Therapeutic response of metastatic angiomatoid fibrous histiocytoma carrying EWSR1-CREB1 fusion to the interleukin-6 receptor antibody tocilizumab

Abstract

Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumor that has been associated with EWSR1-CREB1 gene fusion. Outcome in patients with unresectable distant metastases is generally fatal. Interleukin-6 (IL-6) secretion has been described in tumors with EWSR1-CREB1 fusion, and may promote tumor growth due to autocrine stimulation. Tocilizumab is an IL-6 receptor antibody that has potential benefit as a targeted therapy in refractory neoplasms with IL-6 secretion. We describe a child with metastatic AFH with EWSR1-CREB1 fusion and elevated IL-6 whose disease progressed during treatment with traditional chemotherapeutic agents, but improved after targeted therapy with tocilizumab.

1 |. INTRODUCTION

Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue neoplasm that typically presents in the extremities of children and adolescents. First described by Enzinger as angiomatoid malignant fibrous histiocytoma in 1979, its name was later revised due to its generally indolent nature.¹ Metastases to regional lymph nodes and/or lung are uncommon and described in less than 5% of patients,^1,2 and associated with poor prognosis. Complete surgical resection of both the primary tumor and metastatic sites is essential for cure; cases with unresectable and disseminated disease are generally terminal.³ Despite systemic therapy, most patients with distant metastases die of the disease.⁴

AFH is associated with three characteristic gene fusions—EWSR1-CREB1, EWSR1-ATF1, and FUS-ATF1. EWSR1-CREB1 is the most common of these fusions and has been reported in up to 90% of cases.⁵ At present, no available therapies are effective in targeting these EWSR1 and FUS fusions, and therefore we searched for alternative therapeutic strategies targeting vulnerabilities associated with this molecular alteration in AFH. Interleukin-6 (IL-6) secretion has been described in tumors with EWSR1-CREB1 fusion and may promote tumor growth due to autocrine stimulation.^6,7 Additionally, it has been suggested that increased IL-6 may cause paraneoplastic syndrome characterized by fever, malaise, and anemia.^6,7 Tocilizumab is an IL-6 receptor antibody that has potential benefit as a targeted therapy in refractory neoplasms with IL-6 secretion. We report a 3-year-old child with DiGeorge syndrome and metastatic AFH harboring EWSR1-CREB1 fusion who achieved partial response to targeted therapy with tocilizumab.

2 |. CASE REPORT

A 3-year-old male with DiGeorge syndrome presented with microcytic anemia, intermittent fever, and a left posterior calf mass that had been present for approximately 1 year. Magnetic resonance imaging showed a 5.6 cm infiltrative mass involving the lateral head of the gastrocnemius with a multiloculated cystic appearance. The biopsied specimen demonstrated features of an infiltrative, bland fibrocollagenous lesion with abundant chronic inflammation and small areas of spindle cell proliferation; EWSR1-CREB1 fusion was detected by reverse transcription polymerase chain reaction, which, in the context of histopathological findings, was consistent with AFH (Supplementary Figure S1). Further imaging found inguinal and pelvic lymph node spread as well as multifocal pulmonary metastasis. The primary tumor was deemed unresectable without above knee amputation due to extensive infiltration of calf muscles.

As a result of systemic involvement, chemotherapy was initiated with vincristine, dactinomycin, and cyclophosphamide with initial improvement and resolution of pulmonary nodules. However, a positron emission tomography (PET) scan performed after five cycles showed active disease in the left calf, as well as in the inguinal, pelvic, iliac, and retroperitoneal lymph nodes (Figure 1). Additionally, the child had a number of adverse effects from the chemotherapy, including bone marrow suppression that, in combination with his underlying illness, resulted in 10 transfusions of packed red blood cells. During this time, we became aware of two cases of IL-6 secretion associated with AFH—one involving a pediatric patient with EWSR1-CREB1 fusion with paraneoplastic symptoms caused by IL-6 production that resolved after tumor excision, and the other an adult patient with an unclassified malignancy associated with high IL-6 production (subsequently classified as AFH) whose symptoms improved using tocilizumab, an IL-6 inhibitor.^6,7

FIGURE 1.

PET Imaging; (A) pre IL-6 inhibitor treatment (after five cycles of traditional chemotherapy); (B) post 21 cycles of tocilizumab

Serum inflammatory cytokines were subsequently tested, revealing an elevated IL-6 level, as well as increased erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and ferritin (Table 1). Treatment was initiated with 10 mg/kg tocilizumab every 4 weeks. Two weeks after treatment initiation, ESR and CRP normalized and anemia improved without further need for transfusion. After five cycles of tocilizumab, a PET scan showed decreased fluorodeoxyglucose (FDG) uptake in the lower extremity mass as well as in the inguinal lymph nodes, with no new areas of metastatic disease. Serum IL-6 was further elevated, suggesting blockage of the IL-6 receptor by the antibody.

TABLE 1.

