Disseminated tuberculosis with central nervous system involvement in a patient with chronic myeloid leukaemia receiving dasatinib: cytochrome P450 3A4-mediated drug interaction and multifactorial cytopenia

Abstract

Concurrent chronic myeloid leukaemia (CML) and tuberculosis presents substantial management challenges when tyrosine kinase inhibitor therapy must be combined with rifampicin-based anti-tubercular treatment. Rifampicin, a potent inducer of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein, reduces the maximum plasma concentration (C_max) and area under the concentration-time curve (AUC) of dasatinib by 81% and 82%, respectively, potentially compromising molecular disease control. We report a 27-year-old man with BCR::ABL1-positive CML in chronic phase, previously in complete cytogenetic and major molecular response on dasatinib 100 mg daily, who presented with generalised tonic-clonic seizures. Magnetic resonance imaging of the brain showed multiple ring-enhancing lesions with leptomeningeal enhancement and vasculitic infarcts. A clinical diagnosis of disseminated tuberculosis with central nervous system involvement was made and treated empirically; the documented findings met, at most, the “possible” category of the Marais consensus case definition for tuberculous meningitis. Rifampicin-containing anti-tubercular therapy was started and dasatinib was escalated to 140 mg daily. Approximately three and a half months later he was readmitted with severe thrombocytopenia (nadir 10.0×10³/µl), a rising leukocyte count (53.3×10³/µl) and life-threatening hypercalcaemia (corrected serum calcium 17.0 mg/dl). Dasatinib was withheld and intensive supportive care was given, after which he was discharged for outpatient follow-up; outcome data beyond discharge were not available. This case illustrates the pharmacokinetic conflict between dasatinib and rifampicin and its clinical consequences when dose escalation within the approved range proves insufficient. Rifabutin substitution, rifampicin-free anti-tubercular regimens, asciminib and therapeutic drug monitoring (TDM) of dasatinib are discussed as management strategies, although none has been validated in this clinical scenario.