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Development of tyrosine kinase inhibitors (TKI) has significantly changed natural course of chronic myeloid leukemia (CML) and increased 10 year overall survival from 10-20% to 80-90%. Until recently, imatinib was the standard first-line treatment in CML. In 2013, nilotinib and dasatinib were approved as alternative front-line options. However, none of three TKI has been shown to have a clear survival advantage so this raised a debate on treatment selection. The early identification of patients expecting poor outcome is crucial for offering an alternative TKI regimen.

to analyze predictive parameters for Imatinib response as first-line treatment of CML patients.

The study was conducted on 168 consecutive patients with chronic phase of Ph+ CML who were diagnosed and treated at single university hospital from December 2000-January 2015. Following data were analyzed in terms of treatment response to Imatinib: demographic characteristics; currently used prognostic scores (Sokal, Hasford, EUTOS); liver and spleen size; laboratory parameters; influence of comorbidities analyzed by three scores (ACE 27, HCI-CI, SCIRS); occurrence of second malignancies; conventional cytogenetic results; therapy, duration of therapy, cytogenetic responses, overall survival (OS) and outcome.

The mean age at diagnosis was 48±14.4 years (range: 18-74) with 87.5% of patients< 65 years. The OS at 5 and 10 years was 97% and 91% respectively. Overall response to Imatinib treatment was as the follows: 131 patients (78%) achieved CCyR, 14 patients (8.3%) majorCyR, 4 patients (2.4%) minorCyR, 16 patients (9.5%) had no cytogenetic response, 2 patients (1.2%) had hepatic toxicity verified by liver biopsy in the first six months of Imatinib treatment and 1 patient (0.6%) was lost from follow-up. After achievement of CCyR, 25 patients (19%) had a progression of disease by losing CCyR or development of AP/BP. Median time to progression was 24 months (range 12-102).

After the median follow up of 87 months in 61 patients (36.3%), the Imatinib failure was verified. All three prognostic scores (Sokal, Hasford, EUTOS), age, gender, hemoglobin level, leukocyte and platelet count, splenomegaly, eosinophils and basophils in peripheral blood were not found to be statistically significant for the Imatinib failure. Cox regression analysis identified hepatomegaly (p=0.001), leukocytosis≥100x109/L (p=0.001), blood blasts≥1% (p=0.002) and presence of additional cytogenetic aberrations (ACAs) (p=0.002) as a predictors of Imatinib failure. Accordingly, we assigned risk scores based on hazard ratios (HR) to hepatomegaly (HR = 4.089; 2 points), leukocytosis ≥100x10⁹/L (HR = 3.158; 1 point), blasts in peripheral blood ≥1% (HR = 2.912; 1 point), and presence of ACAs (HR = 11.110; 2 points). A final 3-tiered prognostic model named IMA-FAIL was thus developed, as low (score 0), intermediate (score 1-3), and high risk (score ≥4), according to which imatinib failure had 17% (8/47) of patients in low, 34.9% (30/86) in intermediate and 76.7% (23/30) in high risk group (HR = 3.973, 95% CI for HR 2.237-7.053, p < 0.001). In addition, presence of comorbidities as well occurrence of second malignancy were not predictors for Imatinib failure.