ma:Karyopharm: Current Employment, Current equity holder in private company. Corona:Karyopharm: Current Employment. Saint-Martin:Karyopharm: Current Employment. Joshi:Karyopharm Therapeutics Inc: Consultancy. Chamoun:Karyopharm: Current Employment. Wang:Curis: Ended employment in the past 24 months; Karyopharm: Current Employment. Shah:Karyopharm: Current Employment, Current equity holder in publicly-traded company. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

e19037 Background: Patients (pts) with myelodysplastic syndrome (MDS) refractory to hypomethylating agents (HMAs) have limited therapeutic options and a dismal prognosis with a median overall survival (mOS) of 4-6 months. Eltanexor (ELTA) is a second-generation, oral, selective inhibitor of nuclear export (SINE) compound that showed anti-tumor activity and lower brain penetration compared to selinexor (SEL) in nonclinical models. It was hypothesized that ELTA could be dosed more frequently than SEL with a lower incidence of centrally mediated nausea. Early results from a phase 1/2 study of ELTA in pts with HMA refractory MDS showed anti-tumor activity with marrow complete response (mCR) and stable disease (SD); side effects were primarily low-grade, dose-dependent, and reversible (Lee et al. ASH 2019). In this abstract, we provide a subgroup analysis of the efficacy evaluable population with an update on mOS in the same population. Methods: This phase 1/2 study (NCT02649790) evaluated single-agent ELTA in pts with higher-risk MDS, ie, high-risk or intermediate-2 MDS by International Prognostic Scoring System (IPSS) and 5%-19% myeloblasts. Out of 20 pts enrolled, 15 pts were evaluable for efficacy and constitute the population studied in this analysis. Two doses of ELTA were evaluated: 10 mg (n=5) or 20 mg (n=15) every day for 5 days per week of a 28-day cycle. Results: As of 1 Feb 2021, the 15 pts evaluable for efficacy (median age 76 years; range 62-89) had a median of 2 prior treatment regimens (range 1-4); 93% had high/int-2 risk per IPSS. Of the 20 enrolled patients, 7 (35%) had mCR, and 5 (25%) had SD for a total disease control (mCR+SD) rate of 60%. Of the 15 pts evaluable for efficacy, 7 (47%) had mCR and 5 (33%) had SD. In the 10-mg cohort (n=5), all pts derived clinical benefit with 3 pts (60%) reaching mCR and 2 pts (40%) SD. In the 20-mg cohort (n=10), 4 pts (40%) had mCR and 3 (30%) had SD. Four pts had hematologic improvement (HI) and became transfusion independent for at least 8 weeks including 2 pts with tri-lineage HI. OS for pts who reached mCR (n=7) was significantly longer than for pts who did not reach mCR (n=8): median 11.86 vs 8.67 months (mo) (hazard ratio [HR]=0.27, p=0.05), and significantly longer than OS for pts with PD (n=3, mOS=3.15 mo, HR=0.23, p=0.04). Pts with disease control (n=12) had numerically longer mOS than pts with PD (9.86 vs 3.15 mo, HR=0.38, p=0.09). Pts with HI had a mOS of 10.58 months. Conclusions: Single-agent oral ELTA was active in pts with high-risk, HMA refractory MDS. Pts with mCR had significantly longer mOS than pts without mCR or with PD. Further evaluation of ELTA in MDS as a single agent and in combination with other agents is ongoing. Clinical trial information: NCT02649790.

Background: Outcome of Multiple Myeloma (MM) patients has improved as the result of the introduction of novel medications and use of autologous hematopoietic cell transplantation. However, this improvement comes at the expense of increased financial burden. It is largely unknown if socioeconomic factors influence MM survival. Methods: We used the National Cancer Database, a database that houses data on 70% of cancer patients in the US, to evaluate the effect of socioeconomic factors on the survival of 117,926 MM patients diagnosed between 2005 and 2014. Results: Patients aged ≥65 years who were privately insured lived longer than patients with Medicare (42 months vs. 31 months, respectively, p &lt, 0.0001). Treatment in academic institutions led to better survival (HR: 1.49, 95% CI: 1.39, 1.59). Younger age, fewer comorbidities, treatment in academic centers, and living in a higher median income area were significantly associated with improved survival. After adjusting for confounders, survival of Medicare patients was similar to those with private insurance. However, the hazard of death remained higher for patients with Medicaid (HR: 1.59, 95% CI: 1.36, 1.87) or without insurance (HR: 1.62, 95% CI: 1.32, 1.99), compared to privately insured patients. Conclusion: Economic factors and treatment facility type play an important role in the survival of MM patients.

Background Patients with CML treated with TKI can have a life expectancy comparable to that of the general population. Due to the extended duration of TKI administration, treatment discontinuation has been increasingly sought. Methods Medical records of 100 patients with CML who were in MR4.5 and discontinued their TKI outside clinical trials were reviewed. Results After a median follow-up of 30 months (range, 5–112 months) after discontinuation, 35% and 17% lost MR4.5 and major molecular response (MMR), respectively. Only six patients lost MMR 12 months or more after discontinuation. Loss of MR4.5 was observed in 29% and 7% of patients with sustained MR4.5 duration of more than 2 and 6 years before discontinuation, respectively. By univariate analysis, there was a higher risk of loss of MR4.5 for patients who were treated for less than 87 months, received second or subsequent line TKI, never received interferon, or those with sustained MR4.5 for less than 6 years. By multivariate analysis, sustained MR4.5 for 6 years or more was the only significant predictor for durable response. Overall, 30% of patients who discontinued while in MR4.5 were retreated with 93% regaining MR4.5 at a median of 5 months. Conclusion These results demonstrate that under proper conditions, treatment discontinuation is feasible outside of clinical trial setting. MR4.5 duration of 6 years or more before discontinuation is associated with very low risk of loss of MR4.5.

