CME/CNE

Can Modern Therapy Improve Outcomes in Adult AML?

Harry P. Erba, MD, PhD

University of Michigan Medical School
Ann Arbor, Michigan

The questions below were submitted by your peers based on a recent CME/CNE activity.
The Course Director, Dr. Harry P. Erba, provides his answers below.

Question 1: What is the clinical consensus on the value of neuclophosmin gene (NPM1) mutations without FMS-like tyrosine kinase-3 (FLT3) mutations in adult acute myeloid leukemia (AML)?

Question 2: What collective conclusions can one draw from the major studies of postremission allogeneic or autologous stem cell transplant in AML? Have more recent data added additional nuances to these findings?

Question 3: What are the major factors, including cytogenetics, that may drive therapy selection in older patients with AML?

Question 4: Prior to being withdrawn from the market, did gemtuzumab show any benefit as induction in AML?

What is the clinical consensus on the value of neuclophosmin gene (NPM1) mutations without FMS-like tyrosine kinase-3 (FLT3) mutations in adult acute myeloid leukemia (AML)?

The work performed by the German Leukemia Study Group and published by Schlenk and colleagues in the New England Journal of Medicine 2 years ago (2008;358:1909-1918) represents a very large data set of young AML patients with normal karyotype, investigating the impact of several different mutations on prognosis.

The data show that the complete remission rates and the disease-free survival of patients with NPM1 without FLT3 were superior to those of the other genotypes that they had identified in these 800 or so patients.

What collective conclusions can one draw from the major studies of postremission allogeneic or autologous stem cell transplant in AML? Have more recent data added additional nuances to these findings?

The HOVON/SAAK presented their data regarding a donor/no donor analysis, as well as a meta-analysis that included the three previously reported European studies (Cornelissen JJ et al. Blood. 2007;109:3658-3666). The meta-analysis demonstrated a statistically significant 12% overall survival benefit in young patients with AML in first remission who had a donor without a favorable cytogenetic profile. So in general, we do not recommend allogeneic stem cell transplantation for patients with favorable-risk cytogenetics, such as the core-binding factor (CBF) translocations, and especially acute promyelocytic leukemia with translocation (15;17).

In patients with intermediate-risk and poor-risk karyotype, stem cell transplant should definitely be considered.

What are the major factors, including cytogenetics, that may drive therapy selection in older patients with AML?

I believe that we have gathered enough information from a variety of phase 2 and phase 3 studies that will allow us to not only prognosticate in the older patient, but will also help us to select the most appropriate therapy. There are older patients who have adequate performance status in the absence of comorbid illness who can tolerate intensive chemotherapy. Patients who are predicted to have high remission rates and prolonged disease-free survival should receive standard AML induction chemotherapy.

Therefore, in my own practice, I use the cytogenetic evaluation of patients. If there are no poor-risk features, I will consider patients for standard induction chemotherapy. And now I believe we can also begin to use the molecular profiles and mutational analyses that have been done.

Most of the data that we’ve had until recently on the prognostic impact of single-gene mutations have come from studies of younger patients with AML. However, there is Southwest Oncology Group (SWOG) data showing that older patients with AML harboring FLT3 internal tandem duplications (ITDs) have a very poor outcome with no long-term survivors, compared with the patients who did not have those mutations (Stirewalt et al. Blood. 2001;97:3589-3595).

Similarly, the Cancer and Leukemia Group B has examined their database of older patients with AML. They found that not only were the remission rates higher in patients with NPM1 mutations (84% vs 48%; P < .001), but they also showed that in these older patients with NPM1 mutations, 3-year disease-free survival was superior (23% vs 10%; P = .047), and there appeared to be a long-term benefit towards intensive therapy (Becker et al. J Clin Oncol. 2010;28:596-604).

So, in summary, for older patients who have adequate performance status and absence of significant comorbid illness and wish to consider a curative approach to this disease, they should receive intensive AML induction chemotherapy with an anthracycline and cytarabine, given the absence of high-risk features according to cytogenetics and molecular analysis.

Prior to being withdrawn from the market, did gemtuzumab show any benefit as induction in AML?

A general approach that has been investigated for the improvement in outcomes in younger patients has been the incorporation of more targeted therapies to induction therapy.

Results from SWOG S0106 were reported at the 51st American Society of Hematology Annual Meeting and Exposition (ASH 2009) by Dr. Stephen Petersdorf (Abstract 790). In this study, patients under the age of 60 were randomized to daunorubicin and cytarabine versus daunorubicin, cytarabine, and gemtuzumab ozogamicin 6 mg/m² IV on day 4. Patients achieving a remission could go on to receive high-dose Ara-C for three cycles, and there was also a postconsolidation question that was asked regarding the administration of three cycles of gemtuzumab ozogamicin, or just continuing with observation.

However, there was a higher mortality rate associated with gemtuzumab. Therefore, increased mortality and lack of significant benefit with the addition of gemtuzumab led to this study’s early closing. These data are in contrast to the relatively positive findings of the AML15 trial, which had been reported several years earlier (Burnett AK et al. Blood. 2006;108: Abstract 13). Based in part on these negative findings, gemtuzumab was withdrawn from the market in June 2010.