Arsenic and Old Lace: Novel Approaches

in Elderly Patients With Acute Myeloid Leukemia

Gail J. Roboz

Arsenic has been used for more than 2,000 years in the treatment of a variety of medical
conditions, including plague, hysteria, syphilis, and cancer. Numerous potential mecha-
nisms of action have been identified. Arsenic trioxide has remarkable efficacy in acute
promyelocytic leukemia and is approved by the US Food and Drug Administration for this
indication. It has also been studied in acute myeloid leukemia (AML), myelodysplastic
syndrome (MDS), and multiple myeloma and has limited single-agent efficacy in these
diseases. We have completed a phase I/II trial of arsenic trioxide combined with low-dose
ara-C (LDAC) in 49 patients with Int-2/high-risk MDS and 64 patients age 60 years and
older with untreated AML. The regimen was generally well tolerated and complete remis-
sions were observed in both MDS and AML patients, including in patients with poor
baseline performance status and unfavorable cytogenetics. Manuscript has been accepted
for publication.
Semin Hematol 45(suppl 2):S22-S24 © 2008 Elsevier Inc. All rights reserved.

A rsenic has been used to treat a wide variety of medical

conditions for more than 2,000 years. In an article on
arsenic from 1886, William Osler wrote that “in therapeutics
we do not so much need new remedies as a fuller knowledge
of when and how to use the old ones.”1 Arsenic has been
called “the therapeutic mule” due to its availability, low cost,
and ease of use.2 In the 1930s, Fowler’s solution of potassium
arsenate was the mainstay of treatment for chronic myeloid
leukemia (CML). At Harbin University in the 1970s, studies
of Ai-ling-1, an ancient Chinese remedy containing 1% ar-
senic trioxide and trace mercury, prompted further study of
the use of this drug in acute promyelocytic leukemia (APL).
Arsenic was shown to induce high complete response (CR)
rates and was generally well tolerated in relapsed APL, a
condition that had previously been almost universally fatal.
The US Food and Drug Administration (FDA) approved its
use in September 2000 and it has become the standard of care
for relapsed APL. It is also effective in newly diagnosed APL,
both as a single agent and in combination with chemother-
apy. The success of arsenic in APL led researchers to specu-
late about its potential efficacy in acute myeloid leukemia
(AML).
Weill Medical College of Cornell University, New York, NY.
STATEMENT OF CONFLICT OF INTEREST: Research support/Principal
Investigator: Cephalon; Consultant/Scientific Advisory Board: Cephalon.
Address correspondence to Gail J. Roboz, MD, Associate Professor of Med-
icine, Weill Medical College of Cornell University, 520 E 70th St, Starr
340A, New York, NY 10021. E-mail: gar2001@med.cornell.edu
There has been substantial experimental work on the
mechanism of action of arsenic trioxide. A 2002 review lists
119 references3 and another review in 2004 had 200 refer-
ences.4 Most researchers agree that arsenic affects malignant
cell growth, differentiation, and apoptosis. Several mecha-
nisms of action, listed in Table 1, are of particular interest in
nonpromyelocytic acute myeloid leukemia. Data have shown
that arsenic can induce cell death via cell cycle arrest, apo-
ptosis, and autophagic cell death. Other important mecha-
nisms include the generation of oxygen species and accumu-
lation of intracellular hydrogen peroxide; the release of
cytochrome C and activation of the caspase cascade; inhibi-
tion of glutathione peroxidase activity; downregulation of
BCL2 protein expression; inhibition of nuclear factor-␬B
(NF-␬B) activity; promotion of differentiation; induction of
histone hyperacetylation; activation of MAP kinase; and
modulation of cytokine release.3,5
Arsenic trioxide has also shown potential antiangio-
genic effects.6 Arsenic trioxide induced time- and dose-
dependent apoptosis in human umbilical vein endothelial
cells (HUVECS) but not in fibroblast populations. After treat-
ment with arsenic trioxide, the production of vascular endo-
thelial growth factor was inhibited, and capillary tubule and
branch formation were prevented in an in vitro endothelial
cell assay. Autocrine and paracrine loops generated by vas-
cular endothelial growth factor (VEGF)/VEGF receptor 2
(VEGFR2) signaling pathways are essential for the growth of
certain leukemias, and arsenic may be able to interrupt the

