DISCUSSION
Our study showed a predominance of T-LLy phenotype similar to what is
reported in other areas of the world, however, the proportion of B-LLy
was higher. 3-5 In our Latin American cohort, 47.6 %
of the patients had T-cell phenotype and 38.9% with B-LLy phenotype,
while reported series from Europe and North America indicate a different
distribution of phenotypes (around 75% and 20%,
respectively).3,5 This tendency to a balanced
proportion of T-cell over B-cell phenotypes in Latin American LLy has
been previously suggested in a smaller Brazilian
report.4 In our cohort most of the cases of B
precursor phenotype LLy are diagnosed in Central America and the Andean
countries. (Table 3). Similar distributions of T and B immunophenotypes
have been observed in acute leukemias in some countries of Latin
America.6 These findings must be confirmed in further
epidemiological studies and possible biological explanations and
implications of these differences further investigated.
Toxic deaths (including induction death and death in complete remission)
occurred in 6.3% of our patients. This is higher than the observed
rates in high income countries which describe toxic mortality between 1
to 3.7% in lymphoblastic lymphomas. However these rates are lower than
the recently reported 6.4% induction mortality rate and 3.8% deaths in
complete remission for patients with acute lymphoblastic leukemia (ALL)
in Latin America. 6,7 Several factors may explain this
finding, seventy-six percent of our cohort presented with advanced
high-risk disease, many had severe clinical complications like
mediastinal compression or tumor lysis syndromes, and 3.2% of the
patients required dialysis. In contrast, tumor lysis was reported in
only 4% of patients included in a recent prospective European study,
and impaired renal function occurred in 2.8% of the
cases.7 Notably our institutions had limited resources
for diagnosis and supportive care, and this may partly explain the
higher risk of fatal toxic events and the delay in diagnosis
confirmation. Local physicians were keen to use empirical tratments
prior to the diagnosis in 18.4% of our cases, a higher proportion
compared to other reports and more frequent than in ALL in a Latin
American cohort that reported a 5%.6 This prephase
approach may explain the relative low percentage of induction deaths
observed especially in T-LLy.
Diagnosis of LLy still constitutes a challenge in our
setting.8 A delay between biopsy and definitive
diagnosis greater than 15 days was reported in 23.8% of our patients.
This factor influenced the therapeutic decisions that were made in cases
with high risk disease. Approximately one fourth of our patients had the
diagnosis confirmed by immunocytology in fresh tissue or fluids,
presenting the opportunity to establish a more timely diagnosis.
However, in approximately one quarter of the cases, the diagnosis of LLy
was achieved after a second pathological consultation.
The fact that in our cohort, patients presented with higher stages of
the disease and with severe clinical complications may be explained by
multiple contextual factors. One of the possible causes is the absence
of optimal local diagnostic techniques like flow cytometry or molecular
biology in some institutions delaying diagnosis and risk stratification
assignment. Additionally, there is insufficient supportive care
treatment in some centers, with drugs like rasburicase not being
available, lack of access to urgent hemodialysis implementation ,
restricted ICU admissions, and/or insufficiently trained pediatricians
and surgeons in the management of oncologic diseases and their emergency
complications.
Treatment regimens used were diverse and were categorized as BFM and non
BFM based ones. There was no significant difference in outcomes, but
there was a tendency favoring BFM-based protocols (Figure 2). The CNS
relapse rate was 5.5%, higher than reports from Europe and North
America reporting less than 3%.7,9 There was wide
variation among institutions participating in our study regarding
CNS-directed therapy and prophylactic cranial radiotherapy was not used
routinely.9 In fact, CNS radiotherapy was applied to
only 11 children (8.7%), including the 4 cases with initial CNS
involvement at diagnosis, and the remaining as CNS cranial prophylaxis
with 1200Gy.
Survival results of patients treated for LLy in our cohort can be
considered acceptable but lower than that observed in high income
countries.7,9-11 Moreover, considering the
abandonment-adjusted outcome it is imperative that we develop strategies
to decrease abandonment rates. Recent work by the PAHO regional working
group as part of the Global Initiative for Childhood Cancer recommends
strategies that could be implemented to address this
problem.12 Among the events observed in this cohort,
there was an increased proportion of non-disease related mortality and
abandonment and may be explained by lack of optimal resources and
socio-economic and cultural factors. Abandonment is a relevant and
prevalent problem in LA countries, occurring in 8.7 % of our cases,
representing a quarter of all clinical events, and has a heterogeneous
distribution being less prevalent in Brazil and Uruguay, as reported
previously for ALL or mature B-cell malignancies.6,13,14
Lastly, despite being a retrospective study that did not include patient
sensitive information and was considered exempt by USA regulations, 9 of
the 16 centers in Latin America initially invited to participate in the
study had difficulties in obtaining local IRB approval. Inconsistency
and non-harmonized IRB approaches to the review and approval of
retrospective data to answer important research questions constitutes a
barrier to research initiatives in Latin America, even for the
collection of non-sensitive data like in the present study.15
Limitations of our study include the retrospective design that may have
missed cases and incomplete clinical data, heterogeneous resources among
participating centers and no uniform therapeutic approach. With these
limitations prognostic factors could not be assessed. Despite these
limitations, our transnational study provides important findings to
establish the landscape of lymphoblastic lymphoma in children across a
wide-range of representative countries in Latin America.
Acknowledgment: This work was supported by the American Lebanese Syrian
Associated Charities (ALSAC).
Conflict of interest: none to declare
Table 1: Clinical characteristics of patients with LLy.