Older patients with chronic myeloid leukemia (≥65 years) profit more from higher imatinib doses than younger patients: a subanalysis of the randomized CML-Study IV

Ulrike Proetel, Nadine Pletsch, Michael Lauseker, Martin C Müller, Benjamin Hanfstein, Stefan W Krause, Lida Kalmanti, Annette Schreiber, Dominik Heim, Gabriela M Baerlocher, Wolf-Karsten Hofmann, Elisabeth Lange, Hermann Einsele, Martin Wernli, Stephan Kremers, Rudolf Schlag, Lothar Müller, Mathias Hänel, Hartmut Link, Bernd Hertenstein, Markus Pfirrman, Andreas Hochhaus, Joerg Hasford, Rüdiger Hehlmann, Susanne Saußele, German Chronic Myeloid Leukemia Study Group, Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung (SAKK)

Abstract

The impact of imatinib dose on response rates and survival in older patients with chronic myeloid leukemia in chronic phase has not been studied well. We analyzed data from the German CML-Study IV, a randomized five-arm treatment optimization study in newly diagnosed BCR-ABL-positive chronic myeloid leukemia in chronic phase. Patients randomized to imatinib 400 mg/day (IM400) or imatinib 800 mg/day (IM800) and stratified according to age (≥65 years vs. <65 years) were compared regarding dose, response, adverse events, rates of progression, and survival. The full 800 mg dose was given after a 6-week run-in period with imatinib 400 mg/day. The dose could then be reduced according to tolerability. A total of 828 patients were randomized to IM400 or IM800. Seven hundred eighty-four patients were evaluable (IM400, 382; IM800, 402). One hundred ten patients (29 %) on IM400 and 83 (21 %) on IM800 were ≥65 years. The median dose per day was lower for patients ≥65 years on IM800, with the highest median dose in the first year (466 mg/day for patients ≥65 years vs. 630 mg/day for patients <65 years). Older patients on IM800 achieved major molecular remission and deep molecular remission as fast as younger patients, in contrast to standard dose imatinib with which older patients achieved remissions much later than younger patients. Grades 3 and 4 adverse events were similar in both age groups. Five-year relative survival for older patients was comparable to that of younger patients. We suggest that the optimal dose for older patients is higher than 400 mg/day. ClinicalTrials.gov identifier: NCT00055874

Figures

Fig. 1
Fig. 1
Flow diagram of randomized and evaluable patients. n number of patients, IM400 imatinib 400 mg/day, IM800 imatinib 800 mg/day, CML chronic myeloid leukemia, CP chronic phase, IC informed consent, OS overall survival, IM imatinib, y years, CCR complete cytogenetic remission, MMR major molecular remission, MR4 molecular remission ≤0.01 % on the international scale
Fig. 2
Fig. 2
Molecular and cytogenetic remissions according to treatment groups. a Cumulative incidences of MMR, b cumulative incidences of MR4, and c cumulative incidences of CCR. MMR major molecular remission, MR4 molecular remission ≤0.01 % on the international scale, CCR complete cytogenetic remission, n number of patients, IM400 imatinib 400 mg/day, IM800 imatinib 800 mg/day, ns not significant
Fig. 3
Fig. 3
Progression to AP and BC according to treatment groups. AP accelerated phase, BC blast crisis, n number of patients, CI cumulative incidence, IM400 imatinib 400 mg/day, IM800 imatinib 800 mg/day, ns not significant

