Liposomal Cytarabine and Daunorubicin (CPX-351) in Combination with Gemtuzumab Ozogamicin (GO) in Relapsed Refractory (R/R) Acute Myeloid Leukemia (AML) and Post-Hypomethylating Agent (Post-HMA) Failure High-Risk Myelodysplastic Syndrome (HR-MDS)
Authors: Rivera Daniel , Kadia Tapan M. , Montalban-Bravo Guillermo , Faderl Stefan , Sasaki Koji , Short Nicholas J. , Daver Naval , DiNardo Courtney D. , Masarova Lucia , Ferrajoli Alessandra , Jabbour Elias J. , Borthakur Gautham , Al Azzawi Hind , Konopleva Marina , Garcia-Manero Guillermo , Andreeff Michael , Kantarjian Hagop , Ravandi Farhad , Alvarado Yesid 
Published: November 2021

Abstract

INTRODUCTION: The outcome of patients (pts) with R/R AML or MDS after failing HMA and/or BCL-2 inhibitor combinations is poor. CPX-351 (Vyxeos™) is a dual liposomal formulation of cytarabine and daunorubicin, at a fixed synergistic 5:1 molar ratio, approved by the US Food and Drug Administration (FDA) for the treatment of newly diagnosed therapy-related AML or AML with myelodysplastic related changes (AML MRC). GO (Mylotarg™) 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 induces 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 patients with R/R AML and post-HMA failure HR-MDS.
METHODS: Here we present updated results of this single-arm, pilot study (NCT03672539) enrolling pts with CD33 positive R/R AML, post-HMA failure HR-MDS (&gt;10% blasts). Pts received induction cycle CPX-351 (daunorubicin 44 mg/m 2 and cytarabine 100 mg/m 2) administered via intravenous (IV) infusion on days 1, 3, and 5. GO was administered at a dose of 3 mg/m 2 (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 2 nd induction cycle of CPX-351 at the same dose, but only on days 1 and 3 with GO 3 mg/m 2 on day 1. Pts 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/m 2 and cytarabine 65 mg/m 2) IV on days 1 and 3 and GO at 3 mg/m 2 on day 1. GO was only administered during the second consolidation cycle if there was evidence of minimal residual disease (+MRD) as measured by flow cytometry. 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-four pts have been enrolled between November 2018 and April 2021. Patient characteristics are summarized in Table 1. Twenty-three pts were diagnosed with R/R AML, and 1 with HR-MDS. Eighteen (75%) pts had previously been treated with venetoclax in combinations with HMA's and/or chemotherapy . We observed an overall response rate (ORR) of 55% (n=13), including CR (n=4), CRi (n=4) and PR (n=5). Responses are summarized in Table 2. Among the eight-pts with CR/CRi, 4 were in an MRD negative remission. None of the pts transitioned to stem cell transplantation (SCT) due to age and comorbidities. One patient in CR after induction cycle was taken off the study on day 40 due to infection and concerns of myelosuppression during consolidation. This patient was transitioned to decitabine monotherapy and remains in remission. Three pts received 2 inductions courses, 5 pts received consolidation and 1 pts received GO maintenance. Among responders, the median time to ANC &gt;0.5 x10 9/L was 46 days (30-101) and PLT &gt;50 x10 9/L was 42 days (33-76), the median time to ANC &gt;1 x10 9/L was 50 days (31-113) and PLT &gt;100 x10 9/L was 42 days (34-104) after induction (Table 3). With a median follow-up of 24 months, the median OS was 5 months [95% CI 1.9-8] (Figure 2), and the median duration of response was 7 months [95% CI 0-9]. Adverse events regardless of causality (Table 4) were mainly due to infectious complications. There were no treatment-related grade 3-4 non-hematological toxicity. Thirty-day mortality was 8% (n=2); both pts died from complications of septicemia. Five additional pts (21%) died within 60 days of treatment, including 2 with progressive disease, 2 with persistent cytopenias and who withdrew care due to worsening performance status, and 1 whose family also withdrew care after the patient was found to have a large hemorrhagic left temporal lobe brain mass.
CONCLUSION: The combination of CPX-351 and GO is feasible and continues to show activity with acceptable toxicities in this high-risk disease population. The presence of significant myelosuppression and infectious complications remain a challenge in patients treated with this regimen.
Figure 1 Figure 1.

Disclosures
Kadia: Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; Liberum: Consultancy; Amgen: Other: Grant/research support; Pulmotech: Other; Cure: Speakers Bureau; AbbVie: Consultancy, Other: Grant/research support; Dalichi Sankyo: Consultancy; BMS: Other: Grant/research support; Novartis: Consultancy; Pfizer: Consultancy, Other; Aglos: Consultancy; Sanofi-Aventis: Consultancy; Cellonkos: Other; Ascentage: Other; Genfleet: Other; Astellas: Other; AstraZeneca: Other. Faderl: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Sasaki: Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Short: Amgen: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy; AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Research Funding; Astellas: Research Funding; Novartis: Honoraria; NGMBio: Consultancy. Daver: Bristol Myers Squibb: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Glycomimetics: Research Funding; Novimmune: Research Funding; Amgen: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Trovagene: Consultancy, Research Funding; Hanmi: Research Funding; Abbvie: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. DiNardo: AbbVie: Consultancy, Research Funding; Forma: Honoraria, Research Funding; Takeda: Honoraria; ImmuneOnc: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Agios/Servier: Consultancy, Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Ferrajoli: Janssen: Other: Advisory Board ; BeiGene: Other: Advisory Board, Research Funding; AstraZeneca: Other: Advisory Board, Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Konopleva: Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Sanofi: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; Ablynx: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; KisoJi: Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Cellectis: Other: grant support; AstraZeneca: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding. Andreeff: Daiichi-Sankyo: Consultancy, Research Funding; ONO Pharmaceuticals: Research Funding; Medicxi: Consultancy; Karyopharm: Research Funding; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; Aptose: Consultancy; Oxford Biomedica UK: Research Funding; Glycomimetics: Consultancy; Breast Cancer Research Foundation: Research Funding; Senti-Bio: Consultancy; Amgen: Research Funding; AstraZeneca: Research Funding; Syndax: Consultancy; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company. Kantarjian: Astra Zeneca: Honoraria; Aptitude Health: Honoraria; Pfizer: Honoraria, Research Funding; Ascentage: Research Funding; Immunogen: Research Funding; Precision Biosciences: Honoraria; Ipsen Pharmaceuticals: Honoraria; KAHR Medical Ltd: Honoraria; Amgen: Honoraria, Research Funding; Astellas Health: Honoraria; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Daiichi-Sankyo: Research Funding; BMS: Research Funding; AbbVie: Honoraria, Research Funding; Taiho Pharmaceutical Canada: Honoraria; NOVA Research: Honoraria. Ravandi: Prelude: Research Funding; Jazz: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding. Alvarado: Daiichi-Sankyo: Research Funding; MEI Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; CytomX Therapeutics: Consultancy; FibroGen: Research Funding; BerGenBio: Research Funding; Sun Pharma: Consultancy, Research Funding.

OffLabel Disclosure:
To determine the safety and efficacy of CPX-351 in combination with GO in patients with R/R AML and post-HMA failure HR-MDS.