Dasatinib Commonly Induces Lymphocytosis in CML Patients

Patients with chronic myeloid leukemia (CML) who are treated with the tyrosine kinase inhibitor (TKI) dasatinib commonly experience lymphocytosis, and the condition is associated with higher response rates and increased survival in patients who are refractory or intolerant of imatinib, according to a new study.

Dasatinib is known to have immunosuppressive effects, potentially including the inhibition of lymphocyte proliferation. “Therefore, it was somewhat surprising that clonal expansion of cytotoxic T cells or natural killer cells was detected after initiation of dasatinib therapy in small studies of CML,” wrote study authors led by Charles A. Schiffer, MD, of the Barbara Ann Karmanos Cancer Institute at Wayne State University in Detroit.

The researchers aimed to expand on observational studies of lymphocytosis in dasatinib-treated CML patients with an analysis of 1,402 patients who were enrolled in three large clinical trials. The results were published online ahead of print in Cancer.

In total, lymphocytosis developed in 32% to 35% of patients, and the condition persisted for at least 12 months in 52% to 77% of patients; the median time to detection after dasatinib initiation was 3 to 5 months. The rate of lymphocytosis was similar across different dasatinib doses and schedules, and was much higher than in imatinib-treated patients; only 8% of imatinib-treated patients in one of the three trials (DASISION) had lymphocytosis, and the authors noted that it was almost always a transient condition.

Lymphocytosis was associated with higher rates of complete cytogenetic response (CCyR) compared to those without lymphocytosis in all phases of CML, including newly diagnosed chronic-phase disease (P = .0166), imatinib-resistant/intolerant CML (P = .0011), accelerated-phase CML (P = .0004), and CML in myeloid blast phase (P = .0030). Major molecular responses were also more common in patients with lymphocytosis in newly diagnosed and imatinib-resistant/inolerant patients.

In the study with the longest follow-up (CA180-034, 7 years), patients with lymphocytosis had both longer progression-free survival (P = .0119) and overall survival (P = .0349); the authors noted that the separation of the survival curves began about 2 years from the start of treatment. Overall, patients with newly diagnosed chronic-phase CML with lymphocytosis did have prolonged progression-free and overall survival, but this was not significant at 5 years of follow-up.

Pleural effusion, an important side effect of dasatinib, was more common in lymphocytosis patients; this reached significance specifically for patients with accelerated-phase disease.

“The mechanism by which dasatinib induces these changes is unclear,” the authors wrote. “Lymphocytosis has not been noted after CML treatment with other TKIs, and we convincingly confirm this observation here through analysis of patients with [chronic-phase CML] who were treated on a randomized study of dasatinib vs imatinib.” They added that the frequency of lymphocytosis occurrence suggests trials using dasatinib, perhaps in combination with other immunomodulatory agents, could be of interest.