Long-Term Follow-up in Very Elderly Patients with Chronic Myeloid Leukemia Treated with Imatinib Frontline
Authors: Latagliata Roberto , Breccia Massimo , Ferrero Dario , Cavazzini Francesco , Trawinska Malgorzata Monika , Castagnetti Fausto , Annunziata Mario , Stagno Fabio , Tiribelli Mario , Binotto Gianni , Fava Carmen , Crisà Elena , Mansueto Giovanna , Gozzini Antonella , Falzetti Franca , Montefusco Enrico , Iurlo Alessandra , Sabina Russo , Cedrone Michele , Russo Rossi Antonella , Gugliotta Gabriele , Pregno Patrizia , Isidori Alessandro , Avanzini Paolo , Endri Mauro , Romano Atelda , Giglio Gianfranco , Celesti Francesca , Sorà Federica , Storti Sergio , D'Addosio Ada , Galimberti Sara , Orlandi Ester Maria , Calistri Elisabetta , Bocchia Monica , Crugnola Monica , Rege Cambrin Giovanna , Vigneri Paolo , Luciano Luigiana , Abruzzese Elisabetta , Alimena Giuliana 
Published: October 2019

Abstract
In the current clinical practice, imatinib is widely used also in very elderly patients with chronic myeloid leukemia (CML) at different doses based on concomitant diseases and physician' judgment. However, data on long-term follow-up of these patients are still lacking. To address this issue, we revised in our retrospective database 233 CML patients aged ≥ 75 years and treated with imatinib frontline in 34 italian hematological centers from 2/2002 to 7/2014. Median age at diagnosis was 78.4 years [interquartile range (IQR) 76.3 - 81.3], there were 113 males (48.5%) and 120 females (51.5%), median WBC, Hb and PLT counts were 45.0 x 109/l (IQR 29.4 - 83.4), 12,4 g/dl (IQR 11.0 - 13.6) and 375 x 109/l (IQR 238 - 680), respectively. Sokal Risk at diagnosis was low in 1 patient (0.4%), intermediate in 149 (67.4%), high in 71 (32.2%) and not evaluable in 12. One or more concomitant diseases requiring specific treatments were present in 225/233 patients (96.5%). Median interval from diagnosis to imatinib start was 0.7 month (IQR 0.2 - 1.4): the initial imatinib dose was 400 mg/day in 161 patients (69.1%), 300 mg/day in 57 (24.5%) and < 300 mg/day in 15 (6.4%). According to WHO, a grade 3 - 4 hematological and extra-hematological toxicity was reported in 44 (18.8%) and 41 (17.6%) patients, respectively. As to cumulative response, 13 patients (5.6%) discontinued IM due to early toxicity, 4 (1.7%) were resistant and 2 (0.8%) died from unrelated cause early after IM initiation: the remaining 214 patients (91.9%) achieved a complete haematological response (CHR). Among these 214 patients in CHR, 13 refused any other karyotipic or molecular evaluation, 23 achieved CHR only and 178 (76.4% of all 233 patients) achieved a cytogenetic response (CyR), which was partial in 16 patients and complete (CCyR) in 162 (69.5% of all 233 patients). In addition, among the 162 patients in CCyR, 125 (53.6% of all 233 patients) achieved a molecular response (MolR) (ratio < 0.1). A blastic phase occurred in 11 patients (4.7%). After a median follow-up from imatinib start of 45.0 months (IQR 22.3 - 72.0), 70 patients have died (9 from disease progression and 61 from unrelated causes), 16 patients were lost to follow-up and 147 are still alive (115 of them still in treatment with imatinib): 5-year event-free survival (EFS) and overall survival (OS) were 51.4% (CI95% 43.9 - 58.9) and 68.5% (CI95% 61.2 - 75.8), respectively. At univariate analysis, only the initial dose of imatinib (400 vs ≤ 300, p=0.03) was a significant predictive factor for CCyR achievement while only PLT count ≤ 500 x 109/l (p=0.031) was a significant predictive factor for MolR achievement. At multivariate analysis for EFS, achievement of a MolR (OR 0.25, 95%CI 0.14 - 0.43, p<0.001), achievement of a CCyR (OR 0.40, 95%CI 0.23 - 0.67, p=0.001) and spleen enlargement (OR 1.56, 95%CI 1.01 - 2.41, p=0.042) were independent prognostic factors; at multivariate analysis for OS, achievement of a MolR (OR 0.30, 95%CI 0.18 - 0.49, p<0.001), age < 80 yrs (OR 0.53, 95%CI 0.33 - 0.86, p=0.011) and male gender (OR 1.80, 95%CI 1.11 - 2.91, p=0.016) were independent prognostic factors. In conclusion, the long term follow-up of very elderly CML patients who started imatinib is very good and justify any effort to treat these patients with standard doses, in order to achieve cytogenetic and molecular responses as in younger subjects.

Disclosures
Castagnetti: BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria. Tiribelli:Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Novartis Farma: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau. Gugliotta:BMS: Honoraria; Novartis: Honoraria. Abruzzese:BMS, Novartis, Pfizer, Ariad: Consultancy.