Acute Leukemias - Republican Scientific Medical Library

a 4.7 · Relapsed and Refractory Acute Promyelocytic Leukemia 67
4.7.3 Studies with Arsenic Trioxide
Arsenic trioxide has shown substantial efficacy in treating
both newly diagnosed and relapsed patients with
APL. As a single agent, it induces prolonged CRs, with
few adverse effects and minimal myelosuppression. Arsenic
trioxide is a highly useful agent in relapsed APL
and studies are underway to establish its role as initial
therapy in combination with ATRA and anthracyclines.
Arsenic trioxide acts on APL cells through a variety
of mechanisms, influencing numerous signal transduction
pathways and resulting in a wide range of cellular
effects. In vitro studies indicate that arsenic trioxide
may exert two effects on APL cells; triggering apoptosis
at relatively high concentrations (1.0–2.0 lmol/L) with
collapse of mitochondrial transmembrane potentials
in a thiol-dependent manner and inducing partial
differentiation at low concentration (0.1–0.5 lmol/L)
(Fig. 4.4) [120, 121].
In 1996, investigators in China reported that 73% of
the 30 patients with previously untreated APL and 52%
of 42 patients with relapsed or refractory disease
achieved CR with arsenic trioxide [122]. Additional
studies conducted in the USA and elsewhere confirmed
that arsenic trioxide can induce CR in relapsed APL patients
[116, 119, 123–125] (Table 4.5). In the US trial 11 of
12 patients with relapsed disease who received 12 to 39
days (median 33 days) of arsenic trioxide at a dose of
0.06–0.2 mg/kg of body weight achieved CR after extensive
prior therapy [123]. Moreover, eight of these 11 patients
in CR also tested negative molecularly by RT-PCR
for the PML-RARa transcript. In a subsequent multicenter
phase II trial 34 of 40 patients (85%) with
relapsed or refractory disease who were treated with arsenic
trioxide at a dose of 0.15 mg/kg/day achieved CR
Table 4.5. Studies with arsenic trioxide in relapsed and refractory acute promyelocytic leukemia (APL)
Study N CR rate (%) Comments
Fig. 4.4. At low concentrations, arsenic trioxide induces differentiation
of malignant promyelocytes through degradation of the
fusion protein PML-RARa; at high concentrations, arsenic trioxide
induces apoptosis of malignant promyelocytes through PML-RARadependent
and -independent mechanisms. PML, promyelocytic
leukemia; RARa, retinoic acid receptor alpha; RXR, retinoic X receptor
[33].
Zhang, et al. 1996 [122] 42 22 (52) 73% of the 30 previously untreated patients achieved CR
Shen, et al. 1997 [125] 10 9 (90) Duration of As2O3 treatment for CR between 28
and 44 days (median, 38 days)
Soignet, et al. 1998 [123] 12 11 (92) 8 of 11 patients in CR also tested negative molecularly
by RT-PCR for the PML-RARa transcript
Niu, et al. 1999 [119] 47 30 (85.1) 31 patients were treated with arsenic trioxide alone:
CR rate 84%
11 patients with combination of arsenic trioxide
and chemotherapy; CR rate 82%
5 patients with arsenic trioxide and ATRA: CR rate 100.0%
Soignet, et al. 2001 [124] 40 34 (85) Using a 10-4 sensitivity level 78% of patients exhibited
molecular conversion form positive to negative by RT-PCR
for the PML-RARa transcript
Kwong, et al. 2001 [116] 8 8 (100) All patients achieved morphological but not molecular
remission after arsenic trioxide, but all patients attained
molecular remission after subsequent idarubicin treatment