Paediatric-Inspired Acute Lymphoblastic Leukemia Protocols, Are They Too Toxic for Young Adults?
Authors: Ooi Melissa G. , Chng Wee J , Ng Chin-Hin , Yuen Yi Ching , Yeoh Allen Eng Juh , Hui Chiew Kean , Seah Elaine 
Published: October 2019

Abstract
BACKGROUND
In children with acute lymphoblastic leukemia, (ALL), current therapies yield complete remission (CR) rates of 98% and event-free survival (EFS) rates of 70% to 80% at 5 years[1]. In adults, even if the CR rate reaches 85% to 90%, therapeutic results remain less satisfactory, with a disease-free survival (DFS) rates of only 30% to 40% at 5 years. The largest adult trial conducted by the British Medical Research Council (MRC) and Eastern Cooperative Oncology Group (ECOG) has recently reported a 90% CR rate with a 5-year overall survival (OS) rate of 43% in patients with Philadelphia chromosome (Ph)-negative ALL [2]. In a study that retrospectively compared two trials, one designed for children and the other for adults, adolescents and young adults age 15 to 20 years old markedly benefited from a pediatric approach[3]. Whether pediatric or pediatric-inspired treatments might also improve the outcome of adults older than age 20 years remained unresolved. The main concern was the perceived worse tolerance of higher cumulative doses of chemotherapy.
MASPORE, a BFM based paediatric ALL protocol, has been used successfully in Singapore and Malaysia's paediatric cohort. In this single centre study, we wanted to investigate if the young adults with ALL (<30 years age) will also benefit from MASPORE and to investigate if they can tolerate a paediatric type regiment.
METHODS
We looked at our young adult patients (18-30 years old inclusive) over a period of 8 years. There was a total of 15 patients who was diagnosed with ALL (either T or B cell). Patients who were Philadelphia positive were excluded from this trial. The grading for the adverse events was done according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.
RESULTS
Our patients appeared to have a number of adverse events on this paediatric protocol. The grade 3/4 adverse events were 50% of all events collected. Table 1 demonstrated the type and incidence of events. As our serious adverse events appear to be L-asparaginase related, we focused in on those events associated with L-asparaginase and compared our data with our paediatric counterpart. Our patients had a high incidence of pancreatitis (13.3%) and thrombosis (40%), compared to the paediatric patients, who reported an incidence of 2.05% pancreatitis and 2.6% thrombosis. If line related thrombosis was removed from the equation, our thrombosis risk was still 13.3% which is 6.5 times the paediatric rate. Interestingly, the pancreatitis that our patients experienced was a biochemical pancreatitis with no clinical symptoms. Although fewer paediatric patients suffer from pancreatitis, there appear to be sicker with pancreatitis needing intervention.
CONCLUSION
The young adult cohort appears to have a much higher incidence of adverse events when compared to the paediatric patients. The thrombosis and pancreatitis incidence rate appear to be 6.5 times more frequent compared to the paediatric patients. The limitation of this study is the small number of young adult ALL.
Our department has instituted a policy change since this data was analysed. To reduce the incidence of line related thrombosis, the use of a peripherally inserted central catheter is discouraged during induction phase. We are also minimising the days off thromboprophylaxis; the low molecular weight heparin is only withheld on the day of the intrathecal chemotherapy. Since this protocol change, there has been no more line related thrombosis and other thrombosis noted. Our future work would be to reanalyse our thrombosis data after this protocol change and to investigate further as to why the young adults suffer more with pancreatitis compared to the children.
References
1. Pui, C.H. and W.E. Evans, Treatment of acute lymphoblastic leukemia. N Engl J Med, 2006. 354(2): p. 166-78.
2. Goldstone, A.H., et al., In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood, 2008. 111(4): p. 1827-33.
3. Boissel, N., et al., Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials. J Clin Oncol, 2003. 21(5): p. 774-80

Disclosures
Chng: Celgene: Honoraria, Research Funding.