Introduction Risk of venous thromboembolism (VTE) is increased in patients (pts) with multiple myeloma (MM) as a result of the biology of the disease and the use of immunomodulatory drugs (IMiDs). These patients frequently undergo autologous hematopoietic cell transplantation (AHCT) transplantation in order to improve disease-free and potentially overall survival. We conducted this study to better understand the incidence and risk factors associated with peri-transplant VTE in this population. Methods 160 MM pts who received IMiD therapy and underwent AHCT between 6/2004 and 11/2016 at our institution were the subjects of this analysis. The peri-transplant period was defined as time from central venous catheter (CVC) insertion up to 60 days post-transplant. None of the pts received VTE prophylaxis during this period. Results All patients received at least one IMiD-based regimen before transplant including thalidomide (31%), lenalidomide (74%), pomalidomide (6%). Imids were stopped at a median of 38 days prior to collection (range 0 days-4 years). CVCs (double lumen n=103, triple lumen n=50, unknown n=7) were inserted a median of 2.5 days prior to mobilized blood collection (range 0-48 days) and were removed a median of 52.5 days after insertion (range 2-303 days). Twenty of 160 patients (12.5%) developed VTE in the peri-transplant period; there was 11 (55%) CVC-related VTE, 6 (30%) lower extremity VTE and 3 (15%) pulmonary embolism. There was no VTE-related death. Median platelet count at the time of VTE was 90 (range, 30-130) x109/L. Eleven VTEs occurred between time of initiation of progenitor cell mobilization and infusion (T-0), and 9 occurred between T-0 and 60 days post-transplant. The rate of catheter-related VTE that occurred before or after T-0 was similar (55%). Thirty-nine percent of pts had a catheter size of less than 14 french; 49% had a catheter size of 14 french or more; the size could not be collected in 12% of the pts. Rate of catheter-related VTE in pts with ≥ 14 and Conclusion In this retrospective single institution analysis, we found a 12.5% incidence of peri-transplant VTEs, which is higher than what was reported in patients receiving transplant for other malignancies [1]. The size of the catheter did not affect the risk of VTE. About half of the VTEs were catheter-related, half of which occurred before T-0. If confirmed on a larger scale, it may be beneficial to give VTE prophylaxis during mobilization to minimize this risk.

Introduction Tacrolimus (tacro) is commonly used for the prevention of graft vs host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT). Due to concerns of inadequate absorption, tacro is commonly administered intravenously (IV) in the immediate post allogeneic transplant period. Advantages to oral (PO) tacro include decreased need for multi lumen IV catheters, improved patients (pts) convenience, and reduced cost. We retrospectively analyzed differences in safety, tolerability, time to achieve therapeutic levels during the 1st 4 weeks and rates of acute GVHD. Methods IV tacro at 0.02 mg/kg by continuous infusion or PO tacro at 0.03 mg/kg twice daily was started between T-3 and T+5. Levels were assessed 3 times weekly. Dose was titrated to achieve a steady level between 7 and 14 ng/ml. GVHD was graded according to CIBMTR criteria. Results 54 pts were treated between Sep 2016 and July 2018. 21 who received PO tacro and 27 who received IV tacro were studied. 6 pts on PO tacro are still within 100 days post-transplant and will be reported in follow up. The median age was 59 years (range, 21-74), 52% were females, diagnoses were AML (54%), MDS (19%), ALL (15%), CML (6%), NHL (4%) and MF (2%). HCT-CI was 0, 1-3 and >3 in 23%, 54% and 23% of pts, respectively. Donors were match-unrelated (58%), match-related (27%), haploidentical (6%) and double umbilical cord (6%). Conditioning regimens were myeloablative (60%) and reduced intensity (40%). 60% of pts received rabbit ATG (3 mg/Kg). GVHD prophylaxis also included mini-MTX on days +1, +3, +5 and +11 (79%), MMF (15%), and MMF + post-transplant Cy (6%). Pts characteristics were similar between the 2 groups. 7 pts (33%) who initially started on PO tacro switched to IV due to poor absorption (3), mucositis (1), toxicity (1), GVHD (1) and patient's concern (1). Target therapeutic level was reached in 67% vs 81% during week 1, 86% vs 96% during week 2, 95% vs 96% during week 3, and 100% vs 96% during week 4, of pts on PO vs IV tacro, respectively. Median tacro level during the 1st 4 weeks was 12.6 ng/ml vs 11.2 ng/ml, acute kidney injury occurred in 23.8% vs 33.3% (p=.47) and increased bilirubin occurred in 4.7% vs 22.2% (p=.09), in pts on PO vs IV tacro. Posterior reversible encephalopathy was observed in 1 patient on PO tacro. Grade I and Grade II-IV acute GVHD incidence was 47.6% vs 14.8% (p=.01) and 47.6% vs 44.4% (p=.82) of pts on PO vs IV tacro. Stage 1-2 skin aGVHD rate was higher in the PO vs. IV group (90% vs 33.3%; p=.0001). There was no difference in rates of stage 3 skin (4.7% vs 3.7%), stage 1 GI (33.3% vs 33.3%), or stage 2-4 GI (14% vs 7.4%) aGVHD. None of the pts had stage 4 skin or any stage liver aGVHD. Conclusion PO tacro is safe and effective in the prevention of aGVHD in pts receiving myeloablative or RIC allo-SCT. The use of PO tacro during the 1st 4 weeks post-transplant was found to be associated with higher rate of stage 1-2 skin aGVHD and warrants further study.

The impact of bone marrow fibrosis grade on the prognosis of patients with chronic myelomonocytic leukemia (CMML) remains controversial. Therefore, we examined the records of 82 patients diagnosed with CMML at our institution and summarized baseline characteristics and molecular profiles by subgroups of absent or mild (grades 0/1) and moderate (grade 2) fibrosis. Cox proportional hazards models were constructed to assess the prognostic significance of fibrosis grade. Grade 2 fibrosis was identified in 63 patients (76.8%), grade 1 in 16 patients (19.5%), and grade 0 in 3 patients (3.7%). Grade 2 fibrosis was associated with reduced hemoglobin levels (median: 9.75 g/dL vs 11.0 g/dL in grade 0/1; p = 0.04) and increased percentages of ringed sideroblasts (7.5% vs 0%; p = 0.008). In multivariable analysis, grade 2 fibrosis was an independent predictor of poor overall survival (OS; 95% CI: 1.32–6.35; HR: 2.90; p = 0.008), but not event-free survival (EFS; 95% CI: 0.62–2.67; HR: 1.28; p = 0.50). Absolute neutrophil count (ANC) was found to impact OS (95% CI: 1.01–1.09; HR: 1.05; p = 0.009), while both ANC (95% CI: 1.00–1.07; HR: 1.04; p = 0.04) and peripheral blood blast percentage (95% CI: 1.02–1.32; HR: 1.16; p = 0.02) impacted EFS. These results implicate fibrosis grade is an important indicator of prognosis, with high-grade fibrosis predicting inferior survival. Given the prevalence of marrow fibrosis in CMML, fibrosis grading should be incorporated into prognostic assessment and therapeutic decision-making.

