AML-353: Molecular Relapse Associated with Central Nervous System Involvement in Patients with Acute Promyelocytic Leukemia – Three Case Reports

Abstract

Context Extramedullary relapse in acute promyelocytic leukemia (APL) is a rare event, but increasingly reported in the all-trans retinoic acid (ATRA) era. The implementation of central nervous system (CNS) prophylaxis is still debatable, and the strategies for further decreasing the rate of CNS relapse in APL patients, while following a risk-based approach, differ between the major study groups. Moreover, there is currently no standard of care for the treatment of CNS relapse in APL. Objective Evaluate the clinical and evolutive features of molecular relapse associated with CNS involvement in APL and assess the response to intrathecal chemotherapy. Design We present three cases of molecular relapse, associated with CNS involvement, in patients with APL who received induction therapy with ATRA and idarubicin, without CNS prophylaxis. Results Three patients (two males, one female) with a median age of 42 years (31 – 53 years) and a median leukocyte count at diagnosis of 5.6 × 109/L (2.74 — 78 × 109/L), who received induction therapy with ATRA and idarubicin, all of them achieving complete remission. Molecular analysis following consolidation showed the absence of the PML/RARα rearrangement in all three cases. The two patients who fell into the low/intermediate risk category showed a molecular relapse at 17 and 20 months respectively, while the high-risk case relapsed at 11 months after complete remission, maintaining morphologic remission. CNS involvement was certified at a median of 7 months (1 — 9 months) after the first documentation of molecular relapse. The therapeutic approach consisted of intrathecal administration of cytarabine, methotrexate and dexamethasone, associated with arsenic trioxide and ATRA, clearing the leptomeningeal disease and inducing a second complete response in two cases. The high-risk patient also underwent neuraxis radiotherapy but showed frank relapse 8 months after the CNS relapse and eventually died of hemorrhagic stroke. Conclusions Despite the low incidence of CNS relapse in APL patients, they should be fully evaluated at onset of neurologic symptoms, regardless of the risk profile. Further studies should be conducted in order to guide clinical management of APL patients with CNS relapse and better define the risk factors associated with CNS involvement in APL.