Experience with IMGN632, a novel CD123-targeting antibody-drug conjugate (ADC), in frontline patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN)

BACKGROUND: BPDCN is a rare, aggressive hematologic malignancy characterized by historically poor overall survival and limited therapeutic options. Despite the recent approval of tagraxofusp-erzs for BPDCN, outcomes remain suboptimal for many patients. Additionally, patients with BPDCN are older and often have co-morbidities at baseline, preventing them from receiving tagraxofusp-erzs. Therefore, novel therapies are needed in the frontline setting for patients with BPDCN. Overexpression of CD123 (IL-3Rα) is present in all BPDCN cases, thereby establishing this surface marker as a target for therapeutic intervention. IMGN632 is a CD123-targeting ADC, comprised of a high-affinity anti-CD123 antibody coupled to a DNA-alkylating payload of the novel IGN (indolinobenzodiazepine pseudodimer) class. IMGN632 has demonstrated favorable safety and promising clinical activity in relapsed/refractory (R/R) BPDCN [Blood (2020) 136 (Supplement 1): 11-13], leading to the FDA granting IMGN632 Breakthrough Therapy Designation (BTD) for R/R BPDCN (Oct 2020). Following BTD and alignment with FDA, a pivotal cohort in frontline (no prior systemic treatment) BPDCN patients was initiated in addition to a continuing cohort of patients with R/R disease, where we have enrolled 33 patients to date. Here we report the initial experience of three frontline patients who are not part of the pivotal cohort. METHODS: IMGN632 was administered IV at a dose of 0.045 mg/kg on day 1 of a 21-day cycle to all patients. Efficacy was assessed using modified Severity Weighted Assessment Tool (for skin lesions), PET/CT, and blast percentage in bone marrow aspirates. The response criteria were adapted from established BPDCN criteria (Pemmaraju NEJM 2019). RESULTS: Three patients with frontline BPDCN (no prior systemic therapy) received IMGN632. All three of these frontline patients achieved a clinical complete remission (CRc). Patient 1 was a 79yo woman who presented with skin, nodal, and extensive bone marrow disease (80% involvement). After one dose of IMGN632, she cleared her bone marrow (0%), and after 3 cycles, her nodal lesions and skin lesions resolved to achieve a CRc. Upon complete response, treatment was held due to patient co-morbidities. With just 3 cycles of IMGN632, this patient achieved duration of response (DOR) of 10.7 months without further therapy. Patient 2 was a 67yo man who had extensive skin disease covering >20% of the body;over several cycles, he achieved a PR then a CRc and bridged to an allogeneic stem cell transplant (SCT). The patient achieved a DOR of 13.5 months, with no evidence of disease relapse when he died from graft versus host disease. Patient 3 was a 66yo woman who presented with extensive skin and nodal lesions. After improvement over 4 cycles, she achieved a CRc with clearing of most of her skin lesions and all nodal lesions. Unfortunately, while still in CRc, the patient died of COVID-19 pneumonia, with a DOR of 3.7 months. CONCLUSION: Administration of IMGN632 to frontline BPDCN patients resulted in clinical complete remission in the initial three patients with durable responses in the two non-COVID impacted patients. None of these patients progressed while on therapy, and one patient successfully bridged to SCT. Enrollment continues in the pivotal frontline and R/R cohorts. (BPDCNtrial.com;NCT03386513).

Efficacy of Oral Decitabine/Cedazuridine (ASTX727) in the CMML Subgroup from the Ascertain Phase 3 Study

