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Approval of midostaurin, a multikinase inhibitor, in combination with chemotherapy for the treatment of adults with newly diagnosed FLT3 mutation–positive acute myeloid leukemia, was based on the p...

Secondary acquisition of t(9;22)(q34;q11.2)/BCR-ABL1 fusion in the context of de novo acute myeloid leukemia (AML) with inv(3)(q21q26)/GATA2-MECOM rearrangement has been rarely reported. Furthermore, t(2;11)(p23;q23)/KMT2A-ASXL2 fusion has been rarely described with only a single case reported to date. We report a 45-year-old male with a diagnosis of de novo AML harboring GATA2-MECOM rearrangement in conjunction with a related subclone with concomitant inv(3) and t(9;22). The patient was treated with a tyrosine kinase inhibitor (TKI) which lead to disappearance of the inv(3)/t(9;22) subclone and subsequent expansion of the inv(3) ancestral clone. The patient was started on a 7+3 induction regimen with TKI but had persistent disease. He was placed on several additional treatment protocols and only achieved morphologic remission with a combination of fludarabine, cytarabine and filgrastim with TKI. Approximately 11.5 months after diagnosis the patient relapsed with the inv(3) clone predominating initially, followed by return of the inv(3)/t(9;22) subclone and the emergence of a second subclone with concomitant inv(3) and t(2;11)(p23;q23). Mate-pair sequencing was performed and identified a KMT2A-ASXL2 in-frame fusion, which was only recently described in a single case of therapy-related AML. For BCR-ABL1 positive AML, which generally carries a poor prognosis, treatment with TKIs has been proposed in combination with standard chemotherapy. In our case, treatment with TKI alone led to initial response of the BCR-ABL1 positive clone, but the ancestral clone quickly expanded and subsequent standard AML therapy may have led to further clonal evolution and re-emergence of the BCR-ABL1 clone in the absence of therapeutic selection.

Background: Alvocidib is an investigational cyclin-dependent kinase-9 (CDK9) inhibitor that can suppress RNA polymerase II-mediated transcription of genes implicated in leukemia cell survival, including myeloid leukemia cell-1 (MCL-1). MCL-1 is an anti-apoptotic BCL-2 family member that is a key mediator of apoptosis in AML. Alvocidib combined in a timed-sequential regimen with cytarabine and mitoxantrone (ACM) has shown clinical activity in newly diagnosed and relapsed/refractory (R/R) AML through Phase I and II clinical trials. Analysis of bone marrow samples from newly diagnosed AML patients (pts) treated with ACM showed an association of complete remission (CR) with MCL-1 dependence by a BH3 profiling biomarker assay. Zella 201 was initiated based on the hypothesis that ACM may have preferential clinical activity in pts with MCL-1 dependence. We report the findings from an exploratory cohort of newly diagnosed high-risk (NDHR) AML pts with MCL-1 dependence treated with ACM. Methods: Zella 201 is a biomarker-driven Phase II study of ACM in R/R AML patients with MCL-1 dependence. Stage 1 included a cohort of R/R AML pts with various levels of MCL-1 dependence and an exploratory cohort of NDHR AML with MCL-1 dependence >40%, as determined by a BH3 profiling assay. Eligibility criteria for the NDHR cohort included pts 18-65 years with high-risk AML defined as one of the following: A) treatment-related AML, B) AML from preexisting MDS/MPN, C) adverse-risk by ELN 2017 criteria. Induction therapy consisted of alvocidib 30 mg/m2 as a 30 minute IV bolus followed by 60 mg/m2 over 4 hours on Days (D) 1-3, cytarabine 667 mg/m2/D by continuous IV infusion D6-8, and mitoxantrone 40 mg/m2 IV on D9. Up to 3 additional cycles of the same regimen (with or without mitoxantrone) were permitted in responders. The primary endpoint was CR/CRi. Key secondary endpoints were overall survival (OS), relapse-free survival (RFS), overall response rate and safety. Results: Thirteen NDHR pts were treated and evaluable in this cohort (Table 1). One pt received alvocidib on days 1-3 and withdrew from the study on day 6 due to grade 4 diarrhea, cytokine release syndrome, and acute kidney injury. This pt was excluded from the efficacy analysis. Median MCL-1 score was 56% (Range: 42-70%). This cohort was influenced by the following poor risk categories: secondary AML (n= 9; 69%), adverse-risk by ELN (n=8; 62%) and TP53 mutations (n=6; 46%). The most common ≥Grade 3 treatment-emergent non-hematologic AEs (n=14) were diarrhea (29%); TLS, hypocalcemia, sepsis, hypotension (21%), pneumonia, colitis, hyperglycemia, anorectal infection, dyspnea, and left ventricular dysfunction (all 14%). Overall, CR/CRi was 62% with 7 (54%) pts responding following 1 cycle of therapy and another pt achieving CR after a second cycle. Two of six pts with TP53 mutation achieved CR. Although all pts included in this cohort were determined to be MCL-1 dependent, there was no association of CR with increasing MCL-1 dependence. Six (46%) pts went on to an allogeneic stem cell transplant (SCT). Sixty-day mortality was 0%. Median follow-up, OS, and RFS were 8.0, 8.5, and 6.1 months, respectively. Five of 8 (68%) CR/CRi pts have relapsed, and 10 pts (77%) have expired to date. The three pts still alive all received a post-study SCT. Conclusion: ACM has clinical activity in a limited cohort of NDHR AML pts with MCL-1 dependence scores >40% in a biomarker assay. Despite observed CR rates, duration of CR was modest and overall outcomes were poor. These results are comparable to historical controls with conventional chemotherapy regimens given the high-risk subset (62% of pts had adverse-risk and 46% had TP53 mutations). Further study is warranted to better define subgroups of ND AML pts who may benefit from alvocidib-containing induction regimens. Disclosures Zeidner: AsystBio Laboratories: Consultancy; AROG: Research Funding; Forty-Seven: Other: Travel Reimbursement, Research Funding; Merck: Research Funding; Sumitomo Dainippon Pharma Oncology, Inc.: Research Funding; Daiichi Sankyo: Honoraria; Genentech: Honoraria; Pfizer: Honoraria; Takeda: Consultancy, Honoraria, Other: Travel Reimbursement, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Other: Independent Review Committee; Agios: Honoraria. Lee:Sumitomo Dainippon Pharma Oncology, Inc.: Research Funding; Novartis: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Bayer: Research Funding; AbbVie: Research Funding; Celgene: Consultancy. Fine:Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Wang:Bristol Meyers Squibb (Celgene): Consultancy; Jazz Pharmaceuticals: Consultancy; Abbvie: Consultancy; Pfizer: Speakers Bureau; Genentech: Consultancy; Stemline: Speakers Bureau; PTC Therapeutics: Consultancy; Macrogenics: Consultancy; Astellas: Consultancy. Bhatt:Incyte: Consultancy, Research Funding; Oncoceutics: Other; National Marrow Donor Program: Research Funding; Jazz: Research Funding; Partnership for health analytic research: Consultancy; Takeda: Consultancy; Omeros: Consultancy; Agios: Consultancy; Rigel: Consultancy; Tolero: Research Funding; Pfizer: Research Funding; Abbvie: Consultancy, Research Funding. Kolibaba:Verastem: Honoraria; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Compass Oncology: Ended employment in the past 24 months; Seattle Genetics: Research Funding; Atara Biotech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sumitomo Dainippon Pharma Oncology, Inc.: Consultancy, Other: Travel, Accommodations, Expenses Paid; Genentech: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Celgene: Research Funding; AbbVie: Research Funding; Acerta: Research Funding; McKesson Life Sciences: Consultancy; Cell Therapeutics: Research Funding; Pharmacyclics: Research Funding. Anthony:Sumitomo Dainippon Pharma Oncology, Inc.: Current Employment; Exact Sciences: Consultancy. Bearss:Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Smith:Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

