Researchers from Germany have reported that Nexavar® (sorafenib) is an active agent for the treatment of acute myeloid leukemia (AML) in patients with internal tandem duplication (ITD) mutations in the Fms-like tyrosine-3 (FLT3) gene. The details of this study appeared in the June 25, 2009 issue of Blood.[1]

FLT3 is a receptor tyrosine kinase with important roles in hematopoietic stem/progenitor cell survival and proliferation. It is mutated in about 1/3 of AML patients, either by ITD or by point mutations usually involving the kinase domain. Both types of mutation constitutively activate FLT3. Many studies have shown that AML patients with FLT3-ITD mutations have poor cure rates due to refractory disease or to relapse. This has led to the development of a number of small molecule tyrosine kinase inhibitors with activity against FLT3. Many of these are still in preclinical development, but several have entered clinical Phase I and II trials as monotherapy in patients with relapsed AML. Because of the poor prognosis, many patients with FLT3 mutations are offered aggressive therapy with an allogeneic stem cell transplantation.

Nexavar is an orally active, multi-kinase inhibitor approved by the U.S. FDA for the treatment of advanced renal cell carcinoma and inoperable hepatocellular carcinoma. Nexavar is also being evaluated in patients with other cancers, including non–small cell lung cancer and melanoma. In vitro studies have shown that Nexavar exhibits potent target inhibition and efficacy in FLT3-driven models.[2] There is one case report of a complete molecular remission in a patient with extramedullary FLT3-ITD(+) AML following treatment with single-agent Nexavar.[3] 

At ASH 2008, researchers from the M. D. Anderson Cancer Center presented Phase I (n=10) and II (n=30) data on treating patients younger than age 65 years with newly diagnosed AML with the combination of Nexavar, idarubicin, and cytarabine.[4] The CR rate for 25 evaluable patients was 88%. In vitro studies suggest greater activity in patients with mutant versus wild type FLT3.

The authors of the present study treated six patients with relapsed or refractory FLT3-ITD-positive AML with Nexavar. Two patients were treated before allogeneic stem cell transplantation, three after allogeneic stem cell transplantation, and one before and after an allogeneic stem cell transplantation. These authors reported that Nexavar treatment produced remissions in two of three refractory patients prior to transplantation. Two of four patients treated after stem cell transplantation with Nexavar remain in complete molecular remission. These authors concluded: “Together, sorafenib monotherapy before or after allo-SCT has remarkable clinical activity in poor risk FLT3-ITD positive AML and deserves further evaluation in prospective clinical trials.”

Comments: This study confirms that Nexavar has significant activity in patients with FLT3-ITD-positive AML. This offers promise for improved therapy for a subset of patients with AML who usually have a very poor survival with conventional treatment.

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