CASE REPORT
A 12-year-old previously healthy Hispanic male initially presented with two weeks of fever, fatigue, and weight loss. Initial labs showed leukocytosis of 549,000 cells/mcL with 96% B-lymphoblasts (CD45 dim+, CD34+, CD19+, CD10+, CD20+, HLADR+, CD9+, CD22+, CD24+, CD38+, CD58+, cytoCD79a+, cytoCD22+, and TdT+). Fluorescent in situ hybridization (FISH) revealed a cryptic translocation Y;14 resulting inCRLF2::IGH rearrangement, consistent with a diagnosis of Ph-like B-ALL. Further molecular analysis detected a KRAS G12D mutation but was negative for other mutations. Due to age, elevated WBC, and CNS3 disease, he was classified high-risk and treated with a standard four drug induction chemotherapy regimen (prednisone, vincristine, daunorubicin, and pegaspargase) and weekly intrathecal methotrexate as previously published.12 At end of induction, he was in morphological remission but had minimal residual disease (MRD) of 0.02% by flow cytometry. Consolidation chemotherapy was started with cyclophosphamide, cytarabine, mercaptopurine.
During consolidation, he developed numerous reddish nodules on his face and scalp that were biopsied (Figure 1A). Immunohistochemical analysis demonstrated histiocytic proliferations positive for CD68 and Factor XIIIa and negative for CD1a, S100, and BRAF V600E (Figure 2), consistent with JXG. Due to persistent non-neutropenic fever with anemia and thrombocytopenia, consolidation chemotherapy was held, and repeat bone marrow (BM) biopsy showed 18% B-lymphoblasts by flow cytometry. He received two doses each of vincristine and low-dose IV methotrexate in preparation for leukapheresis for potential chimeric antigen receptor T-cell therapy which could not be performed due to rapid clinical deterioration with fever, cytopenias, low fibrinogen, high ferritin, and elevated soluble IL-2R consistent with secondary HLH. He started on dexamethasone and anakinra. Computer tomography (CT) demonstrated hepatosplenomegaly with numerous small, ill-defined hypodensities in the spleen,liver (Figure 1B) and an additional pulmonary lesion. A repeat BM biopsy showed disseminated JXG but absent B-lymphoblasts by flow cytometry (<0.01%). Somatic gene sequencing of cutaneous JXG was significant for two variants activating MAPK pathway (BRAF G469R and KRAS G12D) as well as an MTOR S2215Y variant. Germline genetic testing was negative.
As patient’s B-lymphoblasts and JXG cells shared the KRAS G12D mutation, we decided to target the MAPK pathway using the MEK inhibitor (trametinib) while the patient was critically ill. With initiation of trametinib, patient’s clinical status rapidly improved including hematopoietic recovery along with improvement of cutaneous and systemic JXG lesions by exam and imaging (Figure 1C). He received a course of blinatumomab with trametinib followed by TCR alpha beta/CD 19 depleted maternal haploidentical hematopoietic cell transplant (HCT) with a conditioning regimen of total body irradiation with cranial boost, cyclophosphamide, thiotepa, and rabbit anti-thymocyte globulin. Follow-up BM biopsies showed decreasing NGS MRD positivity to a low of 4 dominant clonal cells per million nucleated cells (Figure 2H). The patient was in continuous remission of ALL, HLH, and JXG, until his death 300 days after HCT due to multiorgan injury, severe hemorrhagic shock from gastrointestinal bleeding and disseminated polymicrobial infections secondary to complications of steroid refractory graft-versus-host disease (GVHD).