Pediatr Blood Cancer 2015;62:945–950
Identifying Causes of Variability in Outcomes in Children With Acute Lymphoblastic Leukemia Treated in a Resource-Rich Developing Country Wasil Jastaniah, MBBS, FRCPC,1,2* Naglla Elimam, MD,1 Khalid Abdalla, MD,1 Basheer Ahmed Cittana Iqbal, Taha M. Khattab, MD,1 Sami Felimban, MD,1 and Mohammed Burhan Abrar, PhD1 Background. The outcome of children with acute lymphoblastic leukemia (ALL) in developing countries is less favorable than in developed countries, primarily due to resource constraints. However, it is unknown whether the therapeutic results differ. Thus, we hypothesized that outcomes in resource-rich developing countries would be similar to those in industrialized regions. Procedure. We performed a retrospective analysis of 224 consecutive children with ALL, who were treated according to the Children’s Cancer Group (CCG) protocols between January 2001 and December 2007. High-risk (HR) and standard-risk (SR) patients were treated with modified CCG-1961 and CCG-1991 protocols, respectively. Modifications included substitution of dexamethasone for prednisone in HR patients and addition of two intrathecal methotrexate treatments for CNS2 patients during induction. All patients received double delayed intensification with two interim maintenance phases.
MD,
1
Results. Five-year overall survival (OS), event-free survival (EFS) and disease-free survival (DFS) were 84.7 2.4%, 77.0 2.9%, and 81.4 2.7%, respectively. Remission was achieved in 98.1% of the patients. Induction failure and relapse rates were 1.9% and 15.1%, respectively. Death as the first event occurred in 6.4% of cases, of which 2.7% and 3.7% involved deaths in induction and remission, respectively. Interestingly, a significant reduction in induction deaths was observed over time. Conclusions. Despite the encouraging results observed in the present study, our patients displayed significantly lower survival outcomes compared to subjects treated in major clinical trials conducted by leading leukemia cooperative groups. Furthermore, this work underscores the need for targeted interventions to reduce death as the first event in developing regions. Pediatr Blood Cancer 2015;62:945–950. # 2014 Wiley Periodicals, Inc.
Key words: ALL; children; outcome; mortality
INTRODUCTION Acute lymphoblastic leukemia (ALL) represents the most common pediatric malignancy, accounting for approximately 25% of all cancers in children aged 15 years or younger and 75% of childhood leukemia cases overall. In 2009, ALL accounted for 22.6% of the cancers detected in children under 14 years of age in Saudi Arabia [1]. Since the 1970s, the treatment of childhood ALL has significantly advanced, resulting in impressive survival rates. Indeed, there is a greater than 85% chance of survival in developed countries, such as the US [2,3]. Multiple factors, including collaborative trials and improvement in risk/response directed treatment strategies, have contributed to this success [4]. Nevertheless, developing countries have not reached similar success rates for treatment outcomes. This disparity in therapeutic results may stem from variability in access to care, affordability, treatment withdrawal, supportive care measures, treatment protocols, medical expertise, and/or other factors (socioeconomic, biological, and geographical variables). Indeed, cancer diagnostics and treatment are expensive, imposing heavy financial burdens on patients’ families and healthcare systems. Furthermore, with increasing healthcare costs, the delivery of affordable cancer treatment can exceed the limited treatment resources available in many developing countries. As a result, numerous families abandon treatment before completion of chemotherapy. In fact, it was found that 35% of patients with childhood ALL refused or abandoned treatment due to financial constraints in Indonesia [5]. In contrast, Saudi Arabia is a resourcerich developing country that offers universal healthcare coverage free of charge for cancer patients of Saudi nationals, which allows the possibility to implement protocols proven to be successful in Western countries. In light of this, our institution has followed modified Children’s Cancer Group (CCG) protocols to treat patients with ALL for over 15 years. However, the treatment outcomes of these regimens have C
2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.25374 Published online 31 December 2014 in Wiley Online Library (wileyonlinelibrary.com).
not been evaluated. Thus, the aims of the present study were to report the results of pediatric patients with ALL treated in our center and to compare their therapeutic outcomes with those reported by national, regional, intercontinental, and leading leukemia cooperative groups. Our overall goal was to identify areas of weakness with regard to the delivery of care in order to promote targeted interventions that might optimize outcomes. We hypothesized that treatment results in resource-rich developing countries would be similar to those achieved in resource-rich developed countries, but superior to those of resource-restricted developing countries.
