Treating refractory leukemias in childhood, role of clofarabine
Therapeutics and Clinical Risk Management
Treating refractory leukemias in childhood, role of clofarabine
Theresa M Harned Paul S Gaynon 0
0 Department of Hematology-Oncology, Childrens Hospital Los Angeles , Los Angeles, CA , USA
Approximately 4000 children and adolescents under the age of 20 years develop acute leukemia per year in the US. Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Despite impressive improvements in outcome, relapsed ALL is the fourth most common pediatric malignancy. Therapy for relapsed ALL remains unsatisfactory, and the majority of relapse patients still succumb to leukemia. Between one-third and one-half of patients with acute myelogenous leukemia (AML) relapse, and no standard therapy is recognized for patients with relapsed and/or refractory AML. Novel therapeutic agents are needed to improve the cure rate for relapsed ALL and AML. Clofarabine is a next-generation nucleoside analog, designed to incorporate the best features and improve the therapeutic index of cladribine and fludarabine. Clofarabine inhibits both DNA polymerase and ribonucleotide reductase, leading to impaired DNA synthesis and repair, and directly induces apoptosis. Phase I and II single-agent trials in children have shown that clofarabine is safe and active in both myeloid and lymphoid relapsed/refractory acute leukemias. Clofarabine has been approved by the FDA for pediatric patients with relapsed/refractory ALL after at least 2 prior therapeutic attempts. Rational combinations of clofarabine with other active agents in refractory leukemias are currently under investigation.
Approximately 4000 children and adolescents under the age of 20 years develop acute
leukemia per year in the US. Acute lymphoblastic leukemia (ALL) is the most common
pediatric cancer, accounting for one-fourth of all childhood cancers and approximately
75% of all cases of childhood leukemia. In the US alone, approximately 3000 cases
of pediatric ALL are diagnosed annually, with an incidence of 29.2 cases per million
(Grovas et al 1997; Jemal et al 2004)
Primary treatment of pediatric ALL is “risk-adapted,” ie, treatment allocation is
based on an estimate of risk of relapse based on presenting features, eg, age at diagnosis,
initial white blood cell count, immunophenotype, and cytogenetics and response to
therapy, eg, disappearance of peripheral blasts, microscopic marrow response, and/or
laboratory measurement submicroscopic leukemia, termed minimal residual disease
(Schultz et al 2007)
. Increasingly effective post induction intensification
employing conventional agents has steadily improved event-free survival. According
to the US population-based Surveillance and End Results survey, 5-year survival for
children aged 1–14 years has increased from 53% in 1974–76 to 85% in 1992–1999
(Jemal et al 2004)
Despite the impressive improvements in outcome, relapsed ALL remains the
fourth most common pediatric malignancy, with an incidence of approximately
6 cases per million in 2007
(Gaynon et al 1998)
. Therapy for patients with relapsed
ALL remains unsatisfactory, especially for patients with early bone marrow relapse
within 3 years of diagnosis
(Gaynon et al 1998; Nguyen et al
. Second remissions are common. Four-drug therapy
with vincristine, prednisone, asparaginase, and doxorubicin
induces complete remissions in 38%, 80%, and 95% of
children with initial remissions 18 months, 18–36 months,
and 36 months, respectively. Of patients achieving CR2,
80% remain MRD positive at 10–4 by flow cytometry after
CR1 36 months compared to 50% positive for CR1 36
(Raetz et al 2006)
. Therapeutic options after second
remission (CR2) include further chemotherapy and/or
hematopoietic stem cell transplantation (HSCT)
(Eapen et al 2006;
Gaynon et al 2006)
However, the majority of relapse patients still succumb
to leukemia. For patients enrolled on Children’s Cancer
Group (CCG) 1900 series studies between 1997 and 2002,
the 3-year survival after marrow, CNS, and testes relapse
was 28%, 60%, and 60%, respectively
(Nguyen et al 2006)
Adverse prognostic factors after relapse include early
versus late timing, marrow versus extramedullary relapse, and
T-cell versus B-precursor immunophenotype
1998; Eckert et al 2001; Chessells et al 2003; Einsiedel et al
. MRD after re-induction chemotherapy, as measured
by PCR or flow cytometry, may be predictive of outcome in
CR2 after marrow relapse
(Eckert et al 2001; Coustan-Smith
et al 2004)
. Higher levels of pre-transplant MRD may predict
relapse after hematopoietic stem cell transplant (HSCT)
(Knechtli et al 1998; Bader et al 2002; Goulden et al 2003)
Better pre-transplant chemotherapy is needed that allows
more patients to proceed to transplant with lower MRD and
less deep seated infection or organ damage.
