New Treatments for Acute Myelogenous Leukemia May Improve Patient Outcomes

By Bryan Tutt

Dr. Guillermo Garcia-Manero examines Genevieve Mosley, who is undergoing treatment for leukemia at MD Anderson.

Acute myelogenous leukemia (AML) is an aggressive and deadly malignancy, but new treatments are being developed that may prolong remissions.

According to the American Cancer Society, AML occurs most often in people over the age of 40 years, and about 9,000 people die of AML each year in the United States. While the disease can be curable, response to therapy varies as a result of patient- and disease-related factors.

“The main problem with AML treatment is the high relapse rate,” said Guillermo Garcia-Manero, M.D., a professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. “If you take 100 AML patients, about 75 will respond to therapy, but a lot of them will lose their response.”

Current standard of care

Treatment for AML typically involves an induction phase of high-dose chemotherapy followed by a consolidation phase, which may include additional chemotherapy or allogeneic stem cell transplantation.

Induction chemotherapy usually consists of two cytotoxic drugs, cytarabine (also called Ara-C) and an anthracycline (daunorubicin or idarubicin). One standard regimen is the 7+3 regimen, so called because each cycle comprises 7 days of continuous cytarabine infusion during which either anthracycline is given intravenously for the first 3 days. At MD Anderson, the standard induction therapy is the IA regimen, in which each cycle comprises 4 days of high-dose continuous cytarabine infusion with idarubicin also given for the first 3 days. Dr. Garcia-Manero said the latter regimen is preferred at MD Anderson because patients receive higher doses of the drugs early in treatment with less intensive consolidation therapy, and it is hypothesized that this results in higher remission rates.

The goal of induction therapy is to bring about a first remission. This is followed by stem cell transplantation or consolidation chemotherapy, both of which are aimed at curing the patient or prolonging remission.

“Only a minority of patients are eligible for stem cell transplantation, and these patients need to be in remission before they undergo transplantation,” said Jorge Cortes, M.D., a professor in the Department of Leukemia. “We also want patients who are not eligible for transplantation to stay in remission longer.”

Studies of several new drugs or new combinations of existing drugs are under way in hopes of improving the percentage of AML patients who achieve complete remissions and extending the duration of those remissions.

Experimental treatments

In a recent phase II trial, treatment-naïve AML patients received cytarabine, idarubicin, and vorinostat, an oral histone deacetylase inhibitor approved for use in the treatment of peripheral T cell lymphoma. Eighty-five percent of these patients had a complete or partial response, which is among the highest overall response rates reported in AML treatment studies.

Dr. Garcia-Manero, the trial’s principal investigator, said 19 of 25 eligible patients went on to receive stem cell transplants. “The outcomes were exceptional for the patients who had transplants,” he said, adding that the patients had long-lasting remissions.

In a phase III trial expected to begin enrolling patients at MD Anderson and other institutions later this year, patients will receive cytarabine, idarubicin, and vorinostat; cytarabine and idarubicin (IA regimen); or cytarabine and daunorubicin (7+3 regimen). Dr. Garcia-Manero said the trial will test not only the efficacy of vorinostat but also which standard induction chemotherapy regimen is most effective.

In a multinational phase III study already under way, patients with relapsed or treatment-refractory AML are receiving cytarabine plus a placebo or cytarabine plus vosaroxin, which inhibits the activity of topoisomerase II. Principal investigator Farhad Ravandi, M.D., an associate professor in the Department of Leukemia, said that phase II trials of vosaroxin showed promising results.

Vosaroxin and vorinostat are not gene-specific, which enables the drugs to be effective against a broad range of tumor types but also means the drugs do not target a specific mutation.

“There has been a significant increase in the discovery of genetic abnormalities associated with AML,” Dr. Ravandi said. “For all our newly diagnosed patients, we perform pretreatment tests for a wide array of molecular aberrations.”

“This sort of screening has become standard at MD Anderson and other cancer centers with large leukemia programs,” Dr. Cortes said. “Although this screening is mainly done for prognostic purposes, in a few instances the results can help guide therapy.”

