Imatinib Dose Escalation Is Effective in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP).
Authors: Kantarjian Hagop M. , Druker Brian J. , Guilhot Francois , Cortes Jorge , O’Brien Stephen G. , Krahnke Tillmann , Larson Richard A. 
Published: October 2019

Background: Imatinib mesylate (IM) 400 mg/d is the standard of care for newly diagnosed patients (pts) with CML-CP. Dose escalation to 600 or 800 mg IM has been shown to be beneficial in patients with either an inadequate response or disease progression while on standard therapy (Kantarjian et al Blood 2003). In the International Randomized study of Interferon versus STI571 (IRIS) trial, initiated in 2000, dose escalation was allowed for patients who did not achieve a complete hematologic response (CHR) by 3 months or a minor cytogenetic response (minCyR) by 12 months, lost a major cytogenetic response (MCyR) at any time, or progressed (including increase in WBC); no dose escalation in cases of loss of CCyR were specified. The impact of IM dose escalation for patients on IRIS is presented in this post-hoc analysis.

Methods: Patients were evaluated for hematologic and cytogenetic responses, progression (to accelerated or blast phase) free survival (PFS), and overall survival (OS) following dose escalation. Patients were included if their dose was increased within −0.5 to 3 months following the respective landmark evaluation. Instances of dose escalation (to ≥600 mg/d) on the IM arm were reviewed and classified, where possible, based on either criteria established by IRIS protocol or the European LeukemiaNet recommendations

Results: Of 551 patients receiving first line IM, 106 pts (19%) had dose escalation to 600–800 mg/d. Median time to dose escalation was 22 months (range:3–74 months; 25th–75th percentile: 13–45 months). After dose escalation the median imatinib dose delivered was 604 mg/d (range: 294–800 mg/d; 25th–75th percentile:600–739 mg/d) and remained on treatment for a median of 19.4 months based on current follow-up. Last recorded dose was ≥600mg/d in 85% of these patients. Dose increases in 39 patients were based on the IRIS protocol criteria. Responses among these patients included: 6 of 7 who had not achieved CHR at 3 months achieved a CHR with dose escalation, 2 of these patients subsequently achieved a CCyR. Of 8 patients who had not achieved a minCyR at 12 months, 4 improved to a CCyR, and of 18 patients who lost their MCyR, 9 subsequently re-achieved an MCyR within 12.5 months after dose escalation, of whom 3 also attained a CCyR by 30-months after dose escalation. The 6 patients who received dose escalations upon progression, had an OS of 83% at 2 years after dose escalation. At 36-months after dose escalation the 39 patients dose escalated per IRIS protocol criteria achieved an estimated PFS and OS of 81%. In a separate analysis of these 106 pts, dose escalations in 48 pts were retrospectively classified according to the ELN recommendations. At 36-months follow-up after dose escalation these 48 patients achieved a 90% PFS and 89% OS. For the entire cohort of 106 patients who were dose escalated, estimated PFS was 89% and OS was 84% at 36 months after dose escalation.

Conclusion: Based on these data, IM dose escalation to 600 and/or 800 mg allows poorly responding patients to achieve a clinically important durable response or re-gain responses. These slower responding or progressing patients benefited from IM dose escalation and thus, the data support dose escalation for these patients.