The purpose of this study is to evaluate both the efficacy and toxicity of infusional
arsenic trioxide in the treatment of patients with relapsed or refractory acute
promyelocytic leukemia (APML). In addition, correlation between pharmacokinetic data and
both therapeutic response and therapy-related toxicities will be sought.
OUTLINE: This is a dose-escalation study.
Patients receive arsenic trioxide IV over 2 hours daily for 28 days followed by a 14 day
rest period. Patients may receive up to 3 courses of treatment.
Dose escalation continues in cohorts of 3-6 patients until the maximum tolerated dose (MTD)
or minimum effective dose (MED) is determined. The MTD is defined as the dose preceding that
at which 2 or more patients experience dose limiting toxicity. The MED is defined as the
dose at which 4 of 6 patients achieve a complete cytogenetic or molecular response. After
the MTD or MED is determined, an additional 20 patients are enrolled at this dose level.
Patients are followed monthly for 6 months and every three months for an additional 1.5
1. APML diagnosis based upon morphological, histochemical, and/or flow cytometric
criteria, confirmed upon review by a central, study-designated hematologic
any relapsed acute leukemia bearing a t(15:17) translocation or variant APML
translocations involving the retinoic acid receptor alpha gene on chromosome 15q22,
based on cytogenetics or PCR.
2. disease in first or subsequent relapse, following standard induction and
consolidation chemotherapy (with all-trans retinoic acid) and/or allogeneic bone
marrow/stem cell transplantation;
failure to achieve initial complete remission with ATRA and standard chemotherapy.
1. Availability of a fully HLA-matched sibling donor for patients otherwise felt to be
candidates for allogeneic bone marrow/stem cell transplantation; patients with only a
partially HLA-matched sibling or matched unrelated donor will remain eligible for
3. Patients with significantly impaired left ventricular ejection fraction (<40%) will
be ineligible for the study.
Patients with renal failure and a creatinine clearance of less than 25 ml/min or requiring
hemodialysis will be ineligible for the study. Otherwise, there are no rigid exclusion
criteria based upon age, performance status, or co-morbidity. Decisions regarding
enrollment of patients for whom these factors may be relevant will be individualized and
left to the discretion of the investigators. Central venous access will be required for
all patients. Patients of child-bearing potential must agree to use contraception during
sexual intercourse while undergoing treatment with arsenic trioxide.