Relationship of Line of Therapy to Efficacy for Ponatinib in 3rd-Line Versus 4th-Line Chronic-Phase Chronic Myeloid Leukemia (CML)
Authors: Levy Moshe Yair , McGarry Lisa J. , Lustgarten Stephanie , Yang Mo , Haluska Frank G. 
Published: October 2019

Background: Chronic-phase chronic myeloid leukemia (CP-CML) patients treated with tyrosine kinase inhibitors (TKIs) can expect to achieve high response rates with 1st-line therapy. In 2nd line, however, as many as one-third of patients will not achieve optimal response, and over time, up to one-half of responders will lose response. For patients who require a 3rd line (3L) of therapy, ponatinib and bosutinib provide new treatment options. Relative efficacy and safety are considerations in selecting 3L treatment, and some physicians may reserve ponatinib for patients who fail 3L bosutinib. However, reserving ponatinib for 4th line (4L) after bosutinib may be associated with a decrease in efficacy. We used data from the PACE Phase 2 registrational trial of ponatinib to estimate the efficacy difference associated with reserving ponatinib for 4L after bosutinib failure versus using ponatinib as 3L therapy.

Methods: Using data for CP-CML patients enrolled in PACE, we examined efficacy outcomes among patients treated with ponatinib 3L vs. those treated with ponatinib in 4L or later (4L+) and 4L+ after prior bosutinib failure (reported at PACE study enrollment.) We evaluated major (MCyR) and complete (CCyR) cytogenetic response, major molecular response (MMR), durability of MCyR, and progression-free survival (PFS) at median 42.3 (range 0.1-52.5) months of follow-up.

Results: Treatment response was higher for CP-CML patients treated with ponatinib in 3L (N=98) than those treated 4L+ (N=153, including N=12 >4L) or 4L+ post-bosutinib (N=22) across all measures examined. MCyR was achieved by 67% of 3L vs. 46% of 4L+ and 45% of 4L+ post-bosutinib patients, CCyR by 56% of 3L vs. 37% 4L+ and 27% 4L+ post-bosutinib, and MMR by 42% vs. 34% and 18%, respectively. Patients who achieved MCyR with ponatinib in 3L experienced more durable response, with 92% of the 3L patients estimated to retain response after 2 years vs. 85% of 4L+ and 53% of 4L+ post-bosutinib. Two-year PFS was 75% for 3L, 63% for 4L+ and 53% for 4L+ post-bosutinib.

Conclusions: Based on this post-hoc analysis of the PACE study data in CP-CML patients using a variety of outcome measures, it appears that efficacy may be substantially higher when ponatinib is used as 3L therapy versus when ponatinib is reserved for 4L post bosutinib. These data indicate that more than one-half of CP-CML patients treated 3L with ponatinib achieve CCyR compared with 24% achieving CCyR with 3L bosutinib (Khoury Blood 2012); this suggests that use of ponatinib in 3L may offer physicians the best opportunity to achieve response in these difficult-to-treat patients.

Disclosures

Levy: ARIAD Pharmaceuticals, Inc: Other: abstract publication value, advisory board speaking engagement, advisory board participation. McGarry:ARIAD: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals Inc.: Employment, Equity Ownership, Other: Stock. Yang:ARIAD Pharmaceuticals, Inc: Employment. Haluska:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership.