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Early mortality and the retinoic acid syndrome in acute promyelocytic
leukemia: impact of leukocytosis, low-dose chemotherapy, PMN/RAR-alpha
isoform, and CD13 expression in patients treated with all-trans retinoic
acid
L Vahdat, P Maslak, WH Miller , A Eardley, G Heller, DA Scheinberg and RP Warrell
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York,
NY.
All-trans retinoic acid (RA) has proven a major advance in the treatment of
acute promyelocytic leukemia (APL). However, the proper management of
patients who present with or develop leukocytosis during remission
induction with all-trans RA is not established, nor is there a clear
relation between leukocytosis and the development of the retinoic acid
syndrome. We reviewed the course of our patients who underwent induction
with all-trans RA to identify potential factors that might predict for the
development of this syndrome and to identify which patients, if any, might
specifically benefit from additional treatment with cytotoxic chemotherapy.
Seventy-eight courses of all- trans RA therapy were administered to
patients with a molecular diagnosis of APL. Initial and peak leukocyte
counts, their rate of rise, leukocyte count criteria developed in Europe,
and cell surface marker expression were all analyzed relative to subsequent
development of both the RA syndrome as well as all causes of early
mortality. The outcome of patients who received specific treatment for
retinoid- induced leukocytosis was also examined. No factor was found to
consistently predict for the development of the RA syndrome. Although the
occurrence of the syndrome was positively associated with the peak value of
the peripheral blood leukocyte count (P = .001), neither the initial
leukocyte count nor the rate of rise in leukocyte counts on days preceding
onset of the syndrome were sufficiently well-correlated to be clinically
useful (P = .21). The leukocyte count criteria developed in Europe had a
sensitivity of 62%, a specificity of 69%, and a positive predictive value
that ranged from only 44% to 72%. However, we unexpectedly found that basal
expression of CD13 (aminopeptidase N), a cell surface enzyme previously
linked to tumor cell invasion and an inferior outcome in patients with
acute myeloid leukemia, was highly associated with both development of the
syndrome (P < .05) as well as an elevated leukocyte count (P = .006).
Neither low-dose chemotherapy nor leukapheresis prevented development of
the syndrome nor ameliorated its effects. In fact, 9 of 11 patients who
received these interventions sustained fatal or near-fatal events, most of
which were due to hemorrhage. However, early treatment with a short-course
of high-dose corticosteroids halted progression of the syndrome in most
cases. Finally, we found that expression of the type "A" isoform of
PML/RAR- alpha (also known as bcr3 or "short") was associated with a
significantly shorter duration of relapse-free and overall survival (P =
.005).(ABSTRACT TRUNCATED AT 400 WORDS)
Volume 84,
Issue 11,
pp. 3843-3849,
12/01/1994
Copyright © 1994 by The American Society of Hematology
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