Concomitant Medications and Comorbidities Affect Early Response in CML Patients Treated with Imatinib: A Retrospective Analysis of 340 Patients from the Polish Adult Leukemia Group (PALG) Registry

Background : It has been consistently shown that early molecular response is associated with positive long-term outcome in terms of overall survival and progression-free survival in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs). Achieving a BCR-ABL(IS) <10% at three months has thereby become an important goal of treatment. According to current European LeukemiaNet recommendations, the optimal treatment response is defined as BCR-ABL(IS) ≤ 10% at three months and BCR-ABL(IS)<1% and/or complete cytogenetic response (CCyR) at six months. Factors influencing the early response are still largely unknown.

Our previous study demonstrated that more than half of newly diagnosed CML patients in Poland had comorbid conditions and received concomitant medications. TKIs are metabolized by the CYP3A4 isoenzyme and have been reported to be substrates of ABCB1 (MDR1) and ABCG2 (BCRP) transporters. Importantly, numerous commonly used drugs are transported and metabolized through the same pathways as TKIs. Drug interactions should therefore be considered when administering inhibitors or inducers of CYP3A4, ABCB1 and ABCG2 in combination with TKIs. Furthermore, it has been shown that the presence of comorbidities and the necessity of additional therapies may significantly affect treatment compliance.

Objectives: The primary objective of the study was to investigate whether the presence of comorbidities and additional therapies affected early response in CML patients treated with imatinib.

Patients and methods : We retrospectively analyzed patients with newly diagnosed CML who were receiving imatinib as the initial therapy for CML at nine Polish hematological tertiary care centers. Inclusion criteria were as follows: 1) age ≥18 years and 2) diagnosis of chronic phase CML between January 1st 2005 and December 31st 2014. Data on presence of comorbid conditions, concomitant drugs, cytogenetic and molecular response were anonymously collected through electronic case reports forms. Patients in whom therapy was changed because of imatinib intolerance were excluded. Influence of potential prognostic factors on probability of response at three and six months was tested by univariate and multivariate logistic regression.

Results : We enrolled 340 patients with CML in the chronic phase, with median age 53 years (range, 41-62) where 50 % were males. According to the Sokal score, 190 patients (55.9%) were classified as low risk, 107 (31.5%) as intermediate risk and 43 (12.5%) as high risk. Overall, 142 (41.8%) patients reported no comorbidities, 121 (35.6%) reported one or two comorbidities and 77 (22.7%) had more than two comorbid conditions. The most common comorbidities were: hypertension (30%), hypercholesterolemia (16%), ischemic heart disease (10%) and diabetes (9%). One hundred thirty (38.2%) patients received no additional therapies, 110 (32.4%) patients received one or two therapies and 100 patients (29.4%) more than two. The most frequently used drugs were: beta blockers (22% of patients), ACE inhibitors (19%) and statins (15%). At three months, a molecular analysis was done in 194 patients and 144 (74%) achieved BCR ABL(IS) of less than 10%. At six months, 217 patients underwent molecular analysis and 305 had cytogenetic assessment. One hundred thirty five patients (62%) achieved BCR-ABL(IS) < 1% and 198 (65%) achieved CCyR. Multivariate analysis revealed that at three months patients who had a low Sokal score, more than two comorbidities and received more than two concomitant therapies, significantly more often achieved BCR-ABL <1% (p=0.013, p=0.054 and p=0.005 respectively). At six months, patients who received more than two concomitant medications still tended to have a higher probability of optimal response: BCR-ABL(IS) <1% (p=0.062) and CCyR (p=0.035). Other potential prognostic factors analyzed including patients' age, sex and BMI had no impact on the probability of optimal response.

Conclusions: We found that comorbidities and concomitant therapies did not adversely affect early response to imatinib in CML patients. In contrast, patients with more than two additional therapies and comorbidities seem to more often achieve treatment goals. The potential explanations for these findings are drug interactions that increase imatinib exposure and better adherence to therapy of patients accustomed to systematic use of medications.