Final Evaluation of Randomized CML-Study IV: 10-Year Survival and Evolution of Terminal Phase
Authors: Hehlmann Rüdiger , Lauseker Michael , Saussele Susanne , Pfirrmann Markus , Krause Stefan W. , Kolb Hans-Jochem , Neubauer Andreas , Hossfeld Dieter K. , Nerl Christoph , Gratwohl Alois , Baerlocher Gabriela M. , Heim Dominik , Bruemmendorf Tim Henrik , Fabarius Alice , Haferlach Claudia , Schlegelberger Brigitte , Müller Martin C. , Jeromin Sabine , Proetel Ulrike , Kohlbrenner Katharina , Voskanyan Astghik , Rinaldetti Sébastien , Seifarth Wolfgang , Spiess Birgit , Balleisen Leopold , Goebeler Maria E , Hänel Mathias , Ho Anthony D. , Dengler J , Falge C , Kanz Lothar , Köhne Claus-Henning , Burchert Andreas , Kneba Michael , Stegelmann Frank , Köhne C , Lindemann Hans-Walter , Waller C , Pfreundschuh Michael , Spiekermann Karsten , Berdel Wolfgang E , Müller L , Edinger Matthias , Mayer Jiri , Beelen Dietrich W , Bentz Martin , Link Hartmut , Hertenstein Bernd , Fuchs R , Wernli Martin , Schlegel F , Schlag Rudolph , de Wit M , Trümper Lorenz , Hebarth H , Hahn M , Thomalla Jörg , Scheid Christof , Schafhausen Philippe , Verbeek Walter , Eckart Michael J. , Gassmann Winfried , Pezzutto Antonio , Schenk Michael , Brossart Peter , Geer Thomas , Bildat Stephan , Schäfer E , Hochhaus Andreas , Hasford Joerg 
Published: April 2021

Abstract

Background
Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400mg/day (n=400) could be optimized by doubling the dose (n=420), adding IFN (n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128).
Methods
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. The impact of patients' and disease factors on survival was prospectively analyzed. At the time of evaluation, at least 62% of patients still received imatinib, 26.2% were switched to 2nd generation tyrosine kinase inhibitors.
Results
After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival 80% and 10-year relative survival 92%. In spite of a faster response with IM800mg, the survival difference between IM400mg and IM800mg was only 3% at 5 years. In a multivariate analysis, the influence on survival of risk-group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs. other) was significant in contrast to any form of initial treatment optimization. Patients that reached the response milestones 3, 6 and 12 months, had a significant survival advantage of about 6% after 10 years regardless of therapy. The progression probability to blast crisis was 5.8%. Blast crisis was proceeded by high-risk additional chromosomal aberrations.
Conclusions
For responders, monotherapy with IM400mg 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 and blast crisis, more life-time can currently be gained by carefully addressing non-CML determinants of survival.

Disclosures
Hehlmann: Novartis: Research Funding; BMS: Consultancy. Saussele: Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Pfirrmann: BMS: Honoraria; Novartis: Honoraria. Krause: Novartis: Honoraria. Baerlocher: Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria. Bruemmendorf: Novartis: Research Funding. Müller: Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Jeromin: MLL Munich Leukemia Laboratory: Employment. Hänel: Roche: Honoraria; Novartis: Honoraria. Burchert: BMS: Honoraria. Waller: Mylan: Consultancy, Honoraria. Mayer: Eisai: Research Funding; Novartis: Research Funding. Link: Novartis: Honoraria. Scheid: Novartis: Honoraria. Schafhausen: Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Hochhaus: Incyte: Research Funding; MSD: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; ARIAD: Research Funding.