text: Background/Introduction: Chronic Myelomonocytic Leukemia (CMML) is an uncommon MDS/MPN overlap syndrome that has historically been included under the umbrella of myelodysplastic syndromes (MDS) for clinical trial and treatment. As a result, DNA methyltransferase inhibitors (DNMTi) such as decitabine or azacitidine have been the established standard of care for the treatment of CMML. The oral bioavailability of these agents has been limited due to rapid degradation by cytidine deaminase (CDA) in the gut and liver so treatment has required intravenous infusion or subcutaneous injections daily for 5-7 days every month (m) adding significant burden to older cancer patients due to daily time commitment and travel to treatment centers. In the context of pandemic SARS-CoV-2, parenteral therapy also increases contact with medical settings with increased infection risk. Oral decitabine 35 mg/cedazuridine 100 mg (ASTX727) is an oral fixed dose combination of decitabine and the CDA inhibitor cedazuridine that produced equivalent exposure (99%;90% CI 93% to 106%) to IV decitabine 20 mg/m 2 in a randomized cross-over study (Garcia-Manero et al, ASH 2019), and Median overall survival (mOS) for the entire study population in the ASCERTAIN study was approximately 32 months (Savona, 2021). Here, we present outcome data for this study for the enrolled subpopulation of patients with CMML. Methods: We used a randomized cross over design in which patients were randomized in the first 2 cycles 1:1 to either Sequence A: (decitabine 35 mg/ cedazuridine 100 mg in Cycle 1 followed by IV decitabine at 20 mg/m 2 in Cycle 2), or Sequence B: (IV decitabine in Cycle 1 followed by oral decitabine/cedazuridine in Cycle 2). We conducted an intra-patient comparison of decitabine PK (primary PK endpoint: decitabine AUC equivalence over 5 days of dosing). Cycles were repeated every 28 days (unless delays were needed). All patients received oral decitabine/cedazuridine in Cycles 3 and above until disease progression or unacceptable toxicity. Patients were eligible per the FDA-approved label of IV decitabine (MDS patients by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk patients). Clinical endpoints were best response according to International Working Group (IWG) 2006 response criteria, transfusion independence for at least 8 or 16 consecutive weeks, overall survival, and safety. Adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events (CTCAE) v 4.03. Results: Of the 133 patients enrolled and treated in ASCERTAIN, 16 (12%) had a diagnosis of CMML with demographics and as follows: median age 71.5 years, 69% Male/31% Female, median weight 87kg (range 65-124), 25% ECOG 0, 75% ECOG 1. Population disease characteristics were: 19% poor or intermediate risk cytogenetics, with median baseline hemoglobin 90 g/L, neutrophils 1.27 X 10 9/L, platelets 84 x 10 9/L, bone marrow blasts 5%, with 38% RBC transfusion dependent. Patients received a median of 7 cycles of therapy (range 3-24). Treatment-emergent adverse events of CTCAE Grade 3 or higher in > 10% of patients, independent of relationship to ASTX727, were cytopenias (neutropenia [69%], thrombocytopenia [63%], anemia [56%], leukopenia [19%]), febrile neutropenia (31%), fatigue (13%). Two patients (12.5%) had Complete Responses (CR), 8 (50%) had marrow CR ([mCR], including 3 (19%) with hematologic improvement (HI);Overall Response rate (ORR) [CR + PR+ mCR + HI] was 75%. Of six patients with baseline RBC transfusion dependence 3 (50%) became transfusion independent. Leukemia-free survival was 28.2 months and after a median follow up of more than 33 months, median overall survival had not been reached. Two patients (13%) went on to Hematopoietic Stem Cell Transplant (HCT). Conclusions: In the overall study, oral decitabine/cedazuridine delivered equivalent PK exposure to 5 days of IV decitabine 20mg/m 2 with a resultant clinical activity safety and efficacy profile in CMML patients consistent with the published literature (e.g Zeidan, et a 2017) and the Phase 2 experience. The use of oral decitabine/cedazuridine is a reasonable approach in CMML patients. References: Garcia-Manero, et al ASH 2019 Savona, et al, Int. MDS Symposium, 2021 Zeidan, et al, Cancer 2017: 3754-3762. [Formula presented] Disclosures: Savona: Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees;CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees;Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees;BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees;NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees;Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees;Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees;Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees;TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;ALX Oncology: Research Funding;Astex: Research Funding;Incyte: Research Funding. McCloskey: Pfizer: Consultancy;Takeda: Consultancy, Speakers Bureau;Incyte: Speakers Bureau;Novartis: Consultancy;COTA: Other: Equity Ownership;BMS: Honoraria, Speakers Bureau;Amgen: Speakers Bureau;Jazz: Consultancy, Speakers Bureau. Griffiths: Boston Biomedical: Consultancy;Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding;Abbvie: Consultancy, Honoraria;Taiho Oncology: Consultancy, Honoraria;Genentech: Research Funding;Astex Pharmaceuticals: Honoraria, Research Funding;Takeda Oncology: Consultancy, Honoraria;Novartis: Honoraria;Apellis Pharmaceuticals: Research Funding;Alexion Pharmaceuticals: Consultancy, Research Funding. Yee: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Forma Therapeutics: Research Funding;Geron: Research Funding;Shattuck Labs: Membership on an entity's Board of Directors or advisory committees;Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees;F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding;AbbVie: Honoraria;Janssen: Research Funding;Onconova: Research Funding;Genentech: Research Funding;Otsuka: Membership on an entity's Board of Directors or advisory committees;MedImmune: Research Funding;Jazz: Research Funding;Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding;Tolero: Research Funding;Takeda: Membership on an entity's Board of Directors or advisory committees;TaiHo: Membership on an entity's Board of Directors or advisory committees;Pfizer: Membership on an entity's Board of Directors or advisory committees;Paladin: Membership on an entity's Board of Directors or advisory committees. Zeidan: BeyondSpring: Consultancy;Janssen: Consultancy;Boehringer Ingelheim: Consultancy, Research Funding;BioCryst: Other: Clinical Trial Committees;AstraZeneca: Consultancy;Pfizer: Other: Travel support, Research Funding;Kura: Consultancy, Other: Clinical Trial Committees;Incyte: Consultancy, Research Funding;Ionis: Consultancy;Daiichi Sankyo: Consultancy;Epizyme: Consultancy;Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding;Loxo Oncology: Consultancy, Other: Clinical Trial Committees;Genentech: Consultancy;Geron: Other: Clinical Trial Committees;Cardiff Oncology: Consultancy, Other: Travel support, Research Funding;BMS: Consultancy, Other: Clinical Trial Committees, Research Funding;Gilead: Consultancy, Other: Clinical Trial Committees;Aprea: Consultancy, Research Funding;Astellas: Consultancy;Astex: Research Funding;Jazz: Consultancy;Jasper: Consu tancy;Amgen: Consultancy, Research Funding;Agios: Consultancy;ADC Therapeutics: Research Funding;Acceleron: Consultancy, Research Funding;AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Al-Kali: Novartis: Research Funding;Astex: Other: Research support to institution. Patel: Agios: Membership on an entity's Board of Directors or advisory committees;Celgene-BMS: Membership on an entity's Board of Directors or advisory committees;PVI: Honoraria. Sabloff: Takeda: Membership on an entity's Board of Directors or advisory committees;BMS: Membership on an entity's Board of Directors or advisory committees;Astellas: Membership on an entity's Board of Directors or advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees;TaiHo: Membership on an entity's Board of Directors or advisory committees;Jaxx: Membership on an entity's Board of Directors or advisory committees;Abbvie: Membership on an entity's Board of Directors or advisory committees;Pfizer: Membership on an entity's Board of Directors or advisory committees;ROCHE: Membership on an entity's Board of Directors or advisory committees;Celgene: Membership on an entity's Board of Directors or advisory committees. Dao: Astex Pharmaceuticals, Inc.: Current Employment. Fazal: Janssen Oncology: Consultancy, Honoraria, Speakers Bureau;Taiho Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau;Gilead Sciences: Consultancy, Honoraria, Speakers Bureau;Novartis: Consultancy, Honoraria, Speakers Bureau;Agios: Consultancy, Honoraria, Speakers Bureau;Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau;Takeda: Consultancy, Honoraria, Speakers Bureau;Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau;AMGEN: Consultancy, Honoraria, Speakers Bureau;Incyte: Consultancy, Honoraria, Speakers Bureau;Jazz Pharmaceuticals:Consultancy, Honoraria, Speakers Bureau;Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau;Stemline Therapeutics: Consultancy, Honoraria, Speakers Bureau;Karyopharm Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau. Odenike: Celgene, Incyte, AstraZeneca, Astex, NS Pharma, AbbVie, Gilead, Janssen, Oncotherapy, Agios, CTI/Baxalta, Aprea: Research Funding;AbbVie, Celgene, Impact Biomedicines, Novartis, Taiho Oncology, Takeda: Consultancy. Kantarjian: Ipsen Pharmaceuticals: Honoraria;Astra Zeneca: Honoraria;Astellas Health: Honoraria;Aptitude Health: Honoraria;Pfizer: Honoraria, Research Funding;Novartis: Honoraria, Research Funding;Jazz: Research Funding;Immunogen: Research Funding;Daiichi-Sankyo: Research Funding;BMS: Research Funding;Ascentage: Research Funding;Amgen: Honoraria, Research Funding;AbbVie: Honoraria, Research Funding;KAHR Medical Ltd: Honoraria;NOVA Research: Honoraria;Precision Biosciences: Honoraria;Taiho Pharmaceutical Canada: Honoraria. DeZern: Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees;Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees;Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roboz: Janssen: Research Funding;AbbVie: Consultancy;Actinium: Consultancy;Agios: Consultancy;Amgen: Consultancy;Astex: Consultancy;Astellas: Consultancy;AstraZeneca: Consultancy;Bayer: Consultancy;Blueprint Medicines: Consultancy;Bristol Myers Squibb: Consultancy;Celgene: Consultancy;Daiichi Sankyo: Consultancy;Glaxo SmithKline: Consultancy;Helsinn: Consultancy;Janssen: Consultancy;Jasper Therapeutics: Consultancy;Jazz: Consultancy;MEI Pharma - IDMC Chair: Consultancy;Mesoblast: Consultancy;Novartis: Consultancy;Otsuka: Consultancy;Pfizer: Consultancy;Roche/Genentech: Consultancy. Busque: Novartis: Consultancy. Leber: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Pfizer: Membership on an entity's Board of Directors or advisory committees, peakers Bureau;BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;TaiHo: Honoraria, Membership on an entity's Board of Directors or advisory committees;Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Otsuka: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hao: Astex Pharmaceuticals, Inc.: Current Employment. Keer: Astex Pharmaceuticals, Inc.: Current Employment. Azab: Astex Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees.

Oral Decitabine/Cedazuridine in Patients with Lower Risk Myelodysplastic Syndrome: A Longer-Term Follow-up of from the Ascertain Study

