Imatinib Resistance Restoration with Antioxidants and Immunomodulation in Patients with Chronic Myelogenous Leukemia (CML).

Imatinib mesylate (IM) is potent BCR/abl tyrosine kinase inhibitor in patients with chronic myelogenous leukemia (CML). It has remarkable frontline clinical effects in this disease, however, the leukemic cells become resistant to IM in both chronic and blast phases. BCR/abl kinase can induce reactive oxygen species (ROS) and promote self-mutation which subsequently render IM to resistance and failure to eliminate all leukemia cells. This mechanism of resistance in IM (mutation) is caused by oxidant damage to DNA with kinase domain mutations, reduced IM binding and kinase inhibition. Antioxidants (ascorbic acid, etc.) may help overcome IM resistance and restore sensitivity to IM via suppression of transcription factor Nrf2 that regulates the gene expression gammaglutamylcysteine ((g-GCS), the rate-limiting enzyme in glutathione (GSH) biosynthesis and detoxification. P-glycoprotein (P-gp) drug efflux can also exist and complete molecular response relapse occurs. Leukemic cells that are P-gp positive, and P-gp dependent decline of intracellular

IM levels are associated with retained phosphorylation pattern of BCR/abl and loss of IM effect on apoptosis and cellular proliferation. Modulation of P-gp with HMG-CoA reductase inhibitor simvastatin may help restore IM cytotoxicity. We present a case of an 80+ year old female with CML-chronic phase-II (CML-CP-II) with concommitant cormorbidities of CAD, unstable angina, hypertension, and dyslipidemia treated with aspirin, simvastatin and started on IM 400mg daily. After two months of therapy she developed grade 3 neutropenia, lower extremity edemia, nausea/vomiting and fluid retention requiring IM interruption and supportive care with growth factors. IM dose reduction to 300mg daily and simvastatin 10 mg every other day. Soluble interleukin-2 receptor (sIL-2R) levels were elevated and trending down once proinflammatory cytokines were modulated. Real-time BCR-ABL/abl-PCR ratio increased insignificantly from 0.001% to 0.003%. Betacarotene level significantly decreased to 4, ascorbic level within normal limits, VEGF remained < 31 pg/ml (normal 31–86 pg/ml), fibrinogen level 309.90 mg/dl (normal 162–431), ESR 15 mm/hr, C-reactive protein 5.55 mg/dl and sIL-2R increased to > 3,000 U/mL (normal 200– 1100 U/mL). Betacarotene and ascorbic antioxidants dosage were increased and immunomodulation of preinflammatory cytokines ROS, sIL-2R and betacarotene normalized, 512 and 44 respectively. Serial measurement of BCR-ABL/abl ratio did not exceed 0.02% on three occasions or 0.05% on two occasions, therefore no molecular relapse and persistent low levels of BCR-ABL/abl ratio with no hematologic or cytogenetic relapse. We felt that an acute coronary syndrome with perturbation of CML with some IM resistance was developed.

CONCLUSION: IM, a tyrosine kinase inhibitor may develop resistance when leukemic cells are positive with P-gp and oxidative stress increase ROS along with decreases in IM intracellular levels. Modulation by HMG -CoA reductase inhibitor (simvastatin) via a mechanism of inhibition of P-gp transport and antioxidants reduction of BCR/abl mutagenesis may allow IM to efficently restore normal hematopoiesis in CML patients.