New Ideas and Old Challenges in the Treatment of AML

By Martin Carroll, M.D.

The Education Subcommitte session on Acute Myeloid Leukemia and Acute Promyelocytic Leukemia was presented yesterday by Drs. Bob Lowenberg, James Griffin and Martin Tallman. Although treatment of AML continues to present challenges, recent advances in molecularly targeted therapeutics and the rationale use of cytokines to prime leukemic cells prior to chemotherapy are generating excitement.

Dr. Lowenberg discussed the results of a recent trial using hematopoietic growth factor (HGF) priming as part of a treatment regimen for AML. When G-CSF and GM-CSF first became available, several studies were performed to determine if the administration of HGF throughout the period of neutropenic nadir would decrease the infectious complications from chemotherapy. Although some slight improvement in survival was seen in subsets of older patients, these studies did not conclusively demonstrate an improved cure rate of leukemia. A recent trial has used G-CSF with a different regimen and with a different goal. The authors hypothesized that a short course of HGF prior to and during chemotherapy (but not throughout the period of the neutropenic nadir) would stimulate leukemic stem cells in cell cycle and thereby make the cells more susceptible to S phase specific compounds such as cytosine arabinoside. The authors performed a study of 640 patients randomized to not receive or receive HGF priming and demonstrated that the cohort receiving G-CSF had a decreased relapse rate and an increased disease free survival rate at 4 years of average follow-up. This intriguing result has revitalized interest in this novel strategy to enhance the killing of leukemic cells.

Dr. Lowenberg also discussed interesting results using non-myeloablative or "mini" allogeneic transplant in the therapy of older patients with AML. The goal is to harness the potential graft versus leukemia effect to obliterate residual leukemia without incurring the toxicity of a full transplant protocol. Recent studies have documented the feasibility of such an approach but the jury is still out on the efficacy of this therapeutic strategy.

James Griffin of the Dana Farber Cancer Institute covered the still developing area of the role of Flt3 mutations in the pathogenesis of AML and the use of Flt3 inhibitors for the therapy of AML. Flt3 is a tyrosine kinase receptor expressed in normal hematopoietic stem cells and leukemic cells. Activating mutations of Flt3 have been described in 30-40% of patients with AML and effective pharmacologic inhibitors have been developed. These inhibitors block the growth of AML cells expressing mutant Flt3 but not those expressing wild type Flt3 in in vitro assays. Phase I and II trials are currently underway to determine if these drugs will be therapeutically useful. Preliminary results suggest that these inhibitors are well tolerated and have biologic activity in many patients with Flt3 mutations although the duration of the response may be short-lived.

Dr. Tallmann reviewed the current treatment recommendations for acute promyelocytic leukemia (APML). Cli- nicians treating this form of leukemia have the rare luck of having two non-traditional but effective therapies. Retinoic acid has dramatic differentiation effects through its activity against the causative oncogene, PML/RARa. Arsenic trioxide also leads to degradation of PML/RARa although it induces apoptosis of leukemic blasts rather than differ- entiation. The current question is how to improve the already impressive response and cure rate with these two drugs. Dr. Tallmann reviewed studies combining these therapies with each other or with chemotherapeutic agents.