Acute Leukemias - Republican Scientific Medical Library

a 4.3 · Treatment of Relapsed and Refractory AML 61
invasive fungal infections, reduce mortality from these
infections, and decrease the rate of invasive Aspergillus
infections [30].
A number of chemotherapeutic agents have activity
when used alone or in combination in patients with relapsed
or refractory AML. The management of patients
with relapsed and refractory AML is highly individualized
and based on multiple prognostic factors described
above. Importantly, published data should be interpreted
with caution since response rates may not only
reflect the therapy used, but also patient selection.
The practical challenges in recruiting patients with previously
untreated AML to clinical trials are formidable
[31].
Furthermore, it is likely that even more barriers exist
for accrual of patients with relapsed and refractory
AML related to performance status and prior therapy.
4.3.2 Conventional Cytotoxic Chemotherapy
During the past three decades, a wide variety of salvage
cytotoxic chemotherapy regimens has been studied in
patients with relapsed or refractory AML which result
in modest success. There is no standard chemotherapy
regimen that provides a durable second or greater CR.
One of the most active and the most studied agents is
ara-C. Doses range from 500 mg/m 2 to 3 gm/m 2 every
12 h for up to 6 days given either alone or in combination
with other active agents including anthracyclines,
asparaginase, etoposide, mitoxantrone, or amsacrine
[15, 32–38]. In general, variable second CR rates in the
range of 30 to 65% have been observed with associated
reinduction mortality rates of 12–25%. It is not clear that
the higher doses of ara-C are more effective. A German
AML Cooperative group trial has compared cytarabine
3 g/m 2 with 1 g/m 2 administered twice daily on days 1,
2, 7, and 8 in patients younger than age 60 years [15].
All patients received mitoxantrone. There was no substantial
difference in the CR rate (approximately 47%)
or OS rate. Therefore, although dose-intense cytarabine
is viewed as an essential component of many conventional
salvage programs, dose escalation to 3 g/m 2
may not be justified in many patients given the potential
for increased toxicity. It is desirable to select a salvage
chemotherapy regimen with minimal toxicity since
many suitable patients are subsequently offered HSCT.
Similarly, there is no definitive evidence that additional
agents given with intermediate- or HiDAC im-
proves OS. A large randomized trial conducted by
Southwest Oncology Group (SWOG) failed to demonstrate
a benefit in OS with the addition of mitoxantrone
to HiDAC every 12 h for total of 6 days [37]. Similarly,
nonstatistically significant results were obtained when
etoposide was combined with HiDAC. A CR rate of
45% with combination compared to CR rate of 40% with
HiDAC [39]. Novel regimens with cytotoxic chemotherapy
such as mitoxantrone and etoposide, or purine analogs,
have also been explored, but there is no evidence
that they represent any substantial improvement over
intermediate- or HiDAC-containing regimens [40–44].
4.3.3 Novel Agents Combined with
Conventional Cytotoxic Chemotherapy
Several novel therapies have been combined with conventional
chemotherapy to improve outcome. These
include so-called targeted therapies (discussed in detail
below), many of which are small molecules which
inhibit or perturb signal transduction pathways. Another
strategy has been to promote intracellular drug
retention by inhibiting the efflux pump- p-glycoprotein
(P-gp), a product of the multidrug resistance (MDR)-1
gene. The latter is possible by administration of cyclosporine
(CsA) [45, 46] or its analog PSC-833 [47, 48].
Other novel inhibitors such as Zosuquidar, with pharmacokinetic
properties such that concomitant chemotherapy
doses do not have to be reduced as with other
MDR inhibitors, are currently being investigated [49].
Despite strong preclinical data, trials utilizing these
agents alone or in combination with chemotherapy
and gemtuzumab ozogamicin (GO) [50, 51] have shown
variable and generally disappointing results. However,
a Phase III trial conducted by the SWOG demonstrated
significant improvements in relapse-free-survival (RFS)
and OS when CsA was combined with infusional
daunorubicin and HiDAC [45], but these results are
not validated by other studies using a similar strategy
[46]. In addition, the exact mechanism by which CsA
resulted in a benefit in RFS and OS in the SWOG trial
was not clear.