Molecular “warning” CML patients: a retrospective study of Gruppo Triveneto LMC.

Background: Response to TKI is considered the strongest predictor of long- term outcome in CML patients. As known, effective treatment overcomes the negative impact of most prognostic factors, including Sokal score. Different studies have demonstrated that early molecular response is strictly correlated with outcome: infact, missing the 10% BCR-ABL landmark at 3 months predicts inferior long-term survival. Aims: We investigated the dynamics of 3 months molecular “warning” CML patients at 6 and 12 months landmarks; secondly, we sought to evaluate the impact of Sokal score in the context of this unfavourable group. Methods: A total of 51 patients with BCR-ABL levels >10% at 3 months were identified for the analysis from a cohort of 350 consecutive CML patients treated with front-line standard dose imatinib (400 mg daily). “Optimal”, “warning” and “failure” responses were stated according to ELN2013 recommendations. Com- plete cytogenetic response (CCyR) was defined as 0% Ph+metaphases; major molecular response (MMR) was defined as BCR-ABL <0.1%IS. TTF was meas- ured from the start of imatinib to the date of any of the following events: pro- gression to accelerated or blastic phase, death for any cause at any time, pri- mary or secondary hematologic, cytogenetic or molecular resistance leading to imatinib discontinuation. PFS was measured from the start of imatinib to the date of progression to accelerated or blastic phase or death for any cause at any time. Survival probabilities were estimated by the Kaplan-Meier method and compared by log rank test; differences among variables were evaluated by the Fisher’s exact test or by Cochran–Mantel–Haenszel test. Results: The median age of patients was 56 years (range 25–81), with 33 males and 18 females. The median follow-up was 45.3 months (range 7–110). The distribution of patiens according to the Sokal score was: 11 (21.6%) in the low risk, 24 (47.1%) in the intermediate and 16 (31.4%) in the high risk group, respectively. At 6 months, only 3 of 40 evaluable patients, 1 in each group (11.1%, 5% and 9% respectively), improved their 3 months molecular response, achieving an optimal response. 20 failures, defined as more than 10%IS BCR- ABL transcript level, were recorded (1, 11 and 8 in low, intermediate and high risk group respectively, P=0.008 comparing low vs other risk groups). At 12 months, 21 of 25 evaluable patients were considered failures; only 1 patient gained an optimal response. 27.2%, 50% and 50% of low, intermediate and high Sokal score patients failed to achieve a CCyR at any time (P=0.047), while 72.7%, 45.8% and 31.3% of patients obtained a MMR (P=0.104), respec- tively. Median time to CCyR and MMR was 12, 12.5, 24.5 months (P=0.21), and 30, 25 and 22 months (P=0.21) for low, intermediate and high risk group responding patients. Imatinib discontinuation rate, albeit remarkable in all Sokal groups, was not significantly different (66.7% vs 78.3% vs 93.8% respectively, P=0.22), as well as PFS (P=0.349), TTF (P=0.321) and OS (P=0.812). 9.1%, 12.5% and 25% of low, intermediate and high Sokal risk patients progressed to AP/BC phase, respectively. Summary and Conclusions: These data suggest that although non-low Sokal score CML patients may experience a higher probability of early failure, long term outcomes of molecular “warning” patients seem not to be significantly influenced by Sokal risk. Therefore, 3-months BCR-ABL transcript level higher than 10% IS appears to overcome non only the negative, but also the positive prognostic impact of Sokal score. These observations warrant further confir- mation in larger studies.