Impact of Imatinib Mesylate Dose Escalation on Resistance and Sub-Optimal Responses to Standard-Dose Therapy in Patients (pts) with Chronic Myeloid Leukemia (CML).
Authors: Jabbour Elias , Kantarjian Hagop , Atallah Ehab , Borthakur Gautam , Wierda William , Faderl Stefan , Kornblau Steven , Cortes Jorge 
Published: October 2019

Background: Dose escalation has been reported to be of benefit in some pts after standard-dose imatinib failure. This benefit is based on small series of pts with short follow-up. Although dose escalation is also recommended for pts with suboptimal response to imatinib (as defined by the European LeukemiaNet recommendations), the efficacy of this approach has not been reported.

Methods: We assessed the long-term efficacy of dose escalation in 102 pts with CML in chronic phase who met the criteria of failure (n=85) or suboptimal (n=9) response to imatinib, or had their dose escalated by physician’s choice for responses better than suboptimal (n=8).

Results: Median age was 52 years (range, 18–79). 89 pts were receiving imatinib after interferon failure and 13 as frontline therapy. Median time on imatinib before dose escalation was 19 mos (range, 3–87). Best response to standard-dose imatinib was complete cytogenetic response (CCyR) in 33 (32%), partial (PCyR) in 10 (10%), minor (mCyR) in 14 (14%), complete hematologic response (CHR) in 30 (29%), and partial hematologic response (PHR) in 1 (1%). 86 pts had their dose escalated from 400 to 800 mg/day and 24 from 300 to 600 mg[JC1]. Pts were followed for a median of 50 mos (range 3–83) from dose escalation. Among pts with criteria for failure, 45/61 (74%) treated for cytogenetic resistance (n=31) or relapse (n=30) responded, including complete molecular response (CMR) (n=2), major molecular response (MMR) (n=4), CCyR (n=24), PCyR (n=9), and minor CyR (n=6). Another 24 pts were treated for hematologic resistance (n=5) or relapse (n=19), and 13 (54%) responded: 1 MMR, 2 CCyR, 2 PCyR, 7 CHR, and 1 PHR. Median time to cytogenetic response was 9 mos (range, 2–54). 31/58 (53%) failure pts who responded to dose escalation relapsed after a median of 68 mos (range, 6–79), with relapses in 6/33 pts (18%) who achieved a CCyR. CCyR occurred in 31/77 (40%) pts who escalated to 800mg and 2/9 (22%) of those who escalated to 600mg (p=0.29). Among 9 pts with suboptimal response (8 no MMR at 18 mo, 1 no PCyR at 6 mos), 2 (22%) responded: 1 MMR and 1 PCyR. The later lost his response to minor CyR 2 years after escalation. Among 8 pts with response better than suboptimal, 6 (75%) improved their response to CMR (n=1) and MMR (n=3) from CCyR, and to CCyR (n=2) from PCyR at 3 and 9 mos,respectively. Table 1 summarizes responses and outcome for the 3 categories.

Conclusion: Imatinib dose escalation can induce sustained molecular and cytogenetic responses in patients with failure or suboptimal response to standard-dose imatinib. Many of these responses can be durable.

Table 1. Outcome after dose escalation (%) 2-year (%) from dose escalation CCyR MMR Transformation Event Loss CCyR EFS TFS EFS=Event-free survival; TFS=Transformation-free survival. * One evaluable pt not in CCyR at dose escalation. **4 evaluable pts not in CCyR at dose escalation Failure 33/85 (39) 7/85 (8) 9/58 (15) 31/58 (53) 6/33 (18) 85 86 Cytogenetic 30/61 (49) 6/61 (10) 4/40 (10) 15/40 (37) 5/30 (17) Hematologic 3/24 (12) 1/24 (4) 5/18 (28) 16/18 (89) 1/3 (33) Suboptimal 0/1* (0) 1/9 (11) 0 (0) 1 (11) 0 (0) 88 100 Other 4/4** (100) 4/8 (50) 0 (0) 0 (0) 0 (0) 100 100