Second Generation Tyrosine Kinase Inhibitors (2G-TKI) in the Frontline Treatment of Elderly Patients with Chronic Myeloid Leukemia

Background and Aims. Second generation tyrosine kinase inhibitors (2G-TKI) dasatinib (DAS) and nilotinib (NIL) have been recently licensed for the first-line treatment of patients (pts) with chronic myeloid leukemia (CML) of any age. However, real-life data related to the toxicity and efficacy of 2G-TKI in elderly CML pts are still lacking. To address this issue, we revised a cohort of 126 CML pts in chronic phase aged >65 years and treated frontline with 2G-TKI in 33 Italian Centers.

Methods. Data from all consecutive CML pts aged >65 years treated frontline with 2G-TKI in both clinical trials and in the real-life setting from 10/2007 to 11/2016 at each participating Center were collected, focusing on efficacy and toxicity. Seventy-two pts were treated with DAS and 54 pts with NIL. The main clinical features of the pts at diagnosis are reported in the Table. In the DAS group, pts were significantly older and with a worse ECOG PS.

Results. In the DAS group, the median interval from diagnosis to treatment was 23 days (IQR 14 - 32). The DAS starting dose was 100 mg/day in 61 pts (84.7%) and <100 mg/day in 11 pts (15.3%). Grade 3-4 hematologic and extra-hematologic toxicities were recorded in 8 (11.1%) and 12 (16.7%) pts, respectively. DAS therapy was permanently discontinued in 12 pts (16.6%) due to toxicity (in 6 pts during the first 12 months of treatment and in 6 subsequently). Pleural effusions of all WHO grades occurred in 14 pts (19.4%) after a median period of DAS treatment of 3.6 months (IQR 1.4 - 13.1): in 5 of them, pleural effusion occurred during the first 3 months. Overall, 66/72 pts (91.6%) achieved a complete cytogenetic response (CCyR), 56/72 (77.7%) a major molecular response (MR3) and 29/72 (40.3%) a deep molecular response (MR4.0/4.5). After a median treatment period of 27.8 months (IQR 19.1 - 37.5), 7 pts have died (1 due to a blastic transformation and 6 for unrelated causes). The cumulative overall survival at 24 months was 90.4% (95% CI 82.9 - 97.9).

In the NIL group, the median interval from diagnosis to treatment was 27 days (IQR 15 - 71). The NIL starting dose was 600 mg/day in 49 pts (90.7%), 800 mg/day in 3 patients (5.6%) and <600 mg/day in 2 pts (3.7%), respectively. Grade 3-4 hematologic and extra-hematologic toxicities were detected in 5 (9.3%) and 10 (18.6%) pts, respectively. NIL therapy was permanently discontinued in 7 pts (13.0%) due to toxicity (in 1 pt during the first 12 months of treatment and in 6 subsequently). Grade 3-4 cardiovascular toxicities occurred in 7 pts (13.0%). Overall, 51/54 patients (94.4%) achieved a CCyR, 47/54 (87.0%) a major molecular response (MR3) and 30/54 (55.5%) a deep molecular response (MR 4.0/4.5). After a median treatment period of 41.1 months (IQR 20.3 - 52.6), 5 pts have died from unrelated causes. The cumulative overall survival at 24 months was 95.7% (95% CI 89.8 - 100).

Conclusions. The present data shows that 2G-TKI could have a major role in the treatment of real-life CML pts aged >65 years. Indeed, both DAS and NIL proved very effective and with a favorable safety profile also in elderly subjects with comorbidities.

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