DISCUSSION
To the best of our knowledge, this is the first report of disseminated
JXG in pediatric Ph-like B-ALLwhere identification of a shared mutation
was targeted therapeutically. A few cases of JXG associated with
pediatric B- or T-ALL have been reported in the literature.6,9,13-17 Therefore, there is a lack of understanding
and treatment guidelines about this rare, and complex clinical
condition. As shown in our case and literature, unusual skin lesions
during therapy for leukemia should undergo a timely and thorough workup.
Histiocytoses including JXG frequently contain mutations in the RAS-MAPK
pathway genes that can be therapeutically targeted. Our case is unique
in that the same KRAS G12D mutation was found in both JXG and
B-lymphoblasts, which adds to prior studies suggesting a clonal
relationship between histiocytic disorders and ALL. A similar phenomenon
has been reported in malignant histiocytic sarcoma and Langerhans cell
histiocytosis diverging from prior T or B-ALL precursors that shared
common genetic changes, such as CDKN2A deletion, MYCtranslocation, or RAS mutations.20 Mutations in
RAS-MAPK signaling pathway genes have been identified in a subset of ALL21, especially relapsed or refractory ALL. Whether
trametinib would have a therapeutic benefit for these patients is
unknown. In our patient, this novel approach stabilized him, resolved
HLH, and allowed him to proceed to curative therapies. In addition, the
identical clonal IgH- or TCRγ-gene rearrangements have been reported in
the histiocytic neoplasms and leukemia or lymphomas.22In our patient, the polymerase chain reaction (PCR) for IgH gene
rearrangement was clonal in the skin biopsy of JXG, consistent with a
common clonal origin of patient’s B-ALL and JXG. We were not able to
obtain NGS testing of IgH, IgK and IgL on the skin biopsy; but because
of the known clonal rearrangement of IgH by PCR, we hypothesized that
NGS of IgH, IgK and IgL sequences could be used for MRD monitoring of
both JXG and B-ALL in the BM as previously reported in a single
patient.7 During follow-up, we suspected that the
residual clones identified by NGS were more likely JXG than B-ALL due to
the absence of B-lymphoblasts by flow cytometry based MRD techniques.
In summary, we report the first patient with Ph-like B-ALL complicated
by disseminated JXG due to a shared KRAS G12D who achieved a remission
with targeted therapy using a MEK inhibitor and was able to proceed to
HCT.