Objective: To determine the proportion of treatment-related mortality among mortalities of paediatric acute lymphoblastic leukaemia and to identify probable causes and risk factors.
Methods: The observational retrospective study was conducted in February-March 2019 at the Department of Paediatric Haematology-Oncology and Bone Marrow Transplant, the Children’s Hospital and the Institute of Child Health, Lahore, Pakistan, and comprised data of all paediatric patients of acute lymphoblastic leukaemia who expired during treatment from January 2017 till September 2018. Death due to relapse and deaths before treatment were excluded. Data was analysed using SPSS 16.
Results: Of the 247 deaths during the study period, 144(58.3%) were treatment-related mortality cases; 81(56.2%) males and 63(43.8%) females with an overall mean age of 5.0±3.83 years. The commonest cause was sepsis 126(87.5%), followed by haemorrhagic complications 11(7.6%), drug toxicity 4(2.8%), tumour lysis syndrome 2(1.4%) and thromboembolism 1(0.7%). Significant factors associated with treatment-related mortality were weight-for-age, immunophenotype, the reason for admission, and absolute neutrophil count (p<0.05).
Conclusion: Treatment-related mortality, though potentially avoidable, was found to be a major cause of death among paediatric patients of acute lymphoblastic leukaemia, and sepsis was the most common cause.
Keywords: Acute lymphoblastic leukaemia, Drug-related side effects, Adverse reactions, Developing countries, Infection. (JPMA 71: 2373; 2021)
During the past four decades, there have been exceptional gains in the overall survival (OS) in childhood cancer cases, especially in high-income countries (HICs) (>85%).1,2 However, unfortunately, a substantial number of children with acute lymphoblastic leukaemia (ALL) are present in low- and middle-income countries (LMICs) where the survival rate in children with cancer is far inferior.3,4
Patients of paediatric ALL in Pakistan have been reported to present with higher risk features, have delayed presentation, inferior outcomes, and higher rate of infection, relapse and treatment abandonment compared to data from HICs.5,6
There are several reasons for this OS disparity, and drug/treatment toxicity leading to treatment-related mortality (TRM) is one of the most important causes.7 Few studies that investigated TRM in LICs identified rates of ALL TRM from 11% to 21%.8,9 Recent clinical trials have shown 5% patients dying during induction therapy10-15 and in some trials, seemingly minor changes in therapy resulted in increased deaths due to toxicity.16,17
A vast majority of treatment-related complications are attributed to cytotoxic drugs and high-dose steroids that commonly cause immunosuppression and metabolic derangements. In the developing world, children often have suboptimal nutrition, poor personal hygiene and repeated admissions to hospital with frequent and extensive use of antibiotics increases the risk of infections. On the other hand, leukaemia itself may also cause complications, like haemorrhage, thrombosis, tumour lysis syndrome (TLS), and increased susceptibility to infections.18 It is therefore imperative to identify the reason for mortality in this group of patients and pinpoint the areas for rectification to decrease TRM.
The current study was planned to determine the proportion of TRM among all mortalities encountered in paediatric ALL patients in an LMIC setting.
Materials and Methods
The observational retrospective study was conducted in February-March 2019 at the Department of Paediatric Haematology-Oncology and Bone Marrow Transplant, the Children’s Hospital and the Institute of Child Health, Lahore, Pakistan, and comprised data of all paediatric ALL patients who expired during treatment from January 2017 till September 2018.
The Children's Hospital and The Institute of Child Health, Lahore is a tertiary care public-sector hospital which has the largest paediatric haematology/ oncology centre in the province of Punjab with a 60-bed inpatient unit catering around 100 patients daily. At this centre, curative as well as palliative treatment is offered free of cost not only to the patients who present from all over the country, but also from the neighbouring country Afghanistan.
Data included in the current study related to patients who had been admitted either for remission induction chemotherapy or any other treatment-related complication after achieving remission induction. Data of patients who expired due to either relapsed or progressive disease, or in whom treatment (chemotherapy) had not yet started was excluded. Data was retrieved using non-probability purposive sampling technique after approval from the institutional ethics review board.
