Correspondence
All-trans-Retinoic Acid in Acute Promyelocytic Leukemia
N Engl J Med 1998; 338:393-394February 5, 1998
- Article
To the Editor:
The report by Tallman and colleagues (Oct. 9 issue)1 concludes that “all-trans-retinoic acid as induction or maintenance treatment improves disease-free and overall survival as compared with chemotherapy alone and should be included in the treatment of acute promyelocytic leukemia.” Several cooperative groups have reported rates of remission and event-free survival with all-trans-retinoic acid for induction or maintenance treatment or both that leave no doubt about the therapeutic advantage of including this drug in the treatment of newly diagnosed acute promyelocytic leukemia.2-7
Tallman and colleagues used bone marrow morphology as the only diagnostic tool, but this can be misleading and is now considered insufficient for judging the eligibility of patients for protocols tailored to the treatment of acute promyelocytic leukemia. Demonstration of a PMLRARα rearrangement or the presence of t(15;17) should be mandatory, because the sensitivity of acute promyelocytic leukemia to all-trans-retinoic acid can be predicted on the basis of the presence of this fusion protein in leukemia cells.8 In the ongoing trial of the Spanish Programa Español para el Tratamiento de las Hemopatías Malignas (PETHEMA) group, in which all-trans-retinoic acid and idarubicin are administered immediately after the morphologic diagnosis has been established, 8 of 56 patients were excluded because of the absence of the specific cytogenetic or molecular abnormality in diagnostic specimens. Among the patients with genetically confirmed acute promyelocytic leukemia, the remission rate was more than 90 percent. The less stringent eligibility criteria used in the intergroup study reported by Tallman et al., in which the diagnosis was not genetically confirmed in 40 percent of the patients receiving all-trans-retinoic acid, may well explain the lower rate of complete remission.
The rationale for continuous administration of all-trans-retinoic acid as maintenance treatment is not explained by the authors. Although the most appropriate schedule for maintenance treatment has not yet been established, it is well recognized that prolonged administration of all-trans-retinoic acid induces metabolic inactivation and the development of resistance. Moreover, continuous administration of all-trans-retinoic acid is expected to cause increased toxicity. In fact, 36 percent of the patients assigned to maintenance treatment with all-trans-retinoic acid had severe or life-threatening complications in the study reported by Tallman and colleagues. In contrast, severe toxicity from all-trans-retinoic acid was almost negligible in the two large European trials — Acute Promyelocytic Leukemia 1993 (APL93) and All-trans-Retinoic Acid plus Idarubicin (AIDA), both also started in 1993 — which used intermittent administration of all-trans-retinoic acid (45 mg per square meter of body-surface area per day for 15 days every 3 months) as maintenance therapy.
8 ReferencesMiguel A. Sanz, M.D., Ph.D.
Guillermo Martín, M.D., Ph.D.
University Hospital La Fe, 46009 Valencia, SpainJoaquín Díaz-Mediavilla, M.D., Ph.D.
