Mark G. Frattini, MD, PhD
2010-12-06
Trying to predict which patient will have a long-term response to therapy and which patient will be resistant is a question common to all hematologic malignancies and cancer in general.
On Saturday and Sunday, Dr. Elihu Estey from the University of Washington Fred Hutchinson Cancer Research Center chaired the Education Session on “Understanding and Managing Ultra High-Risk Hematologic Malignancies.” This session detailed the identification of the poor prognostic cases of myeloma, chronic lymphocytic leukemia (CLL), and acute myelogenous leukemia (AML) and how best to begin thinking about a possible therapeutic strategy for each of these diseases.
Dr. Hervé Avet-Loiseau from the University Hospital of Nantes in Nantes, France, opened the session with a discussion on myeloma. He mentioned that for myeloma the ultra high-risk group can be identified as those patients whose survival is likely less than 24 months, independent of age. He then summarized that these patients could be identified as those with an International Staging System (ISS) stage of 3, patients whose cytogenetic analysis reveal a chromosome 17p deletion or poor-risk genomic analysis as determined by gene expression profiling or single nucleotide polymorphism array, and finally by those patients with a leukemic presentation of their disease. In terms of therapy for these patients, Dr. Avet-Loiseau outlined the need for high-dose chemotherapy induction followed by fully myeloablative allogeneic stem cell transplantation in those patients less than 50 years of age. For others, he proposed rotating a combination of active drugs to induce patients into remission, but stressed the need for novel agents in this group of patients where clinical efficacy can be measured by following available genomic data during treatment.
In patients with CLL, Dr. Stephan Stilgenbauer from the University of Ulm in Ulm, Germany, described the ultra high-risk group as those with an expected overall survival of less than two to three years, patients with a chromosome 17p deletion or sole p53 mutation without 17p deletion, patients who are purine analog (i.e., fludarabine or pentostatin) refractory, and lastly those with only a 24- to 36-month remission duration following intensive therapy (e.g., FCR-fludarabine, cyclophosphamide, and rituximab). He stressed the need to treat these patients first-line on a clinical trial with novel agents. In addition, a consolidation strategy including either reduced-intensity allogeneic stem cell transplantation or clinical trial with novel agents should be considered depending on patient age and performance status. In the absence of a clinical trial with novel agents, immunotherapy with ofatumumab or alemtuzumab or other chemoimmunotherapy could be used.
Dr. Estey concluded the session with a discussion of the ultra high-risk AML patient. He equated this patient population with those at high risk for resistance to conventional therapy as determined by monosomal karyotype, presence of an internal tandem duplication (ITD) in the FLT-3 gene and absence of an NPM-1 or CEBPA mutation, patients with mutation in IDH1/2 or DNMT3A, and those patients with poor-risk genomic analysis as determined by gene expression profiling, methylation profiling, or proteomic analysis. He suggested treating these patients on an available clinical trial followed by an allogeneic stem cell transplant in first clinical remission.
Great strides have been made in the last few years in regard to identifying the ultra high-risk patient. Now, research is focused on identifying novel agents and regimens that have activity in these patients allowing for increased survival.
Dr. Frattini indicated no relevant conflicts of interest.
