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Randomized Controlled Trial
. 2017 Nov;31(11):2398-2406.
doi: 10.1038/leu.2017.253. Epub 2017 Aug 14.

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

R Hehlmann  1 , M Lauseker  2 , S Saußele  1 , M Pfirrmann  2 , S Krause  3 , H J Kolb  4 , A Neubauer  5 , D K Hossfeld  6 , C Nerl  7 , A Gratwohl  8 , G M Baerlocher  9 , D Heim  8 , T H Brümmendorf  10 , A Fabarius  1 , C Haferlach  11 , B Schlegelberger  12 , M C Müller  1 , S Jeromin  11 , U Proetel  1 , K Kohlbrenner  1 , A Voskanyan  1 , S Rinaldetti  1 , W Seifarth  1 , B Spieß  1 , L Balleisen  13 , M C Goebeler  14 , M Hänel  15 , A Ho  16 , J Dengler  17 , C Falge  18 , L Kanz  19 , S Kremers  20 , A Burchert  5 , M Kneba  21 , F Stegelmann  22 , C A Köhne  23 , H W Lindemann  24 , C F Waller  25 , M Pfreundschuh  26 , K Spiekermann  4 , W E Berdel  27 , L Müller  28 , M Edinger  29 , J Mayer  30 , D W Beelen  31 , M Bentz  32 , H Link  33 , B Hertenstein  34 , R Fuchs  10 , M Wernli  35 , F Schlegel  36 , R Schlag  37 , M de Wit  38 , L Trümper  39 , H Hebart  40 , M Hahn  41 , J Thomalla  42 , C Scheid  43 , P Schafhausen  6 , W Verbeek  44 , M J Eckart  45 , W Gassmann  46 , A Pezzutto  47 , M Schenk  48 , P Brossart  49 , T Geer  50 , S Bildat  51 , E Schäfer  52 , A Hochhaus  53 , J Hasford  2
Affiliations
Randomized Controlled Trial

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

R Hehlmann et al. Leukemia. 2017 Nov.

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.

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Conflict of interest statement

RH received research support from Novartis and honoraria from BMS, SS research support from Novartis, BMS, Ariad and Pfizer, MP honoraria from Novartis and BMS, SK honoraria from Novartis, GMB honoraria from Novartis, BMS and Pfizer, THB research support from Novartis, MCM grants and honoraria from Novartis, BMS, Ariad and Pfizer, AB honoraria from BMS, JM research support from Novartis and BMS, HL honoraria from Novartis, PS honoraria from Novartis, BMS, Pfizer and Ariad, CS honoraria from Novartis, AH research support from Novartis and honoraria from Novartis, BMS and Pfizer; all other authors reported no conflict of interest.

Figures

Figure 1
Figure 1
Flow diagram of all 1551 randomized patients. Ara-C, cytarabine; CP, chronic phase; IC, informed consent; IFN, interferon-α IM, imatinib; OS, overall survival; SCT, stem cell transplantation; TKI, tyrosine kinase inhibitor.
Figure 2
Figure 2
Long-term survival evaluation. (a) Overall survival and relative survival of all 1536 CML-patients. (b) Overall survival according to treatment groups over time. (c) Survival by landmark analysis at 6 months according to achieving and not achieving the milestone ⩽1% BCR-ABL1IS at 6 months. The 594 responders have a significantly better survival and show a 10-year relative survival of 96%. The 385 non-responders include slow responders with very good prognosis and high-risk patients requiring attention to patients’ and disease risk factors. (d) Survival according to causes of death defined as related or unrelated to CML. AraC, cytarabine; IFN, interferon-α OS, overall survival; RS, relative survival; IM, imatinib.
Figure 3
Figure 3
Overall survival by disease risk (Euro-score). (a) Low, (b) intermediate, (c) high. AraC, cytarabine; IFN, interferon-α OS, overall survival; IM, imatinib.
Figure 4
Figure 4
Incidence of blast crisis over time.
See this image and copyright information in PMC

Comment in

References

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