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All-trans Retinoic Acid for Acute Promyelocytic Leukemia: Results of the New York Study

Stanley R. Frankel, MD; Anna Eardley, BA; Glenn Heller, PhD; Ellin Berman, MD; Wilson H. Miller, MD; Ethan Dmitrovsky, MD; and Raymond P. Warrell, MD
[+] Article and Author Information

From the Memorial Sloan-Kettering Cancer Center and the Cornell University Medical College, New York, New York. Requests for Reprints: Raymond P. Warrell, Jr., MD, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Grant Support: In part by FD-R-000764 from the Orphan Products Division, Food and Drug Administration; by CA-57645 and CA-55449 from the National Cancer Institute; by EDT-47 and PT-381 from the American Cancer Society; and by the Lymphoma Foundation. Acknowledgments: The authors thank Teresa Snyder, RN, Marianne Campbell, RN, and Helen Wrobleski, RN, for clinical support; Susan McKenzie and Angelita Naval for technical assistance; and our colleagues in the Leukemia Service for their expertise in clinical management.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1994;120(4):278-286. doi:10.7326/0003-4819-120-4-199402150-00004
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Objective: To evaluate the safety and efficacy of all-trans retinoic acid to induce complete remission and to examine its effects on duration of remission and survival in patients with acute promyelocytic leukemia.

Design: Phase II evaluation and comparison with historical control patients.

Setting: Tertiary care cancer referral center.

Patients: Consecutive patients with morphologic diagnoses of acute promyelocytic leukemia were treated during a 2-year period with all-trans retinoic acid (daily oral dose, 45 mg/m2). Newly diagnosed patients discontinued the drug approximately 30 days after they achieved complete remission, at which time they received three courses of combination chemotherapy. Patients treated with previous cytotoxic chemotherapy who then relapsed were continued on all-trans retinoic acid as “maintenance” therapy until they relapsed again.

Results: 56 patients entered the study: 34 were newly diagnosed and 22 had relapsed from previous treatment. Fifty-one patients subsequently were found to have the PML/RAR-α gene rearrangement indicative of acute promyelocytic leukemia, and 44 of these patients achieved complete remission (86%; 95% CI, 76% to 96%). A distinctive respiratory distress syndrome developed in 13 patients (23%) during treatment, and 5 patients (9%; CI, 3% to 20%) died of this complication. The 5 patients who lacked PML/RAR-α rearrangements were withdrawn and given chemotherapy. The 13 patients given all-trans retinoic acid alone as maintenance therapy (10 of whom had relapsed from a chemotherapy-induced remission) had a median duration of remission of only 3.5 months (range, 1 to 23 months). Only 3 of 19 patients who relapsed from a remission induced by all-trans retinoic acid could be brought into remission again using this drug. The median survival time of all newly diagnosed patients has not been reached, but it now exceeds 31 months (range, 0.4 to 36+ months). No decrease in the early mortality rate was observed compared with a historical control group composed of 80 consecutive, newly diagnosed patients treated only with chemotherapy at this center; however, overall survival was superior.

Conclusions: All-trans retinoic acid is an effective agent to induce remission in patients with a molecular diagnosis of acute promyelocytic leukemia, but remissions are short and resistance develops rapidly. Although the incidence of early death was not reduced, the use of all-trans retinoic acid to induce remission, followed by cytotoxic chemotherapy for “consolidation,” was associated with longer survival times when compared with historical controls treated only with chemotherapy. Additional studies to prevent or mitigate consequences of the “retinoic acid syndrome” and to identify specific patients who might benefit from earlier intervention with chemotherapy are needed to maximize the advantages of this approach.

Figures

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Figure 1.
Kaplan-Meier plots of the overall survival of 34 newly diagnosed patients with acute promyelocytic leukemia treated with all-trans retinoic acid (left panel, closed boxes) compared with historical control patients treated with conventional chemotherapy (right panel, closed circles) (n = 80).
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Figure 2.
Plot of median total peripheral blood leukocyte count (left axis) of 51 patients with acute promyelocytic leukemia and rearrangements of PML/RAR-α treated with all-trans retinoic acid.

In addition to the early wave of leukocytosis, a secondary wave of leukopenia is shown between 3 and 5 weeks. (The horizontal dotted line represents the lower limit of the normal range for the peripheral blood leukocyte count. The number of patients who had samples taken on each day is represented in the area curve at the bottom of the figure for the right ordinate.)

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