References

    1. Rohrbacher M, Berger U, Hochhaus A, Metzgeroth G, Adam K, Lahaye T, Saussele S, Müller MC, Hasford J, Heimpel H, Hehlmann R. Clinical trials underestimate the age of chronic myeloid leukemia (CML) patients. Incidence and median age of Ph/BCR-ABL-positive CML and other chronic myeloproliferative disorders in a representative area in Germany. Leukemia. 2009;23(3):602–604. doi: 10.1038/leu.2008.245.
    1. Björkholm M, Ohm L, Eloranta S, Derolf A, Hultcrantz M, Sjöberg J, Andersson T, Höglund M, Richter J, Landgren O, Kristinsson SY, Dickman PW. Success story of targeted therapy in chronic myeloid leukemia: a population-based study of patients diagnosed in Sweden from 1973 to 2008. J Clin Oncol. 2011;29(18):2514–2520. doi: 10.1200/JCO.2011.34.7146.
    1. Altekruse SF, Kosary CL, Krapcho M, Neyman N, Aminou R, Waldron W, Ruhl J, Howlader N, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Cronin K, Chen HS, Feuer EJ, Stinchcomb DG, Edwards BK (eds) (based on November 9 SEER data submission, posted to the SEER web site, 2010 ) SEER cancer statistics review, 1975–2007: median age of cancer patients at diagnosis, 2003–2007 by primary cancer site, race and sex. , National Cancer Institute, Bethesda, MD
    1. Rohrbacher M, Hasford J. Epidemiology of chronic myeloid leukaemia (CML) Best Pract Res Clin Haematol. 2009;22(3):295–302. doi: 10.1016/j.beha.2009.07.007.
    1. Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, Deininger MW, Silver RT, Goldman JM, Stone RM, Cervantes F, Hochhaus A, Powell BL, Gabrilove JL, Rousselot P, Reiffers J, Cornelissen JJ, Hughes T, Agis H, Fischer T, Verhoef G, Shepherd J, Saglio G, Gratwohl A, Nielsen JL, Radich JP, Simonsson B, Taylor K, Baccarani M, So C, Letvak L, Larson RA, or the IRIS Investigators Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355(23):2408–2417. doi: 10.1056/NEJMoa062867.
    1. Berger U, Engelich G, Maywald O, Pfirrmann M, Hochhaus A, Reiter A, Metzgeroth G, Gnad U, Hasford J, Heinze B, Heimpel H, Hossfeld DK, Kolb HJ, Loffler H, Pralle H, Queisser W, Hehlmann R, and the German CML-Study Group Chronic myeloid leukemia in the elderly: long-term results from randomized trials with interferon alpha. Leukemia. 2003;17(9):1820–1826. doi: 10.1038/sj.leu.2403042.
    1. Rosti G, Iacobucci I, Bassi S, Castagnetti F, Amabile M, Cilloni D, Poerio A, Soverini S, Palandri F, Rege Cambrin G, Iuliano F, Alimena G, Latagliata R, Testoni N, Pane F, Saglio G, Baccarani M, Martinelli G (2007) Impact of age on the outcome of patients with chronic myeloid leukemia in late chronic phase: results of a phase II study of the GIMEMA CML Working Party. Haematologica 92(1):101–105. doi:10.3324/haematol.10239
    1. Latagliata R, Breccia M, Carmosino I, Cannella L, De Cuia R, Diverio D, Frustaci A, Loglisci G, Mancini M, Santopietro M, Stefanizzi C, Volpicelli P, Vozella F, Alimena G. “Real- life” results of front-line treatment with Imatinib in older patients (≥65 years) with newly diagnosed chronic myelogenous leukemia. Leuk Res. 2010;34(11):1472–1475. doi: 10.1016/j.leukres.2010.07.001.
    1. Cortes J, Talpaz M, O’Brien S, Giles F, Beth Rios M, Shan J, Faderl S, Garcia-Manero G, Ferrajoli A, Wierda W, Kantarjian H (2003) Effects of age on prognosis with imatinib mesylate therapy for patients with Philadelphia chromosome-positive chronic myelogenous leukemia. Cancer 98(6):1105–1113. doi:10.1002/cncr.11629
    1. Gugliotta G, Castagnetti F, Palandri F, Breccia M, Intermesoli T, Capucci A, Martino B, Pregno P, Rupoli S, Ferrero D, Gherlinzoni F, Montefusco E, Bocchia M, Tiribelli M, Pierri I, Grifoni F, Marzocchi G, Amabile M, Testoni N, Martinelli G, Alimena G, Pane F, Saglio G, Baccarani M, Rosti G, and on behalf of the Gruppo Italiano Malattie Ematologiche dell’Adulto CML Working Party Frontline imatinib treatment of chronic myeloid leukemia: no impact of age on outcome, a survey by the GIMEMA CML Working Party. Blood. 2011;117(21):5591–5599. doi: 10.1182/blood-2010-12-324228.
