Liposomal Cytarabine and Daunorubicin (CPX-351) in Combination with Gemtuzumab Ozogamicin (GO) in Relapsed Refractory (R/R) Patients with Acute Myeloid Leukemia (AML) and Post-Hypomethylating Agent (Post-HMA) Failure High-Risk Myelodysplastic Syndrome (HR-MDS)
Authors: Ramos Perez Jorge M. , Kadia Tapan M. , Montalban-Bravo Guillermo , Faderl Stefan , Sasaki Koji , Daver Naval , DiNardo Courtney D. , Masarova Lucia , Ferrajoli Alessandra , Jabbour Elias , Borthakur Gautham , Al Azzawi Hind , Pemmaraju Naveen , Konopleva Marina , Pierce Sherry A. , Garcia-Manero Guillermo , Andreeff Michael , Kantarjian Hagop M. , Ravandi Farhad , Alvarado Yesid 
Published: November 2020

INTRODUCTION: The outcome of patients (pts) with relapsed or refractory AML (R/R AML) or MDS after failing hypomethylating agents (HMA) and/or BCL-2 inhibitor combinations is poor. CPX-351 is a liposomal formulation of cytarabine and daunorubicin, approved by the US Food and Drug Administration (FDA) for newly diagnosed therapy related AML or AML with myelodysplastic related changes. GO is a humanized immunoglobulin G4 antibody directed against CD33 and conjugated to the DNA toxin calicheamicin, also approved by the FDA for the treatment of newly diagnosed or R/R CD33-positive AML. We have hypothesized that the combination of CPX-351 and GO could induce superior antitumor efficacy compared to either agent alone for this patient population.
GOALS: To determine the safety and efficacy of CPX-351 in combination with GO in relapsed refractory pts with AML and post-HMA failure HR-MDS.
METHODS: This is a single arm and single institution, pilot study (NCT03672539) enrolling patients with CD33 positive R/R AML, post-HMA failure High-Risk MDS (&gt;10% blasts), and pts with newly diagnosed secondary AML after receiving HMA therapy. Patients received induction cycle CPX-351 (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) administered via intravenous (IV) infusion on days 1, 3, and 5. GO was administered at a dose of 3 mg/m2 (capped at one 4.5 mg vial) IV on day 1. Pts not attaining complete remission (CR) or CR with incomplete count recovery (CRi) after 1 cycle, could receive a 2nd induction cycle of CPX-351 at the same dose, but only on days 1 and 3 with GO 3 mg/m2 on day 1. Patients attaining CR/CRi could receive up to 2 consolidation cycles, after a minimum of 4 weeks from the start of the last cycle with CPX-351 (daunorubicin 29 mg/m2 and cytarabine 65 mg/m2) IV on days 1 and 3, and GO at 3 mg/m2 on day 1. GO was only administered during the second consolidation cycle if there was evidence of minimal residual disease (+MRD). GO could also be administered as a single agent for maintenance treatment on day 1 every 6 weeks, in case of persistent detection of MRD.
RESULTS: Twenty pts have been enrolled between November 2018 and July 2019. At the time of data cut off 19 pts were evaluable for response, with one patient too early to assess for response. Patient characteristics are summarized on Table 1; of note 14 (70%) pts had previously been treated with venetoclax in different combinations with HMA's and/or chemotherapy. We observed an overall response rate (ORR) of 42% (n=8), including CR (n=5), CRi (n=1) and PR (n=2). Responses are summarized in Table 2. Among the eight responders there were 4 pts with MRD negative (by flow cytometry) remission. One patient who was considered in CR was taken off study on day 40 because of an underlying invasive fungal sinus infection and concerns of myelosuppression. This patient was transitioned to a lower intensity regimen and remains in remission. Four pts completed 2 inductions, 5 pts received consolidation and 2 pts received GO maintenance before progressing. Unfortunately, none could be transitioned to transplantation due to age or comorbidities. Among responders, median time to ANC &gt;500 was 39 days (30-56) and PLT &gt;50k was 40 days (33-46), median time to ANC &gt;1K was 40 days (31-74) and PLT &gt;100K was 43 days (34-53) after induction (Table 3). With a median follow up of 18.6 months, median OS is 9.1 months (Figure 1) and median duration of response was 10.5 months (figure 2). Adverse events regardless of causality (Table 4) were mainly due to infectious complications. We have not observed treatment related grade 3-4 non-hematological toxicity. Thirty-day mortality was 10% (n=2); both pts died from complications of septicemia. Three additional pts (15%) died within 60 days of treatment, including 2 pts with progressive disease and 1 patient on day 58 after withdrawing care due to infections and 2 aplastic bone marrow examinations on days 14 and 46 of treatment, respectively.
CONCLUSION: In this preliminary report, the combination of CPX-351 and GO appears to be active with acceptable toxicities in this high-risk disease population. There are concerns for significant myelosuppression and infectious complications.

Disclosures
Kadia: Cyclacel: Research Funding; Ascentage: Research Funding; Astellas: Research Funding; Novartis: Honoraria; Genentech: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Incyte: Research Funding; Celgene: Research Funding; Pulmotec: Research Funding; Cellenkos: Research Funding; Astra Zeneca: Research Funding; Amgen: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Faderl:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Sasaki:Pfizer Japan: Consultancy; Otsuka: Honoraria; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Daver:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: 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; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. DiNardo:Syros: Honoraria; Agios: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria; Takeda: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Novartis: Consultancy; ImmuneOnc: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Jabbour:Adaptive Biotechnologies: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding. Pemmaraju:Stemline Therapeutics: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; Pacylex Pharmaceuticals: Consultancy; Plexxikon: Research Funding; MustangBio: Honoraria; Roche Diagnostics: Honoraria; Samus Therapeutics: Research Funding; DAVA Oncology: Honoraria; Cellectis: Research Funding; Affymetrix: Other: Grant Support, Research Funding; Daiichi Sankyo: Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Incyte Corporation: Honoraria; SagerStrong Foundation: Other: Grant Support; Celgene: Honoraria; Blueprint Medicines: Honoraria. Konopleva:AbbVie: Consultancy, Research Funding; Kisoji: Consultancy; Calithera: Research Funding; Amgen: Consultancy; Sanofi: Research Funding; Ascentage: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Genentech: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; Forty-Seven: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Ablynx: Research Funding; Agios: Research Funding; AstraZeneca: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding. Garcia-Manero:Acceleron Pharmaceuticals: Consultancy, Honoraria; AbbVie: Honoraria, Research Funding; Novartis: Research Funding; Onconova: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; H3 Biomedicine: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amphivena Therapeutics: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Andreeff:Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Amgen: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding. Kantarjian:Jazz Pharma: Research Funding; Novartis: Research Funding; Agios: Honoraria, Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; BMS: Research Funding; Pfizer: Honoraria, Research Funding; Astex: Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ravandi:Amgen: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding. Alvarado:MEI Pharma: Research Funding; Sun Pharma: Research Funding; FibroGen: Research Funding; BerGenBio ASA: Research Funding; Tolero Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; Jazz Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding.