Central nervous system relapse in acute promyelocytic leukaemia in patients treated with all‐trans retinoic acid

Abstract

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...

Arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: A single center experience

“…It has been observed that CNS relapse with APML is extremely rare, especially in the pre-ATRA era [22][23][24][25]. Following the use of ATRA, there has been some concern about the increase in incidence of extramedullary and CNS relapses.…”

CNS relapse in a low risk acute promyelocytic leukemia patient treated with ATRA-based regimen: is there a role for prophylactic CNS therapy in acute promyelocytic leukemia?

“…After the advent of ATRA, more cases of CNS relapse have occurred; still CNS relapse in low risk (as WBC count at presentation is <10 × 10 9 /l and platelet count is >40 × 10 9 /l) disease is even rarer. Reason for increase in cases of CNS relapse in patients treated with ATRA has been hypothesized to be the upregulation of adhesion molecules on the leukemic cells induced by ATRA which is a differentiating agent [2][3][4]. Or is it simply a consequence of increased survival of AML-M3 patients after the introduction of ATRA?…”

“…Though there is a increase in cases of relapse in the CNS after the introduction of ATRA, still CNS relapse is very rare in AML-M3 [2]. Relapse in the CNS accounts for only 2-3% of all relapses, majority of it occurring in high risk cases.…”

Retinoic acid syndrome: a problem of the past?

“…However, since the era of ATRA, there have been increasing reports of patients relapsing after prior therapy with ATRA in extramedullary sites, primarily in the central nervous system and skin, but other sites as well. 12,13 This is certainly plausible given the fact that we know there is modulation of adhesion molecules with ATRA. If one presumes that retinoic acid syndrome is a syndrome of tissue infiltration by maturing myeloid cells, one can under-stand how perhaps certain sanctuary sites may be capable of withstanding the antileukemic effect of consolidation chemotherapy.…”