Genomics of Acute Myeloid Leukemia Explored

Phoebe Starr

October 2013, Vol 4, No 8 - Personalized Medicine


New York, NY—To paraphrase Winston Churchill, “we are at the end of the beginning” of the era of clinical genomics in acute myeloid leukemia (AML), said Richard M. Stone, MD, Clinical Director, Adult Leukemia Program, Dana-Farber Cancer Insti­tute, Boston, at the 2013 National Comprehensive Cancer Network congress on hematologic malignancies.

Faced with the wealth of information from the recently published genome atlas for AML (Cancer Genome Atlas Research Network. N Engl J Med. 2013;368:2059-2074), oncologists must choose wisely what studies to order for the risk assessment of AML. Dr Stone said that 2 studies should definitely be ordered—FLT3-ITD and CEBP alpha. It is still not clear whether to assess for the KIT mutation, he noted.

“The publication of the genome atlas for AML is very exciting and an important milestone. We understand the molecular biology to a certain degree. AML has fewer mutations than some other cancers,” Dr Stone said.

A total of 23 mutated genes that fall into 9 categories have been identified in AML. Founder mutations could provide the best target for treatment, because they are present throughout the disease. Mutations that confer an unfavorable prognosis include the FLT3-ITD and KIT mutations; the NPM1 and CEBP alpha mutations confer a favorable prognosis.

“Right now, I would not recommend deep genomic sequencing for every patient, but the list will change, and then knowing mutations might influence protocols and trial eligibility for patients,” Dr Stone said.

Prognostic factors for AML include patient age, cytogenetics, type of AML, tumor burden at diagnosis, and other molecular markers. Adverse molecular markers include FLT3-ITD, and good prognosis markers include CEPB alpha.

Key assessments in the workup include bone marrow aspiration; complete blood count with differential; cytogenetics; and mutational analysis for FLT3-ITD, NPM1, CEBP alpha, and c-KIT (but KIT only because it is cheaper to include it in the mutational analysis), Dr Stone said.

Relapse-free survival depends on 2 genes—combined NPM1 and FLT3-ITD. Patients with NPM1-positive and FLT3-ITD–negative have the best prognosis. NPM1-positive patients with FLT3-ITD mutations have worse outcomes.

Older patients with AML have worse outcomes, and it is important to be able to distinguish between those with a bad and a very bad prognosis, Dr Stone said. Perhaps older patients with AML have an intrinsically more difficult biological disease, he suggested.

There are not many options for patients aged <60 years. In younger patients, those treated with 90-mg daunorubicin (Cerubidine) do better than those who receive the 45-mg dose, if they have non-FLT3 mutations and have lower white blood cell counts at presentation. Younger patients who are chemosensitive can probably benefit from intensified therapy, Dr Stone noted.

The role of allogeneic stem-cell transplant is evolving. It appears to be as good as chemotherapy alone in patients in first remission (CR1).

There is no benefit for allogeneic stem-cell transplant in patients with mutated NPM1 and FLT3-ITD wild type, but in all other cases, allogeneic stem-cell transplant may be superior to high-dose chemotherapy.

Chromosomal findings and genetic findings in AML can be integrated.

AML can be separated into 8 subgroups based on clinical genomics: the favorable group does not need stem-cell transplant in CR1.

“Genetic analysis is important at diagnosis for de novo AML—at least for prognosis and choice of post-CR therapy. Mutations may point toward certain clinical trials, and the landscape of important mutations is likely to change with more data,” Dr Stone said. n