8014 Background: Elranatamab (PF-06863135) is a bispecific molecule that activates and redirects the T-cell mediated immune response against multiple myeloma (MM), a plasma cell dyscrasia characterized by expression of B-cell maturation antigen (BCMA). MagnetisMM-1 (NCT03269136), the ongoing Phase 1 first-in-human study for elranatamab, was designed to characterize safety, pharmacokinetics (PK), pharmacodynamics, and efficacy for patients (pts) with relapsed or refractory MM. Methods: Elranatamab was given subcutaneously (SC) at doses from 80 to 1000µg/kg either weekly or every 2 weeks (Q2W). Treatment-emergent adverse events (TEAEs) were graded by Common Terminology Criteria for Adverse Events (v4.03) and cytokine release syndrome (CRS) by American Society for Transplantation and Cellular Therapy criteria. PK, cytokine and soluble BCMA profiling, and lymphocyte subset analyses were performed. Response was assessed by International Myeloma Working Group (IMWG) criteria. Minimal residual disease (MRD) was assessed by next generation sequencing at a sensitivity of 1×10-5 in accordance with IMWG criteria. Results: A total of 55 pts received single-agent elranatamab SC at a dose ≥215μg/kg as of 1-Nov-2021. Median age was 64 (range 42-80) years, and 27% of pts were Black/African American or Asian. Median number of prior regimens was 6 (range 2-15), 91% were triple-class refractory, 56% had prior stem cell transplantation, 27% had high cytogenetic risk, and 22% received prior BCMA-targeted therapy. The most common TEAEs regardless of causality included CRS, neutropenia, anemia, injection site reaction, and lymphopenia. With pre-medication and a single priming dose (600µg/kg or 44mg), the overall incidence of CRS at the recommended dose (1000µg/kg or 76mg) was 67% and limited to Grade 1 (33%) or Grade 2 (33%), with no events Grade 3 or higher. Exposure was dose dependent and Q2W dosing achieved exposure associated with anti-myeloma efficacy. Cytokine increases occurred with the first dose and were reduced by pre-medication. Soluble BCMA decreased with disease response, elranatamab therapy was associated with increased peripheral T cell proliferation, and median time to response was 36 days (range 7-73). With a median follow-up of 8.1 months (range 0.3-21) and including only IMWG confirmed responses, 31% of pts achieved complete response or better and the overall response rate was 64% (95% CI 50-75%). For responders (n = 35), median duration of response was not yet reached, but the probability of being event-free at 6 months was 91% (95% CI 73-97%). Single-agent elranatamab induces durable clinical and molecular responses, and updated data including MRD assessment will be presented. Conclusions: Elranatamab shows a manageable safety profile and achieves durable clinical and molecular responses for pts with relapsed or refractory MM. Clinical trial information: NCT03269136.

Objectives Elranatamab (PF-06863135) is a humanized bispecific monoclonal antibody (IgG2a) that targets BCMA, a member of the tumor necrosis factor receptor superfamily expressed in multiple myeloma, and CD3 on T cells. We reported results for intravenous (IV) dosing (Raje et al. Blood. 2019;134(S1):1869) and now update for subcutaneous (SC) dosing from the ongoing Phase 1 study (MagnetisMM-1; NCT03269136). Materials and methods Patients received elranatamab at 80, 130, 215, 360, 600, and 1000 μg/kg SC weekly. A modified toxicity probability interval method was used for escalation, with monitoring for dose-limiting toxicity (DLT) to end of the first cycle. Treatment-emergent adverse events (TEAEs) were graded by Common Terminology Criteria for Adverse Events (v4.03), and cytokine release syndrome (CRS) by American Society for Transplantation and Cellular Therapy criteria (Lee et al. Biol Blood Marrow Transplant. 2019;25:625). Response was assessed by International Myeloma Working Group criteria. Pharmacokinetics, cytokine profiling, and T cell immunophenotyping were performed. Results 30 patients had received elranatamab as of 4-Feb-2021 at 80 (n = 6), 130 (n = 4), 215 (n = 4), 360 (n = 4), 600 (n = 6), or 1000 (n = 6) μg/kg SC weekly. Patients had a median of 8 prior treatments; 87% had triple refractory disease, 97% had prior anti-CD38 therapy, and 23% (7 patients) had prior BCMA-directed antibody drug conjugate (6 of 7 patients) or chimeric antigen receptor T cell therapy (3 of 7 patients). The most common all causality TEAEs included lymphopenia (n = 25, 83%; 20% G3, 63% G4), CRS (n = 22, 73%; 57% G1, 17% G2, none ≥G3), anemia (n = 18, 60%; 50% G3, 0% G4), thrombocytopenia (n = 16, 53%; 17% G3, 20% G4), neutropenia (n = 16, 53%; 23% G3, 30% G4), and injection site reaction (n = 15, 50%; 43% G1, 7% G2, none ≥G3). Both CRS and immune effector cell-associated neurotoxicity syndrome (n = 6, 20%) were limited to ≤G2 with median durations of 3 and 2.5 days, respectively. No DLT was observed. Exposure increased with dose, and Tmax ranged from 3–7 days. Cytokine increases occurred with the first dose, and increased T-cell proliferation was observed in peripheral blood. The overall response rate (ORR) for doses ≥215 μg/kg was 70% (n = 14/20) including partial response (PR; n = 1), very good PR (VGPR; n = 7), complete response (CR; n = 1), and stringent CR (sCR; n = 5). Median time to response was 22 days, and 3 of 4 patients (75%) with prior BCMA-directed therapy achieved response (VGPR, n = 2 and sCR, n = 1). Updated data, including duration of response, will be presented. Discussion Elranatamab demonstrated a manageable safety profile and, across the efficacious dose range (≥215 μg/kg), achieved ORR of 70% with CR/sCR rate of 30%, including responses after prior BCMA-directed therapy. Conclusion These results demonstrate the safety and efficacy of elranatamab in this relapsed/refractory population and support ongoing development of elranatamab for patients with multiple myeloma, both as monotherapy and in combination with standard or novel therapies.

