Efficacy of BRAF‐Inhibitor Therapy in BRAF^V600E‐Mutated Adult Langerhans Cell Histiocytosis

Abstract

Langerhans cell histiocytosis (LCH) is a rare histiocytic neoplasm. To date, there is a lack of U.S. Food and Drug Administration–approved treatments in adult LCH to establish optimal first‐line therapy. We conducted a retrospective, single‐center case series evaluating the use of BRAF inhibitors in adult patients with BRAF ^V600E‐ LCH proven by biopsy. Our case series is the first to report the use of BRAF inhibitors as first‐line therapy in adults with LCH. We also report the efficacy with single‐agent dabrafenib in adult LCH. All but one of our patients had favorable response to targeted therapy.

Short abstract

Optimal first‐line treatment for Langerhans cell histiocytosis (LCH) has not been established. This case series evaluates the use of BRAF inhibitors in adult patients with LCH.

Background

Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder, which is characterized by aberrant function and differentiation or proliferation of cells from the monocyte‐macrophage lineage. On immunohistochemical studies, the Langerhans cells are characterized by expression of CD68, S100, CD1a, and langerin [1].

To date, there is a lack of U.S. Food and Drug Administration–approved treatments in adult LCH to establish optimal first‐line therapy. Conventional first‐line treatment options for multisystem LCH or single‐system, multifocal LCH include but are not limited to low‐dose cytarabine, cladribine, vinblastine, and prednisone [2]. However, the responses to systemic chemotherapy are not universal, and its use can be limited by toxicities, including a higher risk for second primary malignancies. Molecular studies have revealed BRAF ^V600E to be present in over 50% of LCH cases [3]. Among patients with BRAF ^V600E‐mutated LCH, targeted therapy with BRAF inhibitors represents a novel therapeutic approach. A phase II trial reported four patients with relapsed LCH who were treated with vemurafenib; one patient had a complete response, whereas three had partial responses, as assessed by RECIST [4]. Other data on use of BRAF inhibitors are derived from single case reports of relapsed and refractory LCH [5, 6]. There is also a case report of an adult patient with relapsed or refractory disease who responded to dabrafenib and trametinib after progression from vinblastine and prednisone [7]. However, there is a paucity of literature for the use of BRAF inhibitors as first‐line therapy. The aim of our study was to describe our clinical experience with off‐label BRAF inhibitors as first‐ or subsequent‐line therapy in adult LCH.

Materials and Methods

This is a retrospective, single‐center case series evaluating the use of BRAF inhibitors in adult patients with biopsy proven BRAF ^V600E mutated LCH. A waiver of informed consent and approval of the study was obtained from the Institutional Review Board at the Mayo Clinic. The records of all adult patients with LCH who were seen at the Mayo Clinic from June 2012 to June 2019 were retrospectively reviewed. The diagnosis of LCH was determined by clinical criteria in conjunction with histopathologic findings [1]. Among 77 adult patients with LCH who were evaluated during the study inclusion period, 49 patients (64%) underwent BRAF ^V600E testing. Of these, 28 patients (57%) had this mutation. BRAF ^V600E was determined by immunohistochemistry (n = 20), polymerase chain reaction (PCR; n = 6), and digital droplet PCR (n = 2). [¹⁸F] fluorodeoxyglucose positron emission tomography‐computed tomography (F‐FDG‐PET‐CT) was the imaging study used prior to starting BRAF inhibitors for staging and afterward for response assessment. Magnetic resonance imaging (MRI) of the brain was used to assess central nervous system (CNS) response. For assessment of treatment response, we used the criteria that have been previously described based on imaging studies [4, 8]. Radiologic responses were categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease. The CTCAE version 5.0 was used to assess adverse events [9].

Results

Six patients were treated with a BRAF inhibitor and were included in the study. The median time on therapy was 11.2 months (range, 4–27). Four patients received a BRAF inhibitor as first‐line therapy. Two patients received BRAF‐inhibitor therapy as second‐line therapy. Of the six patients, three (50%) were treated with vemurafenib monotherapy and three had dabrafenib monotherapy.

