Achieving Early Landmark Response Is Predictive of Outcomes in Heavily Pretreated Patients with Chronic Phase Chronic Myeloid Leukemia (CP-CML) Treated with Ponatinib
Authors: Mueller Martin C. , Baccarani Michele , Deininger Michael W. , Guilhot Francois , Hochhaus Andreas , Hughes Timothy P. , Shah Neil P. , Talpaz Moshe , Lustgarten Stephanie , Rivera Victor M. , Clackson Tim , Haluska Frank G. , Cortes Jorge E. 
Published: October 2019

Abstract

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 3rd 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-ABLIS: ≤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-ABLIS ≤0.01%], MR4.5 [BCR-ABLIS ≤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-ABLIS, ≤1% BCR-ABLIS, 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-ABLIS or MMR at 3 months had a significantly increased likelihood of OS after 2 years. Moreover, 3-month BCR-ABLIS levels correlated with achievement of deeper molecular response (MR4 and MR4.5) over time: pts with low BCR-ABLIS levels (≤1%) were more likely to achieve MR4 or MR4.5 compared with those having higher BCR-ABLIS 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.
Table Impact on 2-Year Outcomes* 3-month Molecular n ≤10% BCR-ABL IS n >10% BCR-ABL IS P-valuea 82 PFS = 76% 79 PFS = 57% 0.0366 86 OS = 85% 89 OS = 86% 0.6182 ≤1% BCR-ABLIS >1% BCR-ABLIS 75 PFS = 84% 133 PFS = 59% 0.0001 77 OS = 90% 148 OS = 84% 0.0507 MMR No MMR 32 PFS = 96% 180 PFS = 64% 0.0035 33 OS = 96% 197 OS = 84% 0.0402 3-month Cytogenetic n MCyR n No MCyR P-valuea 97 PFS = 85% 97 PFS = 52% <0.0001 100 OS = 91% 109 OS = 81% 0.0120 CCyR No CCyR 78 PFS = 85% 110 PFS = 59% 0.0002 80 OS = 90% 123 OS = 83% 0.0536 6-month Molecular n ≤10% BCR-ABL IS n >10% BCR-ABL IS P-valuea 84 PFS = 83% 55 PFS = 51% 0.0012 88 OS = 94% 73 OS = 84% 0.0274 ≤1% BCR-ABLIS >1% BCR-ABLIS 95 PFS = 84% 86 PFS = 55% 0.0001 101 OS = 93% 106 OS = 87% 0.1415 MMR No MMR 57 PFS = n/a 128 PFS = 60% 0.0002 61 OS = 95% 150 OS = 87% 0.0580 6-month Cytogenetic n MCyR n No MCyR P-valuea 116 PFS = 72% 57 PFS = 51% <0.0001 118 OS = 91% 73 OS = 86% 0.1051 CCyR No CCyR 95 PFS = 84% 75 PFS = 51% <0.0001 97 OS = 92% 91 OS = 86% 0.1676 *PFS and OS based on Kaplan-Meier estimates, and calculated from landmark time point. Progression defined as death, development of AP or BP, loss of CHR (in absence of cytogenetic response), loss of MCyR or increasing WBC without CHR aLog-rank test

Disclosures
Mueller: ARIAD, Novartis, BMS: Consultancy, Honoraria, Research Funding. Baccarani:ARIAD, Novartis, BMS: Consultancy; ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria; ARIAD, Novartis, BMS, Pfizer, Teva: Speakers Bureau. Deininger:BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding; BMS, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy. Guilhot:ARIAD Pharmaceuticals, Inc.: Honoraria. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Hughes:Novartis, BMS, ARIAD Pharmaceuticals, Inc.: Honoraria, Research Funding. Shah:ARIAD Pharmaceuticals, Inc., BMS: Research Funding. Talpaz:ARIAD Pharmaceuticals, Inc., BMS, Sanofi, Incyte, Pfizer: Research Funding. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Haluska:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Cortes:ARIAD, BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding.