December 2013, Vol 2, No 8

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Genomics of Acute Myeloid Leukemia Explored

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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, Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Boston, MA. Stone updated listeners on this topic at the National Comprehensive Cancer Network (NCCN) 8th Annual Congress: Hematologic Malignancies.

Faced with a wealth of information from the recently published genome atlas for AML (The Cancer Genome Atlas Research Network. N Engl J Med. 2013;368:2059-2074), oncologists must choose wisely on what studies to order for risk assessment of AML. Stone said that 2 studies should definitely be done: 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,” Stone said.

Twenty-three 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, he explained. Mutations that confer 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,” he told listeners.

Established 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.

At diagnosis, key assessments in the workup include bone marrow aspiration, CBCD, 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), he said.

Relapse-free survival depends on 2 genes: combined NPM1 and FLT3-ITD. Patients with the best prognosis are those with NPM1-positive and FLT3-ITD–negative disease. NPM1-positive patients with FLT3-ITD mutations do not have good outcomes.

Older patients with AML have worse outcomes, and it is important to be able to distinguish between those with a bad and very bad prognosis, Stone said. Perhaps older patients with AML have an intrinsically more difficult biological disease, he suggested. The balance of cytogenetics is tilted toward unfavorable ones, he added. They may have comorbidities and may also be more resistant to treatment.

There are not many good options for patients younger than 60 years, Stone said. In younger patients (but not older ones), those treated with daunorubicin 90 mg do better than those receiving 45 mg 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, he noted.

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

“In general we restrict allogeneic stem cell transplant to patients who cannot do well on high-dose chemotherapy. A good matched unrelated transplant is as good as a sibling match, and a young unrelated donor is better than an older sibling,” he told the audience.

There is no benefit from allogeneic stem cell transplantation in patients with mutated NPM1 and wild-type FLT3-ITD, but in all other cases allogeneic stem cell transplantation may be superior to high-dose chemotherapy.
Chromosomal findings and genetic findings in AML can be integrated.

AML can be separated into 9 subgroups based on clinical genomics. The favorable group does not need stem cell transplantation in CR1.

NCCN guidelines for younger patients are as follows. In younger patients, a clinical trial is preferred. Standard induction is with 3×3 therapy (idarubicin, daunorubicin, or doxorubicin). Postremission therapy depends on whether a matched unrelated donor or a sibling donor is available; stem cell transplantation should be considered for those with poor cytogenetics. In intermediate-risk cytogenetics, allogeneic stem cell transplantation is probably preferred, but autologous stem cell transplantation or high-dose chemotherapy can be considered. In patients with a true adverse prognosis who lack a sibling or matched unrelated donor, consider an alternative donor.

For older patients, the guidelines also state that a clinical trial is preferred. “3×7” induction therapy remains the standard (daunorubicin and ara-C). Less intensive therapy can be considered, especially if the response is likely to be poor (older patients, nonfavorable karyotype, and performance status 2). In all patients who achieve a complete remission (CR), consider reduced intensity allogeneic stem cell transplantation.

In cases of relapse, the following targetable mutations may be implicated: FLT3-ITD, FLT3-TKD, RAS, KIT, and IDH1/2.

“In summary, 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,” Stone said.

Investigational therapies for AML include quizartinib, a potent and selective FLT3 inhibitor, and trametinib, a MEK inhibitor, which may be useful in patients with a RAS mutation.

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