Our cohort had the following baseline characteristics: median age at diagnosis of 44 years (range, 33–69), male sex (n = 3, 50%), and white race (n = 6, 100%). The most common sites of involvement were the skeletal system (n = 5, 83%) and CNS (n = 4, 67%). CNS involvement occurred as pituitary (n = 3) and midbrain (n = 1) masses. Other sites of LCH involvement included nodal (n = 2), cutaneous (n = 2), adrenal (n = 1), biliary (n = 1), marrow (n = 1), cardiovascular (n = 1), pancreatic (n = 1), renal (n = 1), hepatic (n = 1), pulmonary (n = 1), and splenic (n = 1). Five patients (83%) had multisystem involvement, whereas one had multifocal skeletal disease. Previous treatment included two patients who received cladribine (n = 2) and one patient who underwent resection of a parietal lesion. All patients had FDG‐PET‐CT prior to initiation of BRAF inhibitor. The median time to the first FDG‐PET‐CT after starting BRAF‐inhibitor therapy was 3.3 months (range, 3–5).

The following best responses were observed: CR (n = 2, 33%), PR (n = 3, 50%), and SD (n = 1, 17%) (Table 1). The median time to best response on FDG‐PET‐CT was 4 months. At 3 months follow‐up, CNS responses were observed via brain MRI imaging (Fig. 1A, B). The median follow‐up duration from starting BRAF inhibitor was 13 months (interquartile range, 9–36), and four (67%) patients were alive at the date of last known follow‐up (Fig. 1C). Two patients died during the follow‐up period, and causes of death were bacterial pneumonia in patient 1 and sclerosing cholangitis in patient 3. Patient 3 had LCH involvement of the skin with the BRAF ^V600E. This patient was subsequently initiated on vemurafenib, and at 5 months follow‐up, the patient was noted to have improved skin lesions. However, he developed sclerosing cholangitis depicted by magnetic resonance cholangiopancreatography and a biopsy of liver was performed. The liver biopsy did not reveal evidence of LCH but showed evidence of biliary tract obstruction, including mixed portal inflammation, bile duct proliferation, and bile ducts with reactive epithelial changes. Immunohistochemical studies for BRAF ^V600E, CD1a, langerin, and immunoglobulin G4‐related disease were negative.

Table 1.

Characteristics of adult patients with Langerhans cell histiocytosis on BRAF inhibitors

Case‐Sex	Age, yr	Organs involved	Prior treatment	BRAF inhibitor	Starting dose	Final dose	Best response at last follow‐up	Modality for response assessment	Time on therapy, mo	Toxicities, grade	Discontinued? (Subsequent therapy)	Alive/dead
1‐M	60	Adrenal, CV, kidney, lung, LN, pancreas, pituitary, skin, spleen	Cl; Cy	V	960 mg b.i.d.	960 mg b.i.d.	SD	18F‐FDG‐PET‐CT, MRI brain	4	None	N	Dead
2‐F	45	Bone	None	V	480 mg b.i.d.	480 mg b.i.d.	CR	18F‐FDG‐PET‐CT	9	Cutaneous (I)	Y (Cl)	Alive
3‐M	71	Bone, marrow, liver, skin	Cl	V	480 mg b.i.d.	720 mg QD	PR	18F‐FDG‐PET‐CT	27	Arthralgias (II)	N	Dead
4‐F	42	Bone, pituitary	Resection	D	75 mg b.i.d.	75 mg b.i.d.	PR	18F‐FDG‐PET‐CT, MRI brain	13	None	N	Alive
5‐M	35	Bone, LN, pituitary	None	D	75 mg b.i.d.	75 mg b.i.d.	CR	18F‐FDG‐PET‐CT, MRI brain	10	None	N	Alive
6‐F	33	Bone, brain	None	D	50 mg b.i.d.	50 mg b.i.d.	PR	18F‐FDG‐PET‐CT, MRI brain	12	None	N	Alive

Abbreviations: 18F‐FDG‐PET‐CT, [18F] fluorodeoxyglucose positron emission tomography–computed tomography; Cl, cladribine; CR, complete response; CV, cardiovascular; Cy, cytarabine; D, dabrafenib; F, female; LN, lymph node; M, male; MRI, magnetic resonance imaging; N, no; PR, partial response; QD, daily; SD, stable disease; V, vemurafenib; Y, yes.

Figure 1.

Efficacy of BRAF inhibitor therapy in adults with Langerhans cell histiocytosis. Sagittal contrast enhanced T1 weighted magnetic resonance imaging of the sella turcica before (A) and 3 months after (B) initiation of dabrafenib 75 mg twice daily, demonstrating marked improved enhancement and thickening of the hypothalamus (brackets) and infundibulum (arrows). (C): Swimmers plot representing time on BRAF inhibitor in months and response rate for each patient. Abbreviation: QD, daily.

