From OncoLog, April 2012, Vol. 57,
New Treatments for Acute Myelogenous Leukemia May Improve Patient Outcomes
By Bryan Tutt
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
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
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
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
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.”
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.”
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.
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