All patients of ALL were treated according to United Kingdom Acute Lymphoblastic Leukaemia (UKALL) 2011 Interim Guidelines.19 The treatment protocol broadly comprises 5 phases of treatment: remission induction, consolidation, interim maintenance, delayed intensification, and maintenance. Remission induction chemotherapy is of two types. Regimen A is a standard-risk option, while Regimen B carries high risk. Induction therapy comprises dexamethasone, vincristine, asparaginase, intrathecal methotrexate for central nervous system (CNS) prophylaxis. In Regimen B, daunorubicin is added. Standard or high-risk treatment regimen is decided as per the National Cancer Institute (NCI)-based risk stratification20 and further phases of treatment are based upon response to treatment assessed by morphological remission in the bone marrow. Cytogenetics and Minimal Residual Disease (MRD) assessment facilities are not available at the study site. All further phases of chemotherapy after remission induction are categorised into Regimens A, B and C. Chemotherapeutic agents used in these phases are cyclophosphamide, cytarabine, asparaginase, vincristine, intrathecal, intravenous (IV) and oral methotrexate as well as doxorubicin and oral 6-mercaptopurine. The major differences among these therapy regimens lie between the consolidation phase of Regimen A with B/C, and the interim maintenance and delayed intensification phases of Regimen C with A/B with the addition of cytarabine blocks and escalating doses of methotrexate. Maintenance therapy for 2-3 years is composed of oral chemotherapy, comprising 6 mercaptopurine and methotrexate, with monthly vincristine and intrathecal methotrexate after every 3 months. In all newly-diagnosed patients, tumour lysis prophylaxis was given in the form of IV hydration (2-3L/m2/day), oral allopurinol, and aluminum hydroxide. Trimethoprim-sulfamethoxazole prophylaxis was given to all patients who were on treatment for ALL. Empirical antibiotics piperacillin-tazobactam and amikacin were given to all patients who were admitted for chemotherapy-induced febrile neutropenia and later on antibiotics were tailored according to the clinical indications or culture and sensitivity reports.
For the purpose of the current study, operational definitions were formulated as given below:
Patients with ALL were diagnosed based on peripheral blood picture and/or bone marrow biopsy with immunophenotyping on flow cytometry suggestive of ALL.
TRM was defined as any death during remission induction chemotherapy or any death occurring on treatment after remission induction chemotherapy with documented complete remission.
Complete remission was defined as morphological remission with <5% blasts in bone marrow biopsy.
Early death due to disease was defined as any newly-diagnosed patient who expired before the institution of remission induction chemotherapy.
The underlying causes of TRM were also defined. Sepsis was defined as clinical or laboratory evidence of infection with systemic inflammatory response syndrome; lower respiratory tract infection (LRTI) was defined as the presence of suggestive auscultation findings (crepitation) along with radiological evidence of pneumonia on chest X-ray or computed tomography (CT) scan; CNS infection was defined as the presence of suggestive cerebrospinal fluid (CSF) findings and/or neuroimaging of meningitis/ meningoencephalitis; gastrointestinal tract (GIT) infection was defined as the presence of acute gastroenteritis (loose stools > grade 3), typhlitis, or septic ileus as well as suggestive clinical signs and radiological studies; blood-stream infection was defined as blood culture positive for bacterial growth; urinary-tract infection (UTI) was defined as urine culture positive for bacterial growth (>105 CFU/mL); mucocutaneous infection was defined as clinical evidence of >grade 2 mucositis; invasive fungal infection was defined as radiological imaging suggestive of 2 or more systems involvement with fungal infection; TLS was defined as per Cairo-Bishop’s classification21 laboratory TLS and/or clinical TLS; pulmonary haemorrhage was defined as clinical evidence of pulmonary haemorrhage along with respiratory failure and suggestive radiological findings on chest X-ray; disseminated intravascular coagulation was defined as clinical evidence of bleed along with pancytopenia and deranged prothrombin time (PT) and activated partial thromboplastin time (aPTT) (D-dimers/fibrinogen degradation products are not available at the study site); intracranial haemorrhage/cerebral thrombosis was defined as CT or magnetic resonance imaging (MRI) suggestive of cerebral haemorrhage/ thrombosis; drug toxicity was defined as per UKALL 2011 interim guidelines; and marrow failure was defined as two of three cytopenias: Absolute neutrophil count (ANC) <500/µl, platelet count <20,000/µl, reticulocyte count <40 x 109/L and bone marrow cellularity <25%.
The primary outcome measured in the study was TRM. The underlying TRM causes were further classified into sepsis, TLS, drug toxicities, haemorrhagic complications, thromboembolic phenomena, and metabolic derangements. Data was analysed using SPSS 16.