A total of four patients had CNS disease. Among the three patients with pituitary disease, two patients were treated with dabrafenib, of which one had a CR and one had a PR, and The third patient with pituitary disease was treated with vemurafenib and had SD (n = 1, 17%). The patient with midbrain involvement was treated with dabrafenib resulting in a PR (n = 1, 17%).

Among the patients who were started on vemurafenib, dosing was initiated at 960 mg twice daily (n = 1, 33%) or 480 mg twice daily (n = 2, 67%), and the median duration of therapy was 9.1 months (range 3.8–26.7 months). Responses while on vemurafenib were CR (n = 1), PR (n = 1), and SD (n = 1), as outlined in Table 1. Dabrafenib was initiated at 75 mg twice daily (n = 2, 67%) and 50 mg once daily (n = 1, 33%). Among these patients, the median duration of therapy was 11.2 months (range, 10.4–11.2). Responses at last known follow‐up while on dabrafenib were CR (n = 1) and PR (n = 2) (Table 1).

BRAF inhibitor‐related adverse effects were seen in two patients (33%), both of whom were on vemurafenib. One patient had a dose reduction of vemurafenib from 480 mg b.i.d. to 720 mg daily because of CTCAE grade 2 arthralgias, whereas another patient had to discontinue therapy because of CTCAE grade 2 maculopapular rash and was later treated with cladribine. None of the patients on dabrafenib experienced drug toxicities requiring dose reductions. Patient #4 was diagnosed with melanoma of the left scapular skin 18 days after starting dabrafenib. Two months following initiation of dabrafenib, the patient was found to have another melanoma lesion of the right upper paraspinal back skin. Both skin lesions were successfully treated with surgical resection.

Discussion

Our case series is the first to report the use of BRAF inhibitors as first‐line therapy in adults with LCH. Four patients (67%) received BRAF inhibitors as first‐line treatment because of CNS involvement in three patients and severe symptomatic bone disease in one patient. We also report the efficacy with single‐agent dabrafenib in adult LCH. It appears that dabrafenib monotherapy may be better tolerated than vemurafenib monotherapy, as none of the three patients on dabrafenib developed adverse effects necessitating drug interruption, dose reductions, or discontinuation. In the melanoma literature, one study reported that 91% of patients with melanoma treated with vemurafenib experienced grade 2 toxicities. A separate study reported that 53% of those treated with dabrafenib experienced grade 2 toxicities [10, 11]. However, it should be noted that these studies were performed on different populations and there has been no head‐to‐head comparison of vemurafenib to dabrafenib to evaluate for efficacy or tolerability.

All but one of our patients had a response to BRAF inhibitor therapy. The patient with SD developed pneumonia‐induced sepsis and died after 4 months of vemurafenib therapy. One patient who had a cutaneous response developed sclerosing cholangitis 5 months after starting vemurafenib therapy. Although unable to be confirmed, the underlying cholangitis may have been present before the initiation of vemurafenib. It is known that adult LCH patients who develop secondary sclerosing cholangitis have very poor outcomes with a survival of less than 2 years. Case reports have described these patients to be refractory to prednisone and standard chemotherapy treatment [12]. Despite continuing treatment with vemurafenib, our patient had worsening sclerosing cholangitis and eventually died. Interestingly, liver biopsies did not show LCH involvement of the biliary ducts or evidence for BRAF ^V600E. Further research is needed to investigate the association of sclerosing cholangitis and LCH.

The major limitation of our study is that the follow‐up duration of our cohort after initiation of BRAF‐inhibitor therapy was short (∼1 year) and the small sample size. Therefore, we cannot comment on long‐term safety and efficacy and generalizability of these agents in LCH. Continued monitoring of these patients to assess response of treatment would provide further insight into the efficacy of BRAF inhibitors in LCH.

Conclusion

Our findings are consistent with prior reports that BRAF inhibitors are efficacious in LCH [4, 5, 6]. Our case series is also the first to show that dabrafenib monotherapy is well tolerated for adult LCH patients. Responses were seen in all disease sites, including the CNS. Given the near universal response rates with BRAF inhibitors among those with BRAF ^V600E, these agents may be preferably considered in patients with critical organ involvement or severe symptomatic disease where a quick response is desired. One of the challenges with targeted therapies is that they may necessitate indefinite treatment, leading to long‐term toxicities [13]. Further studies are needed to ascertain the role of combined BRAF‐ and MEK‐inhibitor therapy or even combination with chemotherapy agents to achieve sustained remissions with limited duration therapy.

Disclosures

Robert Vassallo: Pfizer, Bristol Myers Squibb, Sun Pharmaceuticals (RF). The other authors indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board