[Formula presented] Background/Introduction: Lower-risk (IPSS low risk and Int-1) myelodysplastic syndromes (MDS) are typically treated supportively to address cytopenias. DNA methyltransferase inhibitors (DNMTi) such as azacitidine and decitabine (DEC) are FDA-approved for higher risk MDS patients (pts), and while the DEC USPI includes IPSS Int-1 pts, it is not widely used in this population. Approved intravenous (IV) or subcutaneous (SC) regimens require 5-7 days of treatment every month burdening older cancer pts due to daily travel and treatment time and may increase potential risk from pandemic SARS-CoV-2 infection. Because DNMTis are rapidly degraded by cytidine deaminase (CDA) in the gut and liver, oral availability has only been recently possible. A randomized study with CC-486, an oral formulation of azacitidine, in the Int-1 population showed a median overall survival (mOS) of approximately 17 months for both placebo and treated patients (Garcia-Manero, 2021). Oral DEC 35 mg/cedazuridine 100 mg (ASTX727) or DEC-C, is an oral fixed dose combination (FDC) of DEC and the CDA inhibitor cedazuridine (CED) resulting in equivalent exposure (99%;90% CI 93% to 106%) to standard IV DEC 20 mg/m 2 for 5 days in an intra-patient randomized cross-over study (Garcia-Manero et al, ASH 2019). Here, we present data on patients with lower risk MDS from that study. Methods: We used a randomized cross over design with pts randomized 1:1 in the first 2 cycles to either Sequence A: (DEC 35 mg/ CED 100 mg in Cycle 1 and IV DEC at 20 mg/m 2 in Cycle 2), or Sequence B (IV DEC in Cycle 1 and oral DEC/CED in Cycle 2). Cycles were repeated every 28 days unless delays were needed, and all patients received oral DEC-C in Cycles 3+ until disease progression or unacceptable toxicity. We conducted an intra-patient comparison of DEC PK (DEC AUC equivalence over 5 days of dosing). Pts were eligible as per the FDA-approved label of IV DEC (MDS pts by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk pts). Clinical endpoints were best response as assessed by an independent expert panel according to IWG 2006 response criteria, transfusion independence (TI), overall survival (OS), and safety. Results: Of the 133 pts treated in ASCERTAIN, 69 had a diagnosis of lower-risk MDS (93% Int-1, 7% LR). Median age was 70.0 years (range 45-87), 65% were male, median weight was 84 kg (range 50-127), median baseline hematologic parameters were: hemoglobin 89 g/L (range 69.8-146.5), WBCs 1.50 X 10 9/L (range 0.11-7.1), platelets (plt) 86 x 10 9/L (range 5-703), bone marrow blasts 4% (range 0-18), cytogenetics: 7 (10.1%) poor-risk, 21 (30.4%) intermediate risk, 37 (53.6%) better-risk, 4 (5.7%) missing or not evaluable. 27(39%) of the pts were RBC transfusion dependent (TD) and 6 (9%) plt TD. 17 (25%) had received prior MDS treatment, 3% prior DNMTi. Pts received a median of 9 cycles of therapy (range 1-28). Treatment-emergent adverse events of CTCAE Gr 3 or higher in >10% of pts, independent of relationship to ASTX727, included cytopenias (neutropenia [59%], thrombocytopenia [58%], anemia [48%], leukopenia [26%]), febrile neutropenia (32%), and pneumonia (19%). Sixteen pts (23%) achieved Complete Response (CR), 18 (26%) had marrow CR (mCR), including 9 (13%) with hematologic improvement (HI). Overall Response rate (ORR;CR + PR+ mCR + HI) was 57%. Of those RBC or plt TD at baseline, 13 (48%) became RBC TI and 4 (67%) became plt TI. With approximately 32 months of median follow up, neither median leukemia-free survival (mLFS) nor mOS had been reached (Figure 1). Twelve pts (17%) went on to allogeneic stem cell transplant. Conclusions: Oral decitabine/cedazuridine given as a FDC in MDS pts produced equivalent PK exposure to 20 mg/m 2 IV DEC;in lower risk MDS pts with treatment indicated, the agent was generally well-tolerated with prolonged treatment and could result in mLFS and mOS which exceeds 32 months. This FDC and other dosing regimens of oral DEC-C should be further studied in this patient population. References: Garcia-Mane o, et al, ASH 2019 Savona, et al, Int. MDS Symp. 2021 Garcia-Manero, et al, Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients with Lower-Risk Myelodysplastic Syndromes. J.Clin.Onc. 2021 39:13, 1426-1436 [Formula presented] Disclosures: McCloskey: Pfizer: Consultancy;Jazz: Consultancy, Speakers Bureau;COTA: Other: Equity Ownership;Incyte: Speakers Bureau;Takeda: Consultancy, Speakers Bureau;Novartis: Consultancy;BMS: Honoraria, Speakers Bureau;Amgen: Speakers Bureau. Griffiths: Alexion Pharmaceuticals: Consultancy, Research Funding;Abbvie: Consultancy, Honoraria;Taiho Oncology: Consultancy, Honoraria;Genentech: Research Funding;Novartis: Honoraria;Takeda Oncology: Consultancy, Honoraria;Astex Pharmaceuticals: Honoraria, Research Funding;Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding;Apellis Pharmaceuticals: Research Funding;Boston Biomedical: Consultancy. Yee: Paladin: Membership on an entity's Board of Directors or advisory committees;TaiHo: Membership on an entity's Board of Directors or advisory committees;Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Genentech: Research Funding;Geron: Research Funding;Janssen: Research Funding;Jazz: Research Funding;MedImmune: Research Funding;Onconova: Research Funding;Tolero: Research Funding;AbbVie: Honoraria;Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees;Otsuka: Membership on an entity's Board of Directors or advisory committees;Shattuck Labs: Membership on an entity's Board of Directors or advisory committees;Pfizer: Membership on an entity's Board of Directors or advisory committees;Takeda: Membership on an entity's Board of Directors or advisory committees;F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding;Forma Therapeutics: Research Funding;Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zeidan: Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding;Genentech: Consultancy;Ionis: Consultancy;Astellas: Consultancy;Epizyme: Consultancy;AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding;Jasper: Consultancy;Cardiff Oncology: Consultancy, Other: Travel support, Research Funding;BeyondSpring: Consultancy;Loxo Oncology: Consultancy, Other: Clinical Trial Committees;Janssen: Consultancy;Acceleron: Consultancy, Research Funding;AstraZeneca: Consultancy;Kura: Consultancy, Other: Clinical Trial Committees;Gilead: Consultancy, Other: Clinical Trial Committees;Agios: Consultancy;Daiichi Sankyo: Consultancy;Boehringer Ingelheim: Consultancy, Research Funding;Geron: Other: Clinical Trial Committees;BMS: Consultancy, Other: Clinical Trial Committees, Research Funding;BioCryst: Other: Clinical Trial Committees;Pfizer: Other: Travel support, Research Funding;Aprea: Consultancy, Research Funding;ADC Therapeutics: Research Funding;Jazz: Consultancy;Incyte: Consultancy, Research Funding;Amgen: Consultancy, Research Funding;Astex: Research Funding. Al-Kali: Astex: Other: Research support to institution;Novartis: Research Funding. Patel: Celgene-BMS: Membership on an entity's Board of Directors or advisory committees;PVI: Honoraria;Agios: Membership on an entity's Board of Directors or advisory committees. Sabloff: Pfizer: Membership on an entity's Board of Directors or advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees;Astellas: Membership on an entity's Board of Directors or advisory committees;Takeda: Membership on an entity's Board of Directors or advisory committees;ROCHE: Membership on an entity's Board of Directors or advisory committees;TaiHo: Membership on an entity's Board of Directors or advisory committees;Jaxx: Membership on an entity's Board of Directors or advisory committees;Celgene: Membership on an entity's Board of Directors or advisory ommittees;BMS: Membership on an entity's Board of Directors or advisory committees;Abbvie: Membership on an entity's Board of Directors or advisory committees. Dao: Astex Pharmaceuticals, Inc.: Current Employment. Fazal: Taiho Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau;Stemline Therapeutics: Consultancy, Honoraria, Speakers Bureau;Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau;Novartis: Consultancy, Honoraria, Speakers Bureau;Karyopharm Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau;Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau;Janssen Oncology: Consultancy, Honoraria, Speakers Bureau;Incyte: Consultancy, Honoraria, Speakers Bureau;Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau;Gilead Sciences: Consultancy, Honoraria, Speakers Bureau;Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau;AMGEN: Consultancy, Honoraria, Speakers Bureau;Agios: Consultancy, Honoraria, Speakers Bureau;Takeda: Consultancy, Honoraria, Speakers Bureau. Odenike: AbbVie, Celgene, Impact Biomedicines, Novartis, Taiho Oncology, Takeda: Consultancy;Celgene, Incyte, AstraZeneca, Astex, NS Pharma, AbbVie, Gilead, Janssen, Oncotherapy, Agios, CTI/Baxalta, Aprea: Research Funding. Kantarjian: AbbVie: Honoraria, Research Funding;Novartis: Honoraria, Research Funding;Ascentage: Research Funding;Pfizer: Honoraria, Research Funding;BMS: Research Funding;Daiichi-Sankyo: Research Funding;Amgen: Honoraria, Research Funding;Ipsen Pharmaceuticals: Honoraria;Jazz: Research Funding;Astellas Health: Honoraria;Immunogen: Research Funding;Astra Zeneca: Honoraria;Aptitude Health: Honoraria;KAHR Medical Ltd: Honoraria;NOVA Research: Honoraria;Precision Biosciences: Honoraria;Taiho Pharmaceutical Canada: Honoraria. DeZern: Takeda: Consultancy, Membership on an entity's Board of Directors or advisorycommittees;Taiho: 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;Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roboz: Novartis: Consultancy;Mesoblast: Consultancy;Jasper Therapeutics: Consultancy;Jazz: Consultancy;MEI Pharma - IDMC Chair: Consultancy;Daiichi Sankyo: Consultancy;Otsuka: Consultancy;Bristol Myers Squibb: Consultancy;Blueprint Medicines: Consultancy;Bayer: Consultancy;AstraZeneca: Consultancy;Astellas: Consultancy;Astex: Consultancy;Amgen: Consultancy;Agios: Consultancy;Actinium: Consultancy;AbbVie: Consultancy;Janssen: Research Funding;Celgene: Consultancy;Glaxo SmithKline: Consultancy;Helsinn: Consultancy;Janssen: Consultancy;Pfizer: Consultancy;Roche/Genentech: Consultancy. Busque: Novartis: Consultancy. Leber: Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Otsuka: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;TaiHo: Honoraria, Membership on an entity's Board of Directors or advisory committees;AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hao: Astex Pharmaceuticals, Inc.: Current Employment. Keer: Astex Pharmaceuticals, Inc.: Current Employment. Azab: Astex Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Savona: Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees;Karyopharm: Cons ltancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees;CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees;BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees;NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees;Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees;Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees;Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees;TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;ALX Oncology: Research Funding;Astex: Research Funding;Incyte: Research Funding.