Introduction: Survival of Multiple Myeloma (MM) patients has improved in recent decades due to the advent of novel agents and broader utilization of stem cell transplant. Fatal outcomes occur mostly after multiple lines of therapy due to increasingly resistant disease. Indeed, early mortality after diagnosis is unusual in front line treatment MM trials, where patients are often selected on the basis of good performance status and absence of organ dysfunction. The real world incidence of early deaths is largely unknown. Hereby, we analyze the factors impacting early mortality in the National Cancer Database (NCDB) which covers more than 70% of MM patients in United States. Methods: Patients with MM diagnosed from 2005-2014 were identified in the NCDB. Early mortality (EM) was defined as death within six months of MM diagnosis. The effect of demographic and clinical factors, insurance type, distance to treatment facility, medical facility and facility volume on the probability of EM was estimated by univariate logistic model. The effect of these factors on the probability of EM was further estimated by multivariable logistic regression. The overall performance of multivariable logistic regression was evaluated using the receiver operating characteristic curve (ROC) analysis. The difference of continuous measurements between groups was examined using t-test. The association between categorical variables was examined using Chi-square test. All tests are two-sided and p-value ≤ 0.05 were considered statistically significant. Results: 90,258 patients with ICD-O 9732 were included. 49949 (55%) were male. EM was reported in 15729 (17%) within the first 6 months after MM diagnosis. Median age at diagnosis was 67 years (19-90). 15729 patients (17%) died in the first 6 months after diagnosis. There was no significant change in the percentage of EM over the years from 2005-2014. 11963 (76%) of patients with EM were older than 65 years while 3766 (23%) patients were less than 65 years. 12300 (78.1%) of the patients with EM were white and 2822 (17.9%) were African American. In a multivariable analysis, variables that confer the worst prognosis were increasing age, higher charlson co-morbidity score, lower annual median income of less than 30,000, and being treated in a community hospital. Controlling the effects of other factors (charlson co-morbidity score, hospital type and transplant), the odds ratio of EM was 1.04 per year increase of age (p Conclusion: Taken together our data suggest almost 1 out of 6 MM patients died at the first 6 months after diagnosis. Therefore, EM remains high in MM and a major barrier for continued improvement in survival outcomes. In addition to well-known MM-specific determinants of survival, socioeconomic factors were significantly associated with early mortality. Disclosures Malek: Adaptive: Consultancy; Medpacto: Research Funding; Janssen: Speakers Bureau; Sanofi: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Amgen: Speakers Bureau.

Background: Smoldering multiple myeloma (SM) is a heterogenous clinical entity with a variable rate of progression to symptomatic multiple myeloma (MM). Identification of demographic characteristics and outcomes of SM patients have been hampered by the lack of specific ICD code for SM. Here, we analyzed the National Cancer Database (NCDB) for this purpose, which covers >70% of cancer patients in the U.S. Methods: We reviewed patients in the NCDB who were diagnosed with MM between 2010 and 2014. Patients who did not receive any treatment within 3 months after the diagnosis and still alive were considered to have had SM (Ravindran et al. Blood Cancer J. 2016). Initiation of systemic treatment was considered as a surrogate of progression to symptomatic MM. Overall survival (OS) of SM patients was calculated from initiation of systemic treatment after they progressed to MM, estimated by the Kaplan-Meier method, and compared with the log-rank test. Cumulative incidence of progression from SM to MM was calculated with death as a competing risk and compared with the Gray's test. Multivariable Cox and logistic regression analysis were performed to identify independent predictors of OS and progression to MM, respectively. Results: We reviewed 68,234 patients and identified 12,984 patients with SM. Among SM patients, 3002 (23%) were black, 6796 (52%) were male, and median age at diagnosis was 69 years (range: 22 - 90). SM patients' insurance types were private for 4164 (32%), Medicare for 7420 (57%), Medicaid for 669 (5%), and 260 (2%) were uninsured. Majority of the cases were reported from non-academic hospitals (59%). Patient and treatment characteristics are summarized in Table 1. SM was diagnosed in black patients a median of 4 years younger than in white patients (median age 66 vs 70 years, p Four-year cumulative incidence of progression to MM for SM patients at ages of 70 years was 34% (95% CI: 32 - 35) vs 28% (95% CI: 26 - 29, p Four-year OS of SM patients after progression and MM patients without known preceding SM who received treatment were 63% (95% CI: 61 - 65) and 54% (95% CI: 54 - 55), respectively (p70 vs 60-70 and Conclusion: Taken together, our result shows higher rate of MM progression in younger SMM patients than old ones as well as earlier age of SMM diagnosis in Blacks. Also, this study highlights the importance of known SMM stage before MM in prolonging survival which can be indicative of benefit from screening programs. Disclosures Metheny: Incyte: Speakers Bureau; Takeda: Speakers Bureau. Malek:Celgene: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Medpacto: Research Funding; Janssen: Speakers Bureau; Amgen: Speakers Bureau; Adaptive: Consultancy.

Advent of novel anti-myeloma agents and broader use of stem cell transplant has led to significant improvement in survival of patients (pts) with Multiple Myeloma (MM). However, there are well-described issues with affordability of novel drugs and rapidly escalating price of these agents (Shih et al. JCO 2017), leading to significant disparity among different sociodemographic groups. Hereby, we interrogated the National Cancer Database (NCDB) (which covers 70% of MM patient diagnosed nationwide) to assess impact of insurance type on survival. We also sought to investigate if autologous transplant may overcome socioeconomic effects on survival, by potentially minimizing the need for chronic use of expensive drugs. Methods: Data from 117,926 MM pts diagnosed with MM (ICD-O 9732) between year 2005 and 2014 were analyzed.. The comparison of patient characteristics among insurance types was done using ANOVA for continuous measurements and Chi-square test for categorical factors. OS was measured from the date of diagnosis to the date of death, censored at the date of last follow-up for survivors. Survivor distribution was estimated using Kaplan-Meier methods and difference of OS between groups was examined by log-rank test. The effect of continuous measurements including age, distance to medical facility and facility volume on OS was estimated using Cox proportional hazard model. The effect of insurance type on OS was estimated using multivariable Cox proportional hazard regression after adjusting the effects of confounding factors. Results: Median age at diagnosis was 67 years (19-90); 55% were males. 57% of pts lived in areas where the median income was < $46k/year (individual income data was not available); Primary insurance was Medicare (52%), private insurance (35%) or Medicaid (5%), and 3% were uninsured. 40% were treated in academic institutions. Median follow up was 30.2 (range, 0-145.2) months. By univariate analysis, better OS was observed in pts with primary MM, lower Charlson Comorbidity Index (CCI), treatment in academic institutions, higher median regional income, or private insurance (p 120 miles to the treatment facility than patients with Medicare (3%).Amongst patients younger than 65 years, 33% of patients with private insurance received transplant compared to 20% of those on Medicare (p Conclusions: Although insurance type and regional income are associated with MM survival among patients who relied on non-transplant modalities, there was no significant impact of these socioeconomic factors on survival of patients that received an autologous transplant in this large database. This finding merits further investigation. Disclosures Malek: Janssen: Speakers Bureau; Amgen: Speakers Bureau; Adaptive: Consultancy; Celgene: Consultancy; Medpacto: Research Funding; Takeda: Consultancy; Sanofi: Consultancy.