University Hospital San Carlos, 28040 Madrid, Spain1
Tallman MS ,Andersen JW ,Schiffer CA , et al. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med 1997;337:1021-1028
Full Text | Web of Science | Medline2
Fenaux P ,Le Deley MC ,Castaigne S , et al. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia. Blood 1993;82:3241-3249
Web of Science | Medline3
Fenaux P ,Chastang CI ,Sanz M , et al. Effect of ATRA in newly diagnosed acute promyelocytic leukemia (APL): validation of short term effect in a large multicenter trial (APL 93 Trial) and assessment of long term benefit (APL 91 Trial). Blood 1996;88:Suppl 1:209a-209a abstract.4
Frankel SR ,Eardley A ,Heller G , et al. All-trans retinoic acid for acute promyelocytic leukemia: results of the New York Study. Ann Intern Med 1994;120:278-286
Web of Science | Medline5
Kanamaru A ,Takemoto Y ,Tanimoto M , et al. All-trans retinoic acid for the treatment of newly diagnosed acute promyelocytic leukemia. Blood 1995;85:1202-1206
Web of Science | Medline6
Avvisati G ,Lo Coco F ,Diverio D , et al. AIDA (all-trans retinoic acid + idarubicin) in newly diagnosed acute promyelocytic leukemia. Blood 1996;88:1390-1398
Web of Science | Medline7
Mandelli F ,Diverio D ,Avvisati G , et al. Molecular remission in AML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood 1997;90:1014-1021
Web of Science | Medline8
Miller WH Jr ,Kakizuka A ,Frankel SR , et al. Reverse transcription polymerase chain reaction for the rearranged retinoic receptor α clarifies diagnosis and detects minimal residual disease in acute promyelocytic leukemia. Proc Natl Acad Sci U S A 1992;89:2694-2698
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Our study protocol was written in 1991 and activated in early 1992, before the routine availability of molecular studies to evaluate the presence of the PMLRARα fusion transcript. Furthermore, when our study was begun, it was unknown how patients with leukemia that was morphologically indistinguishable from acute promyelocytic leukemia but without the translocation would respond to all-trans -retinoic acid. We agree that it is now state-of-the-art practice to use either karyotypic or molecular analysis to establish the diagnosis and that such analyses should be required for eligibility when possible in future studies. Although it is true that for approximately 40 percent of the patients in the intergroup study who received all-trans -retinoic acid, t(15;17) was not identified by routine karyotypic analysis (7 percent) or no information on the karyotype was available (32 percent), in the majority of these patients molecular studies performed retrospectively confirmed the diagnosis. Therefore, the absence of genetic confirmation alone does not explain the low rate of complete remission. We believe that other factors contributed to the rate of complete remission. The rate we reported reflects the results in the patients treated with all-trans -retinoic acid alone and excludes the patients who successfully crossed over to chemotherapy. As we suggested in our report, if the latter patients had been included, the rate of complete remission would have been 78 percent. If we had also included patients with inadequate documentation of complete remission (because of missing forms) who were long-term survivors, the complete-remission rate would have been more than 85 percent.
One of the objectives of our study was to evaluate the role of all-trans -retinoic acid as maintenance therapy in patients who had a complete remission with all-trans -retinoic acid. Our trial was designed before the recognition that continuous exposure to all-trans -retinoic acid results in a decrease in the plasma concentration1 and that the administration of all-trans -retinoic acid on an intermittent schedule circumvents this problem by restoring high plasma concentrations.2 However, it is not clear that plasma pharmacokinetics are correlated with the response, the duration of the response, or toxicity. The mechanism may involve not the plasma concentration but rather the intracellular concentration of all-trans -retinoic acid.3 Nonetheless, our study shows that maintenance therapy with all-trans -retinoic acid, as administered in our study, results in prolonged disease-free survival as compared with observation.
3 ReferencesMartin S. Tallman, M.D.
Northwestern University, Chicago, IL 60611Frederick R. Appelbaum, M.D.
Fred Hutchinson Cancer Research Center, Seattle, WA 98104-2092Charles A. Schiffer, M.D.
Wayne State University, Detroit, MI 482011
Muindi J ,Frankel SR ,Miller WH Jr , et al. Continuous treatment with all-trans retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid “resistance“ in patients with acute promyelocytic leukemia. Blood 1992;79:299-303[Erratum, Blood 1992;80:855.]
Web of Science | Medline2
Adamson PC ,Bailey J ,Pluda J , et al. Pharmacokinetics of all-trans-retinoic acid administered on an intermittent schedule. J Clin Oncol 1995;13:1238-1241
Web of Science | Medline3
Agadir A ,Cornic M ,Lefebvre P , et al. All-trans retinoic acid pharmacokinetics and bioavailability in acute promyelocytic leukemia: intracellular concentrations and biologic response relationship. J Clin Oncol 1995;13:2517-2523
Web of Science | Medline
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