Although third remissions are attained with some
frequency, outcomes for patients with second or subsequent
relapse remain poor
(Chessells 1998; Chessells et al 2003)
Several drug combinations have significant CR rates in
refractory first relapse, or second or subsequent relapse
(Table 1). These CR rates cluster around 40%, despite the
use of a variety of drugs with different putative mechanisms
. An overall 8% survival rate was
reported among patients who achieved third remission after
a second marrow relapse
(Chessells et al 2003)
We have proposed that candidate drug combinations with
CR rates 40% are unlikely to be useful for improving cure
rates. Alternatively, novel regimens with CR rates 60%
would be of compelling interest
data are lacking for CR3 and subsequent remissions,
measurement of minimal residual disease (MRD) may be useful
to assess response.
Acute myelogenous leukemia (AML) comprises 15%–20%
of childhood leukemia, but accounts for more than 30%
of deaths from leukemia. In the US, approximately 1000
children per year are diagnosed with AML, with an incidence
of between 5 and 7 cases per million per year
(Grovas et al
1997; Jemal et al 2004)
. Better supportive care and better use
of conventional agents have improved outcomes in childhood
AML. Current therapy for patients with newly diagnosed AML
involves induction therapy with myelosuppressive cytotoxic
agents, including cytarabine and an anthracycline or
anthracinedione, and post-remission intensification with chemotherapy
or HSCT. Three recent large multi-center pediatric studies
yielded remission induction rates of approximately 90%.
Five-year event-free survival is nearing or surpassing 50%
(Aladjidi et al 2003; Creutzig et al 2005, 2006; Gibson et al
. Risk-group stratification based on cytogenetic features,
(Pollard et al 2006)
, and response to therapy
is becoming increasingly important.
One-third to one-half of patients with AML relapse. Most
relapses are isolated to the bone marrow, and are more likely
to occur in the first year after diagnosis. No standard therapy
is recognized for patients with relapsed and/or refractory
AML. Regimens that contain high-dose cytarabine, often in
combination with other agents such as mitoxantrone, etoposide,
fludarabine, or 2-chlorodeoxyadenosine, have significant
(Golub et al 2006)
. Gemtuzamab ozogamicin, a
monoclonal antibody directed against the CD33 differentiation
antigen and coupled to genotoxic calicheamicin, has shown
activity in relapsed and refractory AML in both children and
(Sievers et al 2001; Zwaan et al 2003; Reinhardt et al
2004; Arceci et al 2005)
. Gemtuzamab is currently being
studied in newly diagnosed children and adults in combination
with multiagent chemotherapy
(Burnett et al 2006)
Perhaps 50% of patients with primary induction failure
will achieve CR with subsequent therapy
(Wells et al 2003)
and 70% of patients with CR1 achieve a second remission
employing similar drugs to those used initially
Aladjidi et al 2003; Wells et al 2003)
. However, long-term
survival for children with relapsed AML ranges between
20% and 33%
(Aladjidi et al 2003; Castellino et al 2007)
Prognosis is related to specific cytogenetic abnormalities
and the duration of first remission. Patients relapsing after
a CR1 1 year have a better survival. The need remains
for therapeutic options which are both less toxic and more
effective than the conventional treatment.
New agents for relapsed and refractory childhood leukemias
Novel therapeutic agents are needed to improve the cure
rate of patients with relapsed or refractory ALL and AML.