LBA107 Background: MM is often treated with oral antineoplastic medications (OAM). OAM prices have been rapidly escalating and there are well-described issues with affordability (Shih et al. JCO 2017). We therefore hypothesized that insurance status influences MM patients (pts) survival and interrogated the National Cancer Database (NCDB) to test this hypothesis. Methods: NCDB houses data on 70% of cancer pts in the USA. Data from 117,926 MM pts diagnosed between year 2005 and 2014 was analyzed. Primary outcome was overall survival (OS) which was analyzed using Kaplan-Meier method and Cox model. Results: Median age at diagnosis was 67 years (19-90); 55% were males. 57% of pts lived in areas where the median income was < $46k/year (individual income data was not available); Primary insurance was Medicare (52%), private insurance (35%) or Medicaid (5%), and 3% were uninsured. 40% were treated in academic institutions. Median follow up was 30 months (0-145). By univariate analysis, better OS was observed in pts with primary MM, lower Charlson Comorbidity Index (CCI), treatment in academic institutions, higher median regional income, or private insurance ( p

e18170 Background: Multiple Myeloma (MM) counts the most common hematologic malignance among African-Americans with twice the incidence of whites. The outcomes have greatly improved during the last 15 years, however with changing demographics there is an increasing focus on how various subgroups, based on race and ethnicity may be benefiting from survival improvement in MM. Previous studies showed that if access to care is assured, racial disparity-driven differences in outcome may be mitigated. Here, we conducted a study using the National Cancer Data Base (NCDB), which covers more than 70% of cancer pts in the USA, to evaluate survival patterns by race. Methods: MM patients (pts) diagnosed between years 2005 and 2014 and reported to the NCDB were analyzed (n = 117926). Pts were divided in three groups based on the year (y) of diagnosis (2005-07, 2008-10 and 2011-14). Kaplan-Meier method and log-rank test were used for overall survival analysis (OS). The effect size, hazard ratio (HR), of race on OS was estimated by Cox model adjusted by confounders. Results: Median age at diagnosis was 67 y (19 - 90); 55% were males. Median follow up was 30 months (m) (0 - 145). Median OS for white and black pts was 46 m (95% CI: 45.4 - 46.6) and 50.6 m (95% CI: 49.1 - 52.3), respectively (p < 0.0001). Black had longer OS compared to white pts by univariable analysis in all three study periods, noticeably with a trend toward higher survival benefit in most recent years. After adjusting for a variety of factors there was no statistically significant difference between the two racial groups (Table). Conclusions: This large study confirmed that after adjusting for confounding factors survival is similar for white and black MM pts. [Table: see text]

e13064 Background: SMM is the requisite asymptomatic phase that precedes Multiple Myeloma (MM). Observation until progression to MM has been the standard of care. However, the improvement in risk assessment and utility of chemoprevention strategies stemmed from large trials (e.g. QUIREDEX and E3A06) is beginning to shift the paradigm toward early detection of SMM by implementing screening strategies (e.g., PROMIS study). Lack of specific ICD code for SMM has been a major problem in epidemiologic studies aiming at characterizing the demographics and temporal dynamics of SMM. Here, we used the National Cancer Data Base (NCDB), which covers more than 70% of cancer pts in the USA, for this purpose. Methods: NCDB data from year 2010 to 2014 was analyzed. We defined SMM as pts with ICD-O 9732 that were placed on active surveillance or did not receive any therapy in the first 3 months (m) after diagnosis (Ravindran et al. Blood Cancer J. 2016). Institution size was categorized as small, medium and large if they reported < 10, 10-50, and > 50 cases per year, respectively. Results: Out of a total of 68234 MM pts, we identified 11643 (17%) with SMM. Median follow up was 32 m (0 - 85). Median age was 65 years (26 - 90), 52% were males, 71% were white and 24% were black. Median survival was 77.7 and 49.8 m for pts with SMM and MM, respectively ( p= 0.001). Median age at diagnosis of SMM was 62 and 66 years in blacks and whites, respectively ( p= 0.01). Over 87% of pts were diagnosed in small and medium size institutions (38% and 49%, respectively). Medicare was the main insurance payer (57%), followed by private insurance (32%) and Medicaid (5%), and 3% were not insured. The majority of pts (59.5%) lived in areas where the median income is less than $46K/year. Median distance traveled to treatment facility was 8.5 miles. During the first two years from diagnosis 18% needed treatment which is compatible with known estimated 10% per year risk of progression from SMM to MM. Conclusions: This large study of over 11,000 SMM pts highlights the national demographics of SMM diagnosed between years 2010 and 2014. Our results indicate that targeting small and medium size facilities should be an essential part of SMM screening strategies.

