CHARACTERIZATION OF TREATMENT PARADIGMS FOR PEDIATRIC LANGERHANS CELL HISTIOCYTOSIS Tania P. 1
1 Mamdouhi ,
Christine S.
2 Lai ,
Shaun D.
1,2 Rodgers , Carolyn
Fein
1,2 Levy
Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY | 2 Cohen Children’s Medical Center, New Hyde Park, NY
BACKGROUND Langerhans Cell Histiocytosis (LCH) is a myeloproliferative neoplasm of pathologic dendritic cells. This rare histiocytic disorder varies substantially in presentation, organ involvement and genetic variations. LCH pathogenesis is poorly understood, making treatment determination difficult. Although presence of a BRAF V600E mutation is the most common genetic aberration, other variants in BRAF, MAP2K1 and MEK have also been observed. Therapeutic strategies are often rooted in BRAF V600E mutation status and disease stratification into unifocal (UF), multi-focal (MF), single-system (SS), multisystem (MS), risk-organ involvement and CNS-involved LCH. Specific organ involvement and extent of disease seems to play a large role in disease recurrence and response to specific therapies. Liver, bone marrow and/or spleen involvement is denoted as a ‘risk-lesion’ with higher rates of mortality. Similarly, CNS-risk lesions (Image 1) (mastoid, sphenoid, orbital or temporal bone involvement) have an increased risk for development of neurodegenerative (ND) LCH. In this retrospective analysis, we will correlate patient outcomes, extent of disease and mutation status with the treatment paradigm used in order to gain a better understanding of how to effectively treat LCH in diverse pediatric populations. HYPOTHESIS Retrospectively stratifying pediatric LCH patients based upon organ involvement, presence of BRAFV600E mutation and extent of disease will will clarify which treatment paradigms should be standard of care for certain LCH populations. METHODS LCH pediatric patients treated at Cohen Children’s Medical Center are currently being enrolled in the “A Vital Tool for the Study of Pediatric Oncology Rare tumor and Sarcoma (PORTS)” registry (IRB: #19-0246-CCMC). To date, 28 patients have consented for enrollment. Data was stored using a REDCap database. Some participants were treated for LCH before genome-wide sequencing was readily available and thus were only tested for BRAFV600E positivity. IMAGE 1
RESULTS Of the 28 participants, 15 (53.6%) have SS-UF disease, 6 (21.4%) have SS-MF disease and 7 (25.0%) have MS disease (Figure 1). 16 participants (46.4%) have CNS risk involvement, which includes presentation with neurodegenerative (ND) LCH. Two BRAF mutations, V600D and N486_T491>S, were identified, which have been mentioned only briefly in other reports on LCH.1-4 MAP2K1 variants are often noted as the second most common mutant in LCH populations, with a rate around 25%.5, 6 Treatment regimen, disease stratification and response are depicted in Figure 2. When correlating treatment regimen with BRAF V600E mutation status, high rates of relapse were observed. Out of 8 BRAF V600E positive patients, 3 received surgery plus primary chemotherapy with 1st induction of Vinblastine/Prednisone and 2 received only chemotherapy with 1st induction Vinblastine/Prednisone. All 5 of these participants relapsed. 2 BRAF V600E patients were placed under observation only and neither relapsed. One BRAF V600E positive patient was lost to follow-up after transfer of care. 4 patients (14.2%) progressed to ND LCH; 2 harbored BRAF V600E mutations and 2 were confirmed BRAF V600E negative. 2 patients had presence of risk-organ involvement; one with a BRAF V600E mutation and one with a PD-1 mutation. FIGURE 1 Figure 1: Genetic mutation status distributed by disease stratification. MAP2K1 mutants include Q58_E62del, Q56_G61>R, E102_I103del, Q56P. Other mutants not mentioned: ATMR2486, CUX1 G870_G871insSGG.
FIGURE 2: Treatment paradigm based on disease stratification.
CONCLUSION Of the participants that had genetic analysis results, 50% were identified BRAF V600E positive which aligns with previous statics on BRAF V600E positivity in LCH.5 BRAF V600E mutations have been shown to correlate with more aggressive disease, significant risk organ involvement, higher reactivation risk and lower response to first line vinblastine-steroid combination therapy.7 In our report, there was an equal number of BRAF mutant participants (V600E, V600D, or N486_T491>S) with SS disease (5) and MS disease (5). Of the 8 with BRAF V600E mutations, 62.5% relapsed despite treatment with surgery and/or chemotherapy. However, due to small sample size, statistical significance of this finding could not be determined. 2 out of 8 BRAF V600E positive patients did not relapse; interestingly these patients were placed under observation only, one with SS,UF bone lesion and the other with SS,UF skin lesion. Spontaneous disease regression is seen most in BRAF wildtype SS,UF skin lesions, making both cases rather unique.7 FUTURE DIRECTION Data currently suggests BRAF-V600E significantly increases likelihood of treatment failure or disease reactivation, however prospective validation is needed to determine the exact effect this mutation has on clinical outcome.8 Although our data seems to show a similar trend, lack of statistical analysis due to small sample size limits our ability to ascertain a relationship. Analyzing outcomes of therapeutic strategies could clarify clinical decision making for specific pediatric LCH populations, especially those that are BRAF V600E negative. Future work will be focused on increasing patient recruitment to allow for statistical analysis of results. REFERENCES
Image 1: CNS Risk Lesion of the frontal bone before surgery (left) and during surgical resection (right).
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