Emerging new treatments for ALL include next generation
nucleoside analogs such as the deoxyadenosine analog
clofarabine (Clolar®, Genzyme), which was approved by
the FDA in December 2004 for the treatment of pediatric
patients with relapsed or refractory ALL who have received
at least two prior chemotherapy regimens
(Pui and Jeha
, and the deoxyguanosine analog nelarabine (Arranon®,
GlaxoSmithKline), which has been approved by the FDA
for third-line treatment of patients with T-cell leukemia
. In acute promyelocytic
leukemic, arsenic trioxide has shown benefit in randomized
(Powell et al 2006, 2007)
. In AML, preliminary data
suggest an EFS advantage for addition of gemtuzumab to
conventional induction chemotherapy
(Burnett et al 2006)
and an induction rate advantage for addition of the FLT-3
inhibitor lestaurtinib for patients with AML with FLT-3
internal tandem repeats
(Levis et al 2005)
. Other promising
new agents include monoclonal antibodies against
leukemiaspecific antigens, such as rituximab, a humanized anti-CD20
antibody, and epratuzamab, targeting CD22.
Over 100 gene mutations and genetic abnormalities
have been reported in AML, reflecting the heterogeneity
of the disease and the presence of multiple active pathways
. Mutations that activate signal transduction
pathways lead to proliferative survival advantages and may
be targeted with small molecule inhibitors of the specific
mutations, such as FLT3, C-Kit, and RAS, while mutations
that lead to inhibition of differentiation may be targeted with
differentiating agents (eg, all-trans-retinoic acid [ATRA]
for patients with acute promyelocytic leukemia [APL]).
Targeted therapy may interfere with host support for the
leukemia cell. The mechanisms of treatment failure in ALL
remain to be elucidated. One does well to remember that
neither ATRA alone nor imatinib alone is curative for APL
or chronic myelogenous leukemia, respectively. A gene may
be over-expressed, yet not critically necessary for leukemic
de-differentiation or proliferation.
New agents have been developed for multiple molecular
targets in AML, including antibodies to cell surface antigen
CD33, inhibitors of multi-drug resistance proteins, farnesyl
transferase inhibitors, FLT3-targeted tyrosine kinase
inhibitors, and inhibitors of the antiapoptotic protein Bcl-2 and
the mammalian target of rapamycin (mTOR). New
alkylating agents and purine analogs such as cloretazine and
clofarabine, which target DNA and ribonucleotide
reductases, respectively, are also under investigation. Targeted
agents will likely need to be used in combination with other
targeted agents and/or cytotoxic agents to inhibit the multiple
pathways present in AML and to improve response rates
. Clinical benefit will require the right stuff,
ie, the right drug be used against the right target in the right
disease at the right dose and schedule in the right population
with the right accompanying therapy
development of these therapies is challenging in view of the
multitude of intriguing possibilities, the background
heterogeneity of leukemias, and the current absence of compelling
The nucleoside analog family includes the guanosine analogs,
thioguanine and mercaptopurine, which were among the first
agents to show activity against ALL
(Hitchings et al 1950;
Elion et al 1951; Skipper et al 1954)
. The clinical use of
the deoxyadenosine analogs cladribine and fludarabine
has been restricted due to dose-limiting neurotoxicity
(Kantarjian et al 2007)
(2-chloro-2'-fluoro2'deoxy-9-B-D-arabinofuranosyladenine), a next-generation
deoxyadenosine analog (see Figure 1), was rationally
designed to incorporate the best qualities and improve the
therapeutic index of cladribine and fludarabine. The drug
received accelerated approval by the FDA in December 2004
and EMEA approval in 2006 for the treatment of patients
with childhood ALL who have received two or more prior
Clofarabine retains the 2-halogenated aglycone of the
deoxyadenoside analogs cladribine and fludarabine (Figure 1),
which confers resistance to cellular degradation by adenosine
(Parker et al 1991, 1999; Pui et al 2005)
clofarabine also possesses a second halogen atom (fluorine)
at the 2' carbon in the arabino configuration, which inhibits
cleavage of the glycosidic bond by bacterial purine nucleoside
phosphorylase and stabilizes the compound in acidic
environments, thus improving oral bioavailability and preventing the
release of the neurotoxic halogenated adenine
(Parker et al
1991; Carson et al 1992; Plunkett and Gandhi 2001; Jeha et al
2004; Jeha and Kantarjian 2007; Kantarjian et al 2007)
addition, clofarabine has greater affinity than cladribine or
fludarabine for deoxycytidine kinase, the enzyme required for
intracellular phosporylation to its monophosphorylated form.