2539 Background: AntiCD19 CAR-T cells have shown encouraging anti-lymphoma activity. Decreasing the time from apheresis to CAR-T infusion can make this therapy available to pts with rapid progression. We present the interim results of a phase I clinical trial using on-site CAR-T manufacture. Methods: Adult pts with r/r CD19+ B cell lymphomas who failed ≥ 2 lines of therapy were enrolled. Autologous T cells were transduced with a lentiviral vector (Lentigen Technology, Inc,LTG1563) encoding an antiCD19 binding motif, CD8 linker and TNFRSF19 transmembrane region, and 4-lBB/CD3z domains. GMP-compliant manufacture was done using CliniMACS Prodigy, in a 12-day culture. Dose levels were 0.5, 1 and 2 x 106 CAR-T cells/kg. Lymphodepletion was done with cyclophosphamide (60mg/kg x 1) and fludarabine (25mg/m2/d x 3). Results: 7 pts (4 women, 3 men) were enrolled. Median age was 60y [range 43-69]. Diagnoses were DLBCL (n = 3) PMBCL, follicular lymphoma (FL), transformed FL, and transformed lymphoplasmacytic lymphoma; with a median of 4 previous treatments. Six pts had symptomatic refractory disease. CAR-T cell product manufacture was successful in all pts. Mean transduction rate was 44% [range 29-57]. CAR-T cell doses were 0.5 x 106/kg (n = 3) and 1 x 106/kg (n = 4). Median apheresis to infusion time was 13 days [range 13–20], 5 products were infused fresh. CAR-T persistence based on vector sequence, peaked in peripheral blood MNCs between days 14-21. Five pts are evaluable for safety. CRS grade 1 - 2 (Lee) occurred in 4 pts; with 3 requiring treatment. Grade 4 CRES (CARTOX-10) occurred in 1 pt, with resolution after corticosteroids; considered a DLT as it lasted more than 72 hours. No treatment-related mortality has occurred. 4/5 evaluable pts have achieved complete response. One pt did not respond and died. After a median follow up 3 months, all responding pts are alive and 1 relapsed 6 mo after treatment. Conclusions: Second generation antiCD19 CAR-T cells with TNFRS19 transmembrane domain have clinical activity against refractory NHL. Short manufacture time achieved by local CAR-T cell manufacture with the CliniMACS Prodigy enables treatment of a very high risk NHL population. Clinical trial information: NCT03434769.

Therapeutic improvements are required for primary CNS lymphoma (PCNSL) and secondary CNS lymphoma. PCNSLs are predominantly diffuse large B-cell lymphoma (DLBCL) classified in the non-germinal center (non-GC) subgroup.1 The role of B-cell receptor (BCR) signaling to continuously activate the NF-κB pathway is well-established in non-GC DLBCL.2 Mutations of MYD88 , CD79B , and TBL1XR1 , genes involved in the NF-κB pathway, are frequently encountered in PCNSL.3 Ibrutinib, an inhibitor of BCR signaling, led to an objective response rate of 50% in patients with relapsed or refractory systemic non-GC DLBCL.4 As a small molecule (MW = 440), with promising CNS distribution,5 ibrutinib represents a potential treatment for PCNSL. We report a retrospective case series of patients with relapsed and refractory CNS lymphoma treated with ibrutinib.

Introduction: Clearance of detected somatic mutations at complete response by next-generation sequencing is a prognostic marker for survival in patients with acute myeloid leukemia (AML). However, the impact of allelic burden and persistence of clonal hematopoiesis of indeterminate potential (CHIP)-associated mutations on survival remains unclear. The aim of this study is to evaluate the prognostic impact of allelic burden of CHIP mutations at diagnosis, and their persistence within 6 months of therapy. Methods: From February 1, 2012 to May 26, 2016, we reviewed 562 patients with newly diagnosed AML. Next-generation sequencing was performed on the bone marrow samples to detect the presence of CHIP-associated mutations defined as DNMT3A, TET2, ASXL1, JAK2 and TP53. Overall survival (OS) was defined as time period from the diagnosis of AML to the date of last follow-up or death. Univariate (UVA) and multivariate Cox proportional hazard regression (MVA) were performed to identify prognostic factors for OS with p value cutoff of 0.020 for the selection of variables for MVA. Landmark analysis at 6 months was performed for the evaluation of the impact of clearance of CHIP, FLT3-ITD, FLT3D835, and NPM1 mutations. Results: We identified 378 patients (74%) with AML with CHIP mutations; 134 patients (26%) with AML without CHIP mutations. The overall median follow-up of 23 months (range, 0.1-49.0). The median age at diagnosis was 70 years (range, 17-92) and 66 years (range, 20-87) in CHIP AML and non-CHIP AML, respectively (p =0.001). Of 371 patients and 127 patients evaluable for cytogenetic in CHIP AML and non-CHIP AML, 124 (33%) and 25 patients (20%) had complex karyotype, respectively (p= 0.004). Of 378 patients with CHIP AML, 183 patients (48%) had TET2 mutations; 113 (30%), TP53; 110 (29%), ASXL1; 109 (29%), DNMT3A; JAK2, 46 (12%). Of 378 patients, single CHIP mutations was observed in 225 patients (60%); double, 33 (9%); triple, 28 (7%); quadruple, 1 (0%). Concurrent FLT3-ITD mutations was detected in 47 patients (13%) and 12 patients (9%) in CHIP AML and non-CHIP AML, respectively (p= 0.287); FLT3-D835, 22 (6%) and 8 (6%), respectively (p= 0.932); NPM1 mutations, 62 (17%) and 13 (10%), respectively (p= 0.057). Of 183 patients with TET2-mutated AML, the median TET2 variant allele frequency (VAF) was 42.9% (range, 2.26-95.32); of 113 with TP53-mutated AML, the median TP53 VAF, 45.9% (range, 1.15-93.74); of 109 with ASXL1-mutated AML, the median ASXL1 VAF was 34.5% (range, 1.17-58.62); of 109 with DNMT3A-mutated AML, the median DNMT3A VAF was 41.8% (range, 1.02-91.66); of 46 with JAK2-mutated AML, the median JAK2 VAF was 54.4% (range, 1.49-98.52). Overall, the median OS was 12 months and 11 months in CHIP AML and non-CHIP AML, respectively (p= 0.564); 16 months and 5 months in TET2-mutated AML and non-TET2-mutated AML, respectively (p Conclusion: The VAF of TP53 and NPM1 mutations by next generation sequencing can further stratify patients with newly diagnosed AML. Approximately, each increment of TP53 and NPM1 VAF by 1% is independently associated with 1% higher risk of death, and 2% lower risk of death, respectively. The presence of CHIP mutations except TP53 does not affect outcome. Disclosures Sasaki: Otsuka Pharmaceutical: Honoraria. Short:Takeda Oncology: Consultancy. Ravandi:Macrogenix: Honoraria, Research Funding; Seattle Genetics: Research Funding; Sunesis: Honoraria; Xencor: Research Funding; Jazz: Honoraria; Seattle Genetics: Research Funding; Abbvie: Research Funding; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Orsenix: Honoraria; Abbvie: Research Funding; Jazz: Honoraria; Xencor: Research Funding; Orsenix: Honoraria; Sunesis: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria. Kadia:BMS: Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Celgene: Research Funding. DiNardo:Karyopharm: Honoraria; Agios: Consultancy; Celgene: Honoraria; Medimmune: Honoraria; Bayer: Honoraria; Abbvie: Honoraria. Cortes:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding.

