Diagnosis and treatment of acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL), characterized by a translocation between the promyelocytic leukemia gene (PML) on chromosome 15 and the retinoic acid receptor-alpha (RARalpha) gene on chromosome 17, has become a model for targeted treatment of cancer. Advances in our understanding of the fundamental biology of this disease have led to the development of tools for diagnosis, monitoring of minimal residual disease, and detection of early relapse. Differentiation therapy with all-trans retinoic acid in combination with chemotherapy has significantly improved survival in patients with APL. Moreover, arsenic trioxide, which induces differentiation and apoptosis of APL cells, has become standard treatment for relapsed disease, and its role in the treatment of newly diagnosed APL is under active investigation. The lessons learned from APL have broad applications to other forms of leukemia and to cancer in general, whereby molecularly targeted therapy is directed to specifically defined subgroups.

Phase I and pharmacokinetic study of the novel oral cell-cycle inhibitor Ro 31-7453 in patients with advanced solid tumors.

PURPOSE: To determine maximum tolerated dose, pharmacokinetics (PK), and safety of Ro 31-7453, a novel, oral cell-cycle inhibitor. PATIENTS AND METHODS: Using an accelerated dose-escalation schedule, 48 patients with advanced solid tumors were treated with doses of Ro 31-7453 ranging from 25 to 800 mg/m(2)/d given for 4 consecutive days, every 3 weeks. The total daily dose was taken as a single dose (schedule A) or divided into two equal doses taken 12 hours apart (schedule B). PK samples of blood and urine were collected on the first and last days of dosing in cycles 1 and 2. RESULTS: Forty-five patients completed at least one cycle of therapy. Myelosuppression and stomatitis were dose-limiting toxicities, occurring at the 800 mg/m(2)/d dose level for both schedules. Toxicity was independent of body-surface area, leading to the recommended phase II flat dose of 1,000 mg daily for 4 days for both schedules. Common adverse events included diarrhea, nausea, vomiting, fatigue, alopecia, and elevated liver-function tests. One death, related to neutropenic sepsis, occurred on study. The PK of the parent compound and major metabolites were apparently linear, with a half-life of approximately 9 hours and a maximum concentration of approximately 4 hours. Minor antitumor activity was observed against carcinoma of the lung, breast, pancreas, and ovary. CONCLUSION: Ro 31-7453 was well tolerated, with manageable adverse effects. Significant PK variability (absorption, metabolism, and excretion) was observed, and a substantial number of additional patients are needed to confirm the recommended phase II dose. Additional pharmacology and phase II studies are under way to explore the dose-toxicity relationship.

Effect of arsenic trioxide on QT interval in patients with advanced malignancies.

PURPOSE: Arsenic trioxide is an effective treatment for patients with acute promyelocytic leukemia (APL) who have relapsed from or are refractory to all-trans-retinoic acid and anthracycline chemotherapy. Since arsenic can prolong the QT interval and lead to torsade de pointes, a life-threatening ventricular arrhythmia, this retrospective analysis was conducted to determine the degree of QT prolongation in patients treated with arsenic trioxide. PATIENTS AND METHODS: Clinical data and serial ECGs from 99 patients with advanced malignancies who received 170 courses of arsenic trioxide in either a phase I or phase II investigational study were reviewed. RESULTS: Prolonged QT intervals developed in 38 patients (26 patients had intervals >/= 500 milliseconds). Compared with baseline, the heart rate-corrected (QTc) interval was prolonged by 30 to 60 milliseconds in 36.6% of treatment courses, and by more than 60 milliseconds in 35.4% of patients. The degree of prolongation was higher in men than in women during the first course of therapy, and in patients with hypokalemia. In patients receiving multiple courses, QTc intervals returned to pretreatment levels before the second course, signifying that arsenic trioxide does not permanently prolong the QTc interval. One hypokalemic, arsenic trioxide-treated patient with relapsed APL developed asymptomatic torsade de pointes, which resolved spontaneously and did not recur after electrolyte replacement. There were no sudden or arrhythmia-related deaths. CONCLUSION: This analysis shows that arsenic trioxide can prolong the QTc interval. However, with appropriate ECG monitoring and management of electrolytes and concomitant medications, arsenic trioxide can be safely administered in patients with relapsed APL.

Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies.

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacodynamics (PD) of the proteasome inhibitor bortezomib (previously known as PS-341) in patients with refractory hematologic malignancies. PATIENTS AND METHODS: Patients received PS-341 twice weekly for 4 weeks at either 0.40, 1.04, 1.20, or 1.38 mg/m(2), followed by a 2-week rest. The PD of PS-341 was evaluated by measurement of whole blood 20S proteasome activity. RESULTS: Twenty-seven patients received 293 doses of PS-341, including 24 complete cycles. DLTs at doses above the 1.04-mg/m(2) MTD attributed to PS-341 included thrombocytopenia, hyponatremia, hypokalemia, fatigue, and malaise. In three of 10 patients receiving additional therapy, serious reversible adverse events appeared during cycle 2, including one episode of postural hypotension, one systemic hypersensitivity reaction, and grade 4 transaminitis in a patient with hepatitis C and a substantial acetaminophen ingestion. PD studies revealed PS-341 induced 20S proteasome inhibition in a time-dependent manner, and this inhibition was also related to both the dose in milligrams per meter squared, and the absolute dose of PS-341. Among nine fully assessable patients with heavily pretreated plasma cell dyscrasias completing one cycle of therapy, there was one complete response and a reduction in paraprotein levels and/or marrow plasmacytosis in eight others. In addition, one patient with mantle cell lymphoma and another with follicular lymphoma had shrinkage of nodal disease. CONCLUSION: PS-341 was well tolerated at 1.04 mg/m(2) on this dose-intensive schedule, although patients need to be monitored for electrolyte abnormalities and late toxicities. Additional studies are indicated to determine whether incorporation of dose/body surface area yields a superior PD model to dosing without normalization. PS-341 showed activity against refractory multiple myeloma and possibly non-Hodgkin's lymphoma in this study, and merits further investigation in these populations.

Established practice in the treatment of patients with acute promyleocytic leukemia and the introduction of arsenic trioxide as a novel therapy.

First-line therapy for patients with newly diagnosed acute promyelocytic leukemia (APL) has been established in a series of randomized clinical trials. Remission induction and consolidation are based on the differentiation agent, all-trans retinoic acid (ATRA), and anthracycline-based chemotherapy. Maintenance therapy is also based on ATRA and may involve additional chemotherapy. Established protocols are associated with a high rate of complete responses (CRs) (87% to 97%), and long-term follow-up has indicated a 4-year disease-free survival of greater than 60%. Therapy for patients who relapse or are refractory to ATRA-based regimens is not standardized and there is a need for new approaches. Arsenic trioxide (ATO) has recently been licensed for use in patients with relapsed/refractory APL. Controlled clinical trials have indicated that ATO is associated with a CR rate of 87% in this population. This agent has a manageable toxicity profile and presents a welcome option for patients with relapsed disease for whom other, more debilitating therapies are unsuitable. Several prognostic factors have been defined in patients with APL, and it is possible that novel treatments such as ATO should be differentially applied to specific prognostic groups.