Safety and Efficacy of Cusatuzumab in Combination with Venetoclax and Azacitidine (CVA) in Patients with Previously Untreated Acute Myeloid Leukemia (AML) Who Are Not Eligible for Intensive Chemotherapy;An Open-Label, Multicenter, Phase 1b Study

Background: Acute myeloid leukemia (AML) is driven by aberrant leukemic stem cells (LSCs) that initiate and sustain malignancy. To circumvent resistance to therapy, combination therapies with additive mechanisms of action are needed. CD70, a tumor necrosis factor receptor ligand, and its receptor CD27 are expressed on LSCs and AML blasts, but not on hematopoietic stem cells. Cusatuzumab, a high-affinity humanized monoclonal anti-CD70 antibody, kills CD70-expressing cells by Fc domain-mediated effector functions and is a potent inhibitor of CD70-CD27 signaling. Here we report initial results of a study of cusatuzumab in combination with the current standard of care therapy, venetoclax plus azacitidine (CVA), in patients with untreated AML (de novo or secondary) ineligible for intensive chemotherapy due to age ≥75 years or medical comorbidities. Methods: The primary objective of this open label, multicenter, phase 1b study was to assess safety and tolerability of CVA. Key secondary objectives included response rate per ELN 2017 criteria and time to response. Patients received cusatuzumab 10 or 20 mg/kg IV on Day 3 and Day 17, a 3-day ramp-up of venetoclax (100, 200, and 400 mg PO) followed by 400 mg daily dosing, and azacitidine 75 mg/m 2 SC or IV on Days 1-7 of each 28-day cycle. Results: Based on data through Jul 9, 2021, 44 patients enrolled with median age 75 years (range 32-89), 36.4% had secondary AML, 40.9% had an ECOG performance status of 2, and ELN risk was favorable, intermediate and adverse in 18.2%, 20.5% and 61.4%, respectively. All patients received 20 mg/kg cusatuzumab except for 3 patients who received a starting dose of 10 mg/kg with the option to escalate to 20 mg/kg. Of these 3 patients, 1 escalated to 20 mg/kg. At a median follow-up of 29.1 weeks, the median number of treatment cycles was 4.0 (range 1.0-11.0). Grade 3 or above TEAEs were reported in 97.7% of patients;the most common (reported in ≥10%) were neutropenia (68.2%), thrombocytopenia (65.9%), febrile neutropenia (36.4%), anemia (34.1%), leukopenia (29.5%), sepsis (27.3%), and lymphopenia (15.9%). Treatment-emergent serious adverse events (SAEs) were reported in 75% of patients;the most common (reported in at least ≥5%) were febrile neutropenia (27.3%), sepsis (22.7%), COVID-19 (6.8%), and thrombocytopenia (6.8%). Treatment-emergent SAEs of grade ≥3 were reported in 72.7% of the patients. Infusion-related reactions (IRRs) were reported for 11.4% of patients with 2.3% at grade ≥3. Six (13.6%) patients discontinued treatment due to AEs, and 5 (11.4%) TEAEs resulted in death. The mortality rate within 30 days from start of treatment was 4.5%. Table 1 summarizes best response to study treatment. In the intent-to-treat analysis set (n=44) complete remission (CR) rate was 45.5%, while CR + CR with partial hematologic recovery (CRh) + CR with incomplete hematologic recovery (CRi) was 77.3%;MLFS was observed in 11.4% of patients. Of 34 responders (defined as CR, CRi or CRh), 47% were MRD negative by flow cytometry at or after achievement of response. Median time to first response for patients who achieved CR, CRh or CRi was 4.21 (3.0-25.0) weeks. Best response rates in the post-hoc response evaluable analysis set (n=42) that excluded two patients who died before the first disease evaluation were: CR in 47.6%, CR + CRh + CRi in 81.0% and MLFS in 11.9% of patients (Table 1). The majority (97.1%) of responders experienced at least one cycle delay in administration of CVA post response. Conclusions: Cusatuzumab administered in combination with venetoclax and azacitidine to elderly patients with untreated AML was generally well tolerated and demonstrated a safety profile consistent with that previously reported with venetoclax-azacitidine, with the addition of generally manageable IRRs. Response rates support an additive effect of cusatuzumab to the standard of care with potential for improved clinical outcomes. However, further clinical trials are needed for validation of these initial results. HK and GB contributed equally to this publ cation. [Formula presented] Disclosures: Roboz: AstraZeneca: Consultancy;Janssen: Research Funding;Bristol Myers Squibb: Consultancy;Jasper Therapeutics: Consultancy;Agios: Consultancy;Novartis: Consultancy;Amgen: Consultancy;Blueprint Medicines: Consultancy;Janssen: Consultancy;Helsinn: Consultancy;Daiichi Sankyo: Consultancy;Glaxo SmithKline: Consultancy;Celgene: Consultancy;Jazz: Consultancy;MEI Pharma - IDMC Chair: Consultancy;Mesoblast: Consultancy;Actinium: Consultancy;AbbVie: Consultancy;Astex: Consultancy;Bayer: Consultancy;Astellas: Consultancy;Roche/Genentech: Consultancy;Pfizer: Consultancy;Otsuka: Consultancy. Aribi: Seagen: Consultancy. Brandwein: Astellas: Honoraria;Jazz: Honoraria;Amgen: Honoraria;Taiho: Honoraria;BMS/Celgene: Honoraria;Pfizer: Honoraria;Abbvie: Honoraria;University of Alberta: Current Employment. Döhner: Astellas: Consultancy, Honoraria, Research Funding;AstraZeneca: Consultancy, Honoraria;Berlin-Chemie: Consultancy, Honoraria;Amgen: Consultancy, Honoraria, Research Funding;Abbvie: Consultancy, Honoraria, Research Funding;Agios: Consultancy, Honoraria, Research Funding;Celgene: Consultancy, Honoraria, Research Funding;GEMoaB: Consultancy, Honoraria;Helsinn: Consultancy, Honoraria;Janssen: Consultancy, Honoraria;Jazz: Consultancy, Honoraria, Research Funding;Novartis: Consultancy, Honoraria, Research Funding;Oxford Biomedicals: Consultancy, Honoraria;Pfizer: Research Funding;Roche: Consultancy, Honoraria;Gilead: Consultancy, Honoraria;Bristol Myers Squibb: Consultancy, Honoraria, Research Funding;Astex: Consultancy, Honoraria;Ulm University Hospital: Current Employment. Fiedler: Jazz Pharmaceuticals: Consultancy, Other: support for meeting attendance;Abbvie: Consultancy, Honoraria;Morphosys: Consultancy;Celgene: Consultancy;Pfizer: Consultancy, Research Funding;Novartis: Consultancy;ARIAD/Incyte: Consultancy;Amgen: Consultancy, Other: support for meeting attendance, Patents & Royalties, Research Funding;Servier: Consultancy, Other: support for meeting attendance;Daiichi Sankyo: Consultancy, Other: support for meeting attendance;Stemline: Consultancy. Gandini: argenx: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Geddes: University of Calgary: Current