For example, Dr. Garcia-Manero said, “AML patients with core binding factor abnormalities or with acute pro-myelocytic leukemia [APL, a subtype of AML] have a high cure rate with specific forms of therapy and no stem cell transplant.” Once these patients achieve remission, they are monitored for minimal residual disease so that further treatment can be initiated if necessary.

Dr. Ravandi described two techniques used to check for residual disease. Flow cytometry detects aberrant markers on the surface of leukemia cells, and polymerase chain reaction detects gene fusion products found in some patients with AML, such as those with core binding factor leukemias or APL. “We are one of the few U.S. centers to use flow cytometry to monitor for minimal residual disease in AML patients,” Dr. Ravandi said.

While patients already are benefiting from the prognostic value of pretreatment screening, its potential to guide the choice of drugs used in AML treatment is only beginning to be realized. For example, about 25% of AML patients have mutations in the FLT3 gene.

FLT3 is a receptor kinase found on the surface of most hematopoietic progenitor cells, and AML patients with FLT3 gene mutations have a worse prognosis than patients without mutations, making FLT3 an attractive therapeutic target. “FLT3 inhibitors work very well, but the responses they produce in patients tend to be transient, so we’re combining these with other drugs to see if we can get a more durable response,” Dr. Cortes said.

A pivotal trial of the FLT3 inhibitor PKC412 in combination with conventional cytotoxic drugs was recently completed. Dr. Cortes said that if the results are similar to those of earlier trials of the drug, PKC412 will likely be approved by the U.S. Food and Drug Administration for AML treatment. Dr. Cortes was not involved with that trial, but he is the principal investigator of an ongoing trial in which patients with relapsed or refractory AML or myelodysplastic syndrome receive PKC412 with azacitidine, a hypomethylating agent approved for the treatment of myelodysplastic syndrome. “The early results are encouraging,” he said, “and the treatment is very well tolerated.”

The results of preclinical studies of another experimental drug, AC220, indicate that it may be the most potent of the FLT3 inhibitors currently available. “We did the phase I study at MD Anderson, and the drug showed significant activity,” Dr. Cortes said.

A large phase II study of single-agent AC220 has completed patient accrual. “The preliminary data indicate that more than 50% of patients respond to this therapy even if they did not respond to prior therapies,” said Dr. Cortes, the principal investigator of that trial and of a phase I study of AC220 combined with cytarabine and daunorubicin.

Early trials of sorafenib, a multikinase inhibitor approved for the treatment of renal cell and hepatocellular carcinomas, demonstrated its activity against AML in patients with FLT3 mutations, and a phase II trial combining sorafenib with azacitidine is under way with promising early results.

Another kinase inhibitor, the JAK2 inhibitor ruxolitinib, was the subject of a recent phase II trial. Although the results are still being evaluated, Dr. Ravandi said, “We saw some responses in patients whose myeloproliferative disorders had progressed to AML, so there is potential for combining ruxolitinib with other drugs for these patients. This subset of patients historically has not done well with available strategies, including stem cell transplantation.”

Looking ahead

Clinical trials are helping determine which treatments are effective in which patient populations. “In some studies, patients are chosen because they have a particular mutation, but in others we are trying to see which drugs will work best in which patients,” Dr. Cortes said. “Eventually, we will have more drugs that are specific for genetic abnormalities, and we’re going to need to do a panel of tests to see which patients should be treated how, rather than giving the same chemotherapy regimen to everybody.”

From the studies described above and from studies of several other promising treatments, data are emerging to suggest that targeted therapy is starting to benefit patients in a meaningful way.

“The diagnosis, classification, and management of AML and other leukemias are becoming very complex,” Dr. Cortes said. “It is becoming more and more important for leukemia patients to have a very comprehensive workup done at a center where these treatments that can be targeted to a particular abnormality are becoming available.”

For more information, contact Dr. Jorge Cortes at 713-794-5783, Dr. Guillermo Garcia-Manero at 713-745-3428, or Dr. Farhad Ravandi at 713-745-0394.

Other articles in OncoLog, April 2012 issue:

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