Incidence and Mortality of Second Malignancies In 559 Patients with Chronic Myeloid Leukemia (CML) Treated with Imatinib Frontline: Data From the GIMEMA CML Working Party

Imatinib is the standard of care for CML in early chronic phase. Until now, even in stable complete molecular response, discontinuation of imatinib is not recommended, and imatinib remains a life-saving drug to be taken chronically. Long term side effects, including the incidence of second malignancies, represent a potential relevant issue. Roy et al (Leukemia 2005) reported an unexpected incidence of second neoplasms in patients treated with imatinib after interferon (6/189 patients, 3.2%; urinary tract cancer: 4/6). In contrast, an analysis performed by Novartis Pharma (Pilot et al, Leukemia 2006) on 9518 patients treated with imatinib (including pre-treated patients) did not provided evidence for an increased overall incidence of second malignancies. According to epidemiologic data (Registro Tumori) in Italy, the annual incidence of neoplasms varies from 1%, in the range of age between 50 and 69 years, to 3% for patients over 70 years. AIM. To evaluate the incidence of second malignancies in CML patients treated with imatinib frontline. METHODS. Overall, 559 patients have been enrolled in 3 concurrent clinical studies of the GIMEMA CML Working Party: CML/021, Imatinib 800 mg in intermediate Sokal risk patients (Clin Trials Gov. NCT00514488); CML/022, Imatinib 400 mg vs 800 mg in high Sokal risk patients (Clin Trials Gov. NCT00510926); CML/023, observational, Imatinib 400 mg. We evaluated the incidence of II malignancy notified as severe adverse events reported by the GIMEMA clinical Centers. RESULTS. The median age at the diagnosis of CML was 52 (extr.18 ? 84) years; 308 patients (55%) were ≥ 50 years. The median follow-up is currently 60 months. Eighteen patients (3.2%) developed a second malignancy at a median time of 20 months (extremes 2 ? 52) from the start of imatinib therapy (Table 1); 4 of these malignancies (2 colon cancer and 2 NHL) were diagnosed within 6 months. All patients were older than 50 years (median 64, extremes 50 - 79) at the diagnosis of the second malignancy. Fifteen out of the 559 (2.7%) patients died due to second neoplasm progression. CONCLUSION. In this multicentre nation-wide experience of CML patients treated with imatinib frontline, the incidence of life-threatening or requiring hospitalization secondary neoplasms (severe adverse events), seems not to be superior to the observed incidence of neoplasm in the Italian national population. In particular, in contrast to what previously reported, no increased incidence of urinary tract cancer was observed. Patients Diagnosis of CML Age Secondary Neoplasm Diagnosis of 2nd Neop. IM start to 2nd Neop. (months) Status of CML Alive 1 10/2004 69 Biliar Duct 11/2007 37 CCyR/MMR No 2 08/2005 53 Biliar Duct 08/2008 36 CCyR/MMR No 3 10/2004 50 Breast 02/2009 52 CCyR/MMR Yes 4 10/2005 76 Breast 05/2007 18 PCyR No 5 09/2004 61 CNS 06/2007 33 CCyR/MMR No 6 10/2005 60 CNS 12/2007 26 CCyR/MMR No 7 05/2004 53 Colon 07/2004 2 n.a. No 8 05/2005 63 Colon 03/2007 22 CCyR/MMR No 9 03/2006 60 Colon 05/2006 2 n.a. No 10 08/2005 64 Colon 04/2009 44 CCyR/MMR No 11 11/2004 56 Esophagus 10/2006 23 CCyR/MMR No 12 10/2005 74 Kidney 01/2007 15 CCyR/MMR Yes 13 03/2005 64 NHL 09/2005 6 CCyR/MMR No 14 04/2005 77 NHL 04/2006 12 CCyR/MMR Yes 15 03/2005 64 NHL 07/2005 4 CCyR/MMR No 16 06/2005 70 Pancreas 05/2006 11 CCyR/MMR No 17 03/2005 79 MM 08/2006 17 CCyR/MMR No 18 07/2005 57 Lung 07/2008 36 CCyR/MMR No Table 1: patients that developed II malignancy during imatinib treatment. CNS: Central nervous System; NHL: Non-Hodgkin's Lymphoma; MM: Multiple Myeloma.