Employment;Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees;Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees;Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy;BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees;Amgen: Consultancy;Paladin: Consultancy;Janssen: Research Funding;Geron: Research Funding;Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hou: University of Pittsburgh Medical Center Hillman Cancer Centers: Current Employment;AbbVie: Honoraria;AstraZeneca: Honoraria;Karyopharm: Honoraria;Chinese American Hematology Oncology Network: Membership on an entity's Board of Directors or advisory committees. Howes: Janssen R&D, part of Johnson & Johnson: Current Employment;Johnson & Johnson: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Hultberg: argenx: Current Employment, Patents & Royalties. Huselton: University of Rochester: Current Employment. Jacobs: Argenx BV: Current Employment, Current equity holder in publicly-traded company;University of Antwerp: Ended employment in the past 24 months. Kane: Janssen R&D, part of Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Lech-Marańda: Takeda: Membership on an entity's Board of Directors or advisory committees;AbbVie: Membership on an entity's Board of Directors r advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees;Roche: Membership on an entity's Board of Directors or advisory committees;Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees;Amgen: Membership on an entity's Board of Directors or advisory committees;Sanofi: Membership on an entity's Board of Directors or advisory committees;Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding. Louwers: argenx: Current Employment, Patents & Royalties: Patents (no royalties). Nottage: Janssen R&D, part of Johnson & Johnson: Current Employment;Johnson & Johnson: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Platzbecker: Novartis: Honoraria;AbbVie: Honoraria;Janssen: Honoraria;Celgene/BMS: Honoraria;Geron: Honoraria;Takeda: Honoraria. Rampal: Pharmaessentia: Consultancy;BMS/Celgene: Consultancy;Abbvie: Consultancy;Sierra Oncology: Consultancy;Incyte: Consultancy, Research Funding;Blueprint: Consultancy;Disc Medicine: Consultancy;Jazz Pharmaceuticals: Consultancy;Constellation: Research Funding;Kartos: Consultancy;Stemline: Consultancy, Research Funding;CTI: Consultancy;Novartis: Consultancy;Memorial Sloan Kettering: Current Employment. Salman: Janssen: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Shah: Janssen R&D, part of Johnson & Johnson: Current Employment. Stuart: Clinical Drug Development Consultants LLC: Current Employment;Argenx: Consultancy;Cleave Therapeutics: Consultancy;Triphase Accelerator Corp: Consultancy;IgM Biosciences: Consultancy;Revolution Medicines: Consultancy;Jiya Corp:Consultancy;Geron Corp: Current holder of individual stocks in a privately-held company. Subklewe: Janssen: Consultancy;Pfizer: Consultancy, Speakers Bureau;Takeda: Speakers Bureau;Klinikum der Universität München: Current Employment;MorphoSys: Research Funding;Novartis: Consultancy, Research Funding, Speakers Bureau;Roche: Research Funding;Seattle Genetics: Consultancy, Research Funding;Miltenyi: Research Funding;Gilead: Consultancy, Research Funding, Speakers Bureau;Amgen: Consultancy, Research Funding, Speakers Bureau;BMS/Celgene: Consultancy, Research Funding, Speakers Bureau. Sumbul: argenx: Current Employment. Wang: Takeda: Consultancy, Honoraria, Other: Advisory board;Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board;Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees;Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau;AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees;Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board;GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board;Genentech: Membership on an entity's Board of Directors or advisory committees;BMS/Celgene: Membership on an entity's Board of Directors or advisory committees;DAVA Oncology: Consultancy, Speakers Bureau;Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau;Novartis: Consultancy, Honoraria, Other: Advisory Board;Mana Therapeutics: Consultancy, Honoraria;Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau;Rafael Pharmaceuticals: Other: Data safety monitoring committee;Gilead: Consultancy, Honoraria, Other: Advisory board;Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board;PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board;Genentech: Consultancy;MacroGenics: Consultancy. Wierzbowska: Jazz: Research Funding;Pfizer: Honoraria;Janssen: 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;Astellas: Honoraria, Membership on an entity's Board of Directors or advisory comm ttees;Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees;BMS: Honoraria. Yao: Statagize LLC: Current Employment;Puma Biotechnology, Inc.: Ended employment in the past 24 months;Argenx: Consultancy. Yee: Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding;Janssen: Research Funding;TaiHo: Membership on an entity's Board of Directors or advisory committees;Otsuka: Membership on an entity's Board of Directors or advisory committees;Onconova: Research Funding;Pfizer: Membership on an entity's Board of Directors or advisory committees;Tolero: Research Funding;Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Paladin: Membership on an entity's Board of Directors or advisory committees;MedImmune: Research Funding;AbbVie: Honoraria;Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees;Shattuck Labs: Membership on an entity's Board of Directors or advisory committees;Forma Therapeutics: Research Funding;Takeda: Membership on an entity's Board of Directors or advisory committees;Geron: Research Funding;Genentech: Research Funding;F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding;Jazz: Research Funding. Kantarjian: Immunogen: Research Funding;Astra Zeneca: Honoraria;KAHR Medical Ltd: Honoraria;Astellas Health: Honoraria;Pfizer: Honoraria, Research Funding;NOVA Research: Honoraria;Ascentage: Research Funding;Precision Biosciences: Honoraria;Novartis: Honoraria, Research Funding;Aptitude Health: Honoraria;Ipsen Pharmaceuticals: Honoraria;Jazz: Research Funding;Daiichi-Sankyo: Research Funding;BMS: Research Funding;Amgen: Honoraria, Research Funding;AbbVie: Honoraria, Research Funding;Taiho Pharmaceutical Canada: Honoraria. Borthakur: Protagonist: Consultancy;Ryvu: Research Funding;Astex: Research Funding;GSK: Consultancy;Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees;Takeda: Membership on an entity's Board of Directors or advisory committees;University of Texas MD Anderson Cancer Center: Current Employment;ArgenX: Membership on an entity's Board of Directors or advisory committees.

