P670: early cytogenetic or molecular landmark response to ponatinib treatment predicts outcomes in heavily pretreated patients with chronic-phase chronic myeloid leukemia in pace: 5-year data

Background: For patients with chronic-phase chronic myeloid leukemia (CP-CML), poor outcomes are often associated with sequential use of BCR::ABL1 tyrosine kinase inhibitors (TKI) or the presence of BCR::ABL1 mutations. Ponatinib is the only pan-BCR::ABL1 inhibitory TKI designed to potently inhibit native and single resistance-mutation variants of BCR::ABL1, including T315I. In the phase 2 PACE trial, ponatinib demonstrated clinical efficacy in heavily pretreated patients with CP-CML whose disease was resistant or intolerant to dasatinib or nilotinib or who harbored the T315I mutation. We present a post hoc analysis of patients with CP-CML in PACE who achieved landmark cytogenetic and molecular responses at 3, 6, and 12 months. Aims: This retrospective analysis of patients with CP-CML treated with ponatinib in the phase 2 PACE trial aims to assess the impact of achieving early landmark responses on long-term survival outcomes and depth of molecular response over time. Methods: Ponatinib-treated patients in PACE with CP-CML and valid cytogenetic and molecular assessments were included. Patients were excluded if they met response criteria at entry, had missing or non-evaluable assessments, dropped out, or had disease progression prior to landmark analysis. Patients were classified by landmark molecular (BCR::ABL1IS ≤0.1% [MMR], ≤1% [MR2], ≤10% [MR1], and >10%) and cytogenetic responses (MCyR, ≤35% Ph+ metaphases; CCyR, 0% Ph+ metaphases) at 3, 6, and 12 months. Landmark responses were correlated with progression-free survival (PFS), overall survival (OS), and molecular response over time (MMR, BCR::ABL1IS ≤0.01% [MR4], ≤0.0032% [MR4.5]). Log-rank testing was used to compare PFS and OS outcomes between patients who achieved landmark responses (MMR/MR2/MR1) and patients who did not. Results: In total, 267 patients with CP-CML were included in the analysis: 54% male; median age, 60 (range, 18-94) years; median time from diagnosis, 7 (range, 0.5-27) years; 61% received ≥3 TKIs. At the data cutoff (Feb 6, 2017), 33%, 29%, and 12% of patients had achieved MR1, MR2, and MMR, respectively, at 3 months. These patients had significantly higher 4-year PFS rates vs nonresponders (Table). The trend was similar for OS: patients with MR1, MR2, or MMR at 3 months had numerically higher probability of OS after 4 years. MR2 responders achieved deeper molecular responses (MR4 and MR4.5) at any time at higher rates than patients with >10% BCR::ABL1IS and patients with >1% BCR::ABL1IS at 3 months. Cytogenetic responses of MCyR or CCyR at 3 months were significantly associated with improved PFS and OS at 4 years compared with no MCyR or CCyR response at 3 months (Table). Similar trends for improved long-term outcomes were observed for patients with landmark molecular and cytogenetic responses at 6 and 12 months (Table). Summary/Conclusion: In patients with CP-CML in PACE, rapid and deep responses achieved with ponatinib at 3, 6, and 12 months appear to be associated with higher rates of PFS and OS at 4 years. These analyses confirm that achievement of MR1, MR2, or MMR early in treatment increases the likelihood of improved long-term outcomes in this heavily pretreated patient population.Keywords: Mutation, Chronic myeloid leukemia