Combination of CPX-351 and Gemtuzumab Ozogamicin (GO) in Relapsed Refractory (R/R) Acute Myeloid Leukemia and Post Hypomethylating Agent (HMA) Failure High-Risk Myelodysplastic Syndrome (HR-MDS)
Authors: Senapati Jayastu , Ravandi Farhad , Almanza Emmanuel , Kadia Tapan M. , Montalban-Bravo Guillermo , Faderl Stefan , Sasaki Koji , Short Nicholas J. , Daver Naval , DiNardo Courtney D. , Masarova Lucia , Ferrajoli Alessandra , Haddad Fadi G. , Jabbour Elias , Borthakur Gautam , Tan Sheila , Pierce Sherry , Garcia-Manero Guillermo , Andreeff Michael , Alvarado Valero Yesid 
Published: December 2024

Background:
Outcomes of patients (pts) with HR-MDS or AML who are refractory to or progress after HMA ± Venetoclax (Ven) based therapy is dismal, warranting evaluation of newer agents. CPX-351 (Vyxeos) is a liposomal formulation of cytarabine and daunorubicin, at a fixed synergistic 5:1 molar ratio, and is approved by the US Food and Drug Administration (FDA) for the treatment of pediatric and adult pts with newly diagnosed therapy-related AML or AML with myelodysplasia related changes. GO is a humanized IgG4 antibody-drug conjugate against CD33 and is approved by FDA for the treatment of newly diagnosed or R/R pediatric and adult pts with CD33-expressing AML. We hypothesized that the combination of CPX351 and GO (CPX-GO) could be synergistic in a high-risk population of R/R myeloid neoplasms.
Methods:
We present the updated results of the single-arm pilot study (NCT03672539) of CPX351- GO combination therapy in pts with CD33 positive R/R AML or post-HMA failure HR-MDS. Pts received induction cycle (C) CPX-351 (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) administered via intravenous (IV) infusion on days (D) 1, 3, and 5. GO was administered at a dose of 3 mg/m2 (capped at 4.5 mg) IV on D1. Pts not attaining complete remission (CR) or CR with incomplete count recovery (CRi) after C1, could receive a 2nd induction cycle of CPX at the same dose, but only on D1 and D3 with GO 3 mg/m2 on D1. Pts attaining CR or CRi could receive up to 2 consolidation cycles, after a minimum of 4 weeks from the start of the previous cycle with CPX (daunorubicin 29 mg/m2 and cytarabine 65 mg/m2) IV on D1 and D3 and GO at 3 mg/m2 on D1. GO was only administered during the second consolidation cycle if there was evidence of measurable residual disease (MRD) as measured by flow cytometry. GO could also be administered as a single agent for maintenance treatment on D1 every 6 weeks, in case of persistent MRD. Response was denoted as per the ELN 2017 criteria for AML (CRc= CR+CRi; overall response [OR]=CRc + MLFS) and IWG 2018 criteria for MDS. Relapse free survival (RFS) was calculated from best overall response (OR) to relapse or death and progression free survival (PFS) from therapy initiation to relapse, change of therapy due to inadequate response/toxicity or death, whichever was earlier. Overall survival was calculated from therapy initiation to death and censored at last follow up (FU).
Results:
From Nov 2018-Apr 2024 47 pts have been treated. The median (med) age of the pts was 67 years (range, 21-77 years) and 32 pts (68%) were male. Only one pt had HR-MDS post HMA failure and another pt previously reported as MDS was reclassified to AML. Amongst the 46 pts with AML, 18 pts (39%) had denovo AML at initial leukemia diagnosis, 16 pts (35%) had treated secondary AML and 3 pts (6%) each had untreated secondary AML and post-myeloproliferative neoplasm AML. The med prior lines of therapy were 2 (range, 1-7), 38 pts (81%) had received prior Ven, and 6 pts (13%) had undergone prior HSCT. Prior to trial therapy initiation, amongst 44 evaluable pts, 13 (29%) had diploid karyotype, 9 (20%) pts had complex cytogenetics, 3 (7%) pts had MECOM rearrangement (r) and 2 pts had KMT2Ar. One pt had multiply relapsed core-binding factor AML with additional cytogenetic changes. 8 pts (18%) had a TP53 mutation (6 with complex karyotype). Pts received a med of 1 cycle of CPX-GO (range, 1-4) and 3 pts also received GO maintenance therapy. CRc was attained in 8 pts (17%) and OR in 12 pts (25%), 7 (58%) of whom had prior Ven exposure. Another pt had a partial response. The only pt with HR-MDS did not respond. All responders had wild type TP53, and amongst responders, one pt each had a complex karyotype and MECOM rearrangement. Overall, 2 pts were able to proceed to an HSCT, both in CRc. At a med true follow-up of 6.0 months, the med RFS was 5.4 mos, med PFS 1.7 mos and med OS 5.9 mos. The med OS in responders were 11.2 mos and 17.9 months in those who attained a CRc. At data cutoff 3 pts are alive, and none on trial therapy. For pts who received consolidation therapy, the median time to C2 was 45 days (36-56 days). 14 pts had grade 5 events, all unrelated to therapy. Febrile neutropenia was the most common grade ≥3 event, in 22 pts (47%), followed by sepsis/bacteremia in 20 pts (43%) and pneumonia in 8 pts (17%).
Conclusion
The combination of CPX-GO in pts with R/R AML and HR-MDS led to modest responses. OS was meaningful in responders, considering multiple prior lines of therapy. Infection related events were the most common serious adverse events.