Approval of midostaurin, a multikinase inhibitor, in combination with chemotherapy for the treatment of adults with newly diagnosed

Introduction: MagnetisMM-1 (NCT03269136) is a Phase 1 study of elranatamab (PF-06863135), a humanized bispecific molecule that targets BCMA expressed on multiple myeloma (MM) and engages CD3 on T cells, for patients (pts) with relapsed or refractory MM (RRMM). We report results from the subcutaneous (SC) cohorts: dose escalation (Part 1), monotherapy with priming (Part 1.1), lenalidomide (LEN) combination (Part 1C), pomalidomide (POM) combination (Part 1D), and monotherapy expansion with priming (Part 2A). Methods: In Part 1, pts received elranatamab at 80, 130, 215, 360, 600, and 1000μg/kg weekly guided by a modified toxicity probability interval method. For monotherapy at the recommended Phase 2 dose (RP2D; Parts 1.1 and 2A), a single priming dose (600μg/kg or equivalent fixed dose of 44mg) was followed one week later by the full dose (1000μg/kg or equivalent fixed dose of 76mg) weekly (Q1W) or every 2 weeks (Q2W) thereafter. For LEN or POM combination therapy, a single priming dose (32mg) was followed one week later by the full dose (44mg) Q1W thereafter in combination with either LEN (25mg) or POM (4mg) on Days 1 to 21 of a 28-day cycle. Dose-limiting toxicity (DLT) was monitored to the end of the first cycle. Treatment-emergent adverse events (TEAEs) were graded by Common Terminology Criteria for Adverse Events (v4.03), and cytokine release syndrome (CRS) by American Society for Transplantation and Cellular Therapy criteria. Pharmacokinetics, cytokine profiling, and T cell immunophenotyping were performed. Response was assessed by International Myeloma Working Group (IMWG) criteria. Minimal residual disease (MRD) was assessed by next generation sequencing at a sensitivity of 1×10 -5, in accordance with IMWG criteria. Results: 58 pts received elranatamab SC as a single agent (n=50) or in combination with either LEN (n=4) or POM (n=4) as of 4-Feb-2021. Pts had a median (range) age of 64 (32-86) years, and 26% were Black/African American or Asian. Pts had a median of 6 prior regimens, 98% had triple-class relapsed/refractory disease, 45% had prior high-dose chemotherapy with stem cell transplantation, and 22% had prior BCMA-targeted therapy. The most common all causality TEAEs included CRS (n=48, 83%; none higher than G2), lymphopenia (n=37, 64%; 12% G3, 52% G4), neutropenia (n=37, 64%; 31% G3, 29% G4), anemia (n=32, 55%; 38% G3, 0% G4), injection site reaction (n=31, 53%; none higher than G2), and thrombocytopenia (n=30, 52%; 14% G3, 17% G4). At the RP2D of 1000μg/kg, median duration of CRS decreased by 50% from 4 days to 2 days with priming. Two of 58 pts had DLT including G4 thrombocytopenia (Part 1.1) and G4 neutropenia (POM). Exposure increased with dose, cytokine increases occurred with the first dose, and increased T-cell proliferation was observed in peripheral blood. Median duration of follow-up was 7.5, 2.3, and 1.9 months for the dose escalation, priming, and LEN/POM combination cohorts, respectively. For pts treated across the efficacious dose range (215-1000μg/kg) in Part 1, confirmed overall response rate (ORR) was 70% (14/20) with complete response (CR)/stringent CR (sCR) rate of 30% (6/20). For the 14 pts with confirmed responses, median duration of response had not yet been reached; the probability (95% CI) of responders being event free at 6 months was 92.3% (56.7-98.9). Confirmed ORR at the RP2D was 83% (5/6). Responses in this RRMM population included sCR (n=5), CR (n=1), very good partial response (VGPR; n=7), and partial response (n=1). Median time to response was 22 days. Importantly, 100% (4/4) of evaluable pts with baseline dominant sequence and on-treatment sample at CR/sCR achieved MRD negativity at 1×10 -5 by IMWG criteria, and 75% (3/4) of pts with prior BCMA-targeted therapy achieved response (1 sCR, 2 VGPR). Updated efficacy, safety, and MRD results will be presented for SC parts of the study. Conclusions: Elranatamab as a single agent, administered either Q1W or Q2W, had a manageable safety profile for pts with RRMM. Across the efficacious dose range, elranatamab achieved confirmed ORR of 70% and CR/sCR rate of 30%, with confirmed ORR of 83% at the RP2D. Importantly, elranatamab induces deep and durable clinical responses in RRMM pts with and without prior BCMA-targeted therapy and 100% MRD negativity in MRD evaluable pts. These results, along with emerging combination data, support continued development of elranatamab as a single agent and in combination with standard therapies for MM. Disclosures Sebag: Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Research Funding; Bristol Myers-Squibb: Consultancy, Honoraria. Raje: Celgene, Amgen, Bluebird Bio, Janssen, Caribou, and BMS: Other. Bahlis: GlaxoSmithKline: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Genentech: Consultancy; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Dholaria: Pfizer: Research