Imatinib Mesylate Dose Escalation Improves Disease Response in Chronic-Phase Chronic Myeloid Leukaemia Patients after Cytogenetic or Molecular Suboptimal Responses to Standard Doses of Imatinib.
Authors: Rea Delphine , Etienne Gabriel , Corm Selim , Cony-Makhoul Pascale , Gardembas Martine , Mahon Francois-Xavier , Nicolini Franck 
Published: October 2019

Abstract
In chronic phase-chronic myeloid leukemia (CP-CML), a complete cytogenetic response (CCR) along with a major molecular response (MMR) on imatinib mesylate (IM) at 400mg/d represents a strong factor predicting survival. Suboptimal cytogenetic responders (minimal or minor CR (mCR) by 6 months or partial CR (pCR) by 12 months, ELN) have a probability of further achievement of CCR of only 50%. Suboptimal molecular responders (CCR without MMR by 18 months, ELN) have a decreased probability of remaining event-free survivors when compared to optimal responders. Since non-randomized trials suggest that high-dose IM at CML diagnosis produces high rates of optimal responses, dose escalation can be recommended for suboptimal responders to standard dose of IM, but this strategy has not been yet evaluated. Here, we present the results from a series of 24 CP-CML patients who experienced IM-dose escalation for cytogenetic or molecular suboptimal response to standard doses of IM. Suboptimal cytogenetic responders (n=10) included 9 males, median age was 51.3 years-old (27.7–64.2), all were in early CP. Sokal scores were low (n=5), int (n=2), high (n=2) and unknown (n=1). All patients were treated with IM frontline at 400mg/d (n=9) or 600mg/d (n=1) and 2 received PEGIFN associated with IM at 400mg/d (withdrawn after 3 months for intolerance in 1). Prior to dose escalation, 7 patients were in pCR at 12 months and 3 in mCR at 6 months. The search for BCR-ABL mutations was negative in 6 patients tested. IM was increased to 600mg/d (n=7) or 800mg/d (n=3) after a median time of 13.7 months (5.6–15.2) on initial IM treatment. Median follow-up from IM at standard and escalated doses were respectively 28 (16.1–79.1) and 14.9 months (2.2–73.5). Of 9 patients with cytogenetic evaluation, 100% obtained CCR after a median duration of high-dose IM of 6.2 months (2.4–12.6). Five patients (50%) achieved a MMR after a median duration of high-dose IM of 9.7 months (2.9–45). Only one patient treated with PEGIFN and IM increased to 600mg/d obtained a complete molecular response (CMR) 19.9 months after high-dose IM. Suboptimal molecular responders (n=14) included 11 males, median age was 38.2 years-old (20.9–63.2), 9 were in early CP and 5 in late CP. Six had previously received IFN for a median of 4 months (4–53). Sokal scores were low (n=5), int (n=5), high (n=3) and unknown (n=1). All patients had received IM at 400mg/d, for a median duration of 27.3 months (16.7–73.3). BCR-ABL mutations were detected in 2/8 patients tested (M244V and Q252R). IM was increased to 600mg/d (n=13) or to 800mg/d (n=1). Median BCR-ABL prior to dose increase was 0.79% (0.15–3.06). Median follow-up from standard and escalated doses of IM were respectively 45.2 (26.9–85.9) and 12.5 months (3.3–38.1). Six patients (43%) obtained a MMR after a median of 6.7 months (2–25.4) of high-dose IM, including 1 with the M244V mutation. None achieved a CMR. To conclude, IM-dose escalation is beneficial to suboptimal cytogenetic responders with a rate of achievement of CCR and MMR of respectively 100 and 50%. Regarding molecular suboptimal responders, the rate of MMR after dose increase in only 43% and other strategies should be considered.