Correspondence
Acute Promyelocytic Leukemia
N Engl J Med 1994; 330:140-141January 13, 1994
- Article
To the Editor:
Warrell et al. (July 15 issue)1 do an excellent job of correlating the molecular and clinical aspects of acute promyelocytic leukemia. Less convincing, however, is their attribution of a “syndrome characterized by fever, respiratory distress, radiographic pulmonary infiltrates, pleural effusions, and weight gain” with “extensive infiltration of myeloid cells” to the administration of all-trans-retinoic acid. Before retinoic acid was used in the treatment of acute promyelocytic leukemia, fever and pulmonary manifestations of capillary leakage were described in patients with acute myeloid leukemia with or without hyperleukocytosis2,3 and ascribed to the invasiveness of promyeloblasts or the release of cellular products.
We report on a patient with acute promyelocytic leukemia in whom the so-called retinoic acid syndrome actually occurred before the administration of retinoic acid. A 38-year-old man was diagnosed in 1991 with acute promyelocytic leukemia on the basis of bone marrow characteristics and cytogenetic studies (t(15;17) translocation). He had a leukocyte count of 50,100 per cubic millimeter with 92 percent blasts and a platelet count of 15,000 per cubic millimeter; fresh-frozen plasma, but not heparin, was given. On the second day of induction chemotherapy (cytarabine, 100 mg per square meter of body-surface area per day, given as a continuous intravenous infusion), fever and respiratory distress, with interstitial pulmonary infiltrates and pleural effusions, developed rapidly, requiring intubation and intensive care. All-trans-retinoic acid, which had just become available to us, was started on the third day through a nasogastric tube. The patient slowly improved without steroid treatment and subsequently had a complete remission. In our opinion, instead of causing the complication, retinoic acid may have improved it.
Similar cases of the so-called retinoic acid syndrome in the absence of retinoic acid therapy have been observed elsewhere4. Furthermore, until now the retinoic acid syndrome has not been reported in any patients with nonleukemic cancer treated with retinoic acid. The therapeutic benefit of corticosteroids does not suggest a specific cause of the symptoms. Finally, the presumed pathogenesis through the release of cytokines need not be ascribed to retinoic acid-induced differentiation alone but may also reflect the secretory capacity of leukemic blasts,5 especially, but not exclusively, in the case of a rapidly rising leukocyte count. Until the pathogenesis has been clarified, we suggest that the term “retinoic acid syndrome” be replaced by a more descriptive one, such as “acute promyelocytic leukemia pneumonitis” or “capillary leak syndrome in acute promyelocytic leukemia.”
5 ReferencesMichael Stadler, M.D.
Arnold Ganser, M.D., Ph.D.
Dieter Hoelzer, M.D., Ph.D.
J.W. Goethe University Medical Center, 60596 Frankfurt, Germany1
Warrell RP Jr ,de The H ,Wang Z-Y ,Degos L . Acute promyelocytic leukemia. N Engl J Med 1993;329:177-189
Full Text | Web of Science | Medline2
Lichtman MA ,Rowe JM . Hyperleukocytic leukemias: rheological, clinical, and therapeutic considerations. Blood 1982;60:279-283
Web of Science | Medline3
Tryka AF ,Godleski JJ ,Fanta CH . Leukemic cell lysis pneumonopathy: a complication of treated myeloblastic leukemia. Cancer 1982;50:2763-2770
CrossRef | Web of Science | Medline4
Warrell RP Jr . Fatal all-trans retinoic acid pneumonitis. Ann Intern Med 1993;118:473-473
Web of Science | Medline5
Oster W ,Cicco NA ,Klein H , et al. Participation of the cytokines interleukin 6, tumor necrosis factor-alpha, and interleukin 1-β secreted by acute myelogenous leukemia blasts in autocrine and paracrine leukemia growth control. J Clin Invest 1989;84:451-457
CrossRef | Web of Science | Medline
To the Editor:
Warrell et al. summarized the adverse gastrointestinal effects of all-trans-retinoic acid, such as hepatic toxicity, and the metabolic effects, including hyperlipidemia. We report a case of severe acute pancreatitis during all-trans-retinoic acid therapy that was probably caused by hyperlipidemia.
A 44-year-old woman was admitted with her third relapse of acute promyelocytic leukemia. Her bone marrow had hypercellular features with 72 percent abnormal promyelocytes, and she had the chromosomal translocation t(15;17). Laboratory tests showed normal serum levels of amylase (106 U per milliliter), cholesterol (150 mg per deciliter), and triglycerides (99 mg per deciliter). After the chemotherapy had failed, she received 60 mg of all-trans-retinoic acid per day orally, and after three weeks her hematologic measurements had improved. However, the serum amylase level was 594 U per milliliter, elastase I 2600 ng per deciliter (normal range, 100 to 400), lipase 590 IU per liter (normal range, 10 to 48), trypsin 15,000 ng per milliliter (normal range, 110 to 640), and triglycerides 707 mg per deciliter. After the discontinuation of all-trans-retinoic acid, the triglycerides and pancreas-derived enzymes decreased to normal levels.
