DISCUSSION
The cases presented here represent the first reported instances ofoff-label Vemurafenib use in Brazil for the treatment of
high-risk histiocytosis refractory to first and second-line therapies.
The discovery of the recurrent BRAF gene mutation’s involvement in
histiocytosis pathogenesis is relatively recent. In 2010, Badalian-Very
et al. first described this mutation, suggesting that histiocytosis is a
neoplastic disease driven by the BRAF V600E gain-of-function mutation.
This mutation is found in approximately 57% of histiocytosis cases and
is a key discovery given the disease’s heterogeneity (15). Importantly,
this mutation is not unique to histiocytosis; it is a common oncogenic
mutation observed in about 30 different neoplasms, leading to activation
of the Ras/Raf/MEK/ERK signaling pathway (16). Mutations in MAP2K1 have
been found in 50% of BRAF wild-type patients, indicating the critical
role of the MAPK pathway in LCH pathogenesis (17). Other mutations
affecting ARAF, MAP3K1, NRAS, PI3CA, and other targets are found in the
remaining 25% of patients (18).
These molecular findings suggest that LCH can be characterized as a
clonal myeloid neoplasm driven by activation of the Ras/Raf/MEK/ERK
pathway with inflammatory properties. While the exact pathophysiology
remains unclear, this information has paved the way for more
individualized treatments for LCH (14).
In this context, targeted therapy has opened new possibilities for
treating various neoplasms, including histiocytosis. In the case of
histiocytosis, understanding its pathogenesis with the discovery of
recurrent BRAF mutations has led to the use of the selective BRAF
inhibitor, Vemurafenib (19). Initial reports, including the case by
Heritier et al., demonstrated successful use of VMF in children with
resistant MS-LCH (20). Most studies and case reports describe VMF use in
relapsed or refractory histiocytosis cases that did not respond to first
and/or second-line treatment. These cases often involve severely ill
infants who showed rapid responses to VMF, with resolution of symptoms
and transfusion independence. VMF has proven to be a safe treatment with
no serious adverse effects during its use (21).
Prior to targeted therapy, second-line treatments for histiocytosis were
associated with high toxicity, making them less favorable (22).
Hematopoietic stem cell transplantation (HSCT) was considered a rescue
option, but its toxicity was even higher (23).
However, a major concern with long-term VMF treatment is its potential
for toxicity, as observed in adult patients with Erdheim-Chester disease
(24). Fortunately, VMF’s safety profile appears more favorable in
infants and children, although long-term effects remain unknown (14,25).
Despite these promising developments, many questions remain unanswered.
When is the right time to start VMF? What is the ideal duration of VMF
treatment? What is the optimal maintenance therapy after stopping VMF?
How long can children safely use VMF? Unfortunately, we lack sufficient
data to answer these questions comprehensively. Additionally, Brazil
lacks epidemiological data on histiocytosis and studies evaluating the
budgetary impact of incorporating VMF into the public health care system
(SUS).
While the expense associated with VMF treatment can be significant, it’s
essential to consider that this is a rare disease that primarily affects
young children. Historically, high-risk refractory cases have had low
survival rates, making remission-inducing treatment invaluable. Targeted
therapy has the potential to extend and enhance the quality of life for
patients and their families. These factors should not be underestimated,
as they encompass the reintegration of the child and their family into
society. Nevertheless, it’s crucial to acknowledge that further data is
required to firmly solidify these conclusions.
These two cases represent the first instances of off-labelVemurafenib use in Brazil, and both cases have shown excellent responses
to the medication. However, the long-term safety and efficacy of VMF in
children with histiocytosis require further investigation. Prospective
studies are essential to address critical aspects, including
histiocytosis pathophysiology, the sufficiency of Vemurafenib as a
standalone treatment in cases with BRAF mutations, and the consideration
of targeted therapy as a chronic treatment option.