Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants

Abstract

Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400 mg/day (n=400) could be optimized by doubling the dose (n=420), adding interferon (IFN) (n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128). From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival was 80% and 10-year relative survival was 92%. Survival between IM400 mg and any experimental arm was not different. In a multivariate analysis, risk group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs other) influenced survival significantly, but not any form of treatment optimization. Patients reaching the molecular response milestones at 3, 6 and 12 months had a significant survival advantage. For responders, monotherapy with IM400 mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients’ and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease, more life-time can currently be gained by carefully addressing non-CML determinants of survival.

Tyrosine kinase inhibitor interruptions, discontinuations and switching in patients with chronic‐phase chronic myeloid leukemia in routine clinical practice: SIMPLICITY

“…4,5 Dose escalation of imatinib may be able to overcome resistance in some patients with CP-CML, however the duration of response is short-lived. 4,5 Dose escalation of imatinib may be able to overcome resistance in some patients with CP-CML, however the duration of response is short-lived.…”

Upfront low‐dose ponatinib (15 mg/day) for multi‐TKI resistant chronic myeloid leukemia

“…At present, Imatinib is considered, and appropriately so, as the standard of care for first‐line therapy in CP‐CML. Long‐term follow‐up of patients treated with imatinib has confirmed cumulative complete cytogenetic response (CCyR) rate of ̴ 83%, major molecular response (MMR) rate of ̴ 93% and progression‐free survival (PFS) rate of over 96%; less than 7% of imatinib‐treated patients progressed into advanced phase disease after more than 10 years of follow‐up and overall survival (OS) at 10 years was ̴ 83% . The most important lesson learned from imatinib‐based studies in CML was the fact that the achievement of CCyR, and not necessarily MMR, was the most relevant milestone for OS …”

“…Long-term followup of patients treated with imatinib has confirmed cumulative complete cytogenetic response (CCyR) rate of ̴ 83%, major molecular response (MMR) rate of ̴ 93% and progression-free survival (PFS) rate of over 96%; less than 7% of imatinib-treated patients progressed into advanced phase disease after more than 10 years of follow-up and overall survival (OS) at 10 years was ̴ 83%. 2,3 The most important lesson learned from imatinib-based studies in CML was the fact that the achievement of CCyR, and not necessarily MMR, was the most relevant milestone for OS. 3 Each one of the aforementioned TKIs has been compared headto-head with imatinib, in newly diagnosed patients with CP-CML, and none has shown OS superiority; instead, all of them were found to be less appealing in terms of their safety profile, including AOEs with nilotinib and ponatinib, pleural effusions with dasatinib, and diarrhea with bosutinib.…”

“…2,3 The most important lesson learned from imatinib-based studies in CML was the fact that the achievement of CCyR, and not necessarily MMR, was the most relevant milestone for OS. 3 Each one of the aforementioned TKIs has been compared headto-head with imatinib, in newly diagnosed patients with CP-CML, and none has shown OS superiority; instead, all of them were found to be less appealing in terms of their safety profile, including AOEs with nilotinib and ponatinib, pleural effusions with dasatinib, and diarrhea with bosutinib. In other words, the now familiar and recurring theme of deeper and faster responses with higher dose imatinib or 2G-TKIs appears to have more value for drug companies who are using the information to push for the sale of their products, rather than the patients who might, as a result, be unnecessarily exposed to harmful effects from the new drugs.…”

Analysis of cause of death: Competing risks or progressive illness‐death model?

“…The aim of this trial was to improve the imatinib treatment with regard to the combination with other drugs or dose adjustment. Patient characteristics and results have already been published in detail by Hehlmann et al (2017). We can assume that the follow-up in this clinical trial has been collected persistently, that is by regular data quality and completeness checks, and that follow-up is independent of states.…”