Funding; Poseida: Research Funding; Angiocrine: Research Funding; MEI: Research Funding; Jazz: Speakers Bureau; Takeda: Research Funding; Janssen: Research Funding; Celgene: Speakers Bureau. Solh: Partner Therapeutics: Research Funding; Jazz Pharmaceuticals: Consultancy; BMS: Consultancy; ADCT Therapeutics: Consultancy, Research Funding. Levy: Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Dova: Consultancy, Other: Promotional speaker; Epizyme: Consultancy, Other: Promotional speaker; Novartis: Consultancy, Other: Promotional speaker; GSK: Consultancy, Other: Promotional speaker. Tomasson: Pfizer, Inc.: Research Funding; Rafael Pharmaceuticals: Research Funding; syros Pharmaceuticals: Research Funding; Janssen R&D: Research Funding; Seagen, Inc.: Research Funding. Dube: Pfizer: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Damore: Pfizer: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Lon: Pfizer: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Basu: Pfizer: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Skoura: Pfizer: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Chan: Pfizer: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Trudel: Amgen: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Roche: Consultancy; Janssen: Honoraria, Research Funding; Sanofi: Honoraria; Pfizer: Honoraria, Research Funding; Genentech: Research Funding. Jakubowiak: Gracell: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Chu: Celgene/BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Teva: Consultancy, Honoraria. Gasparetto: Janssen: Consultancy; Sanofi: Consultancy, Honoraria, Speakers Bureau; Oncopeptide: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Speakers Bureau; Gsk: Consultancy, Honoraria, Speakers Bureau. Lesokhin: pfizer: Consultancy, Research Funding; Behringer Ingelheim: Honoraria; Trillium Therapeutics: Consultancy; bristol myers squibb: Research Funding; Genetech: Research Funding; Iteos: Consultancy; Janssen: Honoraria, Research Funding; Serametrix, Inc: Patents & Royalties.

Background Elranatamab (PF-06863135), a humanized bispecific molecule, targets both BCMA expressed in MM and CD3 on T cells. MagnetisMM-1 (ClinicalTrials.gov ID: NCT03269136) is a Phase 1 study of elranatamab with the aim of characterizing the efficacy, safety, pharmacokinetics, and pharmacodynamics of elranatamab as single agent and in combination with immunomodulatory agents for pts with relapsed or refractory MM. Methods Pts received single agent elranatamab 80, 130, 215, 360, 600, or 1000µg/kg/week subcutaneously. A modified toxicity probability interval method was used for escalation, with monitoring for dose-limiting toxicity (DLT) to the end of the first cycle. Treatment emergent adverse events (TEAEs) were graded by Common Terminology Criteria for Adverse Events v4.03, and cytokine release syndrome (CRS) by American Society for Transplantation and Cellular Therapy criteria (Biol Blood Marrow Transplant. 2019;25:625). Responses and minimal residual disease (MRD) status (by next-generation sequencing at a sensitivity of 1 × 10-5) were assessed by International Myeloma Working Group criteria. Pharmacokinetics, cytokine profiling, and T cell immunophenotyping were performed. Results 30 pts had received elranatamab as of 4-Feb-2021 at 80 (n=6), 130 (n=4), 215 (n=4), 360 (n=4), 600 (n=6), or 1000 (n=6) µg/kg. Pts had a median of 8 prior treatments; 87% had triple refractory disease, 97% prior anti-CD38 therapy, and 23% prior BCMA-directed antibody drug conjugate or chimeric antigen receptor T cell therapy. Common all causality TEAEs included lymphopenia (n=25, 83%; 20% G3, 63% G4), CRS (n=22, 73%; none >G2), anemia (n=18, 60%; 50% G3, 0% G4), neutropenia (n=16, 53%; 23% G3, 30% G4), thrombocytopenia (n=16, 53%; 17% G3, 20% G4), and injection site reaction (n=15, 50%; none >G2). Both CRS and immune effector cell-associated neurotoxicity syndrome (n=6, 20%) were limited to ≤G2; median durations were 3 and 2.5 days, respectively. No DLT was observed. Exposure increased with dose, and Tmax ranged from 3–7 days. Cytokine increases occurred with the first dose, and increased T cell proliferation was observed in peripheral blood. For doses ≥215µg/kg, confirmed overall response rate (ORR) was 70% (n=14/20) including partial response (PR; n=1), very good PR (VGPR; n=7), complete response (CR; n=1), and stringent CR (sCR; n=5). The majority of patients with sCR achieved MRD negativity. Median time to response was 22 days. In this dosing group, 3 of 4 pts (75%) with prior BCMA-directed therapy achieved response. Confirmed ORR at the recommended phase 2 dose (RP2D) of 1000µg/kg was 83% (n=5/6). Conclusions Elranatamab achieved confirmed ORR of 83% at RP2D with a manageable safety profile for pts with relapsed or refractory MM. These results confirm the feasibility and potential of BCMA-directed immunotherapy for malignant plasma cell disorders, and support further development of elranatamab for pts with MM. This study was sponsored by Pfizer.

