Achieving Early Landmark Response Is Predictive of Outcomes in Heavily Pretreated Patients with Chronic Phase Chronic Myeloid Leukemia (CP-CML) Treated with Ponatinib

Background: Ponatinib is an approved potent, oral, pan-BCR-ABL inhibitor active against native and mutant BCR-ABL. Ponatinib had substantial clinical activity in the phase 2 PACE trial in patients (pts) resistant or intolerant to dasatinib or nilotinib or with the T315I mutation. In the frontline setting, positive associations between achieving response at an early time point (landmark) and long-term outcomes have been shown for tyrosine kinase inhibitors (TKIs) in CML pts. Since landmark analyses have not been reported for a heavily pretreated population, in particular 3^rd line and beyond, this retrospective analysis investigated the impact of achieving early landmark responses with ponatinib on long-term outcomes in PACE pts.

Methods: Ponatinib treated CP-CML pts in PACE with valid cytogenetic and molecular assessments were included. Pts who met response criteria at entry, were missing assessments or not evaluable (<20 [13] metaphases examined for CCyR [MCyR]) at time of response assessment, who dropped out or who progressed (for PFS analysis) prior to response assessment were excluded. Pts were classified by molecular status (BCR-ABL^IS: ≤0.1% [MMR], ≤1%, ≤10% and >10%) and cytogenetic status (MCyR, <35% Ph+ metaphases; CCyR, 0% Ph+ metaphases) at 3 and 6 months. These landmark responses were correlated with long-term outcomes; namely, PFS, OS, and molecular response over time (MMR, MR4 [BCR-ABL^IS ≤0.01%], MR4.5 [BCR-ABL^IS ≤0.0032%]). The log-rank test was performed to compare pts who met the criteria for response versus pts who did not meet the criteria for response at the landmark with regard to PFS and OS. Data are as of Jan 6 2014. The median follow-up was 27.9 (0.1-39.5) months.

Results: 267 CP-CML pts were included in the analysis: 54% male; median age, 60 (18-94) years; median time from diagnosis, 7 (0.5-27) years. Pts were heavily pretreated: 60% received ≥3 TKIs. At 3 months, 51%, 36%, and 15% pts had reached ≤10% BCR-ABL^IS, ≤1% BCR-ABL^IS, and MMR, respectively. Pts who achieved each of these responses at 3 months were significantly more likely to have improved PFS after 2 years compared with those who did not (Table). The trend was similar for OS: specifically, pts who reached ≤1% BCR-ABL^IS or MMR at 3 months had a significantly increased likelihood of OS after 2 years. Moreover, 3-month BCR-ABL^IS levels correlated with achievement of deeper molecular response (MR4 and MR4.5) over time: pts with low BCR-ABL^IS levels (≤1%) were more likely to achieve MR4 or MR4.5 compared with those having higher BCR-ABL^IS levels (>10%). Furthermore, pts who achieved MCyR or CCyR at 3 months were significantly more likely to have improved PFS after 2 years compared with those who did not. This trend was similar for OS: achievement of MCyR or CCyR at 3 months was associated with an increased likelihood of OS after 2 years (Table). Similar trends were observed for 6-month molecular and cytogenetic landmark analyses (Table).

Conclusions: In these refractory CML pts, the rapid and deep reduction in BCR-ABL levels achieved with ponatinib translated into improved long-term outcomes. These data validate the usefulness of assessing BCR-ABL levels at early time points as a goal of therapy with ponatinib since achieving early landmark response appears to be a strong predictor of better long-term outcomes.