Chemotherapy delivery time affects treatment outcomes of female patients with diffuse large B-cell lymphoma.

Abstract

Chronotherapy is a drug intervention at specific times of the day to optimize efficacy and minimize adverse effects. Its value in hematologic malignancy remains to be explored, in particular in adult patients. We performed chronotherapeutic analysis using two cohorts of diffuse large B cell lymphoma (DLBCL) patients undergoing chemotherapy with a dichotomized schedule (morning or afternoon). The effect of a morning or afternoon schedule of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) on survival and drug tolerability were evaluated in a survival cohort (n = 210) and an adverse event cohort (n = 129), respectively. Analysis of ~14,000 healthy subjects was followed to identify the circadian variation in hematologic parameters. Both progression-free survival (PFS) and overall survival (OS) of female, but not male, patients were significantly shorter when patients received chemotherapy mostly in the morning (PFS hazard ratio [HR] 0.357; P = 0.033 and OS HR 0.141; P = 0.032). The dose intensity was reduced in female patients treated in the morning (cyclophosphamide 10%; P = 0.002, doxorubicin 8%; P = 0.002 and rituximab 7%; P = 0.003). This was mainly attributable to infection and neutropenic fever: female patients treated in the morning suffered from a higher incidence of infections (16.7% vs 2.4%) and febrile neutropenia (20.8% vs 9.8%) as compared to those treated in the afternoon. The sex-specific chronotherapeutic effects can be explained by the larger daily fluctuation of circulating leukocytes and neutrophils in females than in males. In female DLBCL patients, R-CHOP treatment in the afternoon can reduce the toxicity while it improves the efficacy and the survival outcome.