In this patient, acute pancreatitis occurred only during treatment with all-trans-retinoic acid. Elevation of serum triglycerides may have been involved in the pancreatic damage associated with the use of all-trans-retinoic acid.
Tohru Izumi, M.D.
Kiyohiko Hatake, M.D.
Yasusada Miura, M.D.
Jichi Medical School, Tochigi, Japan 329-04Author/Editor Response
The authors reply:
To the Editor: Like the patient described by Stadler and his colleagues, certain patients with acute promyelocytic leukemia have been given a diagnosis of the retinoic acid syndrome even before receiving the agent1. However, such cases are decidedly uncommon (1 of the last 75 in the New York series), whereas we conservatively estimate the incidence of this syndrome to be at least 25 percent in patients with acute promyelocytic leukemia undergoing induction therapy with all-trans-retinoic acid2. This agent has induced other problems (isolated joint effusions, highly focal bone pain, soft-tissue infiltration, and so forth), which also appear to be responsive to corticosteroids. Although the syndrome of respiratory distress has not been observed in patients with solid tumors, it clearly is not restricted to those with acute promyelocytic leukemia, since the original description included one patient with a different type of myeloid leukemia2. In part, the phenomenon may be related to cytodifferentiation that occurs to a limited extent in the natural history of the disease and occasionally during its treatment with standard cytotoxic drugs3,4. Possible explanations that have been proposed include an increase in the expression of cell-surface adhesion molecules, the release of vasoactive cytokines, and the enhanced migratory capacity of maturing granulocytoid cells2. Although no evidence currently favors one mechanism over another, the problem is clearly not hyperleukocytosis. We, too, have known patients to survive without the use of steroids; unfortunately, however, death has been more common. The mortality associated with this problem is substantial, and until better information is available, clinicians are strongly advised to treat patients receiving all-trans-retinoic acid with a short course of high-dose corticosteroids at the first sign of dyspnea. Neither of the alternative terms proposed by Stadler et al. appears to be especially informative, and they imply that there is more knowledge about this disorder than currently exists.
Striking hypertriglyceridemia has been observed with all-trans-retinoic acid and other retinoids5. Izumi and colleagues have reported a finding that may become increasingly important if this drug is used for protracted periods.
5 ReferencesRaymond P. Warrell, Jr., M.D.
Memorial Sloan-Kettering Cancer Center, New York, NY 10021Laurent Degos, M.D.
Hopital St. Louis, 75010 Paris, France1
Warrell RP Jr . Fatal all-trans-retinoic acid pneumonitis. Ann Intern Med 1993;118:473-473
Web of Science | Medline2
Frankel SR ,Eardley A ,Lauwers G ,Weiss M ,Warrell RP Jr . The “retinoic acid syndrome” in acute promyelocytic leukemia. Ann Intern Med 1992;117:292-296
Web of Science | Medline3
Kantarjian HM ,Keating MJ ,McCredie K , et al. A characteristic pattern of leukemic cell differentiation without cytoreduction during remission induction in acute promyelocytic leukemia. J Clin Oncol 1985;3:793-798
Web of Science | Medline4
Stone RM ,Maguire M ,Goldberg MA ,Antin JH ,Rosenthal DS ,Mayer RJ . Complete remission in acute promyelocytic leukemia despite persistence of abnormal bone marrow promyelocytes during induction therapy: experience in 34 patients. Blood 1988;71:690-696
Web of Science | Medline5
Marsden JR . Lipid metabolism and retinoid therapy. Pharmacol Ther 1989;40:55-65
CrossRef | Web of Science | Medline
- Citing Articles (4)
Citing Articles
1
Pierre Fenaux, Christine Chomienne, Laurent Degos. (2001) Treatment of acute promyelocytic leukaemia. Best Practice & Research Clinical Haematology 14:1, 153-174
CrossRef2
Pierre Fenaux, Christine Chomienne, Lament Degos. (2001) All-trans retinoic acid and chemotherapy in the treatment of acute promyelocytic leukemia. Seminars in Hematology 38:1, 13-25
CrossRef3
Leigh F. Callahan, David S. Cordray, George Wells, Theodore Pincus. (1996) Formal education and five-year mortality in rheumatoid arthritis: Mediation by helplessness scale scores. Arthritis Care & Research 9:6, 463-472
CrossRef4
J. F. Tomás, J. L. Lopez-Lorenzo, A. Escudero, J. M. Fernández-Rañada. (1995) More on acute promyelocytic leukemia pneumonitis. American Journal of Hematology 50:4, 315-315
CrossRef