S22 0037-1963/08/$-see front matter © 2008 Elsevier Inc. All rights reserved.
doi:10.1053/j.seminhematol.2008.07.005
Novel approaches in elderly AML patients
Table 1 Possible Mechanisms of Action of Arsenic Trioxide3-5
Mechanism of Action
Induction of cell death via cell cycle arrest, apoptosis, and
autophagy
Generation of reactive oxygen species and accumulation of
intracellular hydrogen peroxide
Release of cytochrome c and activation of caspase
cascade
Inhibition of glutathione peroxidase activity
Downregulation of BCL2 protein expression
Inhibition of NF-kB activity
Promotion of differentiation: Induction of histone
hyperacetylation, activation of MAPk
Modulation of cytokine release
reciprocal signaling loop in which leukemic cells release
VEGF and cause autostimulation.
Elderly AML Patients
AML carries a dismal prognosis in elderly patients, and con-
ventional chemotherapy strategies are often both ineffective
and toxic. The well-known combination of 7 days of infu-
sional cytarabine and 3 days of daunorubicin has been the
standard of care for many years, but is not a feasible option
for many older patients with AML. Low-dose ara-C (LDAC)
has been included in the literature since the 1960s and is a
frequently used lower intensity alternative to conventional in-
duction. LDAC is currently being used as the control arm in
several ongoing randomized trials in elderly AML. Supportive
care with antibiotics, hydroxyurea, and transfusions is often of-
fered to older patients who are felt to be “unfit” for active treat-
ment, even though it has been shown to be inferior to LDAC in
a randomized trial from the UK Medical Research Council.7
Older patients with AML should be offered participation in a
clinical trial whenever logistically feasible.
It is clear that novel approaches are needed to treat older
AML patients. Parmar et al8 conducted a phase II trial of
arsenic trioxide in 11 patients with AML, seven of whom
were untreated and four with relapsed or refractory dis-
ease. None of the 11 patients achieved a response to sin-
gle-agent arsenic trioxide. Douer et al9 treated nine pa-
tients with arsenic trioxide combined with ascorbic acid,
which may have synergistic mechanisms of action via the
glutathione peroxidase pathway. Of the nine patients, five
(56%) experienced a response, with one CR, one CR with
incomplete platelet recovery (CRp), one reduction of bone
marrow blasts to less than 5%, and two reductions in
peripheral blood blasts. Four patients had progression of
disease. We have recently completed a phase I/II study of
arsenic in combination with LDAC in untreated patients
greater than 60 years of age with AML. The phase I dose-
escalation study used a fixed dose of 0.25 mg/kg of arsenic
trioxide on days 1 to 5 and 8 to 12. LDAC was started at 5
mg/m2 subcutaneously twice a day and then escalated to
7.5 mg/m2, with a target dose of 10 mg/m2 twice a day.
Patients were treated for 14 days on an outpatient basis if
S23
possible and a bone marrow aspirate was collected on day
21. If residual disease was present, patients were treated
with an additional cycle of arsenic and cytarabine, with the
addition of ascorbic acid. Patients with an aplastic marrow
at day 14 were observed and given supportive measures
until peripheral blood count recovery. Patients who
achieved CR and were not eligible for reduced-intensity al-
logeneic stem cell transplantation were treated with an iden-
tical cycle of consolidation, followed by monthly outpa-
tient maintenance. CR was observed in 34% of patients,
including ones with poor baseline performance status and
unfavorable cytogenetics. Myelosuppression, febrile neutro-
penia and bacteremias were observed frequently, but ex-
tramedullary toxicity was generally mild and reversible. Tox-
icities that occurred in greater than 50% of the patients were
fatigue, nausea, diarrhea, rash, peripheral edema, hyperbiliru-
binemia, headache, and elevated transaminases. There were no
clinically significant arrhythmias. The 30-day induction mortal-
ity was 8%. Overall survival was as expected in an older AML
population, with median survival of 157 days; responders
had a median survival of 562 days versus 81 days for
nonresponders. Publication of the complete data from this
trial is expected imminently and a phase III, multicenter,
randomized study comparing arsenic trioxide and LDAC to
LDAC alone in elderly patients is ongoing.10
Conclusions
Arsenic trioxide is a highly effective agent in APL. Its multi-
faceted mechanism of action and favorable toxicity profile
make it an attractive choice for other hematologic malignan-
cies, but single-agent efficacy has been limited. Treatment
with arsenic trioxide and LDAC has had promising prelimi-
nary results in older patients with AML and further efforts to
optimize this regimen are underway in AML, myelofibrosis,
and advanced myeloproflierative diseases.
References
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S24
8. Parmar S, Rundhaugen LM, Boehlke L, Riley M, Nabhan C, Raji A, et al:
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