A Novel Approach to a Retrospective Longitudinal Analysis of Dose Change or Discontinuation of Imatinib Therapy in Chronic Phase–Chronic Myeloid Leukemia
Authors: Merante Serena , Pascutto Cristiana , Elena Chiara , Rocca Barbara , Zappatore Rita , Cavigliano Paola Maria , Cazzola Mario , Orlandi Ester 
Published: October 2019

Abstract

Imatinib (IM) is a cornerstone in the treatment of chronic myeloid leukemia (CML). Dose change or discontinuation of IM in patients who experience sustained molecular response is a subject of debate.
We retrospectively studied 142 CML patients in chronic phase (Table 1) treated with IM and followed-up during 2000-2013 at our institution. Dose changes, discontinuation of therapy, cytogenetic and molecular analyses were regularly recorded during follow-up. Patients’ history was subdivided into 483 treatment time-periods at constant dosage. Response was evaluated at the end of each treatment period. We assessed whether the probability of observing a complete cytogenetic response (CCyR) or a molecular response (MR: complete, CMR or major, MMR) or a progression were influenced by treatment dose and/or duration.
We applied generalized estimating equation (GEE) logistic models for the analysis of longitudinal panel data. These models are designed to account for individual patient variation due to repeated measurements during each patient’s follow-up.
Out of 483 time periods at constant IM dose, 236 were followed by dose modification, 116 by IM discontinuation, 29 by a change to other treatments due to tolerability issues or non-response; 102 were still ongoing without dose changes.
Treatment response: 74% of time periods resulted in a CCyR and 2.3% showed no response; 31.9% showed a CMR, 29.6% showed a MMR (MR3, MR4, MR4.5), 35.6% a suboptimal response, 2.9% no MR. CMR+MMR was observed in 61.5% time periods.
Periods at standard dose showed a higher response rate, both when considering CCyR (response rate after low, standard, high dose: 69.3%, 79.6%, 68%, respectively, P=0.023) and when considering MR (CMR after low, standard, high dose: 27%, 40.5%, 15.4%, respectively, P&lt;0.001; CMR + MMR after low, standard, high dose: 53.4%, 69.8%, 52.3%, respectively, P=0.001).
After adjusting for length of treatment period in a multivariate GEE model, dose lost significance and treatment duration was the only significant predictor of CCyR (P&lt;0.001).
In a GEE analysis of MR accounting for treatment duration, reduction in CMR rate after periods at high dose compared with periods at standard dose remained significant (P=0.025). Treatment dose lost significance when considering CMR+MMR.
In 32 patients who discontinued IM therapy for &gt;1 mos and then re-started IM, the CR rate after a period preceded by a treatment suspension was significantly higher than in other periods (CCyR: 85.7% vs. 73%, P=0.058; CMR 55.1% vs. 29.3%, P=0.001). In a GEE model with dose category, duration of treatment and previous suspension as covariates, both duration and previous suspension maintained a positive significant association to CCyR (P&lt;0.001, P=0.034, respectively), to CMR (both P&lt;0.001) and to CMR+MMR (P&lt;0.001, P=0.006, respectively).
Cytogenetic progression rate at the end of a period of IM treatment was 7.1% while molecular progression rate was 12.8%.
Treatment dose was not associated to progression: cytogenetic progression after low, standard, high dose: 6.1%, 6.7%, 10.5%, respectively, P=0.428; molecular progression after low, standard, high dose: 14.8%, 11.3%, 13%, respectively, P=0.584. In a multivariate GEE analysis, neither dose nor duration of treatment predicted progression. After adding type of previous treatment (IM, other drug, no treatment) as a covariate, treatment periods preceded by at least 1 month of discontinuation had a significantly lower molecular progression rate (P=0.011).
The possibility of varying dosage is often considered in “real-life” patient clinical management. In our study, 62% of time periods were followed by a dose change, but this did not affect response and progression rate after accounting for length of treatment period. The prompt response to resumed IM therapy suggests that patients may be candidates for intermittent therapy.
Future studies could use the same statistical model to pick up individual patient variation in longitudinal data collected over time, including trials at reduced IM dose or of “on-off” therapy or on new TKI.
Table 1. Patients’ characteristic Variable Description N. of patients 142 Sex M/F 58%/42% Age at diagnosis (years), median (range) 52 (18-78) N. of IM treatment periods 483 IM dosage, N (%) Low dose (100-300 mg/day) 163 (34%) Standard dose (400 mg/day) 242 (50%) High dose (450-800 mg/day) 78 (16%) Duration of IM at constant dosage (days), median (range) 258 (7-4526)

Disclosures
No relevant conflicts of interest to declare.