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To the Editor:
In the May 2020 issue of Pediatric Blood & Cancer, Dr. Helmig and
colleagues describe a case of an infantile fibrosarcoma (IFS) diagnosed
at 17 days of life and treated successfully
with larotrectinib1, an oral tropomyosin
receptor kinase (TRK) inhibitor targeted against the fusion protein
product of the ETV6-NTRK gene rearrangement identified on genetic
analysis of the biopsy.
We report a similar case of a lower extremity mass in an
ex-36 week male infant that was first noted at birth and thought to be a
hemangioma. The mass continued to grow (Figs. 1A and 1B) and presented
with acute rupture at 37 days of life (Fig. 1C). Due to
extensive bleeding he rapidly deteriorated into hemorrhagic shock
requiring aggressive fluid resuscitation with a massive transfusion
protocol. Emergent direct puncture embolization using hemostatic
slurry was performed by interventional radiology (Fig. 1E) which
successfully controlled the bleeding. MRI revealed a large,
infiltrative, heterogeneous enhancing mass extending from the foot
posteriorly up into the knee measuring 11.4 x 4.8 cm (Fig.
1F), and biopsy revealed a spindle cell sarcoma with a
“hemangiopericytomatous pattern”, possibly representing IFS. While
awaiting molecular confirmation, due to rapid life threatening tumor
growth one cycle of vincristine, actinomycin and cyclophosphamide was
given (Fig. 1G). Molecular analysis confirmed the presence of an
ETV6-NTRK fusion and he was started on oral larotrectinib at standard
dosing of 100mg/m2/dose twice daily. He responded well
to larotrectinib with rapid response to therapy within 2
weeks (Fig. 1H), continued response at 4 weeks (Fig. 1I) and 10 weeks
(Fig. 1J), and near-total resolution of the mass by 19 weeks (Figs. 1K
and 1L). As of this report he is 55 weeks on therapy (14 cycles) with
minimal visible disease with post-sclerotherapy scarring and full use of
the extremity including normal ambulation.
As the previous authors were concerned that their patient was 19 days
old and weighed only 4 kg, they initiated larotrectinib cautiously at a
low dose of 1 mg/kg/dose twice daily. Our case demonstrates that we were
able to safely administer the full dose in a patient who was 50
days old and weighed only 3.35 kg at the time of initiation of
treatment. Furthermore, although our patient presented in critical
condition, upon stabilization of his hemorrhage and one cycle of
bridging chemotherapy, we were able to successfully initiate targeted
therapy. We observed an excellent response to larotrectinib with rapid
regression of the lesion, allowing us to spare the limb and preserve
function. Helmig et al reported a drop in hemoglobin after one week
on larotrectinib, attributed to intra-tumoral hemorrhage. In our
patient’s case, rupture of the tumor preceded onset of therapy,
suggesting that rupture was a natural progression of the disease rather
than a drug effect. They reported significant weight gain and growth in
head circumference on larotrectinib. Although our patient has remained
along the first percentile for weight throughout treatment, we have seen
an enlargement of his head and his head circumference has crossed two
percentile curves. Further investigation regarding a possible connection
to larotrectinib is warranted.
Our case demonstrates the natural history of IFS and the importance of
early recognition of these lesions postnatally to prevent severe
complications. Taken together, these cases highlight the safety and
efficacy of larotrectinib, even in infants in the first months of life.
It is well-tolerated, easy to administer, and allowed for
limb preservation in both cases.