There were 742 ALL patients registered during the study period and 247(33.2%) deaths. Of the mortalities, 144(58.3%) were TRM cases, 88(35.6%) deaths were because of relapsed disease and 15(6.1%) were early deaths due to the disease (Figure-1).
Among the TRM cases, 81(56.2%) were males and 63(43.8%) were females, with an overall mean age of 5.0±3.83 years. The commonest cause was sepsis 126(87.5%), followed by haemorrhagic complications 11(7.6%), drug toxicity 4(2.8%), TLS 2(1.4%) and thromboembolism 1(0.7%) (Figure-2; Table-1).
Significant factors associated with TRM were weight-for-age (WFA), immunophenotype, the reason for admission, and ANC (p<0.05) (Table-2).
In the current study, TRM constituted the major proportion (58.3%) of all deaths in patients with ALL. Therefore, a decline in the rate of TRM will have a significant effect on the outcome and OS of these patients.
Chemotherapy-induced febrile neutropenia predisposes the patients to a number of infections. Infectious complications/sepsis is the major cause of mortalities among all paediatric oncology patients22-25 and the same was observed in the current study.
Wasting and undernutrition always pose challenges in paediatric patients and paediatric oncological patients pose even more challenges when concomitant chemotherapy-induced complications are present. It has already been proven that malnutrition has a significant effect on various aspects of management of paediatric ALL patients.26-29 The remission induction phase of chemotherapy is the most toxic phase of treatment in ALL26-29 and the current study also showed that most of the cases with TRM occurred during this phase of chemotherapy. The factors found to be statistically significant in association with the Treatment-related mortality in this study were: WFA of patients, the immunophenotype of ALL, the reason for admission in the hospital, and ANC at the time of death.
Treatment-related mortality, though potentially avoidable, was found to be a major cause of death among paediatric patients of acute lymphoblastic leukaemia, and sepsis was the most common cause. Infection prevention and control are vital in improving overall survival of ALL patients in developing countries.
Disclaimer: The Abstract was presented at the 4th International Conference of the Pakistan Society of Paediatric Oncology, Karachi, in March 2019, MASCC-ISOO 2019 Annual conference, San Francisco, United States of America, in June 2019, and at the 51st Congress of the International Society of Paediatric Oncology, Lyon, France, in October 2019.
Conflict of interest: None.
Source of Funding: None.
1. Pui CH, Campana D, Pei D. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 2009; 360: 2730-41.
2. Moghrabi A, Levy DE, Asselin B. Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia. Blood 2007; 109: 896-904.
3. Mostert S, Sitaresmi MN, Gundy CM. Influence of socioeconomic status on childhood acute lymphoblastic leukemia treatment in Indonesia. Pediatrics 2006; 118: 1600-6.
4. Metzger ML, Howard SC, Fu LC. Outcome of childhood acute lymphoblastic leukaemia in resource-poor countries. Lancet 2003; 362: 706.
5. Mushtaq N, Fadoo Z, Naqvi A. Childhood acute iymphoblastic leukaemia: Experience from a single tertiary care facility of Pakistan. J Pak Med Assoc 2013; 63: 1399-404.
6. Fadoo Z, Nisar I, Yousuf F, Lakhani LS, Ashraf S, Imam U, et al. Clinical features and induction outcome of childhood acute lymphoblastic leukemia in a lower/middle income population: A multi‐institutional report from Pakistan. Pediatr Blood Cancer 2015; 62: 1700-8.
7. Howard SC, Wilimas JA. Delays in diagnosis and treatment of childhood cancer: where in the world are they important? Pediatr Blood Cancer 2005; 44: 303-4.
8. Aziz Z, Zahid M, Mahmood R, Maqbool S. Modified BFM protocol for childhood acute lymphoblastic leukemia: a retrospective analysis. Med Pediatr Oncol 1997; 28: 48-53.
9. Howard SC, Pedrosa M, Lins M. Establishment of a pediatric oncology program and outcomes of childhood acute lymphoblastic leukemia in a resource-poor area. JAMA 2004; 291: 2471-75.
10. Schrappe M, Reiter A, Ludwig WD. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results ofTrial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood 2000; 95: 3310-22.
11. Silverman LB, Gelber RD, Dalton VK. Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood 2001; 97: 1211-18.
12. Wheeler K, Chessells JM, Bailey CC, Richards SM. Treatment related deaths during induction and in first remission in acute lymphoblastic leukaemia: MRC UKALL X. Arch Dis Child 1996; 74: 101-7.
