Ponatinib As Initial Therapy For Patients With Chronic Myeloid Leukemia In Chronic Phase (CML-CP)
Authors: Cortes Jorge E. , Borthakur Gautam , Pemmaraju Naveen , Daver Naval , Quintas-Cardama Alfonso , Ravandi Farhad , Gachimova Evguenia , Estrov Zeev , Jabbour Elias , O'Brien Susan , Kantarjian Hagop 
Published: October 2019

Abstract

Background
Ponatinib has excellent clinical activity and an acceptable toxicity profile in patients with CML who have experienced resistance or intolerance to multiple tyrosine kinase inhibitors (TKI). In vitro, ponatinib at concentrations achieved in the clinic (40nM) prevents the emergence of resistant clones. We hypothesized that ponatinib could result in high rates of early responses and prevent resistance when used as frontline therapy for patients with CML-CP.

Methods
Patients with CML-CP were treated with ponatinib 45 mg orally daily as initial therapy for CML in a single-arm, single-institution clinical trial. Other eligibility included age ≥18 years (yrs), PS 0-2, normal organ function, and absence of significant cardiac history or prior pancreatitis. Patients with clonal evolution at time of diagnosis were eligible if no other evidence of accelerated phase. Dose adjustments were indicated for adverse events to 30mg/d, 15 mg/d, or 15 mg every other day. Patients 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) criteria were standard. Initial plan was for 50 patients to be treated with interim analysis and early stopping rules for efficacy and toxicity, with the primary endpoint being the rate of complete cytogenetic response (CCyR) at 6 months.

Results
From May 2012 to July 2013, 41 patients have been treated. The median age is 51 yrs (range, 21-75), and 1 patient had clonal evolution. Sokal risk score was low in 73%, intermediate in 17% and high in 10%. The median follow-up is 7.8 months. Overall, complete hematologic response (CHR) has been achieved in 87% of patients, CCyR in 89%, major molecular response (MMR) in 74% and molecular response 5-log (MR5) in 29%. At 3 months, 89% of 35 evaluable patients have achieved a CCyR, and at 6 month 93% of 27 evaluable patients have this response. The median transcript levels at 3 months is 0.091 and at 6 months 0.007. Rates of MMR at 3 and 6 months are 51% and 78%, respectively, and rates of MR5 are 0% and 22%. No patient has suffered progression, including no transformations to accelerated or blast phase and all patients are alive. Two patients have discontinued therapy: one for skin toxicity (lowest dose used 30mg/d) and one for persistent, recurrent idiosyncratic neutropenia (lowest dose used 15 mg every other day + filgrastim). Most common adverse events (AEs) of any grade are rash (61%), lipase elevation (56%), constipation (51%), dry skin (44%), abdominal pain (41%), and headache (39%), nearly all mostly grade 1-2. The most common grade 3/4 AEs have been lipase elevation in 39%, usually asymptomatic, with pancreatitis grade 3/4 in 15%. Other non-hematologic grade 3/4 AEs seen in more than 1 patient include elevated amylase (7%), abdominal pain (7%), hypertension (7%), rash (5%), and elevated ALT (5%). Grade 3-4 neutropenia or thrombocytopenia occurred in 10% each, transient in all except one. Twenty-nine (71%) patients have required treatment interruptions and 24 (59%) a dose reduction. The median duration of treatment interruptions is 9 days (range, 1-48). The median dose for all patients is 30mg daily. At 3 months 37% had reduced to 30mg or lower and at 6 months 56%.

Conclusion
Ponatinib is effective as initial therapy for CML-CP resulting in high rates of cytogenetic and molecular responses at early timepoints. Therapy with ponatinib is well tolerated with transient elevated lipase being the most common toxicity. In view of the frequency of dose reductions and considering the excellent responses achieved, the trial has been modified to explore 30 mg as initial dose.

Disclosures:
Cortes: Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding. Off Label Use: Ponatinib is not approved for use as initial therapy for CML, only for patients who have developed resistane or intolerance. This presentation involves the use as initial therapy. Jabbour:Novartis: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. O'Brien:Ariad: Research Funding.