Venetoclax, Obinutuzumab and Atezolizumab (PD-L1 Checkpoint Inhibitor) for First-Line Treatment for Patients with Chronic Lymphocytic Leukemia (CLL)

Background: Dysfunction of T cells, NK cells and other immune subsets is common in patients (pts) with CLL. Venetoclax (VEN), a BCL-2 inhibitor and obinutuzumab (OBIN), a CD20 monoclonal antibody (mAb) are approved for pts with CLL (Fischer, NEJM 2019). Atezolizumab, a PD-L1 checkpoint inhibitor (CPI), is approved for melanoma, lung cancer and other solid tumors. Preclinical studies showed synergy of VEN and CD20 mAb with CPI (Kohlhapp, Cancer Discovery 2021;Westin, Lancet Oncology 2014). Clinical studies showed activity of PD1 inhibition in pts with Richter's transformation, but not CLL (Ding, Blood 2017;Jain, ASH 2018). To our knowledge, no prior study has evaluated PD-L1 inhibition in pts with CLL, nor combined CPI, VEN and OBIN. We hypothesized that combined VEN, OBIN and atezolizumab will be synergistic. Methods: This is an investigator-initiated Phase II trial of combined VEN, OBIN and atezolizumab in pts with previously untreated CLL meeting 2008 IWCLL treatment criteria (NCT02846623). Eligibility criteria included age ≥18 years, adequate organ function (total bilirubin ≤1.5 x ULN, ALT and AST ≤2.5 x ULN, creatinine ≤1.5 x ULN). OBIN was given at a flat dose of 100mg IV Cycle (C)1 Day (D)1, 900 mg C1D2, 1000mg on C1D8, 1000mg on C1D15 and then 1000mg on C2-9 D1. Atezolizumab was given at a flat dose of 1680 mg IV (split over 2 days) on C1D3-4 and then C2-9D1-2. VEN was initiated at the start of C3 with the weekly dose-escalation (20mg daily to a target dose of 400mg daily) and continued daily until end of C14 (total 12 cycles of VEN). All pts stopped therapy at the end of C14. Response assessments were done with CT imaging and bone marrow aspirate/biopsy with MRD assessment (multi-color flow cytometry;sensitivity 10 -4) at the end of C2 (prior to VEN initiation), end of C6, end of C9, and end of C14. Results: From July 2019 to December 2020, a total of 26 pts were enrolled. The median age was 60 years (range, 21-74). The baseline characteristics are shown in Table 1. A total of 19/26 (73%) had unmutated IGHV gene. Though the study did not restrict pts with del(17p) or mutated TP53, no pt in the current cohort had del(17p)/ mutated TP53. A total of 14 (54%) pts had a baseline lymph node >5cm. The median follow-up is 13.3 months. One pt came off study in C1 (details below). A total of 25 pts initiated VEN. The TLS risk categories at the start of C1 were high (n=9, 36%), medium (n=12, 48%), and low (n=4, 16%). After 2 cycles of OBIN and atezolizumab (prior to VEN initiation), the majority of pts had downgrading of TLS risk category [high (n=2, 8%), medium (n=3, 12%), and low (n=20, 80%)]. After C6 (about 3 cycles of VEN 400mg daily), bone marrow undetectable (U)-MRD rate was 19/25 (76%);4/25 (16%) had low+ MRD and 2/25 (8%) had high+ MRD. After C9 (about 6 cycles of VEN 400mg daily), among the 21 pts (4 pts have not reached this time-point), the bone marrow U-MRD rate was 18/21 (86%);2/21 (10%) had low+ MRD and 1/21 (5%) had high+ MRD. A total of 14 pts completed C14 (9 pts have not reached this time-point;2 pts came off study prior to completing C14, details below);13/14 (93%) achieved bone marrow U-MRD and 1/14 (7%) has low+ MRD. No patient had disease progression or MRD relapse so far. One pt died (details below). Three pts came off study (one developed retroperitoneal hematoma after receiving enoxaparin for DVT in C1;one developed CPI-induced colitis and removed from the study in C10;one died from COVID-19 pneumonia in C14 while in bone marrow U-MRD remission). Grade 3-4 neutropenia occurred in 14/26 (54%) pts. Grade 3 thrombocytopenia occurred in 5/26 (19%) pts;no pt had G4 thrombocytopenia. A total of 4 pts developed CPI-induced toxicities (colitis, G3, n=1;mucositis, G3, n=1;nephritis, G2, n=1;myositis, G2, n=1). A total of 10/25 (40%) pts had dose reduction of VEN, the majority due to neutropenia. Atezolizumab was discontinued early in 3 pts due to CPI-induced toxicities. Laboratory correlative studies including scRNAseq and CyTOF are ongoing. Conclusions: Treatment with combined VE , OBIN and atezolizumab leads to high rate of early U-MRD remission with 76% bone marrow U-MRD remission at the end of C6 (about 3 cycles of VEN 400mg daily). Four pts had CPI-induced toxicities. The enrollment in this trial continues and updated data and correlative studies will be presented at the ASH meeting. [Formula presented] Disclosures: Jain: Pfizer: Research Funding;Bristol Myers Squibb: Honoraria, Research Funding;Precision Biosciences: Honoraria, Research Funding;Aprea Therapeutics: Research Funding;AstraZeneca: Honoraria, Research Funding;Servier: Honoraria, Research Funding;Incyte: Research Funding;Pharmacyclics: Research Funding;Genentech: Honoraria, Research Funding;AbbVie: Honoraria, Research Funding;TG Therapeutics: Honoraria;Janssen: Honoraria;Beigene: Honoraria;Fate Therapeutics: Research Funding;Adaptive Biotechnologies: Honoraria, Research Funding;Cellectis: Honoraria, Research Funding;ADC Therapeutics: Honoraria, Research Funding. Ferrajoli: Janssen: Other: Advisory Board;AstraZeneca: Other: Advisory Board, Research Funding;BeiGene: Other: Advisory Board, Research Funding. Yilmaz: Daiichi-Sankyo: Research Funding;Pfizer: Research Funding. Thompson: AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding;Gilead: Other: Institution: Advisory/Consultancy, Honoraria;Janssen: Consultancy, Honoraria;Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding;Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony;Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding;Amgen: Other: Institution: Honoraria, Research Grant/Funding. Konopleva: Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights;Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights;Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding;KisoJi: Research Funding;Stemline Therapeutics: Research Funding;Sanofi: Other: grant support, Research Funding;Rafael Pharmaceuticals: Other: grant support, Research Funding;AstraZeneca: Other: grant support, Research Funding;Cellectis: Other: grant support;F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support;Calithera: Other: grant support, Research Funding;Ascentage: Other: grant support, Research Funding;Ablynx: Other: grant support, Research Funding;Genentech: Consultancy, Honoraria, Other: grant support, Research Funding;Forty Seven: Other: grant support, Research Funding;AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding;Agios: Other: grant support, Research Funding. Neelapu: Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties;Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding;Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees;Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria. Takahashi: Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees;Celgene/BMS: Consultancy;Novartis: Consultancy;GSK: Consultancy. Burger: TG Therapeutics: Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau;Beigene: Research Funding, Speakers Bureau;Novartis: Other: Travel/Accommodations/Expenses, Speakers Bureau;Pharmacyclics LLC: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau;Gilead: Consultancy, Other: Travel/Accommodations/Expenses, Rese rch Funding, Speakers Bureau;AstraZeneca: Consultancy;Janssen: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau. Khoury: Stemline Therapeutics: Research Funding;Kiromic: Research Funding;Angle: Research Funding. Kantarjian: Jazz: Research Funding;NOVA Research: Honoraria;Novartis: Honoraria, Research Funding;KAHR Medical Ltd: Honoraria;Precision Biosciences: Honoraria;Amgen: Honoraria, Research Funding;Astra Zeneca: Honoraria;AbbVie: Honoraria, Research Funding;Ipsen Pharmaceuticals: Honoraria;Pfizer: Honoraria, Research Funding;Astellas Health: Honoraria;Aptitude Health: Honoraria;Taiho Pharmaceutical Canada: Honoraria;Immunogen: Research Funding;Daiichi-Sankyo: Research Funding;BMS: Research Funding;Ascentage: Research Funding. Wierda: Karyopharm: Research Funding;Miragen: Research Funding;Acerta Pharma Inc.: Research Funding;Cyclacel: Research Funding;Oncternal Therapeutics, Inc.: Research Funding;Pharmacyclics LLC, an AbbVie Company: Research Funding;Sunesis: Research Funding;Juno Therapeutics: Research Funding;Gilead Sciences: Research Funding;AstraZeneca: Research Funding;Genentech: Research Funding;Loxo Oncology, Inc.: Research Funding;Janssen: Research Funding;Xencor: Research Funding;GSK/Novartis: Research Funding;KITE Pharma: Research Funding;Genzyme Corporation: Consultancy;AbbVie: Research Funding. OffLabel Disclosure: Atezolizumab is not approved for CLL

Combined Ibrutinib and Venetoclax for First-Line Treatment of Patients with Chronic Lymphocytic Leukemia (CLL): Focus on Long-Term MRD Results

