All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results [see comments]

Abstract

Twenty-two patients with acute promyelocytic leukemia were treated with all-trans retinoic acid (RA, 45 mg/m2 per day) for 90 days. Of the 22, four patients were previously untreated, two were resistant after conventional chemotherapy, and 16 were in first (n = 11), second (n = 4), or third (n = 1) relapse. We observed 14 complete response, four transient responses, one failure, and three early deaths. Length of hospitalization and number of transfusions were notably reduced in complete responders. Correction of coagulation disorders and an increase of WBCs were the first signs of all-trans RA efficacy. Morphologic analysis performed at days 0, 15, 30, 45, 60, and 90 showed that complete remissions were obtained without bone marrow (BM) hypoplasia. Presence of Auer rods in the maturing cells confirmed the differentiation effect of the treatment. At remission, the t(15;17) initially present in 20 patients was not found. The in vitro studies showed a differentiation in the presence of all-trans RA in 16 of the 18 tested cases. The single nonresponder to all trans RA in vitro did not respond in vivo. Adverse effects of RA therapy--skin and mucosa dryness, hypertriglyceridemia, and increase of hepatic transaminases-- were frequently noted. We also observed bone pain in 11 patients and hyperleukocytosis in four patients. Whether maintenance treatment consisted of low-dose chemotherapy or all-trans RA, early relapses were observed. Five patients are still in complete remission (CR) at 4 to 13 months. Our study confirms the major efficacy of all-trans RA in M3, even in relapsing patients. Remissions are obtained by a differentiation process.

All‐trans retinoic acid prevents apoptosis of human marrow CD34+ cells deprived of haematopoietic growth factors

“…Alltrans retinoic acid (ATRA), a natural metabolite of retinol, plays an important role in the growth and differentiation of haematopoietic cells (Blomhoff & Smeland, 1994). The differentiating activity of ATRA has been demonstrated in vivo in acute promyelocytic leukaemia (Huang et al, 1988;Castaigne et al, 1990;Chen et al, 1991). Although it has been clearly established that ATRA-terminally differentiated cells undergo apoptosis (Martin et al, 1990), little is known regarding the effects of ATRA on the apoptosis of human marrow CD34 + cells.…”

Early haemorrhagic morbidity and mortality during remission induction with or without all‐trans retinoic acid in acute promyelocytic leukaemia

“…The introduction of ATRA for the treatment of APL may improve the complete remission rate and has de®nitely improved the overall survival compared with treatment with chemotherapy alone (Huang et al, 1988;Castaigne et al, 1990;Chen et al, 1991;Warrell et al, 1991;Fenaux et al, 1992;Hernandez et al, 1992;White et al, 1992;Dompret et al, 1993;Xingzhong et al, 1993;Frankel et al, 1994;Falanga et al, 1995;Kanamaru et al, 1995;Avvisati et al, 1996;Mandelli et al, 1997). In addition, the severe coagulopathy, which is characteristic of APL and is usually exacerbated by cytotoxic effect of chemotherapy, ameliorates rapidly with ATRA (Castaigne et al, 1990;Dompret et al, 1993;Fenaux et al, 1993;Falanga et al, 1995).…”

“…Indeed, early pilot studies with ATRA (Huang et al, 1988;Castaigne et al, 1990;Chen et al, 1991;Warrell et al, 1991;Fenaux et al, 1992;Hernandez et al, 1992;White et al, 1992;Xingzhong et al, 1993;Frankel et al, 1994;Kanamaru et al, 1995) showed that the higher complete remission (CR) rate was mainly due to a lower incidence of early haemorrhagic deaths and resistant cases (usually less than 10%).…”

Characterization of apoptosis induced by protein kinase C inhibitors and its modulation by the caspase pathway in acute promyelocytic leukaemia

“…The finding that all trans retinoic acid (ATRA) induced terminal differentiation of human APL cells in vitro, which was supported by clinical evidence, altered the therapeutic approach to APL (Breitman et al, 1981;Huang et al, 1988). Although ATRA is markedly effective as an induction therapeutic regimen in APL, several studies have demonstrated that it is much less effective as a post-remission treatment as clinical relapses were frequently reported (Huang et al, 1988;Castaigne et al, 1990). In addition, patients in clinical remission after ATRA treatment continued to show the PML/RARa rearranged gene by molecular assays, indicating the presence of residual malignant clones Lo Coco et al, 1992).…”