Background: The combination of all-trans-retinoic acid (ATRA) plus arsenic trioxide (ATO) has revolutionized the treatment of pts with APL. However, despite a remission rate exceeding 96% and 5-year disease-free and overall survival rates reaching 96% and 88%, respectively, death during induction still occur in 4% of the patients. We conducted this study to identify factors that were associated with 30-day mortality, ICU admission, intubation, or differentiation syndrome in patients with APL receiving this combination therapy. Methods: We retrospectively analyzed the charts of 187 pts with APL who were treated with ATRA and ATO at MD Anderson Cancer Center. Pts with white blood cell count (WBC) > 10x109/L at presentation or during induction received one dose of Gemtuzumab Ozogamicin (GO) (9 mg/m2). Analyzed variables were age, gender, admission (baseline) weight, change in weight (percentage) from baseline to ICU admission or to maximum weight throughout induction cycle, WBC, hemoglobin, platelets, peripheral blasts, lactate dehydrogenase (LDH), creatinine, albumin, and bilirubin at presentation. Results: The median age was 50 years (range, 14-84 years), 52% were male, and median WBC count at presentation was 2x109/L (range, 0.3-188x109/L). Median weight at presentation was 91 Kg (range, 49.1-177.6 Kg). During induction, weight increased ≥ 10% from baseline in 26 patients and ≥ 5% in 63 patients. Median increase in weight from baseline to maximum was 3.2% (range, 0-27.5%) and median increase in weight from baseline to ICU admission was 5% (range, 0- 21.6%) after excluding patients who were in ICU before start of treatment (n=27). Differentiation syndrome was reported in 22 (11.8%) patients; four were admitted to ICU and one required intubation. A total of 45 (24.1%) patients were admitted into ICU; 12 of them (26.7%) required intubation. Reasons for ICU admission (one or more reason per patient) included respiratory insufficiency (n=27), intracranial hemorrhage (n=15), leukocytosis (n=7), disseminated intravascular coagulation (n=5), differentiation syndrome (4) and diabetic ketoacidosis (n=1). A total of 7 (3.7%) patients died during induction; 6 of them were in ICU. Causes of death were disseminated intravascular coagulation (DIC) and multi-organ failure in 2 patients, diffuse alveolar hemorrhage (DAH) in 2 patients, intracranial hemorrhage in 1 patient, sepsis in 1 patient, and respiratory arrest in 1 patient. Univariate analysis for 30-day mortality showed that age, high creatinine, low hemoglobin and albumin, were significantly associated with increased risk of death within 30 days. After excluding 27 patients who were already admitted to ICU prior to or at the time of treatment, univariate analysis showed that increase in weight, high WBC, creatinine and bilirubin, and low platelets, were significantly associated with higher risk of ICU admission (Table 1). Based on the fitted multiple logistic regression model, increase in weight of ≥ 13% (p=0.003) and WBC ≥ 10x109/L (p=0.02) were associated with increased risk of ICU admission (Table 2). Increase in weight and low albumin were significantly associated with higher probability of intubation. Additionally, univariate analysis for differentiation syndrome suggested that increase in weight, high WBC and bilirubin were significantly associated with the probability of developing differentiation syndrome. However, based on the fitted multiple logistic regression model, only increase in weight of ≥ 9% (p Conclusion: Fluid overload, measured by weight gain, is an unrecognized complication in patients with APL receiving ATRA + ATO +/- GO. In addition to high WBC, fluid overload is associated with an increased risk of ICU admission and intubation but not death during induction. Disclosures Jabbour: Pfizer: Consultancy, Research Funding; Novartis: Research Funding; Takeda: Consultancy, Research Funding; Abbvie: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Kadia:Takeda: Consultancy; Celgene: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Research Funding; BMS: Research Funding; Abbvie: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Jazz: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Novartis: Consultancy; Takeda: Consultancy; BMS: Research Funding; Amgen: Consultancy, Research Funding. Daver:ARIAD: Research Funding; Kiromic: Research Funding; ImmunoGen: Consultancy; Pfizer: Research Funding; BMS: Research Funding; Karyopharm: Research Funding; Incyte: Consultancy; Daiichi-Sankyo: Research Funding; Otsuka: Consultancy; Incyte: Research Funding; Novartis: Consultancy; Pfizer: Consultancy; Novartis: Research Funding; Alexion: Consultancy; Sunesis: Research Funding; Sunesis: Consultancy; Karyopharm: Consultancy. DiNardo:Celgene: Honoraria; Abbvie: Honoraria; Karyopharm: Honoraria; Medimmune: Honoraria; Agios: Consultancy; Bayer: Honoraria. Jain:Cellectis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Verastem: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Servier: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Celgene: Research Funding; Infinity: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Incyte: Research Funding; Adaptive Biotechnologioes: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Astra Zeneca: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; ADC Therapeutics: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Abbvie: Research Funding; Seattle Genetics: Research Funding; Incyte: Research Funding; Celgene: Research Funding; Astra Zeneca: Research Funding; Servier: Research Funding; Verastem: Research Funding; Cellectis: Research Funding; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konopleva:Stemline Therapeutics: Research Funding. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding. Ravandi:Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Sunesis: Honoraria; Xencor: Research Funding; Jazz: Honoraria; Sunesis: Honoraria; Orsenix: Honoraria; Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Orsenix: Honoraria; Seattle Genetics: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Seattle Genetics: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Research Funding; Xencor: Research Funding; Jazz: Honoraria.

