Ponatinib As Frontline Therapy for Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Background: Ponatinib is a third generation tyrosine kinase inhibitor (TKI) that has demonstrated efficacy in patients (pts) with CML who have failed multiple therapies and those with a T315I mutation or other BCR-ABL mutations. In this study, we have assessed the efficacy and safety of ponatinib as a frontline therapy in pts with CML-CP.

Methods: Fifty one pts with CML-CP were treated with ponatinib as initial therapy for CML in a single-arm, single-institution clinical trial. The starting dose of ponatinib was 45 mg orally daily in 43 pts and, after an amendment, 30 mg in 8 pts. Other eligibility criteria included age ≥18 yrs, ECOG PS 0-2, normal organ function, and absence of significant cardiac history or prior pancreatitis. Pts with clonal evolution at time of diagnosis were eligible without other evidence of accelerated phase. Dose reductions to 30mg/d, 15 mg/d, or 15 mg every other day were indicated for adverse events. Pts were followed with cytogenetic analysis and PCR every 3 months for the first 12 months, then every 6 months. Cytogenetic and molecular (by International Scale) response criteria were standard.

Results: From May 2012 to June 2014, 51 pts were treated. The median age was 48 yrs (range, 21-75), 1 patient had clonal evolution, and 3 started therapy while in CHR. Sokal risk score was low in 69%, intermediate in 22% and high in 10%. The median follow-up was 15.6 months (range 5.6-23.7 months). Complete hematologic response (CHR) was achieved in 95% of pts, complete cytogenetic response (CCyR) in 95%, major molecular response (MMR) in 80%, molecular response 4.5-log (MR4.5) in 55% and undetectable BCR-ABL in 38%. At 3 months, 90% of 50 evaluable pts achieved CCyR, and at 6 months 93% of 45 evaluable pts had CCyR. The median transcript levels at 3 months was 0.096 and at 6 months 0.005. Rates of MMR at 3 and 6 months were 50% and 80%, and rates of undetectable BCR-ABL1 were 0% and 22%, respectively. None of the pts progressed, including no transformations to accelerated or blast phase and all pts were alive.

Forty three (85%) pts required treatment interruptions. The median duration of treatment interruptions was 9 days (range, 1-48). The median dose for all pts was 30 mg/d. As of June 2014, all pts were taken off study – 38 per FDA recommendation for concerns of risk of thrombotic events and 13 due to adverse events. Of these 13 pts – 3 had vasoocclusive disease grade 3 (peripheral arterial disease, femoral artery thrombosis, gastrointestinal ischemia), 2 with acute coronary syndrome (grade 3), 2 had cerebrovascular events grade 3 (1 transient ischemic attack and 1 Moya Moya disease), 2 multiple toxicities, 1 grade 3 hypertension, 1 with resistance and grade 2 arthralgia, 1 grade 3 skin xerosis, 1 grade 4 myelosuppression.

Cardiovascular events were observed in 24 (47%) pts, of which 11 had >1 cardiovascular event. Hypertension in 14 pts (7 were grade 3), chest pain in 8 (one pericarditis grade 2), acute coronary syndrome in 2 (grade 3), vasoocclusive disease in 3 (one suspected gastrointestinal ischemia; all grade 3), stroke in 3 (one TIA and one carotid arterial disease both grade 3), Raynaud’s phenomenon in 2 (grade 1-2), one each had toe cramps with tingling, palpitations, prolonged QTc. Non-cardiovascular adverse events included - skin rash in 35 (2 pts with grade 3/4), dry skin in 22 (all grade 1/2), lipase elevation in 32 (23 with grade 3/4), symptomatic grade 3 pancreatitis in 10 pts, constipation in 26 pts (all grade 1/2), and memory loss in 6 pts (all grade 1/2). Grade 3-4 myelosuppression occurred in 14 pts.

Conclusion: Ponatinib therapy leads to fast and deep cytogenetic and molecular responses in pts with CML-CP. Cardiovascular toxicities, skin toxicity and lipase elevation were observed in several patients. Dose adjustment, regular monitoring and counselling of the pts for thromboembolic events can be used to manage pts on ponatinib. However, considering the risk of vascular thrombotic events and the availability of alternative options for these patients, the study has been terminated at the recommendation of the FDA.