To the Editor,
Limited data exist in children regarding the long-term use of agents
inhibiting the RAS/MAP-kinase pathway including both BRAF and
MEK-inhibitors (BRAF/MEKi). We report a 7-year-old girl with low-grade
glioma presenting with BRAF/MEKi induced sarcoidosis/sarcoid-like
reaction (S/SLR).
Our patient’s initial diagnosis at 2-months of age with a BRAF-V600E
mutant hypothalamic-chiasmatic glioma, and her dramatic response to
dabrafenib after failure of chemotherapy were previously
reported1. Progression at 5-years of age mandated
addition of trametinib. Following two uneventful years on dual
BRAF/MEKi, the child presented with significant swelling of her right
eyelid (Fig.1A). Bilateral dacryoadenitis (Fig.1B,C) elevated ACE levels
(115 U/L; normal range: 8-76), and bilateral pulmonary nodules (Fig.1D)
with enlarged bilateral hilar and axillary lymph nodes on CT chest were
suggestive of S/SLR2,3. Though initially started on
antibiotics, she was shifted to prednisone (0.5 mg/kg/day) after
withholding BRAF/MEKi, resulting in complete resolution of symptoms
within 10-days. PET-CT and pulmonary function tests were normal, with no
evidence of additional organ involvement. Work-up for genetic
predisposition did not reveal any deleterious variants in the nucleotide
binding oligomerization domain-2 (NOD2 ) gene. A novel frameshift
variant in the nucleotide-binding leucine-rich repeat-containing
receptor 12 (NLRP12 ) gene (c.654_656delinsAGGA;
p.Ala219Glyfs*27) was detected. This was predicted to cause premature
protein translation and has not been described in population databases.
Within 2-weeks of stopping BRAF/MEKi, there was glioma progression
(Fig.1E) that mandated a carefully considered re-challenge of BRAF/MEKi
with rapid tumor control. Inflammatory biomarkers were closely
monitored, in addition to surveillance for clinical symptom flare.
Persistently elevated ACE (310 U/L) indicating S/SLR burden, and
significantly elevated SAA levels (15,280 ug/ml; normal range:
1000-5000) consistent with subclinical long-term biochemical
inflammation, warranted reinstitution of low-dose steroids (0.1
mg/kg/day) following multi-disciplinary consensus after 6-months of
reinitiating BRAF/MEKi. Interestingly, an elevated SAA level can
upregulate Th17-cell proliferation and cytokine production, and has been
linked to a higher risk of pulmonary fibrosis in
sarcoidosis4. The child is currently doing well on
low-dose steroid, dabrafenib and trametinib.
The immune effects of BRAF/MEKi are increasingly
appreciated5. BRAF/MEKi are associated with increased
intra-tumoral T-cell infiltration, immunogenic antigen expression,
upregulation of HLA class I, suppression of M2-type macrophages, myeloid
derived suppressor cells and T-regulatory cells, and increased TNF-α and
INF-γ levels5,6. Sarcoidosis is a multisystem,
granulomatous disease rarely diagnosed in children2,7.
However, both sarcoidosis and sarcoid-like reactions (that do not
fulfill all the diagnostic criteria) are reported in adults treated for
cancer, most frequently in patients with melanoma treated using
BRAF/MEKi. The reported incidence was 5.7%, and 11% for vemurafenib
monotherapy and dabrafenib/trametinib combination,
respectively8-10. Onset following BRAF/MEKi initiation
was at 9-months (median) (range: 1-21). Most patients had mild
manifestation, with the skin reported as a commonly involved
site8,10. Discontinuation of BRAF/MEKi was not needed
in the majority, except for vital organ involvement. Only one fatality
with granulomatous myocarditis was reported. For those needing
discontinuation, usually lesions resolved soon after stopping BRAF/MEKi
and initiating steroids. Anecdotal reports on re-challenge support that
S/SLR may not always recur on reinitiating
BRAF/MEKi11. Additionally, limited data suggest that
oncologic outcomes of patients who develop S/SLR can be superior to
those without such immune adverse events8.
In drug-induced S/SLR, whether the medication acts as trigger in
patients with genetic predisposition, or exacerbates subclinical
sarcoidosis, or just causes a similar granulomatous reaction, remain
unknown8. In contrast, in young children, early-onset
sarcoidosis is linked to deleterious variants in NOD2 , also
termed caspase recruitment domain–containing protein 15
(CARD15 ), mapped on chromosome 16q122.
Genome-wide association studies in adults have linked sarcoidosis to
multiple genes affecting immune function, including BTNL-2,
C100RF67, ANXA11, XAF1, IL23R and specifically, autophagy-related genes
and two regulatory hubs, mTOR and Rac112,13. Our
patient did not harbor mutations in any of these genes, but did have a
novel frameshift variant in NLRP12 gene. Interestingly,NLRP12 is a negative regulator of innate immune activation and
type-1 interferon production14. The spectrum of the
rare and relatively novel, monogenic NLRP12- related
autoinflammatory disease syndrome has currently evolved beyond the
classical presentation of cold-induced periodic fever, polyarthralgia
and rash14,15. Not only can NLRP12 mutations
lead to varied systemic autoimmune manifestations, reduced NLRP12
expression has been linked to more severe phenotypes of other autoimmune
disorders like lupus in preclinical models16. Though
no reports of S/SLR have been reported, it is intriguing to postulate
whether the novel variant in NLRP12 could have contributed to the
risk of a drug-induced S/SLR in our patient.
In conclusion, to the best of our knowledge, no reports exist on
BRAF/MEKi-induced S/SLR in children. In our patient, a very young age of
initiation and prolonged exposure could have exacerbated the risk of
S/SLR, especially in the backdrop of a possible genetic aberration
involving the innate immune pathway. She had to be restarted on her
oncologic treatment following the well-known phenomenon of rebound
glioma growth after sudden termination of BRAF/MEKi17.
Subclinical inflammation mandated prolonged treatment with low-dose
steroids. These observations highlight that pediatric oncologists need
to be aware of relatively rare, immune toxicities that may manifest in
young children following prolonged therapeutic exposures and may need
complex multi-disciplinary management. Collaborative studies are needed
to optimize a weaning strategy for targeted therapies, including use of
combinatorial approaches, to mitigate such long-term immune toxicities.