Clofarabine is then serially phosphorylated by other kinases
to its active metabolite, clofarabine triphosphate
(Bonate et al
. Clofarabine triphosphate is retained in acute
leukemia cells for longer periods of time than the metabolites
of the other purine nucleoside analogs
(Xie and Plunkett 1995,
1996; Bonate et al 2006; Gandhi et al 2006,)
Mechanism of action
Purine analog triphosphates inhibit ribonucleotide reductase
and are substrates for DNA polymerases for
incorporation into DNA
(Gandhi et al 2006)
. Fludarabine primarily
inhibits DNA polymerases and cladribine mainly inhibits
ribonucleotide reductase, while clofarabine inhibits both
DNA polymerases and ribonucleotide reductase
et al 1991, 1999; Xie and Plunkett 1995, 1996; Jeha et al
. Inhibition of DNA polymerases leads to impairment
of DNA synthesis and/or repair through the incorporation
of clofarabine monophosphate into the DNA chain
Plunkett 1996; Bonate et al 2006)
. Inhibition of
ribonucleotide reductase depletes the deoxynucleotide pool primarily
of dCTP and dATP
(Xie and Plunkett 1996; Bonate et al
. The reduction in dCTP concentrations limits DNA
synthesis, while the reduction in dATP creates a favorable
environment for clofarabine triphosphate to compete with
dATP for incorporation into DNA
(Xie and Plunkett 1996;
Bonate et al 2006)
. A third mechanism of action is
induction of apoptosis initiated by DNA strand breaks, resulting
in the release of cytochrome c and activation of apoptotic
(Genini et al 2000; Bonate et al 2006)
has also been shown to act directly on the mitochondria in
primary chronic lymphocytic leukemia (CLL) cells, altering
the transmembrane potential and releasing pro-apoptotic
mitochondrial factors, which may explain the mechanism
of cell death in cells not actively synthesizing DNA for cell
division or DNA repair. This direct mitochondrial activity
was not seen with fludarabine and may partly explain the
enhanced cytotoxicity of clofarabine
(Carson et al 1992;
Genini et al 2000; Bonate et al 2006)
In the blast cells of adults with refractory leukemias, the
accumulation of clofarabine triphosphate was associated with a
decrease in DNA synthesis
(Gandhi et al 2003)
. DNA synthesis
was 75% to 95% inhibited at the end of an infusion with
clofarabine at doses ranging from 22.5 to 55 mg/m2. At 24 hours,
partial recovery of DNA synthesis occurred in the blasts of
patients treated with 22.5 and 30 mg/m2, while the inhibition of
DNA synthesis was maintained at 24 hours after 40–55 mg/m2
(Gandhi et al 2003; Kantarjian et al 2007)
Pharmocokinetics and metabolism (Table 2)
The population pharmacokinetics of plasma clofarabine
and intracellular clofarabine triphosphate was studied in
40 pediatric patients aged 2–9 years (21 males/19 females)
with relapsed or refractory ALL or AML. Clofarabine
pharmacokinetics was weight dependent, suggesting the
importance of dosing on a body surface area (BSA) basis,
although similar concentrations were obtained over a wide
range of BSAs at the given 52 mg/m2 dose
(Bonate et al
. Clofarabine was 47% bound to plasma proteins,
mainly albumin. Systemic clearance and volume of
distribution at steady state were estimated to be 28.8 L/h/m2 and
172 L/m2, respectively. The terminal half-life was estimated
to be 5.2 hours
(Bonate et al 2004)
. The half-life of the active
clofarabine triphosphate metabolite could not be adequately
characterized in the pediatric phase 2 studies but was
estimated to be greater than 24 hours
(Bonate et al 2004)
. It is
believed that the conversion from the monophosphate to the
diphosphate moiety is the rate-limiting step in the formation
of the triphosphate. It appears that clofarabine triphosphate
formation is very rapid, and once formed, it remains trapped
in the cell with a prolonged elimination half-life
Plunkett 1995; Bonate et al 2004)
. In pediatric patients
49%–60% of the clofarabine dose is excreted unchanged
in the urine. The pathways of non-renal elimination remain
(Gandhi et al 2003; Bonate et al 2004)
does not appear to be metabolized by the cytochrome P450
enzymes and CYP450 inhibitors and inducers are not likely
to affect the metabolism of clofarabine, although no clinical
drug-drug interaction studies have been conducted to date
(Clolar® package insert).
