Clinical News
Moderate-Dose Cyclophosphamide
for Severe Aplastic Anemia
Potential Toxicity Outweighs
Potential Benefit
While cyclophosphamide at high
or more moderate doses can be
active in severe aplastic anemia,
a new study published in Blood
reveals that a moderate dose of
the drug failed to prevent relapse
or clonal evolution and was associated with significant upfront
toxicity. Even when optimal
prophylactic strategies were
used, this toxicity could not be
circumvented.
Phillip Scheinberg, MD, study
author and chief of clinical hematology at the Antônio Ermírio
de Moraes Cancer Center Hospital, São José, Brazil, and colleagues devised the current study
to investigate more “moderate”
doses of cyclophosphamide
given the better transfusional
and antimicrobial (particularly
antifungal) supportive care to
prevent the complications associated with prolonged neutropenia. From September 2010 to
February 2012, they assigned 22
patients with severe aplastic anemia to receive a “moderate” dose
of cyclophosphamide (120 mg/
kg) plus low-dose cyclosporine.
All patients received antibacterial, antiviral, and antifungal
prophylaxis.
The low cost
and ready
availability of
cyclophosphamide does
not justify its
routine use
in the face of
its significant
toxicity.
In March 2012, the Data Safety
Monitoring Board recommended
terminating the study due to unacceptable rates of toxicity, clonal
evolution, and deaths.
ASHClinicalNews.org
Patients in the study receiving a
moderate dose of cyclophosphamide experienced an average of
two months of severe neutropenia,
during which they had serious and
frequent infections.
“Despite the attractiveness of
cyclophosphamide – low cost,
readily available – its use cannot be
justified given the insurmountable
upfront toxicity when other, much
better, and effective alternatives are
available,” study author Dr. Scheinberg told ASH Clinical News. “The
prolonged hospitalizations and frequent admissions for complications
associated with neutropenia negate
the initial low cost associated with
cyclophosphamide.”
The current standard of
treatment for severe aplastic
anemia is immunosuppressive
therapy with horse antithymocyte globulin (ATG); according
to Dr. Scheinberg, investigations in severe aplastic anemia
occurring over the last two
decades have focused on finding
alternative immunosuppressive
regimens that could improve on
the results of standard immunosuppressive therapy and work
around their limitations. Despite
earlier encouraging research
with the drug, moderate-dose
cyclophosphamide does not
seem to hold much promise.
“In patients who tolerated the
prolonged period of severe neutropenia, hematologic responses
were observed, suggesting activity
of this regimen,” Dr. Scheinberg
said. “Thus, cyclophosphamide
continued to be attractive due to
its low cost and worldwide availability — an aspect particularly
important in developing countries where ATG is either not
available or too costly.”
Over a median follow-up of
2.2 years, the researchers found
that neutropenia was profound
and prolonged, and resulted in
hospitalizations for serious infections, including fungal infections.
Five patients required granulocyte transfusions for uncontrolled
infections. The average number
of hospitalizations within the first
six months after cyclophosphamide was 2.1.
At six months, 41 percent
of patients responded to the
cyclophosphamide, with four
complete responses and five
partial responses. At one year,
22 percent of patients had clonal
evolution.
Based on these results, Dr.
Scheinberg said that cyclophosphamide should not be used
routinely in severe aplastic anemia
outside clinical research protocols.
“Other regimens which include
alternative, less toxic immu-
nosuppressants and/or bone
marrow–stimulating agents (such
as eltrombopag) likely represent
more appealing strategies to be
investigated in severe aplastic
anemia,” he noted.
Reference
• Scheinberg P, Townsley D, Dumitriu B, et al. “Moderate”
dose cyclophosphamide for severe aplastic anemia has
significant toxicity and does not prevent relapse and
clonal evolution. Blood. 2014 September 3. [Epub ahead
of print]
The Earlier the Better
Early Response to Imatinib Predicted
Outcomes in Children with CML
While imatinib has been proven
effective for the majority of pediatric
patients with chronic myeloid
leukemia (CML), 13 to 25 percent of
children still have a poor response.
In a recent study published in
Blood, Frédéric Millot, MD, of the
Department of Pediatrics, University Hospital, Poitiers, France, and
colleagues questioned whether it
was possible to predict how patients
would respond to treatment and
determined, essentially, “the earlier
the better.”
An early molecular response to
treatment with imatinib — as measured by BCR-ABL1 transcript level
and defined as a BCR/ABL ratio of
<10 percent at three months postinitiation of imatinib — predicted
greater response at one year and
improved progression-free survival
(defined as absence of accelerated
phase, blast crisis, and death from
any cause), compared with those
children who did not have an early
response.
“CML occ