MATERIALS AND METHODS This retrospective cohort study enrolled 224 consecutive children with newly diagnosed ALL, who were treated between January 2001 and December 2007 at the Princess Norah Oncology Center (Jeddah, Saudi Arabia). In Saudi Arabian institutions, children are considered to be pediatric patients up to their 14th birthday. Therefore, the present study included patients from 1 to 14 years old. However, patients were excluded if they were under 1 year of age, presented the Philadelphia chromosome, or had missing data. The Hospital Research and Ethics Review Committee 1
Princess Noorah Oncology Center, King Saud Bin Abdulaziz University and King Abdulaziz Medical City, Jeddah, Saudi Arabia; 2 Department of Pediatrics, Faculty of Medicine, Umm AlQura University, Makkah, Saudi Arabia Conflict of interest: Nothing to declare.
Correspondence to: Wasil Jastaniah, Department of Pediatrics, Umm AlQura University and Chairman, Princess Noorah Oncology Center, Consultant Pediatric Hematology/Oncology/BMT, King Abdulaziz Medical City, Princess Noorah Oncology Center, P.O. BOX 9515 Jeddah 21423, Saudi Arabia. E-mail: [email protected] Received 22 September 2014; Accepted 3 November 2014
946
Jastaniah et al.
(HRERC ref. #: S1108–106) approved this study. The following data were collected from medical records: age at diagnosis, sex, white blood cell (WBC) count, relevant dates (i.e., diagnosis, remission, induction, relapse, death, last follow-up), causes of death, cytogenetics, immunophenotype, central nervous system (CNS) status, response to chemotherapy based on bone marrow (BM; day 7, 14, and 28).
Risk Stratification At the time of diagnosis, patients were stratified into two groups based on the National Cancer Institute (NCI)-Rome criteria and immunophenotype. The high-risk (HR) group was defined as patients presenting T-cell or precursor B-cell immunophenotype along with an age 10 years and/or 50 109 WBC/L. The standard-risk (SR) group was defined as patients showing a precursor B-cell immunophenotype along with 1–9 years of age and
Identifying Causes of Variability in Outcomes in Children With Acute Lymphoblastic Leukemia Treated in a Resource-Rich Developing Country Wasil Jastaniah, MBBS, FRCPC,1,2* Naglla Elimam, MD,1 Khalid Abdalla, MD,1 Basheer Ahmed Cittana Iqbal, Taha M. Khattab, MD,1 Sami Felimban, MD,1 and Mohammed Burhan Abrar, PhD1 Background. The outcome of children with acute lymphoblastic leukemia (ALL) in developing countries is less favorable than in developed countries, primarily due to resource constraints. However, it is unknown whether the therapeutic results differ. Thus, we hypothesized that outcomes in resource-rich developing countries would be similar to those in industrialized regions. Procedure. We performed a retrospective analysis of 224 consecutive children with ALL, who were treated according to the Children’s Cancer Group (CCG) protocols between January 2001 and December 2007. High-risk (HR) and standard-risk (SR) patients were treated with modified CCG-1961 and CCG-1991 protocols, respectively. Modifications included substitution of dexamethasone for prednisone in HR patients and addition of two intrathecal methotrexate treatments for CNS2 patients during induction. All patients received double delayed intensification with two interim maintenance phases.
MD,
1
Results. Five-year overall survival (OS), event-free survival (EFS) and disease-free survival (DFS) were 84.7 2.4%, 77.0 2.9%, and 81.4 2.7%, respectively. Remission was achieved in 98.1% of the patients. Induction failure and relapse rates were 1.9% and 15.1%, respectively. Death as the first event occurred in 6.4% of cases, of which 2.7% and 3.7% involved deaths in induction and remission, respectively. Interestingly, a significant reduction in induction deaths was observed over time. Conclusions. Despite the encouraging results observed in the present study, our patients displayed significantly lower survival outcomes compared to subjects treated in major clinical trials conducted by leading leukemia cooperative groups. Furthermore, this work underscores the need for targeted interventions to reduce death as the first event in developing regions. Pediatr Blood Cancer 2015;62:945–950. # 2014 Wiley Periodicals, Inc.
