View larger version (17K): [in this window] [in a new window]   Figure 1. Molecular structures of Am80 and all-trans retinoic acid.

Case Reports

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Patient 1

A 44-year-old man presented in February 1993 with generalized bleeding tendency and leukocytosis (95% of leukocytes were promyelocytes). A bone marrow smear showed hypercellular marrow in which 96% of the leukocytes were promyelocytes. Chromosome analysis showed t(15; 17)(q22; q21), and acute promyelocytic leukemia was diagnosed. Treatment with ATRA at a daily dose of 45 mg/m² body surface area was administered. Complete remission was attained on 18 May 1993. The patient then received three courses of consolidation and six courses of maintenance chemotherapy ending in March 1994, according to the AML92 protocol of the Japan Adult Leukemia Study Group [4].

The patient again presented with severe bleeding tendency in March 1995. A bone marrow smear showed hypercellular marrow in which 90% of the leukocytes were promyelocytes containing Auer bodies. Laboratory tests showed the following: erythrocyte count, 3.8 x 10¹²/L; platelet count, 38 x 10⁹/L; and leukocyte count, 1.4 x 10⁹/L (2% of the leukocytes were promyelocytes, 2% were monocytes, 51% were neutrophils, and 45% were lymphocytes). Chromosome analysis showed t(15; 17)(q22; q21). Coagulation profiles were compatible with disseminated intravascular coagulation: Prothrombin time was 40%, partial thromboplastin time was 94%, fibrinogen concentration was 0.75 g/L, and fibrin degradation products-D dimer was 37.4 µg/mL (normal less than 1.0 µg/mL). After we obtained approval from the institutional review committee of Hamamatsu University Hospital and written informed consent from the patient, therapy with Am80 was started on 29 March at a daily oral dose of 6 mg/m² body surface area. The patient's clinical course is shown in Figure 2. Bleeding tendency was alleviated within 1 week, and platelet, neutrophil, and reticulocyte counts recovered gradually. Complete remission was confirmed on 15 May by bone marrow examination, which showed normocellular marrow (0.8% blast cells and 0% leukemic promyelocytes). Skin rash, headache, and the retinoic acid syndrome did not develop. The only side effects seen were hypertriglyceridemia (maximum triglyceride level, 13.16 mmol/L) and hypercholesteremia (maximum cholesterol level, 9.62 mmol/L); these conditions were easily controlled with pravastatin and bezafibrate. Therapy with Am80 was discontinued after complete remission was attained. The patient was treated with two courses of consolidation chemotherapy, and received a bone marrow transplant from an unrelated HLA-matched donor on 18 January 1996.

View larger version (27K): [in this window] [in a new window]   Figure 2. Clinical course of patient 1 after initiation of treatment with Am80. Vertical bars indicate the differential count of bone marrow cells. Black represents blasts and promyelocytes, stripes represent normal myeloid cells, dots represent normal nucleated erythroid cells, and white represents the other cells. aPT = activated partial thromboplastin time; FBG = fibrinogen; FDP-DD = fibrin degradation products-D dimer; FFP(5) = fresh frozen plasma transfusion (5 units); Plt = platelet count; Plt.(10) = platelet transfusion (10 units); PT = prothrombin time; RBC = erythrocyte count; Ret = reticulocyte count; T-cho = total cholesterol level; TG = triglyceride level; WBC = leukocyte count.

Patient 2

A 21-year-old woman presented in July 1993 with severe bleeding tendency and pancytopenia. A bone marrow smear showed hypercellular marrow in which 88% of leukocytes were promyelocytes. Chromosome analysis showed t(15; 17)(q22; q21), and laboratory findings confirmed a diagnosis of acute promyelocytic leukemia accompanied by disseminated intravascular coagulation. We administered ATRA at a daily dose of 45 mg/m² body surface area. Complete remission was attained on 24 August 1993. The patient then received three courses of consolidation and six courses of maintenance chemotherapy ending in October 1994, according to the AML92 protocol [4].

