EARLY MORTALITY AND THE RETINOIC ACID SYNDROME IN ACUTE PROMYELOCYTICLEUKEMIA - IMPACT OF LEUKOCYTOSIS, LOW-DOSE CHEMOTHERAPY, PMN RAR-ALPHA ISOFORM, AND CD13 EXPRESSION IN PATIENTS TREATED WITH ALL-TRANS-RETINOIC ACID/

All-trans retinoic acid (RA) has proven a major advance in the treatme nt of acute promyelocytic leukemia (APL). However, the proper manageme nt of patients who present with or develop leukocytosis during remissi on induction with all-trans HA is not established, nor is there a clea r relation between leukocytosis and the development of the retinoic ac id syndrome. We reviewed the course of our patients who underwent indu ction with all-trans RA to identify potential factors that might predi ct for the development of this syndrome and to identify which patients , if any, might specifically benefit from additional treatment with cy totoxic chemotherapy Seventy-eight courses of all-trans RA therapy wer e administered to patients with a molecular diagnosis of APL. initial and peak leukocyte counts, their rate of rise, leukocyte count criteri a developed in Europe, and cell surface marker expression were all ana lyzed relative to subsequent development of both the RA syndrome as we ll as all causes of early mortality. The outcome of patients who recei ved specific treatment for retinoid-induced leukocytosis was also exam ined. No factor was found to consistently predict for the development of the RA syndrome. Although the occurrence of the syndrome was positi vely 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 le ukocyte 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 my eloid leukemia, was highly associated with both development of the syn drome (P < .051 as well as an elevated leukocyte count (P = .006). Nei ther low-dose chemotherapy nor leukapheresis prevented development of the syndrome nor ameliorated its effects. In fact, 9 of 11 patients wh o received these interventions sustained fatal or near-fatal events, m ost of which were due to hemorrhage. However, early treatment with a s hort-course of high-dose corticosteroids halted progression of the syn drome in most cases. Finally, we found that expression of the type ''A '' isoform of PML/RAR-alpha (also known as bcr3 or ''short'') was asso ciated with a significantly shorter duration of relapse-free and overa ll survival (P = .005). Our data indicate that leukocytosis has little direct relationship to the development of this respiratory distress s yndrome. CD13 expression suggests a mechanistic link and offers a poss ibility of further therapeutic modulation, but additional study is req uired to determine the importance of this association. The majority of patients with APL treated with all-trans RA do not require additional chemotherapy during induction although almost half wilt need corticos teroid prophylaxis. Further studies are critically needed to identify and optimize the management of patients who are at highest risk for ea rly fatal hemorrhage and to reduce the risk of late relapse in patient s who express the type A isoform of PML/RAR-alpha. (C) 1994 by The Ame rican Society of Hematology.