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.