Acute Leukemias - Republican Scientific Medical Library

240 Chapter 19 · Novel Therapies in Acute Lymphoblastic Leukemia
malignancies < 21 years of age [20]. Depending on salvage
status, doses of 400 mg/m 2 up to 650 mg/m 2 daily
for 5 days every 21 days were used. The initial dose of
1.2 g/m 2 daily proved too neurotoxic. Among patients
with T-cell leukemia in first relapse (650 mg/m 2 ), response
rates exceeded 50% and were lowest in those
with extramedullary relapse (400 mg/m 2 ). Although
nelarabine was well tolerated at these dose levels,
peripheral neuropathy remained the most significant
adverse event. The efficacy of nelarabine in T-cell leukemias
notwithstanding, doses and schedules need to be
further investigated in particular subsets of adults and
children. Combinations of nelarabine with other nucleoside
analogs such as fludarabine based on biochemical
modulation of intracellular ara-GTP levels have
been reported [21].
Clofarabine is a second-generation nucleoside analog
that has been synthesized as a rational extension
of the experience with other deoxyadenosine analogs
such as fludarabine and cladribine. After cellular uptake,
clofarabine is converted to the monophosphate
compound by the enzyme deoxycytidine kinase
whereby phosphorylation of clofarabine by deoxycytidine
kinase is substantially more efficient than that of
fludarabine or cladribine. Furthermore, retention of
the triphosphate form of clofarabine in cells is also
longer than that of fludarabine and cladribine. Clofarabine
is active by inhibition of DNA synthesis,
ribonucleotide reductase (resulting in depletion of
normal deoxynucleotides and increased DNA incorporation
of the analog referred to as self-potentiation),
and various DNA polymerases [22].
In a phase I study of clofarabine in children with relapsed
and refractory acute leukemias, the MTD has
been established at 52 mg/m 2 daily for 5 days every
month with the DLT defined by reversible hepatotoxicity
and skin rash at doses of up to 70 mg/m 2 daily [23].
Out of 17 patients with heavily pretreated ALL, four
(24%) achieved CR and one (6%) PR, which made for
an overall response of 30%. In a subsequent larger phase
II study, which included 49 children with ALL, 31% responded
(six CR, four CRp, five PR) with a median survival
of 42 weeks (range 7 to 63.1 +) for these patients
[24]. Among the patients who were refractory to the last
prior chemotherapy, 23% (7/30) patients with ALL responded.
Based on the positive experience and the response
rates in pediatric ALL, clofarabine received Food
and Drug Administration (FDA) approval in December
2004 for children with relapsed/refractory ALL who
have at least received two prior regimens. Phase I studies
in adults with acute leukemias defined the MTD for
clofarabine at 40 mg/m 2 /day [25]. Less experience exists
with clofarabine in adult ALL. A large phase II study of
62 patients with relapsed acute leukemias included 12
ALL patients, two-thirds of whom received clofarabine
in their second or subsequent salvage [26]. Two patients
responded (one CR, one CRp) for an overall response of
16%. The complete responder had Ph-positive disease
and was primary refractory to induction with the
VAD regimen. The potential of clofarabine for adult
ALL remains to be explored. Clinical studies of clofarabine
combinations (e.g., with cyclophosphamide) are
underway.
19.2.3 Epigenetic Therapy
Aberrant methylation of promoter-associated CpG islands
and silencing of tumor-related genes due to hypermethylation
is an epigenetic modification that is
frequently observed in human cancers and leukemias
[27]. A particularly high frequency of this process has
been observed in ALL both at presentation and at relapse
where methylation of genes can be demonstrated
in up to 80% of patients [28, 29]. Several groups have
been able to identify a number of genes involved in
hypermethylation, which identified subsets of patients
with a “hypermethylator” phenotype that has prognostic
significance. Roman-Gomez et al. evaluated the
methylation status 15 genes in 251 ALL patients [30].
In more than 75% of the patients, at least one gene
was hypermethylated with ³ 4 genes hypermethylated
in about 36%. Although there was no difference in CR
rates among the groups with variable numbers of
genes affected, DFS and overall survival were significantly
different: 75.5% and 66.1%, respectively, for the
nonmethylated group compared to only 9.4 and 7.8%
for patients with ³4 involved genes (p < 0.0001 and
p