Background: Ibrutinib (IBR) and venetoclax (VEN) combination is a highly effective therapy for patients (pts) with CLL (Jain, NEJM 2019;Wierda, ASH 2020;Kater, EHA 2021). We previously reported results of the first-line cohort of a phase II trial of combined IBR and VEN for high-risk pts with CLL (Jain, NEJM 2019;Jain, JAMA Oncology 2021). Here we report updated data for these pts with focus on MRD. Methods: Pts with previously untreated CLL meeting IWCLL treatment criteria were enrolled. All pts had at least one high-risk feature: del(17p), mutated TP53, del(11q), unmutated IGHV, or age ≥65 years (yrs). Pts received IBR 420 mg daily for 3 cycles followed by addition of VEN (weekly dose-escalation to 400mg daily). Combined therapy was given for 24 cycles (28 days/cycle). Pts with bone marrow (BM) undetectable MRD (U-MRD) (flow cytometry;sensitivity 10 -4) at 24 cycles of combined therapy discontinued both VEN and IBR;MRD+ pts continued IBR. A trial amendment allowed an additional 12 cycles of combined VEN and ibrutinib for pts who remained BM MRD+ after Cycle 24. Response assessments were performed using BM and CT imaging studies (2008 IWCLL criteria). U-MRD was defined as <0.01%;low MRD+ 0.01% to <1%;high MRD+ ≥1%. Progression-free survival (PFS) was assessed as the time from the start of study drug to CLL progression, Richter transformation, or death from any cause. Blood MRD was monitored every 6 months in pts off treatment or on ibrutinib monotherapy beyond 24 cycles of combined treatment. Results: A total of 80 pts were enrolled. Baseline characteristics are shown in Table 1. The median follow-up was 44.1 months. Five pts came off study during 1 st 3 cycles of IBR monotherapy;75 pts initiated VEN. We previously reported that after 12 cycles of the combination, 45/80 (56%) achieved BM U-MRD remission;24/80 (30%) were BM MRD-positive (low MRD+, n=19;high MRD+, n=5). After 24 cycles of the combination, 53/80 (66%) achieved BM U-MRD remission;14/80 (17%) were BM MRD+ (low MRD+, n=13;high MRD+, n=1). Overall, 60/80 (75%) achieved BM U-MRD as the best response. Updated PFS is provided in Figure 1. Of the 53 pts who were BM U-MRD at the end of cycle 24 of the combination, 52 pts had a subsequent blood MRD assessment done in follow-up (1 missed due to COVID-19);51/53 discontinued all therapy, 2 pts continued IBR per treatment physician discretion. With a median time of 18.4 months post Cycle 24, 8 pts had recurrence of blood MRD (defined as MRD ≥ 0.01% in 2 consecutive visits) in follow-up with 1 pt with CLL progression. The sole pt with CLL progression had mutated IGHV with del(11q) and NOTCH1 mutation. The pt had delayed achievement of BM U-MRD with the pt achieving U-MRD for the first time at the end of Cycle 24 of combined therapy. She was noted to have disease progression 22 months off therapy;BTK or PLCG2 mutation were not detected and the patient is currently in clinical remission on acalabrutinib. The time to MRD conversion for these 53 pts is shown in Figure 2. There were 14 pts who were BM MRD+ at the end of cycle 24 of the combination (low MRD+, n=13;high MRD+, n=1). The only pt with high-MRD+ at end of cycle 24 was noted to have Richter transformation at that time. The remaining 13 pts (all low MRD+ in BM, range 0.01-0.56%) continued IBR monotherapy. With a recent trial amendment, MRD+ pts after Cycle 24 could get 12 additional cycles of venetoclax;9/13 pts have resumed VEN. 6/9 pts have achieved U-MRD remission. 2 pts had Richter transformation and 3 pts have died (Jain, JAMA Oncology 2021). Conclusions: We report long term follow-up of combined IBR and VEN in first-line CLL. Remissions were durable with some pts having recurrence of blood MRD in follow-up, which may be an early indicator of relapse. In a small subset of the pts with BM MRD+ disease at 24 cycles of combined therapy, additional VEN appears to lead to U-MRD remission in majority of the pts. Whether this will lead to improved long-term PFS remains to be determined. [Formula presented] Disclosures: Jain: TG Therapeutics: Honoraria;Beigene: Honoraria;Janssen: Honoraria;Fate Therapeutics: Research Funding;Aprea Therapeutics: Research Funding;Precision Biosciences: Honoraria, Research Funding;Incyte: Research Funding;Adaptive Biotechnologies: Honoraria, Research Funding;Cellectis: Honoraria, Research Funding;ADC Therapeutics: Honoraria, Research Funding;Servier: Honoraria, Research Funding;Pfizer: Research Funding;Bristol Myers Squibb: Honoraria, Research Funding;AstraZeneca: Honoraria, Research Funding;Genentech: Honoraria, Research Funding;AbbVie: Honoraria, Research Funding;Pharmacyclics: Research Funding. Thompson: AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding;Amgen: Other: Institution: Honoraria, Research Grant/Funding;Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding;Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony;Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding;Janssen: Consultancy, Honoraria;Gilead: Other: Institution: Advisory/Consultancy, Honoraria. Ferrajoli: BeiGene: Other: Advisory Board, Research Funding;Janssen: Other: Advisory Board;AstraZeneca: Other: Advisory Board, Research Funding. Burger: Novartis: Other: Travel/Accommodations/Expenses, Speakers Bureau;TG Therapeutics: Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau;Janssen: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau;Beigene: Research Funding, Speakers Bureau;Pharmacyclics LLC: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau;Gilead: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau;AstraZeneca: Consultancy. Borthakur: GSK: Consultancy;ArgenX: Membership on an entity's Board of Directors or advisory committees;University of Texas MD Anderson Cancer Center: Current Employment;Protagonist: Consultancy;Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees;Astex: Research Funding;Ryvu: Research Funding;Takeda: Membership on an entity's Board of Directors or advisory committees. Takahashi: Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy;Celgene/BMS: Consultancy;GSK: Consultancy. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees;Pfizer: Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy, Research Funding. Kadia: Cellonkos: Other;Aglos: Consultancy;Dalichi Sankyo: Consultancy;AbbVie: Consultancy, Other: Grant/research support;BMS: Other: Grant/research support;Amgen: Other: Grant/research support;Cure: Speakers Bureau;Jazz: Consultancy;Genentech: Consultancy, Other: Grant/research support;Liberum: Consultancy;Novartis: Consultancy;Pfizer: Consultancy, Other;Pulmotech: Other;Sanofi-Aventis: Consultancy;AstraZeneca: Other;Astellas: Other;Genfleet: Other;Ascentage: Other. Konopleva: Sanofi: Other: grant support, Research Funding;Cellectis: Other: grant support;Calithera: Other: grant support, Research Funding;KisoJi: Research Funding;Agios: Other: grant support, Research Funding;Ascentage: Other: grant support, Research Funding;AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding;Ablynx: Other: grant support, Research Funding;Stemline Therapeutics: Research Funding;Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding;AstraZeneca: Other: grant support, Research Funding;Rafael Pharmaceuticals: Other: grant support, Research Funding;Genentech: Consultancy, Honoraria, Other: grant support, Research Funding;F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support;Forty Seven: Other: grant support, Research Funding;Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights;Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights. Alvarado: BerGenBio: Research Funding;Jazz Pharmaceuticals: Research Funding;Astex Pharmaceuticals: Research Funding;Sun Pharma: Consultancy, Research Funding;MEI Pharma: Research Funding;FibroGen: Research Funding;Daiichi-Sankyo: Research Funding;CytomX Therapeutics: Consultancy. Yilmaz: Pfizer: Research Funding;Daiichi-Sankyo: Research Funding. DiNardo: Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees;Novartis: Honoraria;Takeda: Honoraria;Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding;Forma: Honoraria, Research Funding;AbbVie: Consultancy, Research Funding;GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees;Bristol Myers Squibb: Honoraria, Research Funding;ImmuneOnc: Honoraria, Research Funding;Agios/Servier: Consultancy, Honoraria, Research Funding;Foghorn: Honoraria, Research Funding. Bose: Kartos Therapeutics: Honoraria, Research Funding;Sierra Oncology: Honoraria;Novartis: Honoraria;Constellation Pharmaceuticals: Research Funding;NS Pharma: Research Funding;Celgene Corporation: Honoraria, Research Funding;Blueprint Medicines: Honoraria, Research Funding;Pfizer: Research Funding;Promedior: Research Funding;Astellas: Research Funding;Incyte Corporation: Honoraria, Research Funding;BMS: Honoraria, Research Funding;CTI BioPharma: Honoraria, Research Funding. Pemmaraju: Blueprint Medicines: Consultancy;LFB Biotechnologies: Consultancy;Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding;ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees;Dan's House of Hope: Membership on an entity's Board of Directors or advisorycommittees;Roche Diagnostics: Consultancy;MustangBio: Consultancy, Other;Affymetrix: Consultancy, Research Funding;Samus: Other, Research Funding;ImmunoGen, Inc: Consultancy;ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees;Aptitude Health: Consultancy;Plexxicon: Other, Research Funding;Springer Science + Business Media: Other;Protagonist Therapeutics, Inc.: Consultancy;HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees;Clearview Healthcare Partners: Consultancy;Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding;CareDx, Inc.: Consultancy;Sager Strong Foundation: Other;Daiichi Sankyo, Inc.: Other, Research Funding;Incyte: Consultancy;Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding;Bristol-Myers Squibb Co.: Consultancy;DAVA Oncology: Consultancy;Pacylex Pharmaceuticals: Consultancy;Celgene Corporation: Consultancy;Cellectis S.A. ADR: Other, Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Wang: Stemline Therapeutics: Honoraria. Kantarjian: Taiho Pharmaceutical Canada: Honoraria;Precision Biosciences: Honoraria;Immunogen: Research Funding;Daiichi-Sankyo: Research Funding;Jazz: Research Funding;BMS: Research Funding;AbbVie: Honoraria, Research Funding;Pfizer: Honoraria, Research Funding;Novartis: Honoraria, Research Funding;NOVA Research: Honoraria;KAHR Medical Ltd: Honoraria;Ipsen Pharmaceuticals: Honoraria;Astra Zeneca: Honoraria;Astellas Health: Honoraria;Aptitude Health: Honoraria;Amgen: Honoraria, Research Funding;Ascentage: Research Funding. Wierda: Juno Therapeutics: Research Funding;AstraZeneca: Research Funding;Xencor: Research Funding;Janssen: Research Funding;Loxo Oncology, Inc.: Research Funding;Cyclacel: Research Funding;Oncternal Therapeutics, Inc.: Research Funding;Miragen: Research Funding;KITE Pharma: Research Funding;Sunesis: Research Funding;Gilead Sciences: Research Funding;Acerta Pharma Inc.: Rese rch Funding;Pharmacyclics LLC, an AbbVie Company: Research Funding;Karyopharm: Research Funding;Genentech: Research Funding;GSK/Novartis: Research Funding;Genzyme Corporation: Consultancy;AbbVie: Research Funding. OffLabel Disclosure: The combination of ibrutinib and venetoclax is not FDA approved

