Faster and deeper reductions in BCR-ABL levels with ponatinib translate into better long-term outcomes for patients with refractory CML
A retrospective analysis of the phase II PACE study demonstrated that achieving a rapid and deep reduction in the BCR-ABL levels with ponatinib therapy translated into improved long term outcomes in patients with refractory CML.
Ponatinib is an approved, potent, oral, pan-BCR-ABL inhibitor active against native and mutant BCR-ABL, which showed substantial clinical activity in the phase II PACE trial in chronic phase (CP) CML patients resistant or intolerant to dasatinib or nilotinib or with a T315I mutation. The presented retrospective analysis investigated the association of achieving early cytogenetic and molecular landmark responses with ponatinib with the long-term outcomes of patients in the PACE study. In total 267 CP-CML patients treated with ponatinib in the PACE study with valid cytogenetic and molecular assessments were included in this analysis. All patients were classified according to their molecular and cytogenetic status at 3 and 6 months. These landmark responses were then correlated with long-term outcomes.
At 3 months, respectively 51%, 36%, and 15% patients had reached ≤10% BCR-ABLIS, ≤1% BCR-ABLIS, and MMR. Patients who achieved each of these responses at 3 months were significantly more likely to have an improved progression-free survival (PFS) after 2 years as compared to patients who did not. The 2 year PFS rate for patients with ≤1% BCR-ABLIS at 3 months compared to patients without ≤1% BCR-ABLIS at that stage was 87% vs. 62% (p= 0.0003). Similarly, the 2 year PFS rates for patients with or without MMR at 3 months were 97% vs. 67% (p= 0.0006).
A similar trend was seen for overall survival (OS). In fact, patients who reached ≤1% BCR-ABLIS or MMR at 3 months had a significantly increased likelihood of OS after 2 years (90% vs. 84% [p= 0.0357] and 97% vs. 84% [p= 0.0324], respectively). Moreover, the 3-month BCR-ABLIS levels correlated with achievement of a deeper molecular response (MR4 and MR4.5) over time. Furthermore, patients who achieved a MCyR or a CCyR at 3 months were significantly more likely to have improved PFS after 2 years compared with those who did not (p< 0.0001 and p= 0.0002, respectively). With respect to OS, reaching a MCyR, a CCyR, a MMR or ≤1% BCR-ABLIS at 3 months were all significantly associated with a longer 2-year OS.1 Similar associations were seen in the 6 and 12 month molecular and cytogenetic landmark analyses.
In summary, in this heavily pretreated population, rapid and deep reduction of BCR-ABLIS levels achieved with ponatinib translated into improved long-term outcomes. These data demonstrate the usefulness of assessing BCR-ABLIS levels at early time points as these are strong predictors of better long-term outcomes.
Reference
1. Müller M, Baccarani M, Deininger M, et al. Achieving Early Landmark Response Is Predictive of Outcomes in Heavily Pretreated Patients with Chronic Phase Chronic Myeloid Leukemia (CP-CML) Treated with Ponatinib. Presented at ASH 2014; Abstract #518.
