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.