Overall and cause specific changes in mortality of patients with myelofibrosis over the last 3 decades

Background: Patients with myelofibrosis (MF) have decreased overall survival with a median of 5 years. Leading causes of death are believed to be directly or indirectly related to MF progression or complications, including transformation to acute leukemia (AML) and infections. Aims: We aimed to compare survival, mortality rate and causes of death of MF patients referred to our institution before (≤) and after the years of 2010. Methods: This retrospective study included patients with MF diagnosed within one year prior to their presentation to our institution (between January 1990 and February 2020, 4% presented < year 2000). Patients with unknown cause of death or loss to follow-up were excluded (final cohort, n = 995). Causes of death were divided into groups: i) MF progression;ii) AML (≥ 20% blasts);iii) sudden multi-organ failure or vascular event (possibly related to MF, Vasc/MOF);iii) infections (MF had to be controlled or in remission);iv) other (unrelated medical conditions). We calculated crude mortality rate per 1000 person - years of observation (comparison by Poisson's regression) and overall survival (by Kaplan Meier method with log rank test). To account for variations in age groups (< 49;50-59;60-69;and 70+ years), we assessed age-adjusted mortality rates per 1000 person-years standardized for the entire cohort. Results: The study included 378 and 617 patients ≤ and > 2010, respectively, 59% of which were males. Sixty-five percent of patients were ≥60 years. Distribution of age groups between periods was comparable, except for higher proportion of 70+ year old patients > 2010, counterbalanced by lower proportion of < 60 years. Over the observation time of 1942 and 1608 person-years for ≤ and > 2010, 206 (55%) and 100 (16%) of patients died, respectively (p < 0.001, RR 0.54, CI 0.48-0.63). Crude, age-adjusted and cause-specific mortality per 1000 person-years in both periods is outlined in Table. Overall mortality, both crude and age-adjusted, was significantly higher ≤ 2010 irrespectively of gender and age. As expected, crude mortality steadily increased with age in both periods. For each of the respective age groups, more patients died ≤ 2010 than > 2010. In both periods, males COVID-19 (n= 30 PV, n= 30 ET, n= 30 PMF) (45 men, 45 women, mean age 50 years, range 30-60). All patients gave written informed consent for study enrollment. The mean duration of disease was 12 years. All patients were on ASA 100 mg once daily. Concerning presentation and therapy, our MPNs patients with COVID-19 and without COVID-19 had not comorbidities and drug treatment was consistent with therapeutic standards (hydroxyurea, interferon, anagrelide, ruxolitinib). All patients were on ASA 100 mg once daily. IL-6 was measured by multiplex bead array (Millipore Sigma), TF and DD, and TAT by ELISA and Fib by Clauss method. PF4 was determined by ELISA. Whole blood viscoelastic analysis including clotting time (CT), and clot formation time (CFT) were measured by thomboelastometry method. Results: MPNs with COVID-19 had high IL-6 and TF (50±12pg/ml and 1950±500 pg/ml) compared with MPNs without COVID-19 (3±2pg/ml and 19±2 pg/ml), as well as DD, TAT and Fib (549±100 □g/l, 69±10 □g/l and 590±20mg/dl) compared with MPNs without COVID-19 (59±5□g/l, 2±1□g/l and 149±10 mg/l). PF4 was elevated (150.1□62.7 IU/ml) in MPNs with COVID-19 compared with MPNs without COVID-19 (2□1 UI/ml). A positive correlation was found between inflammatory, endothelial and coagulation mediators. A p-value of <.05 was considered statistically significant. Shortened CT (CT, unit: s. n.v. 100-240 s) (40±20 s) and shortened CFT (CFT, unit: s, n.v. 30-160 s (14±10 s) there were in MPNs with COVID-19 compared with MPNs without COVID-19 (CT 99±10 s and CFT 39±5 s). Summary/Conclusion: These data suggest that COVID-19 infection in MPNs patients may increase the thrombotic risk and get worse prognosis. In our opinion, this study can serve as a baseline study of COVID-19 thrombotic risk in MPNs and it is worthy of dissemina ion amongst patients and clinician communities.

Phase II study of the IDH2- inhibitor enasidenib in patients with high-risk IDH2-mutated myelodysplastic syndromes (MDS)

Background: Isocitrate dehydrogenase 2 (IDH2) mutations occur in 5% of patients (pts) with MDS. Enasidenib (ENA) is a selective oral inhibitor of the mutant IDH2 enzyme with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We report the results of the open label phase II study designed to evaluate the efficacy and tolerability of ENA, as monotherapy or in combination with azacitidine (AZA) in pts with higher-risk IDH2-mutated MDS (NCT03383575). Methods: Pts with higher-risk [Revised International Prognostic Scoring System risk > 3 or high molecular risk (HMR)] MDS/CMML or LB AML naïve to hypomethylating agents (HMA) received ENA100 mg orally daily for 28 d of each 28-d cycle + AZA 75 mg/m2 IV or SC on d 1-7 of each cycle (ENA+AZA), and pts with refractory or progressive MDS to prior HMA therapy received ENA alone (ENA), in 28-d cycles until unacceptable toxicity, relapse, transformation to AML, or progression. The primary endpoint was overall response rate (ORR) [complete remission (CR), marrow CR (mCR), partial remission (PR) and hematologic improvement (HI)]. Other endpoints include safety, and survival outcomes. Results: 48 pts received ENA+AZA (n = 26) or ENA (n = 22). The median age was 73 yrs (range, 46-83). Most pts (72%) had HMR: ASXL1 (39%), and RUNX1 (17%). Median number Tx cycles was 4 (2-32) in the ENA+AZA, and 7 (1-23) in the ENA arm. Common Tx-related grade 3-4 AEs in the ENA+AZA arm were neutropenia (64%), thrombocytopenia (28%), and anemia (8%);these occurred in 10%, 0%, and 5%, in the ENA arm. Grade 3-4 infections occurred in 32% (ENA+AZA) and 14% (ENA). IDH differentiation syndrome occurred in 3 pts (12%) in the ENA+AZA and 5 pts (24%) in the ENA arm. Two deaths occurred during the initial 60 d, both unrelated to study and due to COVID. In response-evaluable pts (n=46), ORR was 84% (n = 21/25;24% CR + 8% PR+44% mCR+ 8% HI] in the treatment naïve ENA+AZA and 43% (n = 9/21;24% CR+5%PR+5% mCR+10% HI) in the HMA failure ENA arm (Table). Most common reason for Tx discontinuation was disease progression (ENA+AZA 20%, ENA 33%).5 pts (20%) received HCT in the ENA+AZA and 1 (5%) in the ENA arm. 7 pts in the ENA+AZA and 5 in the ENA arm were ongoing at data cutoff (Dec 31, 2020). After a median follow up of 12.6 mo, median OS was 32.2 mo in the ENA+AZA and 21.3 mo in the ENA arm. Conclusions: ENA is well tolerated and shows promising efficacy in IDH2-mutated higher risk MDS. Follow up and accrual is ongoing to better define duration and biomarkers of response.