CPX-351 are strong, according to Dr. Roboz. Also, in veneto-
clax trials, response rates were nearly three times higher than
those seen with standards of care like single-agent cytarabine or
hypomethylating agents, prompting questions about the benefit
of these new combinations for fit patients.
“Historically, we did not want to deprive patients who are
fit to receive 7+3 induction from the benefit of this chemo-
therapy regimen,” said Elizabeth Griffiths, MD, from Ros-
well Park Comprehensive Cancer Center in Buffalo, New
York. However, “now, we may need to think twice about
whether this is the best way to dichotomize treatment deci-
sions. We may be able to improve on our standard induction
with additional drugs or de-escalate to a venetoclax-based
regimen.”
Yet Dr. Griffiths advised caution. Venetoclax was approved
based on phase II results; clinicians and the FDA are awaiting
the results of the ongoing phase III clinical trial of the same
combinations to validate the current approval.
In addition, the new combinations carry their own unique
side-effect profiles. “Treatment with venetoclax plus azaciti-
dine is a risky venture,” she said. “While the combination is
potentially an outpatient treatment, many of us are treating
some of our patients in the hospital setting, particularly for the
first treatment cycle, because of the potential for profound and
prolonged cytopenias and high rates of infection.”
To Transplant or Not To Transplant
Because the newly approved AML agents offer only modest
improvements in OS, alloHCT remains the treatment goal for
patients who can tolerate the procedure and whose disease is
not likely to be cured with chemotherapy alone.
“The goal is always to try to move people to transplant us-
ing the novel agents,” said Dr. Michaelis. “A transplant is most
effective when the disease is under control, so that the newly
transplanted cells work like an immune agent to continue to
control the disease.”
Clinicians are refining approaches for determining wheth-
er a patient’s disease is under control, including by measur-
ing disease burden through minimal or measurable residual
disease (MRD) using genetic sequencing or flow cytometry.
Yet, researchers are still learning the optimal method for
detecting MRD and interpreting assay results. “It’s not clear
whether detection of MRD is a contraindication for trans-
plantation or, if no MRD is detected, which patients might
not need a transplant to stay in remission,” Dr. Michaelis
noted. “This is one of the reasons why MRD testing is not yet
standard of care.”
Still, “just because a patient has a specific mutational target
does not necessarily mean that the choice of therapy is obvi-
ous,” Dr. Roboz noted. “The paradigm of AML treatment is a
complex Venn diagram. Patients have features that make them
candidates for several potential treatment regimens, and it is
not advisable to mix and match agents that are not approved
to work in combination with each other.”
New Agents, New Combinations
Ongoing clinical trials are testing novel agents and combina-
tion therapies, including bispecific antibodies that bind to two
targets. In the case of AML, these targets include CD33 and
CD123. Preliminary data also suggest that chimeric antigen
receptor T cells might hold promise in this population.
“These immune-targeted agents are still in the early stages
of evaluation, Dr. Roboz noted. “The promising aspect of these
drugs is that they are likely agnostic to specific mutations
expressed by the leukemia cells.”
Dr. Roboz emphasized that the continued development of
new drugs for AML is welcome because, despite the availabil-
ity of newly approved drugs, survival for many patients is still
measured in weeks to months, not years.
“The enthusiasm for the novel therapies should not make
anyone believe that AML has been solved,” she said. “The
enthusiasm from clinicians, researchers, and patients should
be higher now than ever to take part in clinical trials to
understand how to use these drugs – and even newer ones in
development.” —By Anna Azvolinsky ●
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May 2019
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