Context Elranatamab (PF-06863135), a humanized bispecific monoclonal antibody (IgG2a), targets BCMA expressed in MM and CD3 on T-cells. Objective Characterize efficacy, safety, pharmacokinetics, and pharmacodynamics of elranatamab. Design Phase 1 study (MagnetismMM-1; NCT03269136). Data cut-off: 4 February 2021. Patients Relapsed or refractory MM. Intervention 80, 130, 215, 360, 600, or 1000 µg/kg/week subcutaneously. Main Outcome Measures 1) Treatment-emergent adverse events (TEAEs) graded by CTCAE v4.03 and cytokine release syndrome (CRS) by ASTCT criteria. 2) International Myeloma Working Group criteria-assessed response. 3) Pharmacokinetics, cytokine profiling, and T-cell immunophenotyping. Results Thirty patients received elranatamab at 80 (n=6), 130 (n=4), 215 (n=4), 360 (n=4), 600 (n=6), or 1000 (n=6) µg/kg. Patients had a median of 8 prior treatments; 87% had triple refractory disease, 97% prior anti-CD38 therapy, and 23% prior BCMA-directed antibody drug conjugate or chimeric antigen receptor T-cell therapy. Common all causality TEAEs included lymphopenia (n=25, 83%; 20% G3, 63% G4), CRS (n=22, 73%; none >G2), anemia (n=18, 60%; 50% G3, 0% G4), neutropenia (n=16, 53%; 23% G3, 30% G4), thrombocytopenia (n=16, 53%; 17% G3, 20% G4), and injection site reaction (n=15, 50%; none >G2). CRS and immune effector cell-associated neurotoxicity syndrome (n=6, 20%) were limited to ≤G2; median durations were 3 and 2.5 days, respectively. No dose-limiting toxicity was observed. Exposure increased with dose and Tmax ranged from 3–7 days. Cytokine increases occurred with the first dose, and increased T-cell proliferation was observed in peripheral blood. For doses ≥215 µg/kg, the confirmed overall response rate (ORR) was 70% (n=14/20); partial response (PR; n=1), very good PR (VGPR; n=7), complete response (CR; n=1), and stringent CR (n=5). Median time to response was 22 days. In this dosing group, 3 of 4 pts (75%) with prior BCMA-directed therapy achieved response. Confirmed ORR at the recommended phase 2 dose (RP2D) of 1000 µg/kg was 83% (n=5/6). Conclusions Elranatamab achieved confirmed ORR of 83% at RP2D with a manageable safety profile for patients with relapsed or refractory MM. These results support further development of elranatamab for patients with MM. This study was sponsored by Pfizer.

Primary CNS lymphoma is a rare condition, with annual incidence of about 1400 cases in the US. Patients with aggressive systemic lymphomas also have high incidence of CNS involvement, with poor overall prognosis. Use of high dose methotrexate based therapies has substantially altered the outlook for these patients. We present the outcomes data of patients with primary CNS lymphoma and those with secondary CNS involvement treated with high dose methotrexate from a single , FACT accredited academic transplant center. We reviewed patients treated at our center over a 42 month period between Jan 2017- June 2020. There were 19 patients with primary CNS lymphoma and 24 with secondary CNS involvement who received high dose methotrexate. There were equal number of men and women, and were mostly Caucasian. Median age at diagnosis was 60 years. Majority were HIV negative (95%). 3 of the 19 patients had EBV infection at the time of diagnosis. Majority had performance status of ECOG 1 (range: 0-4). 1 patient had CNS lymphoma in the post transplant setting (had bilateral lung transplant). 2 out of 19 patients had concurrent solid organ malignancies. 17 patients (90 %) had newly diagnosed primary CNS lymphoma. 2 patients (10 %) had relapsed disease. Patients received a median of 6 induction treatments (range 1-12) . Majority of patients (17/19) received high dose methotrexate with rituximab. 1 patient received only high dose methotrexate. 1 patient received methotrexate, procarbazine, rituximab and vincristine (R MPV). 5 patients (26%) progressed during induction. There were 7 deaths (37 %) during induction phase. Majority of the deaths occured early during induction. Majority had partial response. 1 patient had complete response . No patient has received stem cell transplant. There were no chemotherapy delays due to COVID 19 . No patient with primary CNS lymphoma was hospitalized or died due to COVID 19. 1 patient elected to defer chemotherapy due to fear of contracting COVID 19 in the hospital. No patient received the full,planned doses of high dose methotrexate during induction. Dose reductions were due to poor performance status or impaired renal function. Consolidation was mainly with high dose methotrexate. Those progressing received whole brain radiation, Ara C , or best supportive care. The PFS and OS are being evaluated at the time of this submission. There were 24 patients with secondary CNS involvement . 12 had concurrent systemic and CNS involvement. 12 patients had history of systemic lymphoma but with CNS only relapse. There were equal males and females. Median age at diagnosis was 64 years. (range 33-81). They had good performance status, with majority having PS of ECOG 1 (range 1-3). Majority were caucasian. There were 4 patients (17%) with EBV infection. 2 patients (8 %) had HIV. They received a median of 2 high dose methotrexate inductions (range: 1-10). 4 patients (17%) eventually received stem cell transplants. PFS, survival data are being evaluated at the time of this submission. In general, high dose methotrexate was well tolerated in both primary CNS lymphoma and systemic lymphoma with CNS involvement. Stem cell transplants are still being done infrequently for these patients. Disclosures Finn: Jazz Pharmaceuticals:Speakers Bureau;Celgene:Speakers Bureau;Seattle Genetics:Speakers Bureau.

