Clarithromycin Enhances tyrosine Kinase Inhibitor – Induced Cell Death by Inhibition of Late Stage Autophagy in Patients with Chronic Myeloid Leukemia At Diagnosis or with Resistant Stage of Disease

Abstract 3777

Recent laboratory studies have demonstrated that clarithromycin (CAM) is effective at increasing the sensitivity of chronic myeloid leukemia (CML) cells to tyrosine kinase inhibitors (TKIs). The mechanism of induction of cell death by CAM combined with TKI appears to be via inhibition of late stage autophagy inhibitor chloroquine. This is clearly demonstrated by an increase in LC3-II protein levels and a concomitant increase in cellular vacuole formation (L. Shafranek, T.P. Hughes, Leukemia & Lymphoma 2012, early online 1–4). On our protocol, approved by our Ethical Committee, we treated 8 CML patients. Four consecutive patients, with advanced CML, who were in all cases resistant to TKI alone, achieved remarkable responses to the combination of TKI and CAM (Table 1). According to this positive experience, we thought that the combination CAM + TKI could be employed upfront at diagnosis, in the attempt to increase a faster complete molecular remission. Until now we have treated four patients at diagnosis. The median age was 45 years (range, 40 – 52). Two patients had intermediate and 2 patients high Sokal/Euro risk (Table 2). Two patients received imatinib 400 mg/die and 2 patients nilotinib 600 mg/die. CAM was given at a dose of 500 mg b.i.d. when the patients reached <20×10⁹/L WBC after TKI alone. Since TKIs can inhibit CYP3A3, all patients were evaluated weekly for GOT/GPT/gGT, bilirubin, lipase, amylase; moreover imatinibemia or nilotinibemia were evaluated every 7–10 days. In case of the increase of TKIs value >1.000 ng/mL, we reduced the dose of CAM to 500 mg/die or we discontinued the drug if the value was >2.000 ng/mL. In six patients this combination did not result in liver, renal or cardiac toxicity. In two patients (one resistant and one at diagnosis) the TKI plasma levels reached values over 2.000 ng/mL and an increase of indirect bilirubinemia combined with amylase/lipase increase was achieved. We stop CAM and reduced TKIs with prompt renormalization of all values. With this adjustment the value of TKIs were maintained under 1.000 ng/mL. Three out four patients treated at diagnosis achieved CCyR and MMR at 3, 3, 6 months and 5, 10 and 12 months, respectively. No patient has gone off study for toxicity and in no case we observed grade 3–4 myelosuppression. The remarkable responses obtained in these patients support the hypothesis that inhibition of autophagy may make CML cells sensitive to killing by TKIs.

Ly/BCR-CML: Lymphoid blast crisis/CML d'emblee; CHR: Complete Hematologic Remission, CCyR: Complete Cytogenetic Remission; PCyR: Partial Cytogenetic Remission; MMR: Major Molecular Remission