Reduction of imatinib absorption after gastric bypass surgery

Imatinib mesylate is an orally bioavailable inhibitor of several protein tyrosine kinases, including BCR– ABL. Imatinib has considerable activity in chronic phase chronic myeloid leukemia (CML) [1] leading to Food and Drug Administration (FDA) approval for BCR–ABL-positive CML. This oral agent has approximately 98% oral bioavailability independent of a meal, achieves maximum plasma concentration approximately 2–4 h after ingestion, and has a plasma half-life of approximately 18 h [2,3]. The drug is eliminated by biliary excretion and hepatically metabolized, primarily by CYP3A4 to CGP74588. CGP74588 has similar biologic activity and represents approximately 20% of the imatinib plasma concentration [2,3]. Better clinical outcomes have been associated with higher steady-state imatinib trough levels for both CML and gastrointestinal stromal tumors (GIST) [4,5]. Because imatinib is absorbed, excreted, and possibly recycled in the gastrointestinal tract, gastrointestinal disorders impairing absorption may hinder achieving therapeutically effective imatinib levels. We present the case of a woman with CML who underwent biliopancreatic diversion with duodenal switch for weight loss, leading to a marked reduction in imatinib concentration, and inadequate suppression of her CML. A 54-year-old African-American woman was diagnosed with chronic phase CML. Her medical history was remarkable for asthma, diabetes mellitus, gastroesophageal reflux disease, obstructive sleep apnea, and morbid obesity, with a weight of 122 kg and a height of 166 cm resulting in a body mass index of 50. The time course of her imatinib treatment, blood levels, and response is summarized in Table I. Imatinib was started at 400 mg daily. A bone marrow (BM) evaluation at 3 months showed a reduction to 35% Philadelphia chromosome-positive cells (Phþ) by metaphase cytogenetics from 95% at diagnosis, achieving partial cytogenetic response. BM aspiration at 6 months revealed 15% Phþ cells. Imatinib was increased to 800 mg daily in two divided doses at month 8 because of a concern of an inadequate response. At month 11, the patient achieved a complete cytogenetic remission (CCyR) as demonstrated by 0% Phþ cells on BM examination. Molecular analysis by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) on bone marrow cells showed BCR–ABL-1.3% by the international scale (IS). However, on the higher imatinib dose, she experienced toxicities of abdominal pain, nausea, diarrhea, and muscle cramping. She was briefly switched to dasatinib at 100 mg/day but continued to have side effects of fluid retention, leg cramping, and nausea. She was evaluated at the University of Chicago for bariatric surgery for morbid obesity. A BM exam approximately 13 months after diagnosis on dasatinib confirmed CCyR and quantitative RT-PCR for BCR–ABL-0.16% (IS), approaching the threshold of BCR–ABL of50.1% (IS) required for a major molecular response (MMR). The IS was BCR–ABL0.29% on a concomitant blood sample. Since the patient had achieved an adequate response according to the current European LeukemiaNet guidelines (i.e. partial cytogenetic response at month 6) to