Novel Agents in Pediatric Leukemia
Terzah M. Horton, M.D., Ph.D., and
Stacey
L. Berg, M.D.
Although cure rates for children with newly diagnosed leukemia
are 75 percent to 85 percent, the prognosis for children with recurrent leukemia
is guarded despite aggressive chemotherapy and stem cell
transplant. Novel approaches are needed for these children.
Three new agents recently have been approved for patients with
recurrent pediatric leukemia and several more agents are being
developed that show promise for improving outcome in patients
with either high risk or recurrent disease. The newly approved
agents include two new cytotoxic drugs — clofarabine and
nelarabine — that have efficacy in patients with recurrent
disease as well as the immunotoxin gemtuzumab (Mylotarg). These
new drugs have received FDA approval for use in leukemia and are
being assimilated into existing treatment regimens for pediatric
leukemia patients.
Clofarabine
The nucleoside analogue clofarabine structurally is related to
both fludarabine and cladribine. Clofarabine disrupts nucleotide
metabolism by 1) inhibiting nucleoside incorporation into DNA,
2) preventing nucleotide pool recycling by inhibiting the enzyme
ribonucleotide reductase (RnR), and 3) disrupting mitochondrial
integrity, resulting in the release of mitochondrial proteins
that trigger apoptosis. The latter mechanism may be responsible
for the increased efficacy of clofarabine in patients who previously
were treated with other nucleoside analogues such as cytarabine.
Clofarabine has been studied as a single agent in
two phase two studies in the United States.1,2 One trial in 61
pediatric patients with relapsed ALL showed an overall response
rate of 30 percent (seven patients with a complete response,
five patients
with a CR without platelet recovery (Crp) and six partial
responses)1. The other trial is an ongoing phase two AML trial
with a current response rate of 26 percent.2 Toxicities have included myelosuppression, nausea/vomiting, fever, skin rash, hand-foot
syndrome and transient elevations in liver transaminases.2 This
drug is seen as a potential “bridge to transplant” since half of
the responding acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients were able to receive a
subsequent stem cell transplantation.
Clofarabine is being tested in combination with other cytotoxic
agents. A recent Phase 1-2 study showed that clofarabine could
be safely combined with cytarabine in adults.3 This small study
showed that the clofarabine/cytarabine combination had a 38
percent
response rate in 32 adults with relapsed leukemia.3 Studies of
the clofarabine/cytarabine combination in children are ongoing
through the Children’s Oncology Group (COG).
Nelarabine
Nelarabine (compound 506U78, ArranonÒ) is a nucleoside analogue
that has received FDA approval for the treatment of relapsed
T-cell leukemia and lymphoblastic lymphoma in adults and
children. Nelarabine is a prodrug of Ara-G, which is
phosphorylated to ara-GTP and incorporated into DNA, leading to
apoptosis. Nelarabine is selectively toxic to T cells because
these cells slowly eliminate ara-GTP. Nelarabine trials have
included two phase two trials with T-lymphoid malignancies. One
study included 106 evaluable pediatric patients with relapsed
T-cell ALL.4 The response rate was 55 percent for those patients in
first bone marrow relapse and 27 percent for patients in second or
greater relapse. One adult phase two study had a response rate of
23 percent (reviewed in 5). Neurotoxicity was common and included
headache (17 percent), and peripheral neuropathy (12 percent). Other side
effects have included myelosuppression, increased transaminases
and hyperbilirubinemia.4
Gemtuzumab
Another agent with FDA approval for treatment of
relapsed AML is the immunotoxin gemtuzumab ozogamicin (MylotargÒ).
This agent is a humanized monoclonal anti-CD33 antibody linked
to the toxin calicheamycin. AML cells internalize the agent and
the calicheamycin binds to the minor groove of DNA, resulting in
double-stranded DNA breaks and the induction of apoptosis.
Gemtuzumab was tested in 29 children in a pediatric phase
one
study and shown to have a response rate of 28 percent (4 CR, 4 CRp).6
Grade 3 and 4 toxicities included myelosuppression (100
percent), hyperbilirubinemia (7 percent), increased hepatic transaminases (21
percent),
and sepsis (24 percent). Importantly, of the 13 patients who underwent
stem cell transplant shortly after treatment, six of 13 (40
percent)
developed severe vaso-occlusive disease (VOD).6 Other
retrospective pediatric clinical trials of gemtuzumab in have
yielded similar response rates and toxicities.7,8
Gemtuzumab has been tested in combination with a variety of
cytotoxic agents in adults with AML.9 In general, full-dose gemtuzumab has resulted in prolonged myelosuppression and
hepatotoxicity. Two ongoing Phase three U.S. pediatric trials are testing gemtuzumab in patients with newly
diagnosed AML. One study is testing gemtuzumab as a single agent
in the setting of minimal residual disease and a second COG
study is testing gemtuzumab as an adjuvant to conventional
chemotherapy.
Future perspectives
Targeted agents are designed to interfere with specific
molecular pathways important in maintaining the malignant cell
phenotype. In the near future, it is hoped that targeted
therapies will help improve response rates, particularly for
patients with high-risk leukemia. Overall survival in infants
with leukemia, for instance, is only 40 percent to 50 percent despite aggressive
chemotherapy.10
Infant ALL has a unique gene expression profile
and is characterized by both the t(4;11) MLL gene rearrangement
and elevated expression of the FLT-3 gene which encodes a
tyrosine kinase receptor. The Flt-3 protein often contains
activating mutations in both infant ALL and AML11. The Flt-3
internal tandem duplication (ITD) mutation is detected in 15
percent of
patients with AML and is associated with poor outcome (reviewed
in 11). Several Flt-3 inhibitors are in development.
Summary
Several newer agents hold great promise for improving the
survival of pediatric patients, particularly those in high-risk
populations or patients with recurrent disease. Although in
their infancy, molecularly targeted therapies may substantially
improve efficacy in the future and have the advantage of
non-overlapping and frequently minimal additional toxicities.
Ultimately, these new agents will help improve event-free
survival while decreasing the side effects that are an
inevitable consequence of today’s standard chemotherapy using
cytotoxic drugs.
About the authors
Terzah M. Horton, M.D, Ph.D.
and Stacey L. Berg, M.D.,
are pediatric oncologists/hematologists with Texas Children's
Cancer Center.
Dr. Horton's research focuses on the molecular changes in cell
cycle genes/proteins that might cause leukemias and lymphomas.
Her goal is to identify molecular defects contributing to
leukemia/lymphoma. Dr. Horton is an assistant professor of
pediatrics at Baylor College of Medicine.
Dr. Berg's primary area of interest is pharmacology and
experimental therapeutics, with a special emphasis on the
development of new anticancer drugs for children. She also has a
strong interest in clinical trial design and biomedical ethics.
Dr. Berg is an associate professor of pediatrics with Baylor.
References
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