Laboratory value trends during treatment course

Lab values	Ref. range	Pretxt	Postchemo	Post cycle 1 IL-6 Ab	Post cycle 5 IL-6 Ab	Post cycle 10 IL-6 Ab	Post cycle 21 IL-6 Ab	2 months off therapy	3 months off therapy	Post cycle 22 IL-6 Ab
Hgb (g/dl)	11.5–14	7.4	8.6	11.1	10.8	10.9	11.7	8.3	6.7	10.0
ESR (mm/hr)	0–20	129	116	22	15	7	4	106	91	9
CRP (mg/dl)	<1.0	12.8	22.6	<0.5	<0.5	<0.5	<0.5	8.9	7.1	<0.5
Ferritin (ng/ml)	10–60	499	1,850	1,540	–	391	–	–	–	–
IL-6 (𝜌g/ml)	≤5	–	76	56	263	300	364	45	–	175

Ref., reference; Pretxt, pretreatment; Postchemo, postchemotherapy; IL-6, interleukin-6; Ab, antibody; Hgb, hemoglobin; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein.

Tocilizumab was increased in frequency to every 3 weeks, as it was well tolerated, and the patient completed 1 year (21 doses) of therapy. Repeat PET scan performed after the patient’s 20th dose showed stable activity within the left upper calf as well as stable to mildly decreased activity in the inguinal and internal iliac lymph nodes. ESR and CRP remained normal, as did hemoglobin (Hgb); IL-6 levels remained elevated (Table 1). At this point, tocilizumab infusions were discontinued as the patient had completed 1 year of therapy was no longer symptomatic.

Follow-up after 2 months off therapy showed an increase in ESR and CRP, as well as a decrease in Hgb, although on physical examination there was no increase in the size of the calf mass or inguinal lymphadenopathy (Table 1). At 3 months off therapy, the patient had worsening anemia (Hgb 6.7) with a decrease in reticulocyte count; therefore, treatment with tocilizumab was re-initiated with the decision to begin at an interval of every 2 weeks due to the severity of symptoms. Once again, after a single treatment the patient’s ESR and CRP normalized. Currently, the patient is doing well on tocilizumab, which has been spaced to every 4 weeks without any adverse events.

3 |. DISCUSSION

We report a clinical response to tocilizumab, an IL-6 receptor inhibitor antibody, in a child with treatment-refractory metastatic AFH with EWSR1-CREB1 fusion and elevated serum IL-6. Clinical response to this precision oncology approach was rapid and dramatic, with resolution of paraneoplastic symptoms and normalization of anemia and CRP after only a single dose of tocilizumab. Moreover, the treatment was well tolerated without adverse side effects.

The pathogenesis of tumoral cytokine production as a result of EWSR1-CREB1 fusion is thought to be related to the nature of the chimeric protein. The EWSR1 protein is a member of the TET family (whose members contain characteristic COOH-terminal RNA-binding domains) that likely acts as an adapter between transcription and RNA processing.^6,8 The CREB1 protein is a transcription factor that plays a role in the regulation of cell differentiation, proliferation, and survival.⁸ The EWSR1-CREB1 fusion gene results in continuous activation of CREB1 motifs which upregulate IL-6 production.⁶ It has been postulated that IL-6 in AFH may function as an autocrine growth factor, as observed in other malignancies such as prostate cancer and multiple myeloma.^7,8 If so, this would explain why tocilizumab therapy treated both the patient’s paraneoplastic symptoms and his malignancy.

The sustainability of this response and required duration of tocilizumab therapy are unclear. In this case, we attempted to discontinue tocilizumab after 1 year; however, the disease reactivated within 3 months. We suspect that this patient may continue to need this therapy for months to years to come, similar to the treatment of children with systemic juvenile idiopathic arthritis.

For pediatric patients with metastatic EWSR1-fusion-driven AFH and elevated IL-6 levels, treatment with tocilizumab may be considered as a salvage regimen. Additionally, there is some rationale for considering its use either in combination with or in place of traditional chemotherapeutic agents for patients with metastatic AFH with EWSR1-CREB1 fusion, paraneoplastic syndrome, and elevated serum IL-6. While there are case reports of metastatic AFH responding to chemotherapy,⁹ given the high mortality rate of this disease and the risk of significant adverse effects from traditional chemotherapeutic agents, tocilizumab, which is generally well tolerated, may be a suitable alternative. The rarity and specificity of this entity precludes adequately powered randomized clinical trials of tocilizumab for this indication; however, as the EWSR1-CREB1 fusion gene is prevalent not only in AFH, but also in other malignancies (such as pulmonary myxoid sarcoma and clear cell sarcoma¹⁰), this is an area that warrants further investigation.

Supplementary Material

SUPPORTING INFORMATION

Additional supporting information may be found online in the Supporting Information section at the end of the article.

Abbreviations:

AFH

angiomatoid fibrous histiocytoma

CRP

C-reactive protein

ESR

erythrocyte sedimentation rate

Hgb

hemoglobin

IL-6

interleukin 6

PET

positron emission tomography