Clofarabine pharmacokinetics is similar in patients with ALL
and AML or in males and females. The pharmacokinetics
of clofarabine remains to be evaluated in patients with renal
or hepatic dysfunction
(Bonate et al 2004)
. According to
the manufacturer, its use in patients with hepatic or renal
dysfunction should be undertaken only with the greatest
Clofarabine was found to be teratogenic in reproductive
studies conducted in rats and rabbits, with reduced fetal
body weight, increased fetal loss, and skeletal malformations
observed. Therefore, although there are no adequate studies
in pregnant women using clofarabine, women of childbearing
potential should be advised to avoid becoming pregnant while
receiving treatment with clofarabine (Clolar® package insert).
Phase I studies in pediatrics
Based on a 16% overall response rate seen in adults with
leukemia in a phase I single-agent trial of clofarabine
(Gandhi et al
2003; Kantarjian et al 2003b; Faderl et al 2005a)
, a pediatric
phase I trial was conducted to define the dose-limiting toxicity
(DLT) and maxinimu tolerated dose (MTD) for children with
(Jeha et al 2004)
. Six dose levels, ranging from
11.25 to 70 mg/m2 for 5 days, were studied in 25 pediatric
patients (8 patients with AML and 17 patients with ALL).
Most patients were heavily pretreated, with 36% having
undergone prior stem cell transplantation
(Jeha et al 2004)
Hyperbilirubinemia and skin rash were dose-limiting and the
recommended dose schedule for the phase 2 pediatric studies was
52 mg/m2 daily for 5 days. Complete response (CR) was reported
in 4 (24%) of 17 patients with ALL (Table 3). One patient
(6%) had a partial response (PR), for an overall response rate
(CR + PR) for ALL of 30%. Complete responses were seen
at 30 mg/m2, 40 mg/m2, and 52 mg/m2
(Jeha et al 2004)
Responders included a 13-year-old female with t(9,22) refractory to
3 consecutive induction attempts including idarubicin,
fludarabine, and cytarabine, as well as a 17-year-old female with T-cell
ALL refractory to 3 consecutive inductions including nelarabine
(Jeha et al 2004)
. The overall response rate for patients with AML
was 38% (Table 3). One out of 8 patients (13%) achieved CR
and 2 patients (25%) achieved PR
(Jeha et al 2004)
Phase II studies in children with acute leukemia
A phase II, open-label, multicenter clofarabine study was
conducted in 61 pediatric patients in the US with refractory
or relapsed ALL at 52 mg/m2 for 5 days
(Jeha et al 2006b)
Patients were heavily pretreated, with a median of 3 prior
induction regimens. Approximately one-third had received
at least 1 prior transplantion, and 57% were refractory to
the last therapeutic regimen. Twelve of 61 ALL patients
achieved complete remission (CR) or complete remission
without platelet recovery (CRp). Only 1 of 42 AML patients
achieved CRp. Of those who were refractory to their most
recent prior regimen, the overall response rate was 17%.