103Background: Until recently, therapy options for AML patients (pts) were limited. The advent of NGS and novel targeted agents raise the question of how broader use of testing will impact treatmen...

e18543 Background: GVHD remains the main limitation of alloSCT and is exacerbated by the intensity of the conditioning regimen. In a recent study, the risk of acute grade II-IV GVHD and extensive chronic GVHD (cGVHD) after a nonmyelobaltive (NMA) regimen was 11%, and 26%, respectively (Khouri I. Blood 2014 124:2306). Higher rates were previously observed (32% and 54%, respectively) with the BEAM regimen. Based on clinical data showing a reduction in GVHD with the use of rituximab or bortezomib, we conducted a phase I/II study evaluating the addition of bortezomib to rituximab+BEAM in patients (pts.) who were not eligible for NMA alloSCT. Methods: Bortezomib was administered at 1.3 mg/m2 IV on days -13, -6, -1 and +2. The dose was later reduced to 1 mg/m2 after the occurrence of C. Difficile colitis in the first 3 pts. leading to 2 deaths. Rituximab was given on day -13 at a dose of 375 mg/m2, then at 1000 mg/m2 on days -6, +1, and +8 of alloSCT. BEAM was administered between days -6 and -1. All pts. received our standard GVHD prophylaxis with tacrolimus and methotrexate. In addition, thymoglobulin 1 mg/kg IV was given on days -2, and -1 in patients receiving matched unrelated donor (MUD) or mismatched (MM) transplants. Results: Thirty-nine pts. were studied. Median age was 54 yrs. Thirteen (33%) and 26 (67%) pts. had indolent or aggressive lymphoma histologies, respectively. Sixteen (41%) pts. were refractory. Twenty-two (56%) received alloSCT from HLA-compatible siblings, 16 (41%) from MUDs and 1 (3%) from mm donors. Peripheral blood was the source of stem cells in 97% of pts. ABO and CMV-mismatch rates were 56% had 50%, respectively. Median follow up surviving patients was 65 mos. Five-year OS and PFS rates were 35% and 28%, respectively. The CI of acute grade II-IV, III-IV, and cGVHD were 55%, 34%, and 41%, respectively. No predictor for acute GVHD was identified. Instead, we found that sex-mismatched transplants were predictive of a higher risk of cGVHD ( P= 0.01). Conclusions: The current trial is the first one evaluating the safety and efficacy of bortezomib plus rituximab as a part of the BEAM regimen for alloSCT. A better prophylaxis regimen is needed to lessen the risk of GVHD in this setting. Clinical trial information: NCT00439556.

7011 Background: AML LSC are believed to be responsible for residual and resistant leukemic disease leading to relapse. Understanding differences between bulk AML and the LSC subpopulation may allow the identification of novel LSC targets, especially for the most adverse risk AML where few patients are cured. Targeting LSC may be needed to eradicate AML, and immune-based therapies provide an approach for eliminating LSC. The transcriptional landscape of immune-related genes in LSC is not well understood. Methods: Samples were collected at diagnosis from 12 patients with high-risk AML prior to therapy. Bulk (CD45-dim blasts) and LSC (Lin-CD34+CD38-CD123+) AML marrow cells were FACS-sorted and analyzed using whole genome RNA-sequencing. Transcriptomes were analyzed using AltAnalyze software to identify differentially expressed genes in bulk AML cells and in AML LSC populations. These genes were further assessed by gene enrichment analysis using data from Gene Ontology (GO) and the Cancer Genome Atlas Project (CGAP). Results: Sixty-eight genes were identified with greater than 3-fold differential expression between bulk AML and LSC. GO enrichment analysis demonstrated more than 10-fold enrichment of genes involved in the molecular functions, biologic processes, and cell components related to the antigen presentation pathway, with the comparative down-regulation occurring in LSC. Among the top differentially expressed gene clusters, both the MHC class II and interferon-gamma signaling/response pathway gene expression was blunted in LSC. Additional expression analysis revealed that 42% of a CGAP-curated list of 201 antigen-processing and -presentation genes had significantly decreased expression in the LSC subpopulation compared to bulk AML. Conclusions: LSC from primary AML patient samples are characterized by reduction in expression of MHC class II receptor and antigen presentation genes compared to bulk AML. These results suggest that impairment in the presentation and/or processing of tumor associated antigens by MHC class II on LSC, along with tonic sponging of immune response cells and diversion away from LSC by bulk AML, may contribute to LSC evasion of immune surveillance and response.

