Central nervous system relapse in acute promyelocytic leukemia in the arsenic era: A case series and review of emerging evidence

Abstract Background: Acute Promyelocytic Leukemia (APML) is highly curable with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, Central Nervous System (CNS) relapse, although rare, remains a serious complication, particularly in high-risk patients. ATO and ATRA have limited CNS penetration, achieving cerebrospinal fluid (CSF) levels of only ~17.7% of plasma levels, which may allow the CNS to act as a sanctuary site. The predictive factors, optimal management, and role of prophylactic CNS therapy remain poorly defined in the arsenic era.Methods: We present a case series of four high-risk APML patients diagnosed between 2013 and 2024, who developed CNS relapse during or shortly after remission. Clinical presentations, CNS imaging, cerebrospinal fluid findings, treatment modalities, and outcomes were reviewed retrospectively.Results: CNS relapse occurred as isolated (n=1) or combined with bone marrow relapse (n=3). Median time to CNS relapse was 5.5 months post-remission. One patient had confirmed FLT3-ITD mutation; others were untested. All four patients had high risk APML and were initially treated with ATRA and Idarubicin. Notable findings:Case 1: 56F, isolated CNS relapse. Treated with ATO/ATRA, intrathecal therapy, high-dose cytarabine (HiDAC), craniospinal radiotherapy in preparation for autologous transplant. Initial presentation showed subdural hematoma on imagingCase 2: 67M, early combined CNS and marrow relapse post-MRD-negative remission. Second isolated CNS relapse occurred post-stem cell harvest. Imaging on initial presentation showed PCA infarct with punctate hemorrhages.Case 3: 64M, relapsed post-autograft with CNS involvement, treated with ATO/ATRA, intrathecal therapy, craniospinal radiation, followed by allograft. FLT3-ITD positive.Case 4: 62F, presented with severe neurological symptoms three months post-chemotherapy. CNS and marrow relapse confirmed. Treated with ATO/ATRA and HiDAC; died shortly after.Discussion: Our findings echo recent data suggesting CNS relapse is rare but not eliminated in the arsenic era. A large 2025 study of 910 patients receiving ATO/ATRA reported a 1.4% CNS relapse rate, with FLT3-ITD mutations found in 61.5% of CNS relapse cases compared to 20.9% in those without. Prior CNS hemorrhage and high initial WBC counts remain associated with relapse risk. In our series, 3 of 4 patients had neurologic symptoms and/or CNS bleeding prior to or during relapse. Standard induction agents like ATRA, ATO, and idarubicin have limited CNS penetration. Studies suggest that HiDAC and prophylactic intrathecal therapy during consolidation may reduce CNS relapse risk, as shown in the APL 2000 trial.Conclusion: CNS relapse in APML remains a rare but challenging clinical entity in the ATO era. Risk factors may include FLT3-ITD mutation, prior CNS hemorrhage, and high-risk disease features. Our cases highlight the importance of early neurologic assessment and raise consideration for CNS-directed prophylaxis in select high-risk patients.Notably, ATO/ATRA is now available for the treatment of high-risk APML in the UK. While this expanded access may help reduce overall relapse rates, our findings demonstrate that CNS relapse can still occur despite arsenic-based therapy. This suggests that additional strategies—such as risk-adapted CNS surveillance or prophylaxis—may be warranted for certain high-risk individuals.