All-Trans-Retinoic Acid andBleeding/Thrombosis

Abstract

Hematology-Oncology Department Ospedali Riuniti Largo Barozzi, 1 24128 Bergamo (Italy) Tel. 39 035 269492, Fax 39 035 266659 E-Mail annafalanga@yahoo.com All-trans-retinoic acid (ATRA) inhibits cell growth and proliferation by inducing cyto-differentiation and/or apoptosis in several cell types. These effects have become a therapeutic objective in human cancers. In addition to these functions, ATRA has been shown to affect cellular hemostatic properties [1]. Much understanding in this field has come from the clinical and experimental studies of human acute promyelocytic leukemia (APL), a distinct subtype of acute myelogenous leukemia (AML-M3), cytogenetically characterized by the balanced reciprocal translocation between chromosomes 15 and 17. In these cells, the fusion of the nuclear retinoic acid receptor (RAR ) gene on chromosome 17 with part of the PML gene on chromosome 15 results in the expression of a chimeric PML/RAR protein, which is involved in the leukemogenesis and is the target for the myeloid differentiation effect induced by ATRA. The disease typically presents with a life-threatening hemorrhagic diathesis, which is worsened by cytotoxic chemotherapy. The bleeding disorder is particularly severe in the microgranular variant of APL (M3v), which is characterized by marked hyperleukocytosis. Before the introduction of ATRA for the management of APL patients, fatal hemorrhages due to the associated coagulopathy were a major cause of induction remission failure. In a large retrospective study, the overall remission rate was 62% and the prevalence of hemorrhagic deaths in induction 14% [2]. The use of ATRA for the remission induction therapy of APL has raised the complete remission rate to greater than 90%, together with a rapid resolution of the coagulopathy, without causing bone marrow hypoplasia. ATRA promotes the terminal differentiation of leukemic promyelocytes, which is accompanied by prompt improvement of the coagulopathy typical of this disease [3]. Consistent with that, normalization in the plasma levels of hypercoagulation markers and downregulation of the two major blast cellassociated procoagulants (i.e. tissue factor, TF, and cancer procoagulant, CP) were observed [4]. A number of laboratory studies have subsequently confirmed the decrease or normalization of clotting and fibrinolytic variables during the first 1 or 2 weeks of therapy with ATRA. Inspite of that, the impact of ATRA therapy on early hemorrhagic deaths and CR rate in APL remains uncertain compared to chemotherapy alone. In nonrandomized studies, APL patients administered ATRA showed 9% to 20% improvement of CR rate and 5% to 6% reduction of early hemorrhagic deaths, compared to historical controls receiving conventional chemotherapy [1, 5–8]. These preliminary findings have been more recently confirmed by randomized clinical trials. APL patients treated with different combinations of ATRA plus chemotherapy show a prevalence of early hemorrhagic deaths from 2.4% to 6.5% [9–13]. However, both nonrandomized and randomized clinical trials clearly show an improvement of event free and overall survival in patients receiving induction therapy All-Trans-Retinoic Acid and Bleeding/Thrombosis