Chronic myeloid leukemia (CML) patients who achieve a complete cytogenetic response (CCyR) with tyrosine kinase inhibitor (TKI) have an expected survival rate comparable to that of the general population. It is practice to continue TKI therapy indefinitely. However, this chronic therapy may impact patient's lives either by its associated adverse events, or its influence on real-life events (eg. pregnancy, financial burden). Therefore, treatment discontinuation has been increasingly sought. Discontinuation of therapy for patients with sustained MR4.5 has been associated with 30-50% sustained molecular response in previous studies. However, patients may sometimes choose to discontinue therapy for various reasons regardless of the response. We retrospectively analyzed the outcome of 95 patients with CML who discontinued TKI therapy at a single institution. Median age at diagnosis was 50 years (range 26 - 75), 56 (59%) were females. Median follow up from diagnosis to treatment discontinuation was 120 months. TKI was the initial therapy in 62 patients (41 imatinib, 7 nilotinib, 12 dasatinib, 1 bosutinib, 1 ponatinib) and interferon in 33 patients (34%). At time of discontinuation, 67 patients (71%) were receiving their first TKI (48 imatinib, 6 nilotinib, 12 dasatinib, 1 ponatinib) while 25 (26%) and 3 (3%) patients were receiving their second and third TKI respectively. All patients achieved complete cytogenetic response (CCyR) and major molecular response (MMR) in a median of 3 (range 2-93) and 9 months (range 2-132) respectively. MR4.5 was achieved in 92 (97%) patients at a median of 17 months. Three patients had MMR as their best response. Patients received TKI for a median of 104 months (range 8-203) before discontinuation. Fifty two patients (54%) discontinued therapy due to adverse events, 27 (28%) electively due to sustained MR4.5, 7 (7%) due to pregnancy, 6 (6%) for financial reasons and 3 (3%) due to the occurrence of a second cancer. At time of discontinuation all patients were in CCyR; 90 patients (95%) were in MR4.5 and 5 patients (5%) in MMR. The median MR4.5 duration before discontinuation was 75 months (range 1-178); 84 had a sustained MR4.5 for at least 2 years and 59 for at least 5 years. After a median follow-up from treatment discontinuation of 23 months (0 to 113 months), 38 (40%) patients have lost their response at a median of 4 months (range 1-34) after discontinuation; 10 patients lost response after 12 months from discontinuation. Among patients with MR4.5 at discontinuation, molecular relapse occurred in 33 patients (37%) at a median of 4 months (range 1-34; 8 after 12 months from discontinuation). All 5 patients with MMR at discontinuation loss their response at a median of 8 months (range 2-14). Patients receiving imatinib, dasatinib or nilotinib had a median TKI treatment duration of 117, 64 and 65 months before discontinuation, and lost their response at a rate of 33%, 56% and 46%, respectively. Relapse rate for patients with MR4.5 sustained >2 years was 32%, whereas those with This analysis shows that patients with less than MR4.5 at time of discontinuation have higher risk of relapse. The lower percentage of relapse seen in patients who had been on imatinib likely represents the longer period of treatment before discontinuation compared to the 2nd generation TKIs. Late relapses (e.g., beyond a year) occur in a subset of patients. Although the majority of patients who lose their response after discontinuation respond to retreatment, treatment discontinuation is still not recommended outside clinical trials. Disclosures Jain: Pfizer: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Genentech: Research Funding; Servier: Consultancy, Honoraria; Seattle Genetics: Research Funding; Abbvie: Research Funding; Infinity: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Novimmune: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Incyte: Research Funding; BMS: Research Funding. Daver:BMS: Research Funding; Karyopharm: Honoraria, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Research Funding; Kiromic: Research Funding; Sunesis: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria. Konopleva:Calithera: Research Funding; Cellectis: Research Funding. DiNardo:Abbvie: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Background: CPX-351 is a liposomal formulation of cytarabine and daunorubicin encapsulated at a synergistic 5:1 molar ratio. Previous studies (including a pivotal phase 3 for pts with secondary AML) have shown lesser toxicity, higher response rates and improved overall survival (OS) with CPX-351 compared to 3+7 regimen, especially among poor risk and secondary AML patients. Phase I and II studies have shown complete responses (CR) occurring at doses below the maximum tolerated dose (MTD; i.e 100 U/m2), suggesting that 75 and 50 U/m2 doses used as induction therapy could be effective and potentially better tolerated in AML patients considered at high risk (30-50%) for 60-day mortality. We herein report interim results from a randomized open-label, single institution, phase II study of first-line CPX-351 in patients with AML at high risk of induction therapy (NCT 02286726). Methods: Pts with newly diagnosed AML considered at high risk for induction mortality defined as having at least 1 (if ≥60 years) or 2 (if 1.3 g/dL. This is a 2- or possibly 3-arm trial with one study arm receiving 50 U/m2 and the other 75 U/m2 of CPX-351 on days 1, 3, 5 for induction. If no excess toxicity is identified at 75 U/m2, a 3rd arm using 100 U/m2 is to be opened. The primary objective is to evaluate efficacy (determined by the rate of CR+CRi) for each arm. Other endpoints include the rate of dose limiting toxicities (DLTs) (comprising induction mortality at day 60), OS and event free survival (EFS). For each arm, CR/CRi and DLTs rates will be estimated with 95% confidence intervals (CI). Fisher's exact test will compare response and toxicity rates between the two dose levels. Results: 30 patients were randomized in 1:1 ratio to CPX-351 50 U/m2 or 75 U/m2. The median age was 67 years (range: 54-83). The 2 study arms were well balanced for sex, race, age, PS, cytogenetics and prior therapy with hypomethylators (Table 1). All patients were evaluable for response and toxicity. The CR+CRi rate was not significantly different between the 2 arms (20% vs 33.33%, P=0.681); the higher-dose arm resulted in superior OS (HR=0.202; p=0.005; 95% CI (0.06-0.62); median OS 5.1 mo vs not reached) and EFS (HR=0.25; p=0.019; 95% CI (0.08-0.75); median EFS 1.8 mo vs not reached). 60-day mortality favored the 75 units/m2 dose of CPX-351 (20% vs. 0%) Grade 3-5 treatment-emergent adverse events were similar and equal for the 2-dose levels (80%) and there have been no treatment-related deaths and no DLTs in either arm. Conclusion: In AML patients at high risk of induction mortality, the 2 sub-MTD dose levels of CPX-351 (50 and 75 U/m2) appear safe and show clinical benefit. Since there appears to be equal or better clinical benefit with 75 U/m2 without an increase in 60-day mortality, the third arm testing the MTD (100 U/m2) in this high risk group will open. Clinical trial information: NCT02286726 Disclosures Konopleva: Calithera: Research Funding; Cellectis: Research Funding. DiNardo:Daiichi Sankyo: Other: advisory board, Research Funding; Abbvie: Research Funding; Agios: Other: advisory board, Research Funding; Celgene: Research Funding; Novartis: Other: advisory board, Research Funding. Daver:Kiromic: Research Funding; Karyopharm: Honoraria, Research Funding; Ariad: Research Funding; Sunesis: Consultancy, Research Funding; BMS: Research Funding; Otsuka: Consultancy, Honoraria; Pfizer: Consultancy, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Wierda:Acerta: Research Funding; Novartis: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Abbvie: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

SummaryAntimicrobial resistance is closely linked to antimicrobial use and is a growing concern worldwide. Antimicrobial resistance increases healthcare costs substantially in many countries, including Lebanon. National data from Lebanon have, in the most part, been limited to a few academic hospitals. The Lebanese Society of Infectious Diseases conducted a retrospective study to better describe the antimicrobial susceptibility patterns of bacterial isolates in Lebanon. Data were based on records retrieved from the bacteriology laboratories of 16 different Lebanese hospitals between January 2011 and December 2013. The susceptibility results of a total 20684 Gram-positive and 55594 Gram-negative bacteria were analyzed. The prevalence rate of methicillin-resistant Staphylococcus aureus was 27.6% and of vancomycin-resistant Enterococcus spp was 1%. Streptococcus pneumoniae had susceptibilities of 46% to oxacillin, 63% to erythromycin, and 98% to levofloxacin. Streptococcus pyogenes had susceptibilities of 94% to erythromycin and 95% to clindamycin. The mean ampicillin susceptibility of Haemophilus influenzae, Salmonella spp, and Shigella spp isolates was 79%, 81.3%, and 62.2%, respectively. The extended-spectrum beta-lactamase production rate for Escherichia coli was 32.3% and for Klebsiella spp was 29.2%. Acinetobacter spp showed high resistance to most antimicrobials, with low resistance to colistin (17.1%). Pseudomonas spp susceptibilities to piperacillin–tazobactam and imipenem were lower than 80% (79.7% and 72.8%, respectively). This study provides population-specific data that are valuable in guiding antimicrobial use in Lebanon and neighbouring countries and will help in the establishment of a surveillance system for antimicrobial resistance following the implementation of a nationwide standardization of laboratory methods and data entry.