Downloaded from http://journals.lww.com/jpho-online by BhDMf5ePHKbH4TTImqenVGmuFTCffgFKPfn9IheZd3hEA8l8OqdO654zRWOiHWk2 on 10/12/2020 Isolated Central Nervous System Relapse Following Treatment Reduction in Low-risk Acute Lymphoblastic Leukemia at the Children’ s Cancer Center of Lebanon Habib El-Khoury, MD,* Mohamad Chahrour, MD,* Khaled M. Ghanem, MD,† Omran Saifi, MD,* Hani Tamim, PhD,‡ Hassan El-Solh, MD,† Dima Hamideh, MD,† Nidale Tarek, MD,† Raya Saab, MD,† Miguel R. Abboud, MD,† and Samar A. Muwakkit, MD† Summary: The aim of this trial was to decrease the incidence of life-threatening infections by decreasing the dose and the duration of dexamethasone treatment during maintenance therapy. This was a pro- spective, nonrandomized trial of low-risk acute lymphoblastic leukemia patients 1 to 18 years of age who were treated at the Children’ s Cancer Center of Lebanon (CCCL). Patients consecutively diagnosed between 2002 and 2013 were divided into groups 1 and 2 receiving total dex- amethasone doses of 1144 and 618 mg/m 2 , respectively. A total of 84 patients were assigned to group 1 and 33 patients to group 2. The 5-year cumulative incidence of isolated central nervous system relapse increased from (n = 0% [95% confidence interval: 0%-4.4%]) in group 1 to 9.1% [95% confidence interval: 3%-23%]; P = 0.021) in group 2. Decreasing cumulative dose of dexamethasone for low-risk childhood acute lym- phoblastic leukemia patients aiming to avoid serious viral infections led to a signi ficant increase in isolated central nervous system relapse. Key Words: decreasing dexamethasone dose, childhood acute lym- phoblastic leukemia, isolated CNS relapse, Lebanon (J Pediatr Hematol Oncol 2020;42:e428–e433) BACKGROUND The optimal outcome of acute lymphoblastic leukemia (ALL) therapy is achieved through an adequate balance between treatment intensity, disease control, and therapy-related toxicities. 1 In children, intensive risk-strati fied treatment proto- cols have resulted in significant improvement in outcomes, with survival rates exceeding 90% in most developed countries. 2 Efforts are currently shifted toward preventing short-term and long-term therapy-related toxicities. Infections are among the most common and serious toxicities during childhood ALL treatment due to the immunosuppressive nature of most che- motherapeutic agents used. Since 2002, we adopted the St. Jude Total XV protocol with minor modi fications. 3,4 Our interim analysis in 2012 showed a 5-year overall survival (OS) and event- free survival (EFS) rates of 88.5% (95% confidence interval [CI]: 77.1%-94.4%] and 78.7% (95% CI: 69.8%-88.4%), respectively. More precisely, for our low-risk patients, the 5-year OS and EFS rates were 96.4% (95% CI: 90%-99%) and 92.9% (95% CI: 85.3%-97.7%), respectively. 4 Infection is known to be the major cause of treatment-related mortality. 5 Serious viral infections occurred in 11% of all patients treated between 2002 and 2012 according to the St. Jude Total XV protocol; those included disseminated varicella (5.4%), cytomegalovirus (CMV) infection (3.6%), and progressive multifocal encephalopathy (0.9%). Three of the patients who had fulminant infections belonged to the low-risk group. Two patients died of fulminant CMV infection early during the maintenance phase of treatment. One other patient passed away from disseminated varicella during late maintenance. The most important predisposing factor to the development of such infections in ALL patients is the exposure to high doses of corticosteroids combined with mye- losuppressive agents. 6 Dexamethasone is an essential part of therapy in most current protocols due to its excellent central nervous system (CNS) penetration and antileukemic effect. 6 The dose and duration of dexamethasone treatment vary across clinical trials. 3,7 Until 2013, our protocol included intensive monthly dexamethasone pulses during reinduction and during continuation therapy for a total of 100 weeks. As of 2013, and in an attempt to decrease the incidence of treatment-related serious infections, our institution implemented a decrease in the dose and duration of dexamethasone during continuation therapy. METHODS Aim The main aim of this trial was to decrease the incidence of treatment-related serious infections while maintaining the OS and EFS rates of the historical control patients. Patients and Study Design This is a historical control study of consecutive patients diagnosed and treated for low-risk ALL between the years 2002 and 2015, 1 to 18 years of age, treated at the Children’s Cancer Center of Lebanon (CCCL). Historical control patients who completed therapy before June 2013 and patients on therapy who completed more than half of their planned maintenance dexamethasone pulses (week 50) by June 2013 were assigned to group 1. Patients who were diagnosed between June 2013 and January 2015 and those who had received less than half of their planned maintenance dexamethasone pulses (week 50) by June 2013 were assigned to group 2. The study was approved by the Institutional Review Board at the American University of Beirut. Written informed consents were obtained from parents or guardians, as appro- priate. Patients were stratified into 1 of 3 risk groups: low, intermediate, or high risk, as per the St. Jude risk stratification Received for publication December 9, 2019; accepted February 27, 2020. From the †Department of Pediatrics and Adolescent Medicine; *Faculty of Medicine; and ‡Clinical Research Institute, American University of Beirut, Beirut, Lebanon. The authors declare no conflict of interest. Reprints: Samar A. Muwakkit, MD, Department of Pediatrics and Adolescent Medicine, Children Cancer Center of Lebanon, American University of Beirut Medical Center, Bliss Street, PO Box 11-0236, Beirut, Lebanon (e-mail: sm03@aub.edu.lb). Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. ORIGINAL ARTICLE e428 | www.jpho-online.com J Pediatr Hematol Oncol  Volume 42, Number 6, August 2020 Copyright r 2020 Wolters Kluwer Health, Inc. All rights reserved.