Introduction: PF-06863135 (PF-3135) is a full-length, humanized, bispecific monoclonal antibody (mAb, IgG2a) targeting BCMA, which is highly expressed on multiple myeloma cells, and CD3 expressed on T cells. Intravenous (IV) dosing of PF-3135 has been previously evaluated at 0.1 - 50 μg/kg weekly with preliminary evidence of anti-myeloma activity in RRMM, without reaching the maximum tolerated dose (MTD). SC dose escalation was subsequently initiated given the potential to reduce the maximum concentration (Cmax), which is believed to be associated with cytokine release syndrome (CRS) and inflammatory response, with the intent of achieving a more favorable therapeutic window. Methods: Patients with RRMM previously treated with immunomodulatory drugs, proteasome inhibitors, and anti-CD38 mAb received SC dosages of PF-3135 at 80, 130, 215, and 360 μg/kg weekly. A modified toxicity probability interval method was used for dose escalation, with dose-limiting toxicities (DLTs) monitored in the first cycle (21 days). AEs were graded by CTCAE criteria except CRS, which was graded by Lee et al. 2014 criteria. Responses were assessed at the end of each cycle by the International Myeloma Working Group (IMWG) criteria. Peripheral blood was evaluated for soluble BCMA, cytokines, and immunophenotyping. PF-3135 pharmacokinetics and immunogenicity were also characterized. Results: As of April 15, 2020, 18 patients had received PF-3135 SC at 80 (n=6), 130 (n=4), 215 (n=4) and 360 (n=4) μg/kg weekly. The median number of prior anticancer treatment regimens was 7; all patients had received prior daratumumab therapy; 4 (22%) patients had received prior BCMA-targeted antibody-drug conjugate or chimeric antigen receptor T-cell therapy. All patients completed the DLT-monitoring period and none were observed. At cut-off date, dose escalation was ongoing with MTD not reached. All patients experienced treatment-emergent AEs (TEAEs); the most common were CRS reported in 11 (61%) patients, anemia in 9 (50%), thrombocytopenia in 7 (39%), and injection site reaction and lymphopenia in 6 (33% each). Grade (G) 3-4 TEAEs were observed in 12 (67%) patients, including G3 anemia in 8 (44%), G3 thrombocytopenia, lymphopenia, neutropenia, hypoalbuminemia, and bone pain in 2 (11% each), G4 lymphopenia in 4 (22%), G4 thrombocytopenia in 3 (17%), and G4 neutropenia in 2 (11%) patients. G5 TEAEs occurring in 3 (17%) patients (80 μg/kg group) were considered not treatment-related (disease progression [n=2] and sepsis [n=1]). CRS, the most common treatment-related AE, was observed across all dose levels in 11 patients (61% overall; 50% at 80 and 130 µg/kg; 75% at 215 and 360 µg/kg). Of these, 9 (50%) patients experienced G1 CRS and 2 (11%) had G2 CRS. CRS began within the first 2 days of treatment, with a median duration of 2 days (range 0-4). Per IMWG criteria, the objective response rate was 33% in the overall SC-dosed population and 75% at the top 2 dose levels (215 and 360 μg/kg). Two patients each achieved a best response of partial response (PR), very good PR (VGPR), and stringent complete response (sCR). Seven patients had best response of stable disease. Exposure to PF-3135 increased with dose in an approximately dose-proportional manner. SC administration resulted in a lower dose-normalized Cmax relative to IV administration and a prolonged absorption phase, with median time to Cmax ranging from 3 to 7 days. Consistent with the observed CRS, cytokine increases were the highest following the first dose and diminished significantly at subsequent doses. Levels of free, soluble BCMA decreased with increasing doses and demonstrated sustained decreases throughout each dose interval. Conclusions: AEs were generally manageable; CRS reported in the majority of patients was grade 1-2. Responses were achieved with SC dosing of PF-3135 in 6 of 8 (75%) patients at the 2 highest dose levels evaluated. Compared to IV, SC dosing did modulate the Cmax, so higher doses could be administered without observing increased severity of CRS. SC dose escalation is ongoing and additional results, including biomarkers and data from higher dose cohorts, will be presented. Clinicaltrials.gov identifier: NCT03269136. Funding: Pfizer. Disclosures Lesokhin: Janssen: Research Funding; Genentech: Research Funding; Takeda: Consultancy, Honoraria; Juno: Consultancy, Honoraria; GenMab: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Serametrix Inc.: Patents & Royalties. Levy:Baylor University Med Center: Current Employment; Seattle Genetics: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Research Funding, Speakers Bureau. Bahlis:Sanofi: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Solh:Amgen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Partner Therapeutics: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding. Sebag:Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding. Jakubowiak:AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Costello:Takeda: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Poseida Therapeutics: Research Funding; Janssen: Research Funding. Chu:BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Teva: Consultancy, Honoraria. Savona:Boehringer Ingelheim: Patents & Royalties; Ryvu: Consultancy; Astex: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Karyopharm: Consultancy, Current equity holder in publicly-traded company; Gilead: Consultancy; AbbVie: Consultancy; BMS: Consultancy; TG Therapeutics: Consultancy, Research Funding. Trudel:Sanofi: Honoraria; Takeda: Honoraria; Amgen: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; GSK: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; AstraZeneca: Honoraria; Karyopharm: Honoraria. Chou:Pfizer: Current Employment, Current equity holder in publicly-traded company. Udata:Pfizer: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Basu:Pfizer: Current Employment, Current equity holder in publicly-traded company. Krupka:Pfizer: Current Employment, Current equity holder in publicly-traded company. Raje:Immuneel: Membership on an entity's Board of Directors or advisory committees; Caribou: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Astrazeneca: Consultancy; Takeda: Consultancy; Bluebird, Bio: Consultancy, Research Funding; Karyopharm: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Amgen: Consultancy. OffLabel Disclosure: BCMA/CD3 bi-specific antibody in development for the treatment of patients with relapsed/refractory multiple myeloma

8006 Background: Elranatamab (PF-06863135) is a humanized bispecific monoclonal antibody (IgG2a) that targets BCMA, a member of the tumor necrosis factor receptor superfamily expressed in MM, and CD3 on T cells. We reported results for intravenous (IV) dosing (Raje et al. Blood. 2019;134(S1):1869) and now update for subcutaneous (SC) dosing from the ongoing Phase 1 study (MagnetisMM-1). Methods: Patients (pts) received elranatamab at 80, 130, 215, 360, 600, and 1000μg/kg SC weekly. A modified toxicity probability interval method was used for escalation, with monitoring for dose-limiting toxicity (DLT) to end of the first cycle. Treatment-emergent adverse events (TEAEs) were graded by Common Terminology Criteria for Adverse Events (v4.03), and cytokine release syndrome (CRS) by American Society for Transplantation and Cellular Therapy criteria (Lee et al. Biol Blood Marrow Transplant. 2019;25:625). Response was assessed by International Myeloma Working Group criteria. Pharmacokinetics, cytokine profiling, and T cell immunophenotyping were performed. Results: 30 pts had received elranatamab as of 4-Aug-2020 at 80 (n = 6), 130 (n = 4), 215 (n = 4), 360 (n = 4), 600 (n = 6), or 1000 (n = 6) μg/kg SC weekly. Pts had a median of 8 prior treatments; 87% had triple refractory disease, 97% had prior anti-CD38 therapy, and 23% had prior BCMA-directed antibody drug conjugate or chimeric antigen receptor T cell therapy. The most common all causality TEAEs included lymphopenia (n = 24, 80%; 20% G3, 60% G4), CRS (n = 22, 73%; none > G2), anemia (n = 17, 57%; 43% G3, 3% G4), injection site reaction (n = 16, 53%; none > G2), thrombocytopenia (n = 16, 53%; 23% G3, 17% G4), and neutropenia (n = 12, 40%; 17% G3, 17% G4). Both CRS and immune effector cell-associated neurotoxicity syndrome (n = 6, 20%) were limited to ≤G2 with median durations of 2 and 1.5 days, respectively. No DLT was observed. Exposure increased with dose, and Tmax ranged from 3–7 days. Cytokine increases occurred with the first dose, and increased T-cell proliferation was observed in peripheral blood. The overall response rate (ORR) for doses ≥215μg/kg was 75% (n = 15/20) including partial response (PR; n = 6), very good PR (VGPR; n = 3), complete response (CR; n = 1), and stringent CR (sCR; n = 5). Median time to response was 22 days, and 3 of 4 pts (75%) with prior BCMA-directed therapy achieved response (VGPR, n = 2 and sCR, n = 1). Updated data, including duration of response, will be presented. Conclusions: Elranatamab demonstrated a manageable safety profile, and SC doses ≥215μg/kg achieved ORR of 75% with CR/sCR rate of 30%. These results demonstrate the safety and efficacy of SC elranatamab in this relapsed/refractory population and support ongoing development of elranatamab for pts with MM, both as monotherapy and in combination with standard or novel therapies. Clinical trial information: NCT03269136.

