DISCUSSION
This study shows a significant improvement in 3-year EFS estimates of
children diagnosed with ALL at MTRH (from 18% to 41%). This could be
attributed to a reduction in the abandonment of therapy and relapse.
However, death was the most common cause of treatment failure, with a
significant proportion of deaths occurring during induction in the two
cohorts.
Treatment abandonment as a cause of treatment failure reduced
significantly (from 27% to 14%) in this study. It is modestly lower
than Honduras, 22% and Indonesia, 35%.4-5 However,
this was higher than observed in Pakistan, 7.5%, and Rwanda,
10%.3,7 Abandonment has been directly associated with
low socioeconomic status and long travel time in some
LMICs.3,6 Lack of medical insurance has been
associated with higher rates of treatment abandonment and lower overall
survival of cancer patients in previous studies in
Kenya.16 With most patients abandoning treatment
during maintenance, it is probable that because patients look relatively
well during maintenance, parents may think they are cured. The long
duration of ALL treatment is also likely to cause families to become
lethargic over time. The reduction in abandonment in this study can be
attributed to continuous counseling of parents, assessing for the
economic challenges, and mitigating them whenever possible. That
includes assisting parents in enrolling in health insurance (NHIF) and
parent support groups by the social-work services department.
The relapsed leukemia decreased significantly as a first treatment
outcome. Out of those that achieved remission, the proportion of
children that had a relapse (19%) was similar to what has been found in
other studies where relapses are reported to range between 12% and
20%.17 Due to decreased abandonment, there were
probably more patients at risk of relapse in this study. Like other
centers in LMIC, our patients are treated with a standard treatment
protocol without risk stratification. That means sub-optimal intensity
post-induction therapy for high-risk ALL children and corresponding poor
EFS. In Rwanda, in a study by Rubagumya et al. children with ALL who
were treated with low-intensity treatment had EFS of 22%, with relapse
as the leading cause of treatment failure (53%). However,
treatment-related toxicity was acceptably low.7Therefore, there is a need to adopt a risk stratification criterion at
MTRH, with more intensification of therapy for the high-risk group to
reduce relapses.
Historically, WBC and age at diagnosis, sex, initial treatment response
determined by end induction bone marrow morphological remission, and
immunophenotype have been used to stratify patients’ risk status and
predict the outcome. In this study, we showed that ALL patients with an
initial WBC <50 x 109/L and patients in the
age group 1 to 9 years had better event-free and overall survival with
the current treatment protocol. Patients with CNS involvement were at
high risk of death despite intensified intra-thecal chemotherapy alone,
as there were no radiotherapy services available during the period, and
few patients were referred out for craniospinal radiation. Studies from
HIC have shown that determination of end-induction measurable residual
disease (MRD) by flow-cytometry or PCR has proven to be a reliable
predictor for relapse and overall outcome. Post-induction treatment
intensification for end-induction MRD-positive patients improved overall
survival.18,19 However, treatment intensification for
high-risk patients demands more intensive supportive care that is not
readily achievable in most centers in LMICs. Also, we do not have the
resources to monitor MRD in our setting.
The proportion of patients who died during induction decreased (from
24% to 17%) between the two periods, although the difference was not
statistically significant. Most of the deaths were treatment-related.
These induction deaths approximate what was observed in other LMICs. In
a study by Jabeen, K et al. (2016) in Pakistan, Induction deaths
accounted for 19.2%, most of which were
infection-related.6 In Egypt, in a study by
Abdelmabood S et al. (2020), induction deaths were 23%, the majority
related to infections.3 One factor for the decrease in
deaths in our cohort is likely due to dropping doxorubicin from the
induction regimen when L-asparaginase was more available. Using a less
intensive three-drug induction regimen (prednisone, asparaginase,
vincristine) has been associated with decreased early mortality (toxic
deaths) and improved short-term survival compared to a more intensive
anthracycline-containing induction regimen.20,21 The
other factor includes prompt recognition of neutropenic fever and
initiation of empiric antibiotics. The use of antimicrobial prophylaxis
has been shown to reduce significantly induction deaths related to
infections.22 In our setting, we have used
cotrimoxazole, fluconazole, and ciprofloxacin prophylaxis during severe
neutropenia (<0.5 x 109/L). Invasive
infections are a common complication and cause of death during
induction, requiring more effective infection prevention
strategies.23 Improved supply of blood products,
especially platelets, has also contributed to the supportive care of the
patients during induction. At MTRH, there is an urgent need to create
more space to allow for better isolation, develop antibiotic therapy
guidelines based on local antimicrobial sensitivity patterns, and
improve supplies of blood products to reduce induction deaths further.
Delay in diagnosis and initiation of treatment is also among the reasons
for poor outcomes in LMICs.24 Although the duration of
illness did not significantly influence the outcome in the two periods,
more than half of the patients had had symptoms for more than 1-month
before presentation at MTRH. In India, prolonged symptom-to-diagnosis
interval in childhood acute ALL adversely impacted survival, with those
less than eight weeks having a better median survival of 59 +/- 5
months.25 Dai Q et al. (2022) found that diagnosis
delay was an independent predictor for treatment outcomes in childhood
ALL.26 Longer time interval to the diagnosis of ALL
has been associated with more extensive disease, increased toxicity from
chemotherapy, and death. Almost all the patients diagnosed at MTRH are
referred from lower-level County health facilities, with no adequate
expertise and diagnostic capacity, resulting in a delay in referral,
diagnosis, and initiation of treatment.
Like in the earlier cohort, further analysis of event-free survival
estimates of those with NHIF at diagnosis and those without did not
reveal any statistically significant difference. This could be
attributed to the fact that 40 out of the 43 who did not have health
insurance were assisted to be enrolled through the social work services
department during the first weeks of therapy. Moreover, there is a
possibility of waiver for the poorest.
Being a retrospective study, the limitations experienced included
missing medical records and lack of documentation of information in some
of the retrieved records.
In conclusion, there was an improvement in event-free survival and a
reduction in treatment abandonment and relapse. However, induction
deaths did not reduce significantly. Although the survival outcomes are
much lower compared to HIC, this study highlights the importance of
collaboration with institutions in HIC and LMIC.27 and
continuous quality improvement strategies that are adapted to available
resources. Future strategies to reduce induction mortality should
include working in collaboration with county lower-level facilities to
improve early recognition, referral, diagnosis, and initiation of ALL
treatment. Improved availability of blood products, especially
platelets, adequate ward space for isolation, and other infection
prevention strategies, including handwashing and prophylactic
antimicrobial use, need to be implemented. There is a need for advocacy
for universal health care through NHIF coverage and improved parental
education and counseling to reduce treatment abandonment further. Proper
risk stratification, use of risk-adapted protocols, and treatment of
relapsed disease in resource-limited settings such as MTRH need to be
studied. Collaboration with institutions in HIC through the existing
twinning programs needs to be enhanced for knowledge and skills
transfer. Implementing all or most of this will help us to achieve a
60% cure of patients with ALL by 2030, as stated by the WHO Global
initiative on Childhood Cancer.1