Summary. All-trans retinoic acid (ATRA) is currently recommended as standard treatment for acute promyelocytic leukaemia (APL). However, there has been increasing concern that ATRA is associated with unusual sites of relapse. We present three cases of APL previously treated with ATRA who ultimately relapsed within the central nervous system (CNS) and hypothesize that, by up-regulating intercellular adhesion molecules, ATRA may facilitate the passage of malignant promyelocytes across the blood-brain barrier.Keywords: APL, ATRA, extramedullary relapse.Acute promyelocytic leukaemia (APL) is characterized by the t(15;17) chromosomal translocation leading to a rearrangement between the PML and RARa (retinoic acid receptor alpha) genes. The presence of the resultant PML/RARa fusion protein defines the group of APL patients who are most likely to gain a favourable differentiation response from retinoids such as all-trans retinoic acid (ATRA). ATRA used in combination with chemotherapy has been found to confer significant improvements in disease-free survival compared to chemotherapy alone. Prior to the introduction of ATRA, central nervous system relapse was infrequently reported in APL. We report three cases of APL with CNS disease, all of whom were previously treated with ATRA, and consider whether this treatment could increase the risk of extramedullary relapse.
CASE 1A 49-year-old woman presented with a WBC of 5 . 3 × 10 9 /l and classic APL morphologically, which was confirmed by the finding of the t(15;17) associated with a bcr 1 PML breakpoint by RT-PCR (Grimwade et al, 1996). She received 5 d of oral ATRA and chemotherapy as per MRC AML12 and ATRA trial protocols, and achieved morphological, cytogenetic and molecular remission after one course of MAE (mitozantrone, AraC, etoposide). She required GMCSF to accelerate recovery following prolonged neutropenia and sepsis during the second course of MAE.She represented with headache, visual disturbance and vomiting 1 month after completion of four cycles of chemotherapy. The cerebrospinal fluid (CSF) was heavily infiltrated with blasts. The bone marrow contained 15% promyelocytes. Nested RT-PCR detected PML-RARa transcripts in both CSF and bone marrow. She died 1 month later.
CASE 2A 23-year-old man presented with morphologically classic APL with a WBC of 69 × 10 9 /l in January 1994. He was treated for 5 d with oral ATRA followed by three courses of ARA-C and daunorubicin, and achieved complete remission. He subsequently relapsed in the bone marrow 9 months later [cytogenetics demonstrated the t(15;17)], and after further chemotherapy underwent allogeneic bone marrow transplant in second remission. He presented 6 months later with CNS and bone marrow relapse. He received four donor leucocyte infusions and after a second relapse had FLAG chemotherapy, followed by a second PBSC allograft, but died in remission from hepatic failure due to graft-versus-host disease.
CASE 3The third patient was a 22-year-old man who presented with fever, malaise and a swollen calf. His b...