Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia: a randomized, open-label phase 2 clinical trial.

Abstract

In PACE (Ponatinib Ph+ ALL and CML Evaluation), a phase 2 trial of ponatinib that included patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to multiple prior tyrosine kinase inhibitors (TKIs), ponatinib showed deep and durable responses, but arterial occlusive events (AOEs) emerged as notable adverse events. Post hoc analyses indicated that AOEs are dose dependent. We assessed the benefit/risk ratio across 3 ponatinib starting doses in the first prospective study to evaluate a novel, response-based, dose-reduction strategy for TKI treatment. Adults with CP-CML resistant to or intolerant of at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1 T315I mutation were randomly assigned 1:1:1 to 3 cohorts receiving ponatinib 45, 30, or 15 mg once daily. In patients who received 45 or 30 mg daily the dose was reduced to 15 mg upon response (BCR-ABL1IS transcript levels ≤1%). The primary end point was response at 12 months. From August 2015 through May 2019, 283 patients were randomly assigned to the cohorts: 282 (94 per dose group) received treatment (data cutoff, 31 May 2020). The primary end point (98.3% confidence interval) was achieved in 44.1% (31.7-57.0) in the 45-mg cohort, 29.0% (18.4-41.6) in the 30-mg cohort, and 23.1% (13.4-35.3) in the 15-mg cohort. Independently confirmed grade 3 or above treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 45-, 30-, and 15-mg cohorts, respectively. All cohorts showed benefit in this highly resistant CP-CML population. Optimal benefit/risk outcomes occurred with the 45-mg starting dose, which was decreased to 15 mg upon achievement of a response. This trial is registered on www.clinicaltrials.gov as NCT02467270.

• Authors: Jorge Cortes, Jane Apperley, Elza Lomaia, Beatriz Moiraghi, Maria Undurraga Sutton, Carolina Pavlovsky, Charles Chuah, Tomasz Sacha, Jeffrey H Lipton, Charles A Schiffer, James McCloskey, Andreas Hochhaus, Philippe Rousselot, Gianantonio Rosti, Hugues de Lavallade, Anna Turkina, Christine Rojas, Christopher Kevin Arthur, Lori Maness, Moshe Talpaz, Michael Mauro, Tracey Hall, Vickie Lu, Shouryadeep Srivastava, Michael Deininger
• Journal: Blood (Blood) Vol. 138 Issue 21 Pg. 2042-2050 (11 25 2021) ISSN: 1528-0020 [Electronic] United States
• PMID: 34407543 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial)
• Copyright: © 2021 by The American Society of Hematology.

Chemical References

• Antineoplastic Agents
• BCR-ABL1 fusion protein, human
• Imidazoles
• Protein Kinase Inhibitors
• Pyridazines
• ponatinib
• Fusion Proteins, bcr-abl

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, adverse effects, therapeutic use)
• Dose-Response Relationship, Drug
• Female
• Fusion Proteins, bcr-abl (genetics)
• Humans
• Imidazoles (administration & dosage, adverse effects, therapeutic use)
• Leukemia, Myeloid, Chronic-Phase (drug therapy, genetics)
• Male
• Middle Aged
• Protein Kinase Inhibitors (administration & dosage, adverse effects, therapeutic use)
• Pyridazines (administration & dosage, adverse effects, therapeutic use)
• Treatment Outcome
• Young Adult