RAS Mutated, APL
Leukemia Insights - Summer 2011
- Ph II GSK1120212
- Ph I/II Mek Inhibitor MSC1936369B
Both GSK1120212 (Gilmartin A, Clin Cancer Res, 2011, 17, 989-1000) and AS703026 (Yoon J, Cancer Res, 2011, 71, 445-53) are inhibitors of MEK 1/2 and are expected to be active in hematological malignancies associated with activation of RAS/RAF/MAP kinase pathway, a pro-survival pathway activated through mutations or otherwise in myeloid malignancies. All patients with AML, MDS or CMML are routinely tested for RAS at MD Anderson Cancer Center.
Data from a phase I study of GSK1120212 presented at the 2010 ASH annual meeting showed that GSK1120212 administered at 2mg/day orally was tolerable in subjects with relapsed or refractory AML and other leukemias. This dose regimen achieved plasma concentrations sufficient for target inhibition and showed preliminary anti-leukemic clinical activity. Based on these results, a phase II study in AML, MDS and CMML has been initiated (Borthakur G, Blood, ASH Annual Meeting Abstracts, 2010, 116, 3281). Eleven patients were treated with MSC1936369B at our institution. Stable disease lasting 12 weeks or more has been reported in 3 patients with relapsed/refractory AML, 1 of 3 patients had transient clearance of blasts from peripheral blood (Ravandi F, Blood, ASH Annual
Meeting Abstracts, 2010, 116, 3296). This study continues to accrue.
Tamibarotene is a synthetic retinoid that has been shown to be well-tolerated and effective in both the newly diagnosed and relapsed/refractory APL populations in studies in Japan (Takeuchi M, Leuk Lymphoma, 1998, 31, 441-51). Compared to ATRA, Tamibarotene is 10 times more potent as it shows lower affinity for the cellular retinoic acid binding protein allowing for greater drug availability in the nucleus (Ohnishi K, International Journal of
Clinical Oncology, 2007, 12, 313-317).
Tamibarotene is currently approved in Japan for treatment of recurrent APL. There is a Special Protocol Assessment (SPA) in place with the FDA for a phase II clinical trial, known as STAR-1, which is evaluating the efficacy and safety of Tamibarotene as a third-line treatment for APL. The STAR-1 trial is ongoing and currently includes six clinical sites in the U.S. Of the 11 patients enrolled in the STAR-1 trial to date, three (27%) achieved a hematologic complete response, and four (36%) a morphologic leukemia-free state (Cortes-Franco J, Blood, ASH Annual Meeting Abstracts, 2009, 114, 2050).
Recent discoveries confirm the complexity involved in understanding and treating acute leukemia. Targets for therapeutic intervention have been identified in both AML and ALL and further investigation of novel therapies will hopefully improve outcomes in patients with leukemia.
Although considered less toxic than traditional chemotherapy, targeted therapy will produce new adverse effects necessitating updated management strategies. Identifying disease characteristics and determining prognosis will continue to be important for directing treatment. With advancements in personalized therapy aimed at molecular or cytogenetic features of disease, long-term survival of patients with leukemia appears promising.