title: 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.
abstract: 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)
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: L
authors.initials: L
authors.lastname: Vahdat
authors.forename: P
authors.initials: P
authors.lastname: Maslak
authors.forename: W H
authors.initials: WH
authors.lastname: Miller
authors.forename: A
authors.initials: A
authors.lastname: Eardley
authors.forename: G
authors.initials: G
authors.lastname: Heller
authors.forename: D A
authors.initials: DA
authors.lastname: Scheinberg
authors.forename: R P
authors.initials: RP
authors.lastname: Warrell
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis; D018826:CD13 Antigens / Q000096:biosynthesis*; D002423:Cause of Death; D002543:Cerebral Hemorrhage / Q000209:etiology / Q000401:mortality; D003131:Combined Modality Therapy; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007937:Leukapheresis; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology; D007964:Leukocytosis / Q000139:chemically induced*; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D011654:Pulmonary Edema / Q000139:chemically induced* / Q000401:mortality / Q000517:prevention & control; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis* / Q000235:genetics; D012074:Remission Induction; D000072482:Retinoic Acid Receptor alpha; D012189:Retrospective Studies; D016019:Survival Analysis; D013577:Syndrome; D016896:Treatment Outcome; D014212:Tretinoin / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D000305:Adrenal Cortex Hormones; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; D018826:CD13 Antigens