13. Conter V, Arico M, Valsecchi MG. Long-term results of the Italian Association of Pediatric Hematology and Oncology (AIEOP) acute lymphoblastic leukemia studies, 1982-1995. Leukemia 2000; 14: 2196-204.
14. Kamps WA, Bokkerink JP, Hakvoort-Cammel FG. BFMoriented treatment for children with acute lymphoblastic leukemia without cranial irradiation and treatment reduction for standard risk patients: results of DCLSG protocol ALL-8 (1991-1996). Leukemia 2002; 16: 1099-111.
15. Vilmer E, Suciu S, Ferster A. Long-term results of three randomized trials (58831, 58832, 58881) in childhood acute lymphoblastic leukemia: a CLCG-EORTC report. Children Leukemia Cooperative Group. Leukemia 2000; 14: 2257-66.
16. Liang DC, Hung IJ, Yang CP. Unexpected mortality from the use of E. coli L-asparaginase during remission induction therapy for childhood acute lymphoblastic leukemia:a report from the Taiwan Pediatric Oncology Group. Leukemia 1999; 13: 155-60.
17. Hurwitz CA, Silverman LB, Schorin MA. Substituting dexamethasone for prednisone complicates remission induction in children with acute lymphoblastic leukemia. Cancer 2000; 88: 1964-69.
18. Christensen MS, Heyman M, Mottonen M. Treatment-related death in childhood acute lymphoblastic leukaemia in the Nordic countries: 1992–2001. Br J Haematol 2005; 131: 50-8.
19. Leukemia& Lymphoma Research [Internet]. Birmingham: Children’s Cancer Trials Team, Cancer Research UK Clinical Trials Unit (CRCTU), University of Birmingham; 2013. UKALL 2011 Trial: United Kingdom National Randomised Trial For Children and Young Adults with Acute Lymphoblastic Leukaemia and Lymphoma 2011. [Online] [cited 2021 June 05] Available from: URL: https://www.northerncanceralliance. nhs.uk/wp-content/ uploads/2019/01/UKALL2011-Protocol-v3.0-01-Oct-2013.pdf
20. Smith M, Arthur D, Camitta B, Carroll AJ, Crist W, Gaynon P, et al. Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. J Clin Oncol 1996; 14: 18-24.
21. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 2004; 127: 3-11.
22. O’Connor D, Bate J, Wade R, Clack R, Dhir S, Hough R, et al. Infection-related mortality in children with acute lymphoblastic leukemia: an analysis of infectious deaths on UKALL2003. Blood 2014; 124: 1056–61.
23. Kuo FC, Wang SM, Shen CF, Ma YJ, Ho TS, Chen JS. et al. Bloodstream infections in pediatric patients with acute leukemia: Emphasis on gram-negative bacteria infections. J Microbiol Immunol Infect 2017; 50: 507–13.
24. Hafez HA, Soliaman RM, Bilal D, Hashem M, Shalaby LM. Early Deaths in Pediatric Acute Leukemia. J Pediatr Hematol Oncol 2019; 41: 261–6.
25. DePasse J, Caniza MA, Quessar A, Khattab M, Hessissen L, Ribeiro R, et al. Infections in hospitalized children and young adults with acute leukemia in Morocco. Pediatr Blood Cancer 2013; 60: 916–22.
26. Martín-Trejo JA, Núñez-Enríquez JC, Fajardo-Gutiérrez A, Medina-Sansón A, Flores-Lujano J, Jiménez-Hernández E, et al. Early mortality in children with acute lymphoblastic leukemia in a developing country: the role of malnutrition at diagnosis. A multicenter cohort MIGICCL study. Leuk Lymphoma 2016; 58: 898–908.
27. Yazbeck N, Samia L, Saab R, Abboud MR, Solh H, Muwakkit S. Effect of Malnutrition at Diagnosis on Clinical Outcomes of Children with Acute Lymphoblastic Leukemia. J Pediatr Hematol Oncol 2016; 38: 107–10.
28. Rivera-Luna R, Olaya-Vargas A, Velásquez-Aviña M, Frenk S, Cárdenas-Cardós R, Leal-Leal C, et al. Early Death in Children with Acute Lymphoblastic Leukemia: Does Malnutrition Play a Role? Pediatr Hematol Oncol 2008; 25: 17–26.
29. Loeffen EAH, Brinksma A, Miedema KGE, de Bock GH, Tissing WJE. Clinical implications of malnutrition in childhood cancer patients—infections and mortality. Support Care Cancer 2014; 23: 143–50.