Prolonged complete remission in two cases of acute promyelocytic leukaemia treated with atra alone.

Abstract

The use of all-trans retinoic acid (ATRA) therapy for induction for acute promyelocytic leukaemia (APL) is well established and leads to a complete remission rate of > 70%. However, remissions are short and consolidation with chemotherapy is required. Continuous treatment with ATRA has been associated with a decrease in plasma concentrations of the drug, which may lead to resistance. Recently, a case has been reported successfully treated with ATRA alone, followed by maintenance with intermittent ATRA and continuous low-dose methotrexate and 6-mercaptopurine (Sanz et al, 2000). Here, we report two cases of APL with prolonged remissions after treatment with ATRA alone. An 81-year-old woman presented with pancytopenia due to APL in October, 1992. Cytogenetic analysis revealed t(15;17) as the sole abnormality, and the rearrangement was confirmed by Southern blot analysis. She was started on ATRA at 45 mg/m2. Chemotherapy was not given because of her age and history of cardiovascular disease. Her leucocyte count increased to 25 × 109/l on day 1. On day 10, bilateral pleural effusions and culture negative fever developed, which was treated successfully with dexamethasone. The dose of ATRA was decreased to 25 mg/m2 on day 30 because of abnormal liver function tests, and she remained on this dose for another 95 d. Bone marrow on day 73 showed morphological remission with persistence of t(15:17). No further bone marrow examinations were performed, but her blood counts remained normal, and reverse transcription-polymerase chain reaction (RT-PCR) for the PML/RAR transcript on peripheral blood was negative, with normal blood counts assessed 4 and 6 years after diagnosis. She died of unrelated cardiovascular complications in November 1999, 7 years after diagnosis. The second case involved a 76-year-old woman who presented in September 1997 with extensive mucosal bleeding. Laboratory investigations showed pancytopenia and disseminated intravascular coagulation due to APL, and RT-PCR confirmed the presence of the short isoform of the hybrid transcript generated by t(15;17). She was treated with ATRA at 45 mg/m2 for 149 d. She declined treatment with chemotherapy. Her coagulation parameters normalized by day 2, and the leucocyte count reached a peak of 40 × 109/l on day 12. She developed a cough and dyspnoea, which responded to dexamethasone. By discharge on day 18, she was feeling well with normal blood counts except for platelets at 60 × 109/l; by day 35, the platelet count was normal. On day 58, bone marrow showed morphological remission, with normal cytogenetics and negative RT-PCR. Further RT-PCR analyses on peripheral blood have remained negative, most recently performed in July 2001. The patient remains alive and well with normal blood counts as of September 2001, 4 years after diagnosis. The mechanism by which our patients achieved prolonged complete remissions is unclear. It is unlikely that we observed spontaneous remissions as they are rare and of short duration (Enck, 1985). It is likely that ATRA was important in inducing the remissions. ATRA in supraphysiological doses causes differentiation of the promyelocyte by dissociation of a transcriptional corepressor complex, that exerts a dominant-negative effect on normal RAR-α-regulated gene transcription (Melnick & Licht, 1999). Continuous treatment leads to decreased plasma concentration and clinical resistance. However, leukaemic cells from relapses can continue to differentiate in vitro, though not in vivo. Moreover, the efficacy of liposomal ATRA suggests that the intracellular concentration of ATRA is critical, as use of this formulation maintains plasma concentrations of tretinoin and response in relapsed patients, but the response does not correlate with plasma concentration (Estey et al, 1996). Furthermore, the use of liposomal ATRA alone can induce prolonged molecular remissions (Estey et al, 1999). Thus, maintaining adequate intracellular concentrations of retinoids in the relevant target cell may permit ongoing differentiation. The prolonged complete responses in our patients indicate that the metabolism of ATRA in some patients may be endogenously altered to permit persistent and clinically effective intracellular concentrations of the ligand. Alternatively, the unusual response to ATRA may indicate that the disease pathogenesis in our patients may have differed from the norm, as it is clear from animal models that the translocation is necessary but not sufficient to produce leukaemia, and that other cytogenetically silent lesions must contribute (Zimonjic et al, 2000). The mechanisms mediating induced differentiation by ATRA have been intensively investigated (Melnick & Licht, 1999), but only recently has the means of cell death been elucidated (Altucci et al, 2001). It is conceivable that differing clinical outcomes to ATRA treatment may be due to intrinsic variations in leukaemic stem cells in their susceptibility to retinoid-induced, TRAIL/DR5-mediated paracrine apoptosis.