211P - Chemotherapy delivery time affects anti-lymphoma treatment outcome in a sex-dependent manner

Background

Chronotherapy is a drug intervention at specific times of the day to optimize efficacy and minimize adverse effects. Although chronochemotherapy has been proven to be effective in solid tumors, its value in hematologic malignancy remains unknown. In this study, we tried to identify a chronotherapeutic effect and underlying mechanism of immunochemotherapy in diffuse large B cell lymphoma (DLBCL) patients.

Methods

We performed chronotherapeutic analysis using two cohorts of DLBCL patients undergoing chemotherapy with a dichotomized schedule (morning or afternoon) at a daycare chemotherapy center. The effect of the chronotherapeutic 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.

Results

In the survival cohort, 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). Consistent with this, the dose intensity of R-CHOP was reduced in female patients in the adverse event cohort (cyclophosphamide 10%; p=0.002, doxorubicin 8%; p=0.002 and rituximab 7%; p=0.003). This reduced dose intensity was mainly attributable to infection and neutropenic fever. In healthy subjects, we found that white blood cell count (WBC) and absolute neutrophil count (ANC) of females were lowest in the morning with exaggerated diurnal fluctuation, which potentially explains the reduced survival and serious adverse effects in female patients receiving morning treatment.

Conclusions

Administration of R-CHOP in the morning reduces the tolerability of chemotherapy and negatively affects the survival outcome of female DLBCL patients, which may be attributable to the diurnal variation of specific hematologic parameters.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Seoul National University Hospital.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.