Decitabine, Venetoclax, and Ponatinib for Advanced Phase Chronic Myeloid Leukaemia and Philadelphia Chromosome-Positive Acute Myeloid Leukaemia: A Single-Arm, Single-Centre Phase 2 Trial

Authors

Nicholas J Short
Daniel Nguyen
Elias Jabbour
Jayastu Senapati
Zhihong Zeng
Ghayas C Issa
Hussein Abbas
Cedric Nasnas
Wei Qiao
Xuelin Huang
Gautam Borthakur
Kelly Chien
Fadi G Haddad
Naveen Pemmaraju
Omer S Karrar
Danielle Nguyen
Marina Konopleva
Hagop Kantarjian
Farhad Ravandi

Language

English

Publication Date

11-1-2024

Journal

The Lancet Haematology

DOI

10.1016/S2352-3026(24)00250-3

PMID

39303729

PMCID

PMC11527552

PubMedCentral® Posted Date

11-1-2024

PubMedCentral® Full Text Version

Post-print

Abstract

BACKGROUND: Advanced phase Philadelphia chromosome-positive myeloid disease-consisting of chronic myeloid leukaemia in the myeloid blast phase and in the accelerated phase, and Philadelphia chromosome-positive acute myeloid leukaemia-is associated with poor outcomes. Although previous studies have suggested the benefit of chemotherapy and BCR::ABL1 tyrosine kinase inhibitor combinations, the optimal regimen is uncertain and prospective studies for this rare group of diseases are scant. Preclinical and retrospective clinical data suggest possible synergy between the BCL-2 inhibitor venetoclax and BCR::ABL1 tyrosine kinase inhibitors. We therefore aimed to design a study to evaluate the safety and activity of a novel combination of decitabine, venetoclax, and the third-generation BCR::ABL1 tyrosine kinase inhibitor ponatinib in advanced phase Philadelphia chromosome-positive myeloid diseases.

METHODS: For this phase 2 study, patients aged 18 years or older with previously untreated or relapsed or refractory myeloid chronic myeloid leukaemia-blast phase, chronic myeloid leukaemia-accelerated phase, or advanced phase Philadelphia chromosome-positive acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0-3 were eligible. Patients were eligible regardless of the number of previous lines of therapy received or previous receipt of ponatinib. Cycle 1 (induction) consisted of a 7-day lead-in of ponatinib 45 mg orally daily (days 1-7), followed by combination therapy with decitabine 20 mg/m

RESULTS: Between July 12, 2020, and July 8, 2023, 20 patients were treated (14 with chronic myeloid leukaemia-blast phase, four with chronic myeloid leukaemia-accelerated phase, and two with advanced phase Philadelphia chromosome-positive acute myeloid leukaemia). The median age was 43 years (IQR 32-58); 13 (65%) patients were male and seven (35%) were female; and 12 (60%) were White, three (15%) were Hispanic, four (20%) were Black, and one (5%) was Asian. 12 (60%) patients had received 2 or more previous BCR::ABL1 tyrosine kinase inhibitors, and 14 (70%) patients had at least one high-risk additional chromosomal abnormality or complex karyotype. The median duration of follow-up was 21·2 months (IQR 14·1-24·2). The complete remission or complete remission with an incomplete haematological recovery rate was 50% (10 of 20 patients); complete remission in one [5%] patient and complete remission with incomplete haematological recovery in nine [45%]). An additional six (30%) patients had a morphologic leukaemia-free state. The most common grade 3-4 non-haematological adverse events were febrile neutropenia in eight (40%) patients, infection in six (30%), and alanine or aspartate transaminase elevation in five (25%). Eight (40%) patients had at least one cardiovascular event of any grade. There were three on-study deaths, none of which was considered related to the study treatment and all from infections in the setting of refractory leukaemia.

INTERPRETATION: The combination of decitabine, venetoclax, and ponatinib is safe and shows promising activity in patients with advanced phase chronic myeloid leukaemia, including those with multiple previous therapies or high-risk disease features. Further studies evaluating chemotherapy and venetoclax-based combination strategies using newer-generation BCR::ABL1 tyrosine kinase inhibitors are warranted.

FUNDING: Takeda Oncology, the National Institutes of Health, and the National Cancer Institute Cancer Center.

Keywords

Humans, Bridged Bicyclo Compounds, Heterocyclic, Middle Aged, Female, Male, Imidazoles, Pyridazines, Sulfonamides, Aged, Antineoplastic Combined Chemotherapy Protocols, Decitabine, Leukemia, Myeloid, Acute, Adult, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Philadelphia Chromosome, Aged, 80 and over

Published Open-Access

yes

Recommended Citation

Short, Nicholas J; Nguyen, Daniel; Jabbour, Elias; et al., "Decitabine, Venetoclax, and Ponatinib for Advanced Phase Chronic Myeloid Leukaemia and Philadelphia Chromosome-Positive Acute Myeloid Leukaemia: A Single-Arm, Single-Centre Phase 2 Trial" (2024). Faculty, Staff and Student Publications. 5873.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5873