The patient again presented with pancytopenia in June 1995. A bone marrow smear showed hypercellular marrow in which 84% of the leukocytes were promyelocytes containing Auer bodies, and relapse of acute promyelocytic leukemia was diagnosed. Laboratory tests showed the following: erythrocyte count, 3.9 x 10¹²/L; platelet count, 80 x 10⁹/L; and leukocyte count, 1.3 x 10⁹/L (2% promyelocytes, 1% monocytes, 1% eosinophils, 17% neutrophils, and 79% lymphocytes). Therapy with Am80 was started on 13 June (after written informed consent was obtained from the patient), beginning with a daily oral dose of 6 mg/m² body surface area. The daily dose was increased to 8 mg/m² body surface area on 28 June. Platelet, neutrophil, and reticulocyte counts recovered gradually, and complete remission was confirmed on 4 July by a bone marrow examination, which showed a normocellular marrow (1.3% blasts and 0% leukemic promyelocytes). The only side effect was mild hypertriglyceridemia (maximum triglyceride level, 10.12 mmol/L). Therapy with Am80 was discontinued after complete remission was attained. The patient was treated with one course of consolidation chemotherapy and received an allogeneic bone marrow transplant from her brother on 9 September 1995.

Discussion

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Since Chinese investigators first reported a complete remission rate of more than 90% in patients with acute promyelocytic leukemia who were treated with ATRA, several investigators have confirmed the remarkable effectiveness of this drug as differentiation therapy for acute promyelocytic leukemia [1-5]. However, patients who have relapse after ATRA-induced complete remission have difficulty obtaining a second complete remission with a second course of ATRA therapy [6]. In our experience, only 3 of 17 patients who had relapse after ATRA-induced complete remission obtained a second ATRA-induced complete remission [3, 9]. Several mechanisms for acquired retinoid resistance have been described [5, 6, 10-12]. Continuous treatment with ATRA results in a progressive decrease in plasma concentrations of the drug [10, 11]. Proposed mechanisms for this phenomenon include an induction of cytochrome P450 oxidases, an increase in other oxidative enzyme activity (particularly that of lipid hydroperoxidases), and an increased expression of cytoplasmic retinoic acid binding proteins that may facilitate sequestration of the retinoid to catabolic enzymes in the endoplasmic reticulum [10-12]. The new potent synthetic retinoid Am80 (which was synthesized and provided by one of us) is a strong inducer of differentiation of HL-60 and NB4 cells and is several times more active than ATRA in these cells [7, 8]. It is administered orally. Pharmacokinetics studies in rats and healthy human volunteers showed that more than 99% of Am80 was bound to serum albumin in humans, and maximum blood levels were achieved within several hours after oral administration. Most Am80 is excreted within 48 hours, mainly in bile. The drug is chemically more stable to light, heat, and oxidation than is ATRA; it has a low affinity for cytoplasmic retinoic acid binding proteins; and it does not bind to the retinoic acid receptor [7, 8]. Am80 would therefore be expected to have therapeutic effectiveness in patients with retinoid-resistant acute promyelocytic leukemia with increased cytoplasmic retinoic acid binding proteins, overcoming the drug resistance created by the retinoic acid receptor , which is the major retinoic acid receptor in the dermal epithelium [13].

Several therapeutic strategies intended to overcome resistance to ATRA are currently being studied, but with little success to date [6]. Miller and colleagues [12] recently reported that treatment with 9-cis retinoic acid resulted in only one complete remission among seven patients with acute promyelocytic leukemia who had had relapse from ATRA-induced complete remission. In summary, treatment with Am80 induced a second complete remission in two patients who had had relapse of acute promyelocytic leukemia from ATRA-induced complete remission. Although our experience with Am80 is limited to only these two patients, the drug seems to be a promising new agent for patients who have had relapse of acute promyelocytic leukemia from ATRA-induced remission.

Dr. Miyawaki: Internal Medicine, Saiseikai Hospital, Kamishinden, Maebashi 371, Japan.

Dr. Shudo: Faculty of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113, Japan.