First-Line Dasatinib in BCR-ABL1+ Chronic Myeloid Leukemia in Early Chronic Phase: A Gimema Prospective Multicentric Observational Study

Background: Dasatinib (DAS) is a 2^nd generation (2^nd gen) tyrosine kinase inhibitor (TKI) approved for 1^st line treatment of chronic myeloid leukemia (CML) patients based on DASISION study results. Most data on 2^nd generation TKIs are from company-sponsored studies, but the patient selection and the high rate of patient switching to other treatments may jeopardize data interpretation. Interestingly, despite significant differences in terms of cytogenetic and molecular response, 2^nd gen TKIs did not produce relevant advantages in terms of overall survival (OS). A post-marketing surveillance in large independent trials is extremely important to confirm efficacy and the safety data.

Aims: To describe, in the clinical practice, the response to DAS and the events leading to permanent treatment discontinuation.

Methods: An italian multicentric prospective observational study of CML patients treated frontline with DAS has been conducted by the GIMEMA CML Working Party. DAS was given at the discretion of investigators, according to prescribing information, without any exclusion criteria, apart from age (<18 years old) and prior treatment with TKIs or interferon. Molecular response was assessed in standardized molecular laboratories (Labnet network): major molecular response (MR3.0 or MMR), BCR-ABL1 < 0.1% IS; MR4.0, BCR-ABL1 < 0.01% IS or undetectable disease with ≥10,000 ABL1 copies; MR4.5, BCR-ABL1 < 0.0032% IS or undetectable disease with ≥32,000 ABL1 copies. Progression was defined as transformation to advanced (accelerated or blast) phase, according to ELN criteria.

Results: 147 CML patients in early chronic phase have been enrolled in 27 italian hematologic centers. The median age was 57 years (65 years or older: 34% of patients). High risk patients according to Sokal, Euro and EUTOS score were 28%, 11%, and 13%, respectively. Median follow-up: 12 months. At 3 months, 88% of patients had BCR-ABL1 transcript levels < 10% IS (at the same timeopoint, < 1% in 66% of patients). At 6 months, 81% of patients had BCR-ABL transcript levels < 1%. The MMR rates at 6 and 12 months were 53% and 72%, respectively. The proportion of patients achieving a MR4 or a MR4.5 at least once was 35% and 16%, respectively. At the last contact, the patients still on treatment with DAS were 88%, while 12% permanently interrupted the study drug. The reasons for study discontinuation were: 1% progression in advanced phase, 2% failure, 1% unrelated death, 1% lost to follow-up, 7% adverse event (1% hematologic toxicity, 4% pleural effusion, 1% tachyarrythmia, 1% other non-hematologic adverse event). No pulmonary hypertension or cardiovascular ischemic adverse events were reported. The probability of OS and progression-free survival at 1 year was 98% and 99%, respectively.

Conclusion: The median age of patients receiving DAS in our observational trial was close to the median age reported in population-based CML registries, with one third of patients at least 65 years old; consequently, we may argue that, outside of clinical trials, the decision to treat or not to treat patients with DAS is probably not influenced by age. The proportion of high risk patients, as expected, was higher than reported by population-based CML registries. High molecular response rates were observed and the most frequent reason of permanent treatment discontinuation was the occurrence of adverse events (in particular, pleural effusion).