Risk Factors and Clinical Outcome of Central Nervous System (CNS) Leukemia In Patients with Acute Promyelocytic Leukemia (APL) on Long-Term Oral Arsenic Trioxide Maintenance.

The prognosis of patients with APL has improved with all trans-retinoic acid (ATRA) and arsenic trioxide (As₂O₃) therapy. An increasing frequency of isolated CNS relapse is reported in APL survivors and intrathecal prophylaxis has been proposed. We have used oral As₂O₃ as prolonged maintenance therapy for APL patients in first remission (CR1) and beyond. During oral As₂O₃ therapy, elemental arsenic penetrates the CNS at meaningful levels. The risk factors for CNS APL in this setting are unknown.

From 2001 to 2009, consecutive APL patients in ATRA +/− chemotherapy-induced CR1, or As₂O₃ +/− chemotherapy-induced CR2 and beyond, were given As₂O₃ maintenance therapy, comprising oral As₂O₃ therapy (10mg daily) and ATRA (30mg twice daily), given two weeks every two months for two years. CNS leukemia was diagnosed by the presence of typical APL cells in the cerebrospinal fluid (CSF). Patients with CNS leukemia were treated with intrathecal methotrexate (12 mg twice weekly until clearing of CSF) and oral-As₂O₃, ATRA and ascorbic acid.

A total of 102 APL patients (46 men, 56 women) at a median age of 43 (13–43) years received oral As₂O₃ maintenance during CR1 (n=63) and CR2 or beyond (n=39). The median follow-up period was 55 (8–143) months. At initial presentation, the hematological parameters were hemoglobin: 8.5 (3–14.6) g/dL, white cell count: 10.1 (0.3–121) × 10⁹/L (with 21 cases >10 × 10⁹/L) and platelet count: 35 (3–162) × 10⁹/L (with 67 cases <40 × 10⁹/L). A total of 25 patients had a history of steroid treatment for APL differentiation syndrome. Leucocytosis (> 15 × 10⁹/L) developing either during ATRA or As₂O₃ treatment occurred in 62 patients. For the whole cohort, the median peak leucocyte count at any time point in the clinical course was 29.3 (0.8–243) × 10⁹/L. Eight patients (7 men, 1 woman, median age 49 years) developed CNS leukemia, at a median of 42 (1–56) months from commencement of As₂O₃ maintenance. All had a history of elevated peak WCC, at a median of 69.5 (26–123) × 10⁹/L. Symptoms included headache (n=3), dizziness (n=2), confusion, blurred vision and leg weakness. The median CSF cell count was 35 (7–2500) × 10⁶/L. Concurrent marrow morphologic relapse was found in 4 cases (first relapse, R1, n=1; R2, n=3). Four patients had normal blood counts and marrow morphology (still in CR1, n=1; CR2, n=3), although their peripheral blood cells were positive for PML-RARA by polymerase chain reaction. All patients responded completely to treatment initially, but recurrent CNS leukemia still occurred in 4 cases after 12–16 months. Additional treatment including cranial radiotherapy (n=6), systemic high dose cytarabine (n=2) and autologous hematopoietic stem cell transplantation (n=1). Three patients ultimately died of refractory APL at a median of 13 months after CNS relapse. On univariate analysis, risk factors for CNS relapse were male gender (RR 6.8, p=0.001), and leucocytosis at any time point (for WCC > 15×10⁹/L, RR 8.4, p=0.004; for WCC > 20×10⁹/L, RR 12.1, p<0.001). There was no significant relation to age, ATRA syndrome, hematologic parameters on presentation and disease status at commencement of oral As₂O₃ maintenance.

With prolonged survival of APL patients, CNS leukemia is emerging as an important problem that curtails survival. Based on the use of oral As₂O₃ maintenance, patients who at any time point in the clinical course developing a leucocytosis of > 15–20 × 10⁹/L are at high risk of CNS relapse and should be considered suitable candidates for CNS prophylaxis.

Off Label Use: Oral arsenic trioxide for maintenance of APL in remission. Kwong:HKU: YL Kwong is an employee of the University of Hong Kong that holds a patent for oral arsenic trioxide.