    1. Cortes JE, Kantarjian HM, Goldberg SL, Powell BL, Giles FJ, Wetzler M, Akard L, Burke JM, Kerr R, Saleh M, Salvado A, McDougall K, Albitar M, Radich J, on behalf of the Rationale and Insight for Gleevec High-Dose Therapy (RIGHT) Trial Study Group High-dose imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: high rates of rapid cytogenetic and molecular responses. J Clin Oncol. 2009;27(28):4754–4759. doi: 10.1200/JCO.2008.20.3869.
    1. Rousselot P, Cony-Makhoul P, Nicolini F, Mahon FX, Berthou C, Réa D, Reiffers J, Bornand A, Saint-Jean O, Guilhot J, Guilhot F, on behalf of the French Intergroup For Chronic Myelogenous Leukemia (Fi-LMC) Long-term safety and efficacy of imatinib mesylate (Gleevec®) in elderly patients with chronic phase chronic myelogenous leukemia: Results of the AFR04 study. Am J Hematol. 2013;88(1):1–4. doi: 10.1002/ajh.23330.
    1. Sánchez-Guijo FM, Durán S, Galende J, Boqué C, Nieto JB, Balanzat J, Gracia A, García I, Avellaneda-Molina C, Moreno M-V, Luño-Fernandez E, Hermosilla M, Sanchez-Varela JM, Dios A, Lopez-Garrido P, Giraldo P, Bargay J, Domingo JM, Soler A, Salinas R, del Cañizo MC. Evaluation of tolerability and efficacy of imatinib mesylate in elderly patients with chronic phase CML: ELDERGLI study. Leuk Res. 2011;35(9):1184–1187. doi: 10.1016/j.leukres.2011.01.017.
    1. Hehlmann R, Lauseker M, Jung-Munkwitz S, Leitner A, Mueller MC, Pletsch N, Proetel U, Haferlach C, Schlegelberger B, Balleisen L, Hänel M, Pfirrmann M, Krause SW, Nerl C, Pralle H, Gratwohl A, Hossfeld DK, Hasford J, Hochhaus A, Saussele S. Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-alpha in newly diagnosed chronic myeloid leukemia. J Clin Oncol. 2011;29(12):1634–1642. doi: 10.1200/JCO.2010.32.0598.
    1. Hehlmann R, Müller MC, Lauseker M, Hanfstein B, Fabarius A, Schreiber A, Proetel U, Pletsch N, Pfirrmann M, Haferlach C, Schnittger S, Einsele H, Dengler J, Falge C, Kanz L, Neubauer A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Spiekermann K, Baerlocher GM, Ehninger G, Heim D, Heimpel H, Nerl C, Krause SW, Hossfeld DK, Kolb HJ, Hasford J, Saußele S, Hochhaus A. Deep molecular response (MR4.5) is reached by the majority of imatinib-treated patients, predicts survival, and is achieved faster by optimized high-dose imatinib—results from the randomized CML-Study IV. J Clin Oncol. 2014;32(5):415–423. doi: 10.1200/JCO.2013.49.9020.
    1. Fabarius A, Leitner A, Hochhaus A, Müller MC, Hanfstein B, Haferlach C, Göhring G, Schlegelberger B, Jotterand M, Reiter A, Jung-Munkwitz S, Proetel U, Schwaab J, Hofmann WK, Schubert J, Einsele H, Ho AD, Falge C, Kanz L, Neubauer A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Spiekermann K, Baerlocher GM, Lauseker M, Pfirrmann M, Hasford J, Saussele S, Hehlmann R, and for the Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung (SAKK) and the German CML Study Group Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV. Blood. 2011;118(26):6760–6768. doi: 10.1182/blood-2011-08-373902.
    1. Hanfstein B, Müller MC, Hehlmann R, Erben P, Lauseker M, Fabarius A, Schnittger S, Haferlach C, Göhring G, Proetel U, Kolb HJ, Krause SW, Hofmann WK, Schubert J, Einsele H, Dengler J, Hänel M, Falge C, Kanz L, Neubauer A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Branford S, Hughes TP, Spiekermann K, Baerlocher GM, Pfirrmann M, Hasford J, Saußele S, Hochhaus A, for the SAKK and the German CML Study Group Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML) Leukemia. 2012;26(9):2096–2102. doi: 10.1038/leu.2012.85.
