DISCUSSION
The introduction of effective treatment for childhood leukemia in a
lower-middle income country is challenging. Reports from Southeast Asia
illustrate limiting factors such as infectious and bleeding
complications in a program established in neighboring Laos10. In Indonesia high rates of treatment refusal were
documented already before and during induction chemotherapy due to
socio-economical limitations 11, but also difficulty
to cope with treatment toxicity and pessimism with respect to chances of
cure are furthermore reported 12 . Similar
observations were made in Latin America with almost 50 % of events due
to abandoned of treatment or treatment related toxicity4. However, encouraging examples have been reported in
lower-middle income countries in Central America using a BFM-adapted
treatment protocol in five countries achieving an overall 3 year
survival rate of 68 % and an event free survival rate of 59 %
including treatment abandonment 13. In Vietnam, 5 year
relapse-free survival was 47.8 % using a French protocol (FRALLE 2000),
excluding patients who had abandoned treatment. Furthermore, only
children from families that could afford treatment costs could be
included 5. The approach of the Kantha Bopha
Foundation was to provide free care building on trained Cambodian
personnel and infrastructure. Taking the reported incidence for Europe
of 46.7 cases of ALL per million children under 15 years old, and given
that 31.9% of the 16.7 million Cambodian population is aged under 15
years, we estimate that we could likely reach about one sixth of the
children with ALL in the country. In this setting, a slightly modified
version of the protocol ALL-MB91, combining treatment elements from the
BFM and Dana-Farber consortia was used, with the intention to provide a
moderately toxic regimen in a context in which the control of infections
was expected to be a major limitation. Analyzing a most recent
three-year period (2015-2017), we show that the estimated 3-year overall
survival of 110 patients was 34.9%. These patients remained
disease-free. We documented a total of 13 relapses in this cohort, but
this may underestimate the number of relapses hidden in other lethal
complications. In this unselected population, adherence to first line
treatment was remarkable. No family abandoned treatment. The experience
in Russia, where the protocol was initially established, showed that an
event-free survival of 67 % could be achieved with this protocol under
challenging socio-economic conditions 7. In Cambodia,
more than half of the patients presented with a large leukemia burden,
which is likely explained by a very delayed access to care. Importantly,
in patients with a lower leukemia burden, overall and disease-free
survival was 50.5 %, implicating that education of care providers and
early access to diagnostic testing is of great importance. Furthermore,
malnutrition was also expected to impact treatment related morbidity as
discussed in ALL studies in India 14.
The majority of events in our cohort included infections and bleeding
complications. Despite a reduction of treatment intensity compared to
ALL protocols in high-income countries, SR patients were still exposed
to total of 8 weeks of 6 mg/m2 dexamethasone and 8
additional 2-day pulses during maintenance, and to cumulative 120
mg/m2 of daunorubicin. In a similar geographical
region, but with a better financial background, a modified BFM-ALL
treatment was developed for Malaysia and Singapore, with a
risk-stratification based on molecular minimal residual disease. In this
study 8, non-HR patients (85.8% of all patients) were
treated without anthracyclines in induction and with cumulative 60
mg/m2 doxorubicin in reinduction. They were exposed to
a total of 6 weeks of 6 mg/m2 dexamethasone after one
week of a prednisone pre-phase and obtained up to 6 pulses with
6mg/m2 dexamethasone for 7 days during maintenance.
Treatment related complications occurred at similar rates compared to
major protocols in the US and in Europe. Only 17 (3 %) non-HR patients
died of a lethal infection. Six-year EFS was 80.6% on this protocol. SR
patients despite significant deintensification of the chemotherapy had
an EFS of 93%, which provides first strongest evidence that a massive
reduction of anthracyclines is possible without compromising outcome for
most of the patients. This concept is further supported by 2 studies in
Brazil and Egypt, developed in cooperation with the St. Judes Children’s
Research Hospital, where patients with very-low-risk ALL based on their
response to induction were treated with a low-intensity regimen
including a maximum of 50 mg/m2 of doxorubicin. In
both studies, 5 year-overall survival was estimated over
95%15,16.
Clearly, further reduction of both anthracyclines and glucocorticoids
will have to be implemented in our treatment strategy in Cambodia.
In order to reduce treatment intensity, an affordable diagnostic set up
will have to be established to reliably identify patients with favorable
leukemia biology. Introduction of flow cytometry (FCM) with a robust
panel to diagnose and follow ALL is warranted. FCM was shown to identify
most HR patients based on response to treatment at day 15 on a BFM
regimen 17. FCM was successfully used to risk-stratify
patients for low-intensity chemotherapy in the studies that we mentioned
above 15,16. This readout can be achieved at
reasonable costs. Improvement of genetic- and molecular classification
will hardly be affordable in the current setting. However, polymerase
chain reaction (PCR) based multiplex ligation-dependent probe
amplification may provide a robust way to determine gene copy number
variations. With this approach, a classifier was established and
validated recently across a number of different ALL study cohorts that
enables to detect patients with favorable risk cytogenetics readily18. Thus it is feasible to improve risk stratification
with the introduction of affordable technology in order to reduce
treatment intensity for most patients.
To reduce treatment related mortality supportive care is also of central
importance. In this cohort bacterial infections during aplasia under
chemotherapy pose the predominant problem. Empirical treatment of
febrile neutropenia should be revisited according to recent guidelines19. The option of antibiotic prophylaxis may possibly
be considered during induction chemotherapy. For the reduction of
bleeding complications, fractionation of platelets will have to be
introduced, the key infrastructure being available on site.
In the near future, promising CD-19 and CD-22 directed immunotherapy
could be explored in a first line setting where patients may clearly
benefit most from reduction of treatment intensity. The
chemoimmunotherapeutic inotuzumab ozogamicin shows promising results in
elderly patients with ALL and the CD19-directed bispecific monoclonal
antibody blinatumomab markedly improved outcome in children with
relapsed ALL, with a clear reduction of treatment related toxicity in
the bridge to stem cell transplantation 20. There is a
strong interest to develop clinical studies also in this region of the
world with the aim to reduce toxicity of chemotherapy by replacing it at
least in part by immunotherapy. The current focus in Cambodia remains to
tailor an even less intensive chemotherapy backbone and to integrate the
team into an international working group in the region, possibly
together with experts of St. Jude VIVA forum to foster the development
of pediatric oncology in Cambodia.
In conclusion, our retrospective analysis shows that the introduction of
a complex chemotherapy protocol is feasible in the context of a
charity-funded public institution in Cambodia but also underscores
current socio-economical, geographical and institutional limitations.
The outcome for patients with SR ALL is very encouraging. Our data
provide the basis to justify modifications of the treatment strategy and
major investments in supportive care to improve outcome for children
with leukemia in Cambodia. We will aim at a further reduction of
treatment intensity for non-HR patients and optimization of supportive
care.