A Refined Regimen for Maximally Eliminating Early Life-Threatening Complications for Patients with High-Risk Acute Promyelocytic Leukemia

Life-threatening complications, such as severe bleeding and/or differentiation syndrome at admission and/or along with induction treatment, among high-risk patients with acute promyelocytic leukemia (APL) are a worldwide puzzle towards the cure of the disease. Taking the rationale that high WBC count, at least in part, may cause cytokine storm related symptoms, we designed this refined regimen with low dose mitoxantrone and ATRA plus arsenic trioxide to determine the safety and efficiency of this WBC reduction, prevention of differentiation syndrome, and supportive care centered approach.

In total there were 50 patients with high risk APL (WBC>10x10⁹) from 2003-2017 were enrolled with a medium follow-up of 39 months (15-72 months). Our treatment strategy and detailed protocol are: 1) WBC reduction: it started with ATRA (25mg/m2/day) and arsenic trioxide (0.15mg/kg/day) based double induction. The advantage of decreased dose of ATRA can help to lower the happening of leukocytosis which will trigger the cytokine releasing related syndrome. Low dose mitoxantrone (3mg/m2) was added from day 2-5 plus hydroxyurea (1.5g, p.o. q6h) started from day 1. The criteria for withdrawal hydroxyurea is once both of the following standard are met: i) the WBC count has continuously decreased for three days after reached the peak value; ii) WBC < 10x10⁹/L. 2) Prevention of Differentiation Syndrome (DS): Dexamethasone (5mg/day) was added once the diagnosis was confirmed at day 1. The criteria to taper dexamethasone are the same as to stop hydroxyurea. We require to withdraw dexamethasone within one week once start the taper process. In general, our goal is to prevent the occurrence of both leukopenia and leukocytosis and maintain the WBC count between 2-20x10⁹. 3) Supportive care: We maintain the PLT count between 20-30x10⁹ and fibrinogen >1.5g/L which helped to decrease the occurrence of myelo-suppression, DS and severe bleeding. 4) CNS Prophylaxis: The Intrathecal injection was given after the CR was achieved. Unless there was evidence of CNS infiltration, we gave intrathecal injection after correcting the coagulation abnormality.

The consolidation began at four weeks after the end of induction. It contained four weeks of an on and off schedule of arsenic trioxide (0.15mg/kg/day), in total four cycles, and two weeks of an on and off schedule of ATRA (25mg/m2/day), in total seven cycles. A total of eight intrathecal injections were given on the first and last day of arsenic trioxide. Two death was observed through our strategy during the induction. All patients reached hCR by the end of induction. Relapse occurred in four out of 50 patients, and there was no treatment-related mortality. All the relapsed patients entered CR again after using the same protocol. Grade 3-4 adverse events were observed among 12% of all the cases. Three-year probability of overall survival (pOS) was found to be 92%. Our strategy focus of reducing WBC count sheds new light on maximally eliminating early mortality of high-risk APL patients.