Introduction: About 50-60% of patients (pts) with AML achieve an initial response to intensive chemotherapy but relapses are common. Measurable residual disease (MRD) and the persistence of leukemia stem cells are thought to be drivers of relapse. CPX-351 (a dual-drug liposomal formulation of daunorubicin/cytarabine) and gemtuzumab ozogamicin (GO; a CD33-directed antibody-drug conjugate) are 2 drugs approved for AML treatment. In this study, we hypothesized the combination of CPX-351 and GO would yield higher and deeper responses in newly diagnosed (ND) CD33+ AML pts.

Methods: This is a phase 1/1b clinical trial (NCT05558124) using CPX-351 (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) (Day 1, 3, 5) combined with GO (Cohort A: 3mg/m2 on Day 1; Cohort B: Day 1, 4; Cohort C: Day 1, 4, 7) for ND CD33+ adult AML pts up to age 70. The primary objective is to determine the safety and maximal tolerated dose/RP2D for this combination. Bayesian optimal interval design was used to guide dose escalation/de-escalation. Reinduction of CPX-351 (Day 1, 3) is allowed if indicated by Day 14-24 bone marrow biopsy. Consolidation, up to 4 cycles, consists of cytarabine (3g/m2 for pts < 60 and 1.5g/m2 for ≥ 60) plus GO (Day 1) (up to 2 cycles). Pts with FLT3 mutations were excluded.

Results: At the time of data cut-off (July 2025), dose escalation was completed with 18 pts (13M/5F, median age 62 [range: 22-68]) enrolled (1/2023-2/2025). By ELN 2022, 6 (33.3%), 2 (11.1%), and 10 (55.6%) pts were favorable, intermediate (int), and adverse (adv) risk, respectively. There were 12 (66.7%) de novo and 6 (33.3%) secondary/therapy-related AML. Two pts had prior HMA for antecedent myeloid diseases. Mutations defining AML-MR by WHO 2022 occurred in 9 (50%) pts. Most common mutations include 33.3% TET2 and 27.8% DNMT3A. There were 22.2% of pts with each of the following: ASXL1, RUNX1, NRAS, and STAG2. No pts had TP53. Most pts, 13/18 (72.2%), received ≥ 1 cycle of consolidation (median: 1, range: 1-4), and 1 had reinduction.

Of all 18 response evaluable pts (Cohort A=12, B=6), 16 (88.9%) achieved ORR (CR/CRi/MLFS) and 15 (83.3%) achieved CR/CRi (CR: 12 [66.7%], CRi: 3 [16.7%]). Among those with CR/CRi, undetectable MRD(-) by multiparametric flow cytometry or PCR core-binding factor when applicable was 93.3% (14/15). For pts with ELN 2022 favorable risk disease, CR/CRi rate was 100% (6/6) and 83.3% (5/6) achieved MRD(-) (3/3 NPM1, 1/2 CBF, and 1/1 bizip CEBPA). For those with int/adv risk, 9/12 (75%) achieved CR/CRi with 100% MRD(-) (Cohort A=6, B=3). Among these responders, 7/9 (77.8%) was able to receive allogeneic hematopoietic cell transplantation (alloHCT). For pts with myelodysplasia-related mutations, 7/9 (77.8%) achieved CR/CRi, all with MRD(-). Among these pts, 5/7 (71.4%) received alloHCT. With a median follow up of 12.7 months (mos), the median overall survival (OS) for the entire cohort was 19.3 mos. Pts who underwent alloHCT (n=8) had significantly longer OS than those who did not (n=10) (NR vs. 16.6 mos, p=0.007).

All pts experienced grade ≥ 3 cytopenias. The median time to neutrophil and platelet recovery to meet CRi (ANC ≥ 1k or platelets ≥ 100k) was 33 days (range: 25-50) (Cohort A only: 32 days [range: 25-43]) and to meet best response was 41 days (same with Cohort A). The only Grade 3/4 adverse event (AE) ≥ 20% was febrile neutropenia (77.8%). Most common non-hematologic AEs Grade ≤ 2 include maculopapular rash (55.6%), nausea (38.9%), and anorexia (27.8%). There were 8 SAEs attributed to treatment (Cohort A=7, B=1) including Grade 3: febrile neutropenia (n=3), sepsis (n=3), and thrush (n=1). DLTs were observed in 3 pts (Cohort A=1, B=2) all related to Grade 4 thrombocytopenia/neutropenia beyond Day 42 of induction. The Cohort A pt achieved CRi with MRD(-) on Day 43 and subsequently proceeded to alloHCT (MRD(-) 2 yrs ongoing). Of the 2 Cohort B pts, 1 similarly achieved CRi and proceeded to alloHCT about 1 yr ago in CR with MRD(-), and the other had multiple adverse risk mutations and achieved MLFS after induction but quickly relapsed.

Conclusions: In this dose escalation study, CPX-351 with GO induced high CR/CRi rate with nearly all responding pts achieving MRD(-), including higher-risk ELN subsets. Safety and tolerability were acceptable and Cohort A (Day 1 GO) was declared the recommended expansion dose with cytopenia duration similar to CPX-351 monotherapy. Dose expansion focusing on pts with ELN int/adv risk is underway.

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2025
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