Even though acute myeloid leukemia (AML) occurs most commonly in adults ≥60 years, the treatment of AML in older patients remains a significant challenge.We reviewed the current literature regarding patient assessment tools, treatment options, and current therapies in clinical trial for patients with AML who are ≥60 years.Our approach to the older patient with AML is evolving with better understanding of the unique disease epidemiology in this population and the development of tools to assess individual patient functional status, including grading systems for comorbidities, geriatric assessment tools, and measurements of frailty. Almost all older patients will benefit from therapy, whether intensive curative therapy, such as allogeneic stem cell transplant that should be considered whenever possible, or low-intensity therapy that should be offered with concurrent palliative care at diagnosis to improve patient survival and quality of life. To achieve the improved survival demonstrated in younger adults, older patients should also be considered for clinical trial enrollment as more studies are being designed to specifically target this unique patient population.Older patients with AML are candidates for and benefit from the entire spectrum of AML therapy, including intense chemotherapy, allogeneic stem cell transplant, and clinical trial participation after thorough patient assessment. Older patients with AML would benefit from increased clinical trial enrollment and early inclusion of palliative medicine.

Introduction: Midostaurin was the first multikinase inhibitor approved in combination with daunorubicin and cytarabine induction and high-dose cytarabine (HiDAC) consolidation chemotherapy for the treatment of adults with newly diagnosed FLT3-mutation-positive (mut+) acute myeloid leukemia (AML). Approval was largely based on the results from the phase 3 RATIFY trial; patients who received midostaurin had significantly improved overall and event-free survival than those who received placebo (Stone et al, N Engl J Med, 2017). RADIUS-X (NCT02624570) is an expanded treatment protocol (ETP) designed to provide access to midostaurin during the US Food and Drug Administration's review process and to extend the understanding of the safety and tolerability of midostaurin in patients with newly diagnosed FLT3-mut+ AML. The safety profile of midostaurin in preliminary data from RADIUS-X was consistent with that in the RATIFY study (Roboz et al, Blood, 2017 [abstract 1338]). Here we report updated safety data for midostaurin during induction and consolidation and safety data during the maintenance phase. Methods: In this open-label, single-arm ETP, patients (aged ≥18 years) received 1-2 cycles of induction therapy (cytarabine plus daunorubicin [60-90 mg/m2/day] or idarubicin [12 mg/m2/day]) and up to 4 cycles of HiDAC consolidation chemotherapy plus midostaurin (50 mg twice daily [bid] on days 8-21 of each 28-day cycle), followed by up to 12 months of single-agent midostaurin (50 mg bid on days 1-28). Patients could enroll at any point before completion of a second cycle of consolidation. Patients achieving complete remission (CR) or CR with incomplete hematologic recovery (CRi) after induction proceeded to consolidation; patients who maintained a response were eligible to proceed to maintenance. The primary endpoints were safety and tolerability of midostaurin. Results: Of 111 patients screened, 103 were enrolled in the study: 47 during induction (46%) and 56 during consolidation (54%) (Figure). The median age was 58 y (range, 19-79 y); all patients were FLT3-mut+ (Table). Of 47 patients enrolled during induction, 15 received daunorubicin and 32 received idarubicin as the anthracycline. Of 35 patients who completed consolidation and entered maintenance, 9 had completed the protocol treatment and 3 remained on therapy at the data cutoff date (March 30, 2018). The CR/CRi rate for the induction phase was 74% (57% CR, 17% CRi). The relapse rate was 14% overall. The most common reason for study discontinuation was proceeding to transplant (overall, 52%; induction, 11%; consolidation, 42%; maintenance, 34%). The median duration of midostaurin exposure was 35 days (range, 3-426 days). Dose adjustment or interruption due to adverse events (AEs) occurred in 26 patients, most commonly due to febrile neutropenia (n=9) and gastrointestinal disorders (n=6). No new safety events were observed with longer follow-up. Most patients (99%) experienced ≥1 any-grade AE, mostly during induction and/or consolidation. Due to the timing of patient enrollment (up to the second cycle of consolidation), hematologic AEs were lower than reported in comparable studies. The most common AEs occurring in ≥20% of patients were febrile neutropenia (53%), nausea (42%), diarrhea (37%), anemia (36%), platelet count decreased (31%), fatigue (23%), headache (22%), and vomiting (22%). Serious AEs occurred in 50% of patients overall, most commonly febrile neutropenia (37%). AEs during induction were generally similar, regardless of anthracycline received. Overall, 9 patients discontinued due to AEs: 5 during induction (febrile neutropenia, blood bilirubin increased, electrocardiogram QT prolonged, renal impairment, and respiratory distress), 1 during consolidation (sepsis), and 1 during maintenance (leukocytosis). During maintenance, 16 of 35 patients (46%) reported any-grade AEs with midostaurin monotherapy; the most common any-grade and grade 3/4 AEs occurring in >1 patient were platelet count decrease (11% and 3%), nausea (9% and 0%), and oropharyngeal pain (6% and 0%).The rate of death during the study was low, with 1 death reported (disease progression). Conclusions: Midostaurin continued to demonstrate a manageable safety profile with longer follow-up and was associated with high transplant and low relapse rates. Maintenance therapy with midostaurin was well tolerated; no new safety signals were observed. Disclosures Perl: Daiichi Sankyo: Consultancy; Arog: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; NewLink Genetics: Membership on an entity's Board of Directors or advisory committees. Sweet:Agios: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; Incyte: Research Funding; Bristol Myers Squibb: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Celgene: Speakers Bureau. Roboz:Novartis: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Consultancy; Eisai: Consultancy; Janssen Pharmaceuticals: Consultancy; Argenx: Consultancy; Orsenix: Consultancy; Aphivena Therapeutics: Consultancy; Daiichi Sankyo: Consultancy; Roche/Genentech: Consultancy; Orsenix: Consultancy; Celgene Corporation: Consultancy; Celltrion: Consultancy; Jazz Pharmaceuticals: Consultancy; Celltrion: Consultancy; Cellectis: Research Funding; Jazz Pharmaceuticals: Consultancy; Sandoz: Consultancy; Otsuka: Consultancy; Otsuka: Consultancy; Roche/Genentech: Consultancy; Pfizer: Consultancy; AbbVie: Consultancy; Janssen Pharmaceuticals: Consultancy; Bayer: Consultancy; Astex Pharmaceuticals: Consultancy; Eisai: Consultancy; Aphivena Therapeutics: Consultancy; Argenx: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Astex Pharmaceuticals: Consultancy; Cellectis: Research Funding; Sandoz: Consultancy. Strickland:Astellas Pharma: Consultancy; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis Pharmaceuticals: Consultancy, Research Funding; Tolero Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bonifacio:Novartis: Employment. Haines:Novartis: Employment. Barbera:Novartis: Employment. Purkayastha:Novartis Pharmaceuticals Corporation: Employment.