Key words: ALL; children; outcome; mortality
INTRODUCTION Acute lymphoblastic leukemia (ALL) represents the most common pediatric malignancy, accounting for approximately 25% of all cancers in children aged 15 years or younger and 75% of childhood leukemia cases overall. In 2009, ALL accounted for 22.6% of the cancers detected in children under 14 years of age in Saudi Arabia [1]. Since the 1970s, the treatment of childhood ALL has significantly advanced, resulting in impressive survival rates. Indeed, there is a greater than 85% chance of survival in developed countries, such as the US [2,3]. Multiple factors, including collaborative trials and improvement in risk/response directed treatment strategies, have contributed to this success [4]. Nevertheless, developing countries have not reached similar success rates for treatment outcomes. This disparity in therapeutic results may stem from variability in access to care, affordability, treatment withdrawal, supportive care measures, treatment protocols, medical expertise, and/or other factors (socioeconomic, biological, and geographical variables). Indeed, cancer diagnostics and treatment are expensive, imposing heavy financial burdens on patients’ families and healthcare systems. Furthermore, with increasing healthcare costs, the delivery of affordable cancer treatment can exceed the limited treatment resources available in many developing countries. As a result, numerous families abandon treatment before completion of chemotherapy. In fact, it was found that 35% of patients with childhood ALL refused or abandoned treatment due to financial constraints in Indonesia [5]. In contrast, Saudi Arabia is a resourcerich developing country that offers universal healthcare coverage free of charge for cancer patients of Saudi nationals, which allows the possibility to implement protocols proven to be successful in Western countries. In light of this, our institution has followed modified Children’s Cancer Group (CCG) protocols to treat patients with ALL for over 15 years. However, the treatment outcomes of these regimens have C
2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.25374 Published online 31 December 2014 in Wiley Online Library (wileyonlinelibrary.com).
not been evaluated. Thus, the aims of the present study were to report the results of pediatric patients with ALL treated in our center and to compare their therapeutic outcomes with those reported by national, regional, intercontinental, and leading leukemia cooperative groups. Our overall goal was to identify areas of weakness with regard to the delivery of care in order to promote targeted interventions that might optimize outcomes. We hypothesized that treatment results in resource-rich developing countries would be similar to those achieved in resource-rich developed countries, but superior to those of resource-restricted developing countries.
MATERIALS AND METHODS This retrospective cohort study enrolled 224 consecutive children with newly diagnosed ALL, who were treated between January 2001 and December 2007 at the Princess Norah Oncology Center (Jeddah, Saudi Arabia). In Saudi Arabian institutions, children are considered to be pediatric patients up to their 14th birthday. Therefore, the present study included patients from 1 to 14 years old. However, patients were excluded if they were under 1 year of age, presented the Philadelphia chromosome, or had missing data. The Hospital Research and Ethics Review Committee 1
Princess Noorah Oncology Center, King Saud Bin Abdulaziz University and King Abdulaziz Medical City, Jeddah, Saudi Arabia; 2 Department of Pediatrics, Faculty of Medicine, Umm AlQura University, Makkah, Saudi Arabia Conflict of interest: Nothing to declare.
Correspondence to: Wasil Jastaniah, Department of Pediatrics, Umm AlQura University and Chairman, Princess Noorah Oncology Center, Consultant Pediatric Hematology/Oncology/BMT, King Abdulaziz Medical City, Princess Noorah Oncology Center, P.O. BOX 9515 Jeddah 21423, Saudi Arabia. E-mail: [email protected] Received 22 September 2014; Accepted 3 November 2014
946
Jastaniah et al.
(HRERC ref. #: S1108–106) approved this study. The following data were collected from medical records: age at diagnosis, sex, white blood cell (WBC) count, relevant dates (i.e., diagnosis, remission, induction, relapse, death, last follow-up), causes of death, cytogenetics, immunophenotype, central nervous system (CNS) status, response to chemotherapy based on bone marrow (BM; day 7, 14, and 28).
Risk Stratification At the time of diagnosis, patients were stratified into two groups based on the National Cancer Institute (NCI)-Rome criteria and immunophenotype. The high-risk (HR) group was defined as patients presenting T-cell or precursor B-cell immunophenotype along with an age 10 years and/or 50 109 WBC/L. The standard-risk (SR) group was defined as patients showing a precursor B-cell immunophenotype along with 1–9 years of age and
