Page 277 - Haematologica Vol. 107 - September 2022

CASE REPORT
Prolonged remission with pembrolizumab and radiation therapy in a patient with multisystem Langerhans cell sarcoma
Langerhans cell sarcoma (LCS) is an exceedingly rare hematologic cancer with approximately ten to 12 new cases reported in the United States each year.1 LCS is a malignant histiocytic neoplasm that frequently involves the reticuloendothelial system (lymph nodes, liver, spleen) and may spread to the skin, lung, bone, or other soft tis- sues.2 Patients with localized or single-system disease are generally treated with surgical resection or radiation ther- apy and tend to do better than those with multi-system involvement. In patients with multi-system disease, out- comes have been dismal with a 5-year overall survival of only 15%.3 The rarity of this diagnosis has limited our understanding of the disease biology and development of effective treatment. A variety of systemic treatment strat- egies have been used in LCS, most of them adopted from treatment of aggressive lymphomas, such as anthracyc- line- and platinum-based regimens.3,4 However, the treat- ment outcomes published in case reports and case series have been disappointing. The identification of mutations in the mitogen-activated protein kinase (MAPK) pathway in other histiocytic neoplasms, especially Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) have led to the utilization of targeted therapies. Data on the efficacy of kinase inhibitors and immunotherapy in LCS and other malignant histiocytosis are limited. In this report, we present a case of LCS with exquisite response to the immune checkpoint inhibitor (ICI) pembrolizumab and radiation therapy after disease progression on the MEK inhibitor cobimetinib.
A 33-year-old Caucasian female with no comorbidities presented with a sensation of fullness in her abdomen without any associated pain, nausea, vomiting, or other systemic symptoms. CT scan of the abdomen revealed a lobulated soft tissue mass centered within the mesentery measuring 8.6 cm with additional para-aortic adenopathy. F18-fluorodeoxyglucose positron emission tomography– computed tomography (FDG PET-CT) revealed a large right mesenteric mass with a maximum standardized uptake value (SUVmax) of 16.4 along with additional FDG-avid left mesenteric, retroperitoneal, and left supraclavicular lymph nodes. The spleen size was normal but showed mild, diffuse FDG uptake, possibly suggestive of involve- ment by LCS. Detailed laboratory evaluation at baseline was unremarkable. CT-guided core biopsy of the mes- enteric mass showed a diffuse infiltrate of large pleomor- phic cells with occasional multinucleation, conspicuous
nucleoli, and abundant pale eosinophilic cytoplasm, in- termixed with eosinophils. By immunohistochemistry, the malignant cells were positive for CD68, CD163 (partial), S100, CD1a (partial), and langerin. They did not express BRAFV600E (VE1), B-cell (CD19, CD20, CD79a, PAX5), or T-cell (CD2, CD3, CD43) markers. The morphology and immuno- phenotypic features were diagnostic of LCS. Additionally, a PD-L1 immunostain (clone 22C3, Dako North America Inc., Carpinteria, CA) showed strong membranous staining in 95% of tumor cells (Figure 1). Multigene next-generation sequencing demonstrated several mutations: SETD2 p.Q2362* stop gain-loss of function (LOF), variant allele frequency (VAF) 22.4%; SETD2 c.4715+1G>C splice region variant-LOF, VAF 5.5%; NRAS p.Q61L missense variant (exon 3)-gain of function, VAF 14.6%; TP53 p.R280T mis- sense variant-LOF, VAF 8.5%; SMARCB1 c.629-1G>c splice region variant- LOF, VAF 5.7%; and PTPN11 p.E76K mis- sense variant-LOF, VAF 10.6%. Tumor mutational burden (TMB) was 3.3 m/MB. Bone marrow biopsy showed no LCS. Given the presence of the activating NRAS mutation, single-agent therapy with a MEK inhibitor (trametinib) was initiated at a dose of 2 mg orally (p.o.) daily. Unfortunately, restaging studies in 2 months demonstrated radiographic progression with new FDG avid lymph nodes in bilateral cervical region along with progression in the dominant right mesenteric mass and a new omental nodule (Figure 2A). Because of the high PD-L1 expression on the tumor specimen, pembrolizumab monotherapy at a dose of 200 mg intranvenously (i.v.) every 3 weeks was initiated. Two months after initiation of pembrolizumab therapy, PET-CT demonstrated stable disease in the large right-sided mes- enteric mass with normalization of the FDG uptake in the bilateral cervical adenopathy and improvement in the FDG avid omental nodule (Figure 2B). After this initial response, imaging 4 months post pembrolizumab revealed slight in- crease in size of the right mesenteric mass from 7.5 cm x 5.8 cm x 8.6 cm to 9 cm x 8.7 cm x 10.5 cm, along with in- crease in the size of the left sided mesenteric nodule with SUVmax increasing from 4.8 to 10.5 (Figure 2C). Due to the anatomic and metabolic progression, external beam radi- ation therapy to the sites of progressive disease (right mesenteric mass and left mesenteric nodule) was com- pleted utilizing four-dimensional CT planning and de- livered via intensity modulated radiation therapy with daily cone-beam CT localization for total dose of 3,600 cGy over 18 fractions. She continued pembrolizumab mono-
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