CML paper summary - August 2025

Favourable rates of cardiovascular events with stringent cardiovascular monitoring and a lowered dose of ponatinib as second-line treatment in chronic phase chronic myeloid leukemia patients failing or intolerant to first-line second-generation tyrosine kinase inhibitor treatment: Results of the prospective PONS Trial

Le Coutre P. et al. Acta Haematol, May 2025

Link to full paper: https://karger.com/aha/article-abstract/doi/10.1159/000545826/926666/Favorable-Rates-of-Cardiovascular-Events-with?redirectedFrom=fulltext

Summary

This prospective phase 2 study evaluated ponatinib at a lowered starting dose (30 mg daily) as a second-line treatment in chronic phase chronic myeloid leukemia (CP-CML) patients who were resistant or intolerant to a first-line second-generation TKI. With stringent cardiovascular (CV) monitoring and patient selection based on low CV risk, ponatinib was found to be both effective and safe. At 12 months, 55.6% of patients achieved major molecular response (MMR), and no grade ≥3 cardiovascular events occurred. These results suggest that careful monitoring enables the use of ponatinib earlier in therapy with manageable toxicity and promising efficacy.

Introduction

While first-line treatment with imatinib, nilotinib, dasatinib, or bosutinib in patients with CML provides high survival rates, a subset of patients experiences treatment failure and/or intolerance. Ponatinib, a third-generation TKI, has broad activity including against the resistant T315I mutation, but earlier trials reported substantial rates of cardiovascular adverse events (CAEs), limiting its use to later lines. The PONS trial (NCT03807479) was designed to evaluate ponatinib as a second-line option at a reduced dose of 30 mg daily with stringent CV monitoring, aiming to improve safety while maintaining efficacy.

Study methods

• Design: Non-randomised, single-arm, prospective phase 2 trial.
• Eligibility: Adults with CP-CML resistant or intolerant to first-line TKI, ECOG 0–2, adequate organ function, and low baseline CV risk. Patients with significant CV history or pancreatitis were excluded.
• Intervention: Ponatinib 30 mg daily (with dose reduction to 15 mg upon achieving MMR, or escalation to 45 mg if needed).
• Monitoring: Rigorous CV surveillance including blood pressure, ankle-brachial index, duplex ultrasonography, ECG, echocardiography, oral glucose tolerance, and fundoscopy every 3 months.
• Endpoints:
  • Primary endpoint: Proportion achieving MMR at 12 months.
  • Secondary endpoints: Complete hematologic remission (CHR), cytogenetic and molecular responses (MR4), safety (especially CV toxicity).
• Recruitment: 22 patients screened, 18 enrolled across 6 German sites 
  (11 with TKI failure, 7 with intolerance).

Key findings

• Efficacy:
  • At 12 months: 72.2% CHR, 55.6% MMR (primary endpoint), 27.8% MR4.
  • Responses occurred in both resistant and intolerant groups.
• Safety:
  • No grade ≥3 CAEs observed.
  • Only mild CV findings (grade 1 carotid artery stenosis, grade 1 hypertension, and one grade 2 coronary artery disease).
  • Hematologic grade 3 toxicity was rare (e.g., thrombocytopenia in 1 patient).
  • Non-hematologic grade 3 events included isolated cases of pancreatitis, diarrhea, hepatotoxicity, glucose elevation, erectile dysfunction, and rash.
• Treatment exposure: 
  • Median treatment duration 17.7 months. 
  • Dose modifications occurred in ~28% of patients.
• Comparisons: Outcomes appeared more favourable than in the OPTIC trial’s 30 mg cohort, likely due to earlier-line use, strict patient selection, and intensive monitoring.

Conclusions

The PONS trial demonstrates that ponatinib at 30 mg daily can be safely used as a second-line therapy in CP-CML patients with low CV risk when combined with intensive CV risk-monitoring. This approach yielded favourable efficacy with no serious CV events. While recruitment was limited, the findings support the feasibility of earlier ponatinib use in selected patients. Implementation outside of clinical trials may be challenging given the intensive monitoring requirements, but the study provides a framework for safer ponatinib integration in clinical practice.

This summary is provided solely for informational purposes. Ponatinib is not generally approved for second-line use in chronic phase CML, except in patients with the T315I mutation. The results of the PONS trial are presented to highlight how careful patient selection and cardiovascular risk monitoring may influence outcomes. The iCMLf does not endorse or recommend any specific drug or treatment approach. Clinical decisions should always follow local regulatory approvals, clinical guidelines, and individual patient considerations.