Clarithromycin Targeting Autophagy Potentiates Tyrosine Kinase Inhibitor-Induced Cell Death in Resistant Chronic Myeloid Leukemia (CML) Patients

Abstract 4450

M-TOR is a key regulator of autophagy. Rapamycin and clarithromycin (structurally similar to rapamycin), have been demonstrated to have in vitro activity in blocking autophagy. In four patients with advanced CML, remarkable response to the combination of clarithromycin and a tyrosine kinase inhibitor was observed. Here we present the results achieved by the combination.

A 43-year-old woman was diagnosed with high-risk Sokal CML in February 2000. She was treated with IFN-alpha and imatinib (400 mg/day) with persistence of 100% Ph-positive metaphases. In March 2006, WBC was no longer controlled and she was treated with nilotinib. Complete hematologic response (CHR) was achieved by the end of April 2006, but there was no cytogenetic response (CyR). She was given dasatinib (70 mg b.i.d.) without complete cytogenetic response (CCyR) and after 7 months the bcr-abl/abl ratio was 6.1% in March 2011. At that time, the patient had an infection (otits/pharyngitis) sensitive to clarithromycin, which was added to dasatinib at a dose of 500 mg b.i.d. April 2011 there was a surprising reduction in the transcript to 0.5%. As of June 2011, the value was 0.05%, and the patient continues to receive clarithromycin (500 mg/day) and dasatinib (100 mg/day). Nowadays (August 1), the patient is in CHR, CCyR and major molecular remission (MMR) (bcr-abl/abl ratio 0.001%). The patient stopped clarithromycin and he is continuing on dasatinib.

A 53-year-old man was diagnosed with de novo lymphoid blast crisis CML in August 2010; bcr-abl/abl ratio was 95.2%. He had a sibling donor. In October 2010 bcr-abl/abl ratio was reduced to 0.2% after chemo + imatinib. In November 2010, bcr-abl/abl ratio was 22% and he was treated with dasatinib (70 mg b.i.d.) with WBC control and a small reduction of bcr-abl/abl ratio (18% in February 2011). Soon thereafter, he underwent allogeneic transplant. Two months after transplant (May 2011) the disease progressed and bcr-abl/abl value had increased to 47%. He was restarted on dasatinib (100 mg/day) but the transcript increased in 4 weeks to 143%. Because of our previous experience, we added clarithromycin to dasatinib on June 2, 2011. Two weeks later, bcr-abl/abl value was reduced to 3.2%, and to 1.5% after another week. We stopped clarithromycin and three weeks later under dasatinib alone the transcript increased to 20%. From one week we added newly clarithromycin to dasatinib.

A 68 year old man was diagnosed with CML in October 1999. A CCyR was achieved after autografting and soon after IFN-alpha was given as maintenance. In October 2000 the patient relapsed. A second CCyR was achieved in December 2001 after imatinib (400 mg/day), which lasted for six years. In October 2006 bcr-abl/abl ratio was 4.5%. He was treated with dasatinib (70 mg. b.i.d.) with WBC control but with no CyR. In March 2011, bcr-abl/abl ratio was 42.5%. Nilotinib (600 mg. b.i.d.) was begun with no change in bcr-abl/abl ratio after 2 months. In June 2011, clarithromycin (500 mg. b.i.d.) was added; 3 weeks later, the bcr-abl/abl ratio had decreased to 17% and two weeks later (July 13, 2011) to 4%. On July 28, bcr-abl/abl is 0,00022%.

A 70 year old woman was diagnosed with CML in November 1998. She was treated with IFN-alpha but only partial CyR was achieved. In January 2001, 100% Ph-positive metaphases were found in BM. She was begun on imatinib (400 mg/day) but the karyotype did not change. In May 2005 she was started on nilotinib (600 mg/daily) since bcr-abl/abl ratio was 26.5%. Blood counts were controlled but there was no change in cytogenetics. In August 2010 WBC increased to 100×10³/l. Dasatinib (70 mg. b.i.d.) was begun. Because blood count control was inadequate, hydroxyurea was added. In December 2010, bcr-abl/abl ratio had increased to 140%, and E255V mutation was found. In May 2011, clarithromycin (500 mg. b.i.d.) was added. In 2 weeks, the WBC had decreased from 76×10³/l to 10×10³/l and bcr-abl/abl ratio was 30% (June 4, 2011). One month later (July 4, 2011) bcr-abl/abl ratio was 3% and the mutation was no longer found in bone marrow. In the last evaluation (July 13, 2011) bcr-abl/abl ratio was 0.00096%. The patient stopped clarithromycin and she is on dasatinib alone.

In conclusion, no patients have gone off study for toxicity. In no case we observed grade 3–4 myelosuppression. The remarkable responses obtained in these 4 patients support the hypothesis that inhibition of autophagy may make CML cells sensitive to killing by tyrosine kinase inhibitors.