Tyrosine-Kinase Inhibitors Well Tolerated, Despite Lack of Tests in Chronic Myeloid Leukemia Patients With Comorbid Conditions

Chronic myeloid leukemia patients likely have comorbid conditions at the time of their diagnosis; however, most tyrosine-kinase inhibitor studies exclude patients with these conditions.

Despite a lack of patients with chronic myeloid leukemia (CML) and comorbid conditions in clinical trials of tyrosine-kinase inhibitors (TKIs), the results of a study appearing in the October 2013 edition of Expert Review of Hematology suggest that imatinib, dasatinib, and nilotinib tend to be well-tolerated by patients.

Despite the general safety of TKIs and the lack of a significant contraindication for the therapies, information on dasatinib and nilotinib remains limited, the authors noted.

“A comprehensive comorbidity evaluation may be useful to improve TKI selection and safety in CML patients, especially in those considered elderly simply on registry age,” the authors wrote.

The median age of CML diagnosis is between 60 and 65, which increases the chances of concurrent conditions such as diabetes mellitus, non-diabetes metabolic syndromes, hyper- or dyslipidemia, and cardiovascular conditions. Many older patients meet the trials’ exclusion criteria, so clinical trials tend to include patients with a median age of 50 years. As a result, the trials are conducted with low comorbidity prevalence, the authors noted.

“Considering the increasing prevalence and public health impact of comorbid patients, clinical trials should not only focus on the index condition but also give higher relevance to patients with comorbidities, limiting the exclusion criteria only to well-established risk conditions, and performing a careful evaluation of comorbidity effect on the treatment outcome,” they wrote.

It can be difficult to assess the impact of comorbid conditions on adverse effects in patients using TKIs because the comorbid conditions are often identified in retrospective studies exclusively, they noted. Their research revealed 4 CML studies using comorbidity indexes: 3 studies evaluated the efficacy and tolerability of imatinib exclusively, whereas a single study evaluated the use of dasatinib in patients who were resistant or intolerant to imatinib. In general, the researchers determined that the treatments were safe in patients with comorbid conditions, and indicated comorbidity scales that may assist in clinical decision-making.

Meanwhile, the researchers also assessed CML, comorbidities, treatment efficacy, and adverse reactions in the DASISION trial, a Phase III trial comparing dasatinib to imatinib in newly diagnosed Philadelphia Chromosome—positive CML patients. Although the trial does not use a comorbidity index, the authors noted frequency each disorder occurred as well as frequency of adverse effects. The most frequently occurring disorders included gastrointestinal disorders, followed by muscle-skeletal disorders, and non-diabetes endocrine-metabolic disorders, they noted. Although drug exposure, dose modification, and treatment discontinuation were similar between patients with preexisting comorbidities and patients without comorbidities, certain adverse effects occurred more frequently in patients with comorbidities.

In particular, nausea and vomiting, and rash tended to appear more frequently in patients with comorbid conditions receiving dasatinib than in patients without comorbidities receiving dasatinib. In addition, diarrhea and superficial edema tended to occur more frequently in patients with comorbid conditions who received imatinib than in patients without comorbidities who received the same therapy.

In addition, certain treatment side effects appeared to have little effect on comorbid conditions, the authors noted. Fluid retention, a toxic side effect of imatinib, was not found to relate to chronic heart failure, despite the conditions’ clinical resemblance. Meanwhile, pleural effusion, a side effect of dasatinib, was found to increase only slightly in patients with comorbid conditions; however, the increase was not statistically significant.

Bleeding complications, another side effect of dasatinib, were more prevalent in patients with known history of bleeding problems, and in those taking antiplatelet or anticoagulant drugs.

In patients with hyperglycemia being treated with nilotinib, therapy had no impact on hyperglycemia rates, the researchers determined. In addition, nilotinib’s safety and efficacy in patients with type 2 diabetes was similar to that of patients without the condition.

“According to available data, we may say that no absolute significant contraindication exist [sic] to treat a given CML patient with imatinib, dasatinib, or nilotinib. … these TKIs are characterized, in general, by a very good profile of safety and tolerability,” the authors wrote.