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Research Article Long-term safety and efficacy of imatinib mesylate (Gleevec1) in elderly patients with chronic phase chronic myelogenous leukemia: Results of the AFR04 study Philippe Rousselot,1,2* Pascale Cony-Makhoul,3 Franck Nicolini,4 Franc¸ois Xavier Mahon,5 Christian Berthou,6 Delphine Re´a,7 Josy Reiffers,8 Anne Bornand,9 Olivier Saint-Jean,10 Joelle Guilhot,11 and Franc¸ois Guilhot11; on behalf of the French Intergroup For Chronic Myelogenous Leukemia (Fi-LMC) Data from registries suggest that the median age of chronic myelogenous leukemia (CML) patients is 10–15 years older than that of clinical trials. We conducted a prospective phase II study to evaluate imatinib mesylate (IM, 400 mg daily) in newly diagnosed chronic phase CML (CP-CML) patients. Patients aged 70 years and over diagnosed with CP-CML within 12 months were eligible. Thirty patients were enrolled from April 2002 to October 2004. Median age was 74.8 years (range, 70–90). Male/female ratio was 1.72. At inclusion, comorbidities were reported in all but one patient, Cumulative Illness Rating Scale for Geriatrics comorbidity mean index was 1.47, and 66% of patients had cardiovascular disease. The median daily IM dose was 392 mg (range, 256–445). IM was interrupted in patients with severe comorbidities. Treatment discontinuation was observed in 36.6% of patients. Cumulative incidence of complete cytogenetic response was 71.4 and 78.5% at 12 and 24 months, respectively. A high level of sustained responses was observed in patients with mild or moderate comorbidities. Seven-year estimated overall survival was 80.8% (95% CI: 59.0–91.7). Two-thirds of the patients were still on long-term therapy at cut-off, and no patients had died from progression. This trial was registered at C 2012 Wiley Periodicals, Inc. www.clinicaltrials.gov as # NCT00219765. Am. J. Hematol. 88:1–4, 2013. V

Introduction Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by the t(9;22)(q34;q11) translocation generating a der(22) chromosome commonly referred as the Philadelphia chromosome. This translocation results in a BCR-ABL fusion gene coding for a fusion protein with enhanced nonregulated tyrosine kinase activity in the cytoplasm of leukemia cells [1]. Median age reported in clinical trials with CML patients range from 50 to 55 years. However, studies from registries indicate that the observed median age in patients with CML at diagnosis is closer to 60–65 years [2,3]. With a difference in median age between registries and clinical trials of 10–20 years, elderly CML patients are underrepresented in prospective clinical trials. Imatinib mesylate (IM, Gleevec1, Novartis Pharma) is a rationally designed tyrosine kinase inhibitor (TKI) and has demonstrated powerful activity against leukemic cells in vitro and in vivo [4,5]. Based on the results of the large phase III IRIS trial, IM was registered as first-line therapy in chronic phase CML (CP-CML) [6]. However, the median age reported for patients included in the pivotal IRIS trial was 50 years, with a range from 18 to 70 years. We thus decided to conduct a prospective study to evaluate the IM treatment in newly diagnosed CP-CML patients aged 70 years old and over.

The MMSE is a scored serie of questions and tests. Scores of 27 or above out of 30 are considered normal [7]. To minimize noncompliance, it was recommended that patients with an MMSE score less than 25 were not included. All patients were scored according to the Manual of Guidelines for Scoring the Cumulative Illness Rating Scale for Geriatrics (CIRS-G) using the following descriptions for a given level of severity: 0 (no problem), 1 (current mild problem or past significant problem), 2 (moderate disability or morbidity/requires ‘‘first line" therapy), 3 (severe/constant significant disability/"uncontrollable" chronic problems), and 4 (extremely severe/immediate treatment required/end organ failure/severe impairment in function) [8]. A total CIRS-G score was calculated for each patients. The mean CIRS-G index was calculated by summing each comorbidity score and dividing by the number of comorbidities. Both the MMSE and CIRS-G scores were calculated for all patients in collaboration with geriatric specialists. IM was administered at 400 mg daily. Dose modifications were allowed according to the criteria of the IRIS study for IM [6].

1 Department of Hematology and Oncology, Hoˆpital Mignot, Universite´ Versailles Saint-Quentin-en-Yvelines, Le Chesnay, France; 2Hoˆpital Saint-Louis, INSERM CIC904, Paris, France; 3Department of Hematology, Centre Hospitalier d’Annecy, Pringy, France; 4Department of Hematology, Hoˆpital Lyon Sud Pierre Be´nite, Lyon, France; 5Laboratory of Molecular Biology, Hoˆpital Haut-Le´ve`que, Pessac, France; 6Department of Hematology, CHU de Brest, Brest, France; 7Department of Hematology, Hoˆpital Saint-Louis, AP-HP, Paris, France; 8Department of Hematology, Institut Bergonie´, Bordeaux, France; 9Department of Internal Medicine and Geriatrics, Hoˆpital Charles Foix, AP-HP, Paris, France; 10Department of Geriatrics, Hoˆpital Georges Pompidou, AP-HP, Paris, France; 11CHU de Poitiers, INSERM CIC0802, Poitiers, France

Patients and Methods This phase II nonrandomized multicenter trial was designed to evaluate the efficacy and tolerability of IM in elderly patients. Male and female patients aged 70 years or older with newly diagnosed CP-CML were eligible. Patients had to have been diagnosed within 12 months of inclusion, with no prior therapy other than hydroxyurea. Other inclusion criteria included serum AST and ALT inferior than three times the institutional upper limit of the normal range (ULN), serum bilirubin less than 1.5 times ULN, and creatinine clearance more than 60 ml/min. Patients were excluded if they had previously been treated with interferon or imatinib or had another uncontrolled malignancy or an Eastern Cooperative Oncology Group (ECOG) performance status more than 2. Patients with Philadelphia chromosome negative CML, CML in accelerated phase, or in blast crisis were also ineligible. Minimental state exam (MMSE) was determined for all patients before inclusion.

Conflict of interest: Dr Philippe Rousselot received research funding from Novartis and Bristol-Myers Squibb. This study was presented in part at the 2007 Annual Meeting of the American Society of Hematology (Atlanta, December 2007). *Correspondence to: Philippe Rousselot, Department of Hematology and Oncology, Hoˆpital Andre´ Mignot and University of Versailles Saint-Quentinen-Yvelines, Le Chesnay, France. E-mail: [email protected] Contract grant sponsor: CHU de Poitiers. Received for publication 17 August 2012; Accepted 17 August 2012 Am. J. Hematol. 88:1–4, 2013. Published online 3 September 2012 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ajh.23330

C 2012 Wiley Periodicals, Inc. V

American Journal of Hematology

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research article TABLE I. Patient Characteristics Number of patients Median age in years (range) Sex ratio (M/F) ECOG PS, N (%) 0 1 2 Sokal score, N (%) Low Intermediate High Median MMSE score (range) Comorbidity CIRS-Ga Median score (range) Mean severity index Median follow-up (years)

TABLE II. Main Adverse Events 30 74.8 (70–90) 1.72 20 (67%) 9 (30%) 1 (3%) 9 11 10 29

(30%) (37%) (33%) (25–30)

Hematological adverse events Anemia