There were an additional 10% of patients who achieved a
partial response (PR). The median duration of response for
patients with ALL who achieved at least a partial response
was 9.7 weeks. Responses were observed in patients with
both B-and T-lineage ALL, and in patients with various
cytogenetic abnormalities. Nine of the 61 ALL patients proceeded
to HSCT, with no apparent increase in transplantation-related
toxicity. The median duration of CR was 7 months in patients
(Jeha et al 2006b; Jeha and Kantarjian
. The most common adverse events, grade 3 or higher,
were fever with neutropenia, anorexia, hypotension, and
nausea. Similar response rates were seen in a European phase
II trial in pediatric patients with ALL, with a reported CR +
CRp rate of 28%
(Kearns et al 2006)
Forty-two children with AML were reported in a separate
pediatric phase II clofarabine trial. The overall response rate
in the heavily pretreated pediatrics was 26% (1 CRp and
8 PRs) (Table 4). The median duration of remission was
16.2 weeks and reported toxicities were similar to patients
(Jeha et al 2006b)
The pediatric phase I and phase II single agent trials
determined that clofarabine was active in pediatric patient with
relapsed and refractory ALL with an acceptable toxicity
profile. Rational combinations of clofarabine with other
agents are being investigated in order to optimize clinical
benefit. In vitro data suggest that clofarabine, an inhibitor of
DNA repair, may enhance the cytotoxicity of DNA-damaging
agents such as cyclophosphamide
(Yamauchi et al 2001)
combination of cyclophosphamide and etoposide is utilized
during consolidation therapy for pediatric ALL patients with
ALL in first relapse (Children’s Oncology Group Protocol
AALL01P2), and a similar ifosfamide/etoposide
combination is active in multiply relapsed ALL
(Crooks and Sato
. A pilot phase I study of clofarabine used in
combination with cyclophosphamide and etoposide is ongoing to
determine the MTD and the dose-limiting toxicities of the
combination. Once etoposide and cyclophosphamide were
escalated to their target doses (100 mg/m2/day and 440 mg/
m2/day, respectively in cohort 3), clofarabine was increased
to 30 mg/m2/day in cohort 4 and would be increased
to 40 mg/m2 in cohort 5
(Hijiya et al 2007)
. To date, 19
patients (15 ALL, 4 AML) have been enrolled in the first
4 dose cohorts (Table 5). Seventeen patients (14 ALL,
3 AML) have response data available. The median number
of prior regimens was 2. Seven of 14 evaluable ALL patients
achieved a CR and 2 ALL patients achieved a CRp, for an
overall response rate of 64% among pediatric patients with
ALL. Three out of 3 patients with AML achieved a CRp. One
patient in cohort 4 experienced a grade 3 elevation of lipase
and possible veno-occlusive disease. Febrile neutropenia was
a common toxicity. Phase 2 studies of this combination will
take place once the MTD is determined
(Hijiya et al 2007)
Other studies are investigating whether clofarabine, a
potent inhibitor of ribonucleotide reductase, will modulate
intracellular cytarabine (Ara-c) triphosphate
accumulation and increase the cytotoxicity of Ara-c
(Cooper et al
2005; Faderl et al 2005b, 2006)
. A phase 1–2 adult study
in 32 adults with relapsed and refractory acute leukemias
demonstrated that the combination of clofarabine at the
adult MTD dose level of 40 mg/m2/day for 5 days (days 2–6)
followed 4 hours later by cytarabine 1 g/m2 administered
as a 2-hour intravenous infusion for 5 days (days 1–5) was
safe and effective
(Faderl et al 2005b)
. The overall response
rate was 38% with 1 death during induction. Adverse events
were mainly less than or equal to grade 2, including transient
liver enzyme elevations, nausea, diarrhea, skin rash,
mucositis, and palmo-plantar erythrodysesthesias. A Children’s
Oncology Group (COG) study (AAML0523) is underway to
explore the safety and effecacy of this combination.
Safety and tolerability
Clofarabine is tolerated at 20 times higher doses in
leukemia patients than in patients with solid tumors, where
myelosuppression is dose-limiting
(Kantarjian et al 2003b)
The dose-limiting toxicity in pediatric leukemia patients is
hyperbilirubinemia and transient elevations in liver enzymes,
which reversed by day 14, as well as grade 3 skin rash
et al 2004)
. Some patients experienced CNS irritability with
the 1-hour infusion, which resolved when the clofarabine
was given over 2 hours. Other adverse events greater than or
equal to grade 3 which occurred in 10% or more of patients
included febrile neutropenia, anorexia, hypotension, nausea,
sepsis, and pleural effusion
(Jeha et al 2006a, b)
fevers and skin rash generally responded to antihistamines
and may require low-dose corticosteroids, once infection is
excluded. Clofarabine administration has been associated
with rapid decreases in blasts even in non-responders; this
may be accompanied by tumor lysis syndrome or systemic
inflammatory response and capillary leak syndrome, with
respiratory distress, fever, and hypotension. Cytokine-release
like events may have contributed to a decline in cardiac
function that was observed in several patients.
