Discussion:
With the current advances in chemotherapy regimens the 5 -year survival rate of newly diagnosed children with ALL has greatly increased over the decades and is now reported at about 90% with a cure rate ranging from 80 - 90% after having received initial treatment, however between 10 – 15% of paediatric patients still experience relapse and have poor outcomes(8-10). Site and time of relapse continues to be reported as the most significant factors in survival after relapse. In this study, we adapt and demonstrate an approach that is based ona risk-stratification when treating children with relapsed or refractory ALL to report our risk-factors and outcomes for survival post – relapse in our cohort of patients.
Relapse rate of 9% was observed in our study , which is comparable to findings reported by several groups and much lower than findings reported by Ali et al. and Nguyen et al. reporting rate of relapse at 24.5% and 20.5% respectively(4, 11, 12). The male-to-female ratio observed in this study is 4.16:1, which is similar to several other studies with a higher relapse rate observed in male than females carrying a poor-prognosis factor(4). Another consistency in the findings with other studies was the higher rate of relapse in high-risk group of patients than low-risk patients (71% vs. 29%).Regarding the relapse site, bone marrow relapse was observed in majority of the cases (61%), which is again similar to several other studies(4).
Amongst the relapsed cases, fifteen patients (64%) patients did not achieve remission and this finding is higher than the reported findings in the literature (4, 12), nevertheless our study too demonstrates early response to re-induction therapy is of prognostic value. The higher failure rate of remission in these patients could be attributed to the relapse site [isolated BM relapse in 12 (60%), BM + CNS relapse in 5 (25%), CNS relapse in 2 (10%) and one-patient (5%) experienced testicular relapse] and based on our assumption that leukemia blast cell were inherently resistant to the therapeutic agents admninistered during the first-line therapy and lack of MRD (minimal residual disease) testing during that time could be a factor attributing to sub-optimal disease response to treatment resulting in poorer outcomes.
Regarding the survival correlation between overall survival between relapse events and survival after diagnosis, response to re-induction was found to be the only strongest predictor of survival in our cohort. Our study adapted a risk-stratification strategy based on the duration of remission after first –line therapy and site of relapse and when OS was performed after disease recurrence a particular good –risk cohort was identified and these finding are comparable to the findings described by Belgaumi et al. With regards to HSCT, no risk group seems to have benefitted and the risk of TRM is worth exploring in this group of patients through a multi-center observational study.
At cut-off for analysis (January 2021), 45% of the children with relapse had passed away while 55% are still alive with a median survival time after relapse to death of 7.5 months, which is similar to findings as reported by Tuong et al(4), however is shorter than the findings reported by other studies and this could be again due to the lack of MRD testing to evaluate response of second line therapy ,use of protocols and / or therapeutic agents that could have been used and / or upgraded(6).
In conclusion, our study shows majority of the relapse events occurred during the first 18-months from first-remission and bone marrow remains the leading site of relapse. Risk-stratification appears to be effective in identifying “better-risk” category but response to re-induction remained the strongest predictor for survival. Patients treated with HSCT who did not fall in the “better-risk” category continues to demonstrate poor outcomes, although it appears that there is no difference of statistical significance in survival outcomes amongst patients who received HSCT vs. Chemotherapy but this could be attributed to a smaller sample size and therefore a multi-institutional observational study is recommended for a larger cohort of patients as follow-up to this study to compare survival outcome and transplant-related toxicity (infectious and non-infectious).
Additionally, Blinatumomab with MRD testing is a significant treatment advancement for children with relapsed or refractory leukemia (13) and may improve overall survival of relapsed patients and therefore a follow-up study at our institution to compare survival outcomes between the two time frames where in Blinatumomab was introduced is also warranted. Findings from this study too corroborates with the need for Novel therapies and approaches to improve universally-reported dismal outcomes in these group of patients.