    1. Saussele S, Lauseker M, Gratwohl A, Beelen DW, Bunjes D, Schwerdtfeger R, Kolb HJ, Ho AD, Falge C, Holler E, Schlimok G, Zander AR, Arnold R, Kanz L, Dengler R, Haferlach C, Schlegelberger B, Pfirrmann M, Müller MC, Schnittger S, Leitner A, Pletsch N, Hochhaus A, Hasford J, Hehlmann R, and for the German CML-Study Group Allogeneic hematopoietic stem cell transplantation (allo SCT) for chronic myeloid leukemia in the imatinib era: evaluation of its impact within a subgroup of the randomized German CML Study IV. Blood. 2010;115(10):1880–1885. doi: 10.1182/blood-2009-08-237115.
    1. Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, Cervantes F, Clark RE, Cortes JE, Guilhot F, Hjorth-Hansen H, Hughes TP, Kantarjian HM, Kim DW, Larson RA, Lipton JH, Mahon F-X, Martinelli G, Mayer J, Müller MC, Niederwieser D, Pane F, Radich JP, Rousselot P, Saglio G, Saußele S, Schiffer C, Silver R, Simonsson B, Steegmann JL, Goldman JM, Hehlmann R. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872–884. doi: 10.1182/blood-2013-05-501569.
    1. Cross NCP, White HE, Müller MC, Saglio G, Hochhaus A. Standardized definitions of molecular response in chronic myeloid leukemia. Leukemia. 2012;26(10):2172–2175. doi: 10.1038/leu.2012.104.
    1. Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-Nelemans JC, Alimena G, Steegmann JL, Ansari H. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst. 1998;90(11):850–858. doi: 10.1093/jnci/90.11.850.
    1. Hasford J, Baccarani M, Hoffmann V, Guilhot J, Saussele S, Rosti G, Guilhot F, Porkka K, Ossenkoppele G, Lindoerfer D, Simonsson B, Pfirrmann M, Hehlmann R. Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood. 2011;118(3):686–692. doi: 10.1182/blood-2010-12-319038.
    1. Gooley TA, Leisenring W, Crowley J, Storer BE. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med. 1999;18(6):695–706. doi: 10.1002/(SICI)1097-0258(19990330)18:6<695::AID-SIM60>;2-O.
    1. Pfirrmann M, Hochhaus A, Lauseker M, Saußele S, Hehlmann R, Hasford J. Recommendations to meet statistical challenges arising from endpoints beyond overall survival in clinical trials on chronic myeloid leukemia. Leukemia. 2011;25(9):1433–1438. doi: 10.1038/leu.2011.116.
    1. Gray RJ. A class of k-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988;16(3):1141–1154. doi: 10.1214/aos/1176350951.
    1. Hughes T, Deininger M, Hochhaus A, Branford S, Radich J, Kaeda J, Baccarani M, Cortes J, Cross NC, Druker BJ, Gabert J, Grimwade D, Hehlmann R, Kamel-Reid S, Lipton JH, Longtine J, Martinelli G, Saglio G, Soverini S, Stock W, Goldman JM. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood. 2006;108(1):28–37. doi: 10.1182/blood-2006-01-0092.
    1. Müller MC, Cross NC, Erben P, Schenk T, Hanfstein B, Ernst T, Hehlmann R, Branford S, Saglio G, Hochhaus A. Harmonization of molecular monitoring of CML therapy in Europe. Leukemia. 2009;23(11):1957–1963. doi: 10.1038/leu.2009.168.
    1. Statistical Yearbook for the Federal Republic of Germany including “International tables” (2011) Federal Statistical Office, Wiesbaden
    1. Cortes JE, Baccarani M, Guilhot F, Druker BJ, Branford S, Kim DW, Pane F, Pasquini R, Goldberg SL, Kalaycio M, Moiraghi B, Rowe JM, Tothova E, De Souza C, Rudoltz M, Yu R, Krahnke T, Kantarjian HM, Radich JP, Hughes TP. Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: tyrosine kinase inhibitor optimization and selectivity study. J Clin Oncol. 2010;28(3):424–430. doi: 10.1200/JCO.2009.25.3724.
    1. Kantarjian HM, Keating MJ, McCredie KB, Walters R, Talpaz M, Smith TL, Freireich EJ. Old age: a sign of poor prognosis in patients with chronic myelogenous leukemia. South Med J. 1987;80(10):1228–1232. doi: 10.1097/00007611-198710000-00007.

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