Drug interactions and concomitant medications
No clinical drug-drug interaction studies have been conducted
to date. Clofarabine is primarily excreted by the kidneys,
thus it may potentiate the toxicity of known nephrotoxic
drugs, including aminoglycoside antibiotics. Tumor lysis
and hyperuricemia may also contribute to renal toxicity. The
concomitant use of medications known to induce hepatic
toxicity should also be avoided, since hepato-biliary toxicities
were observed in pediatric trials. In addition, patients taking
medications known to affect blood pressure or cardiac
function should be closely monitored during the administration of
clofarabine, as symptoms of cytokine release and capillary
leak syndrome, including hypotension, tachycardia, and
pulmonary edema, have been reported in patients undergoing
treatment with clofarabine (Clolar® package insert).
The recommended dose and schedule of clofarabine as a
single agent for pediatric patients is 52 mg/m2 administered
by intravenous (IV) infusion over 2 hours daily for 5
consecutive days. The dosage is based on the patient’s BSA,
calculated using the actual height and weight before the
start of each cycle. Treatment cycles are repeated following
blood count recovery or return to baseline organ function,
approximately every 2–6 weeks (Clolar® package insert).
To prevent drug incompatibilities, no other medications
should be administered through the same intravenous line.
Clofarabine should be administered along with IV infusion
fluids to reduce the effects of tumor lysis and other adverse
events. Allopurinol may be administered prophylactically if
hyperuricemia is expected. The use of prophylactic steroids
(eg, 100 mg/m2 hydrocortisone on days 1 through 3) may
be of benefit in preventing signs or symptoms of systemic
inflammatory response syndrome (SIRS)/capillary leak
syndrome. If signs or symptoms of SIRS or capillary leak occur
(eg, hypotension), clofarabine should be discontinued and the
use of steroids, diuretics, and albumin considered. According
to the manufacturer, clofarabine can be re-instituted when the
patient is stable and organ function has returned to baseline,
generally with a 25% dose reduction.
Better use of existing drugs has dramatically improved
survival rates for childhood acute leukemias over the past
few decades. However, relapsed and refractory childhood
leukemias remain a significant therapeutic challenge. Relapse
after multi-agent therapy may arise from mutations in shared
cell-death pathways, rather than alterations in specific drug
activation, drug elimination, or drug targets. In addition
to resistant disease, heavily pretreated patients often have
underlying infection and pre-existing organ dysfunction. New
candidate agents need be evaluated in combination. Agents
may have substantial single agent activity, yet contribute
nothing in combination, eg, ifosfamide in
(Miser et al 1987; Crist et al 2001)
. Conversely, an
agent may have no single agent activity, yet still contribute
in combination, eg, leukovorin in colon cancer
Clofarabine is safe and active in both myeloid and
lymphoid relapsed/refractory pediatric acute leukemias in
single agent phase I and II trials. Myelosuppression was an
acceptable effect in this population, and the neurotoxicity
associated with previous generation nucleoside analogs
was not observed with clofarabine. Responses in relapsed
pediatric ALL were durable and allowed some patients to
successfully proceed to transplantation. Clofarabine has
been approved by the FDA for the treatment of pediatric
patients with relapsed or refractory ALL after at least
2 prior therapeutic regimens based on the induction of
complete responses. Over the past decade, clofarabine has been
the only anti-cancer agent to receive primary indication for
use in children.
Rational combinations of clofarabine with other active
agents in refractory leukemias are currently under
investigation. The early results of the phase I study of clofarabine
in combination with cyclophosphamide and etoposide
in pediatric patients with relapsed or refractory ALL or
AML indicate that this combination shows significant
activity in children with both subtypes of refractory
leukemia and is well tolerated
(Hijiya et al 2007)
studies of clofarabine in combination with cytarabine to
enhance intracellular Ara-C triphosphate accumulation are
also in progress. Such rationally designed combinations
of clofarabine with standard agents may have a role in
frontline therapy for newly diagnosed patients with higher
risk disease. As of September, 2007 COG plans to study
clofarabine-based combinations in a randomized phase III
trial in patients with “very high risk” B-precursor ALL,
ie, hypodiploidy, higher end-induction MRD, and/or
induction failure. The proposed study tests a clofarabine
blocks against the cyclophophamide/ara-c/thiopurine
blocks that occupy 3 of the first 6 months of post-induction
intensification. Plans in AML await completion of the
current COG trials, AAML0523.
TMH has no conflicts of interest. PSG is on the speakers’
bureaus for Genzyme, Sanofi-Aventis, and Enzon.
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