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C. Michel et al.
ABSTRACT
Standard first-line therapy of chronic myeloid leukemia is treatment with imatinib. In the randomized German Chronic Myeloid Leukemia-Study IV, more potent BCR-ABL inhibition with 800 mg (‘high- dose’) imatinib accelerated achievement of a deep molecular remission. However, whether and when a de-escalation of the dose intensity under high-dose imatinib can be safely performed without increasing the risk of losing deep molecular response is unknown. To gain insights into this clinically rel- evant question, we analyzed the outcome of imatinib dose reductions from 800 mg to 400 mg daily in the Chronic Myeloid Leukemia-Study IV. Of the 422 patients that were randomized to the 800 mg arm, 68 reduced imatinib to 400 mg after they had achieved at least a stable major molecular response. Of these 68 patients, 61 (90%) maintained major molecular remission on imatinib at 400 mg. Five of the seven patients who lost major molecular remission on the imatinib standard dose regained major molecular remission while still on 400 mg imatinib. Only two of 68 patients had to switch to more potent kinase inhibition to regain major molecular remission. Importantly, the lengths of the intervals between imatinib high-dose treatment before and after achieving major molecular remission were associated with the prob- abilities of maintaining major molecular remission with the standard dose of imatinib. Taken together, the data support the view that a deep molecular remission achieved with high-dose imatinib can be safely maintained with standard dose in most patients. Study protocol registered at clinicaltrials.gov 00055874.
Introduction
Approved first-line therapies of chronic myeloid leukemia (CML) are the tyrosine kinase inhibitors (TKIs) imatinib, dasatinib, nilotinib and bosutinib.1-5 Imatinib led to distinctively improved progression-free and overall survival of chronic phase CML patients as compared with previous conventional treatment standards in CML.6,7 Second-gener- ation TKIs, such as nilotinib and dasatinib, but also a higher dose of imatinib (800 mg/day), induce deep molecular response (MR) faster8,9 and in a larger proportion of patients.10,11 As a consequence, deep molecular remission (an essential eligibility criterion for TKI discontinuation) can be achieved earlier and in more patients when compared to imatinib standard dose.12,13 However, the benefit of pursu- ing highly-potent BCR-ABL-kinase inhibition once deep MR has been achieved is less clear. Moreover, for those patients in deep MR, which (for whatever reason) require long-term treatment, the tolerability and prevention of organ damage through clinically relevant and potentially irreversible side effects, such as pulmonary hypertension, diabetes, hypercholesterinemia, and cardiovascular morbid- ity become the most important priority.14-17 Thus, if high- potency BCR-ABL inhibition is not needed to sustain remis- sion or improve survival, then the risk of potentially harm- ful side effects from second- or third-generation TKI must be weighed against the long-term safety of using imatinib,18- 20 especially when also considering that generic imatinib is more cost effective. By analyzing the outcome of 800 mg to 400 mg imatinib dose reductions performed in at least sta- ble major molecular remission (MMR) within the random- ized German CML-Study IV,8,21 we aimed to address the clinically important questions of in which patients and at what time after initiation of strong BCR-ABL inhibition with 800 mg imatinib less potent BCR-ABL inhibition with standard dose imatinib is sufficient to maintain stable MMR.
Methods
Patients and Chronic Myeloid Leukemia-Study IV protocol
All patients investigated in this study were treated within the randomized German CML-Study IV.8,21 Imatinib monotherapy at
800 mg/day was one of the five arms in this trial. The study pro- tocol was registered at clinicaltrials.gov 00055874. Randomization took place from July 2002 through March 2012. During a pilot- phase of 3 years, only high-risk patients according to the Euro score22 were randomized to imatinib 800 mg/day. In 2005, ima- tinib 800 mg/day was started as a full study arm.
To avoid selection bias towards high-risk patients, in this retro- spective analysis, only patients randomized from 2005 were eval- uated.
Definition of high-dose imatinib treatment
Imatinib at a dose of 800 mg/day for at least 6 months was clas- sified as high-dose therapy. Six months was chosen because the presence of MMR after 6 months significantly increased the prob- abilities of patients going on to achieve deep MR later.8 A high- dose treatment interval began with the first dose of 800 mg/day and ended at the time of imatinib dose reduction to 400 mg/day. An intermittent 600 mg/day interval which directly preceded or followed a high-dose treatment interval with 800 mg/day was still considered high-dose treatment because the effective median dose of imatinib in the 800 mg arm was seen to be only 600 mg in the CML-Study IV.8
The molecular analyses are described in the Online Supplementary Appendix.
Statistical analysis
Survival without loss of MMR was defined as the time between the start of reduced imatinib therapy with 400 mg/day either until loss of MMR or until the date of the last evaluation of MR status with the date linkable to the reduction period, as defined in the Online Supplementary Methods. Probabilities of molecular relapse- free survival (RFS) were estimated by the Kaplan-Meier method. The association between a variable and molecular RFS was assessed by Cox regression.23 For identification of cutoffs, the min- imal P-value approach was used while assuming that the smallest group should contain at least 10% of patients.24 Bootstrap resam- pling and kernel density estimation were carried out to assess the stability of a cutoff.25,26
Point estimates are given together with their 95% confidence intervals (95%CI). In the case of the hazard ratios (HR), for esti- mation of the 95%CI, the profile likelihood was used and P-values were calculated from the likelihood ratio test. All analyses are descriptive and exploratory. Apart from the minimal P-value
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haematologica | 2019; 104(5)