Background Multiple studies have shown the clinical activity of alvocidib followed by cytarabine and mitoxantrone in newly diagnosed and relapsed/refractory (R/R) AML. Alvocidib's anti-leukemic pharmacologic activity appears to be predominantly due to the inhibition of transcriptional regulator, CDK9, resulting in suppression of CDK9-regulated genes, such as the BCL-2 family member, MCL-1. Pre-treatment bone marrow samples from newly diagnosed AML patients revealed an increased sensitivity to alvocidib in those with MCL-1 dependence of ≥40% as measured by a BH3 profiling biomarker assay (J Clin Oncol 33, 2015 suppl; 7062). Thus, we hypothesized that alvocidib, followed by cytarabine and mitoxantrone, may be preferentially active in those with MCL-1 dependence (≥ 40%). Here, the findings from stage 1 of the Zella 201 trial in which this biomarker assay is used to select for patients with MCL-1 dependence, are reported. Aims To evaluate the efficacy and safety of alvocidib, in combination with cytarabine and mitoxantrone, in MCL-1 dependent R/R AML patients. Methods The key eligibility criteria were: ages 18-65 years; refractory to 1-2 cycles of induction therapy, or in first relapse AML with complete remission (CR) duration ≤ 2 years; ≥ 40% myeloblast MCL-1 dependency determined by BH3 profiling; ECOG PS 0-2; and no major organ dysfunction. Patients who received prior allogeneic stem cell transplant (alloSCT) were eligible, if it was greater than two months after SCT and there was no active GVHD. Treatment consisted of alvocidib 30 mg/m2 as a 30-minute IV bolus followed by 60 mg/m2 over 4 hours on Days 1-3, cytarabine 667 mg/m2/day by continuous IV infusion days 6-8, and mitoxantrone 40 mg/m2 IV on day 9 starting 12 hours after completing cytarabine. Up to 3 additional cycles of the same regimen (with or without mitoxantrone) were permittedin responders. The primary endpoint was the rate of CR+CR with incomplete recovery (CRi). Stage I was determined to be positive if ≥13 CRs were seenin the first 23 evaluable patients. Key secondary endpoints were overall survival, event-freesurvival, the combinedresponse rate and safety assessed by adverse events and laboratory results. Results A total of 163 patients were screened, of which 47 (29%) were determined to be MCL-1 dependent. Of these, 25 patients were enrolledin Stage 1 (Table 1), with 21 evaluable for response. Median MCL-1 dependence score was 55% (range: 41-98%). Of the 21 evaluable patients, 11 (52%) were refractory to frontline therapy (resistant disease or CR < 90d). The overall CR/CRi rate in evaluable patients was 62% (13/21) meeting the primary endpoint of stage 1. Seven out of 11 (64%) patients with primary refractory disease achieved a CR and five of these patients proceeded to an alloSCT. Overall, 10 patients received a post-study alloSCT. The most common NCI CTCAE ≥Grade 3treatment-emergent nonhematologic AEs noted in >1 patient in the safety population (n=25) were tumor lysis syndrome (20% Grade 3, 8% Grade 4); diarrhea (24% Grade 3); increased AST (12% Grade 3, 8% Grade 4), sepsis (16% Grade 5, 4% Grade 4); and peripheral edema, (8% Grade 3). To date, overall 30- and 60-day mortality rates were 16% and 20%, respectively, due to sepsis (n=4), and mitral valve rupture (n=1). Conclusion Our findings indicate that alvocidib given beforecytarabine and mitoxantrone in MCL-1-dependent AML has clinical activity, particularly in those refractory to frontline therapy. Given these findings, stage 2 of the Zella 201 trial has been initiated,randomizing patients to alvocidib, cytarabine, and mitoxantrone versus cytarabine and mitoxantrone alone in MCL-1 dependent R/R AML. Furthermore, a Phase Ib study of alvocidib followed by 7+3 induction in newly diagnosed AML (Zella 101) is being conducted. Disclosures Zeidner: Rafael Pharmaceuticals: Other: Travel Fees; Takeda: Other: Travel fees, Research Funding; Merck: Research Funding; Asystbio Laboratories: Consultancy; Tolero: Honoraria, Other: Travel Fees, Research Funding; Celgene: Honoraria. Lin:Jazz Pharmaceuticals: Honoraria. Wang:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Amgen: Consultancy. Levy:Takeda (Millennium Pharmaceuticals, Inc.): Consultancy. Montesinos:Daiichi Sankyo: Consultancy, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Anthony:Tolero Pharmaceuticals, Inc: Employment. Bearss:Tolero Pharmaceuticals, Inc: Employment.