Long-term follow-up of central nervous system relapse in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy

Even in the era of treatment of molecularly targeted therapies, the appropriate management of acute promyelocytic leukemia (APL) relapse in the central nervous system (CNS) has not been established. Montesinos et al. reported that predictive factors of CNS involvement were high white blood cell (WBC) count at presentation and prior CNS hemorrhage [1]. While survival rates after CNS relapse had been thought to be significantly lower than after bone marrow (BM) relapse [2], some recent reports indicated intrathecal therapies (ITs) and arsenic trioxide (ATO) as an effective treatment [3,4]. We also previously discussed the efficacy of molecular or cytogenetic monitoring in cerebrospinal fluid (CSF) for the early detection and intervention of CNS relapse [5]. Despite these studies against risk identifications and treatment choices, there was no systemic research describing and analyzing the long-term clinical courses of CNS relapse. Here, we discuss the optimal management of CNS relapse in patients with APL from the long-term perspective. Patients with newly diagnosed APL who received chemotherapy including ATRA between April 2001 and March 2021 at the University of Tokyo Hospital were analyzed in this study. The diagnosis of APL was confirmed by detection of the t(15;17) translocation using fluorescent in situ hybridization (FISH) or the PML-RARA fusion gene using reverse transcriptase-polymerase chain reaction (RT-PCR) in BM examination. Molecular complete remission (mCR) was defined as remission without PMLRARA fusion gene detection by RT-PCR. CNS invasion of APL was defined by detecting promyelocytes, t(15;17) translocation, or the PML-RARA fusion gene. Patients’ baseline characteristics and therapeutic approach were retrospectively evaluated. Survival analysis and comparison were performed using the Kaplan–Meier method and the log-rank test. The Mann–Whitney U-test and Fisher’s exact test were used to evaluate factors associated with each comparison. We identified 41 consecutive patients with newly diagnosed APL. The median age at diagnosis was 49 years (range 18–73), and median WBC counts were 2.4 10/L (range 0.5–111.7). No patient received upfront ATO, and all patients underwent ATRA and anthracycline-based chemotherapy as the first-line therapy. All patients had achieved BM mCR1 after induction and consolidation therapies. The median observation period was 71.4 months (range 2.40–228). A total of 12 patients (26%) had BM relapse after the first-line chemotherapy at a median of 11.0 months (range 6.34–69.5) after diagnosis. Among them, six patients developed CNS relapse at the same time as or after BM relapse. Patient no. 7 developed a sole CNS relapse followed by brain hemorrhage during induction therapy; a lumbar puncture performed just after induction therapy and confirmation of BM mCR1 revealed CNS involvement. In total, seven patients had CNS relapse at a median of 11.9 months (range 1.91–77.8) after diagnosis, shown in Table 1. IT consisted of methotrexate, cytarabine, and prednisone. A patient with a sole CNS relapse (no. 7) underwent ATO with ITs and whole-brain radiation therapy (WBRT) 30Gy, being alive for 116 months. Among the other six patients who developed both CNS and BM relapse, three patients who completed planned treatment with IT, ATO, and subsequent autologous stem cell transplantation (ASCT) maintained mCR2 in both BM and CSF and survived for a median of 154 months (range 26.2–209) after diagnosis. In contrast, the remaining three patients who could not complete planned treatment had multiple BM relapses and died at a median of 47.7 months (range 41.8–107) after diagnosis. One of the three patients (no. 3) was ATO intolerant, and the other two could not undergo ASCT due to failure to achieve BM mCR with ATO. Patients no.