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).