Successful treatment of multiple relapsed–refractory Langerhans cell histiocytosis with cyclosporine

Abstract

Langerhans cell histiocytosis is a rare hematologic disorder and patients who fail first-line treatment have a poor prognosis, and require more intensive treatment. We present an infant diagnosed with multisystem Langerhans cell histiocytosis refractory to multimodal therapy who was successfully treated with cyclosporine. Cyclosporine might be an effective alternative drug as nonmyelosuppressive rescue therapy for multiple relapsed-refractory Langerhans cell histiocytosis that has not achieved remission with cladribine and cytarabine therapy.

Keywords

Langerhans cell histiocytosis cyclosporine relapsed-refractory

Introduction

Langerhans cell histiocytosis (LCH) is a rare clonal disease of the monocyte–macrophage system characterized by uncontrolled proliferation and accumulation of CD1a+/CD207+ dendritic cells due to continuous immune stimulation.¹ The most frequent presenting signs and symptoms of LCH include painful bone lesions and rash. The nonspecific symptoms often become prominent, such as fever, poor appetite, weight loss, fatigue, irritability, and changes in behavior.² LCH is a rare hematologic disorder and patients who fail first-line treatment have a poor prognosis, and require more intensive treatment.

Cyclosporine A (CSA) is a noncytotoxic immunosuppressive agent. Cyclosporine blocks transcription and synthesis of lymphokines such as interleukin-2 and interferon-γ and inhibits cytokine-mediated cellular activation that might contribute to the pathogenesis and progression of LCH.^3,4

We present a case of multiple relapsed LCH that was refractory to conventional chemotherapy drugs and successfully treated with cyclosporine combined with steroid together with literature review.

Case presentation

A 4-month-old boy was admitted to the hospital with skin rashes and swelling in the neck. On examination, he had diffuse erythematous lesions on his skin and enlarged cervical (right anterior cervical 5×4 cm, left anterior cervical 3×2 cm) and axillary lymph nodes (3×3 cm). No hepatosplenomegaly was noticed.

Complete blood count revealed a white blood cell count of 11,500/mm³, hemoglobin 7.2 g/dL, and platelets 345,000/mm³. Peripheral smear showed normocytic normochromic anemia without any atypical cells. Biochemical analysis revealed lactate dehydrogenase level of 548 U/L (100–300 U/L), ferritin level of 418 ng/mL, C-reactive protein of 5.50 mg/dL (0–5 mg/dL), and erythrocyte sedimentation rate of 18 mm/h.

Chest radiography showed bilateral honeycomb appearance of lung. Computed tomography scan of the chest demonstrated a mass measuring 41×32 mm on the left section of the neck, and thymus hyperplasia, widespread frosted glass density, and interstitial calcification and acinar nodules were detected in the upper lobes of both lungs (Figure 1). In addition, multiple lymph node enlargements were determined on bilateral axillary, bilateral supraclavicular, and left lower cervical regions. There was a lytic lesion in petrous bone.

Figure 1.

Computed tomography scan of the chest demonstrated a mass measuring 41×32 mm on the left section of the neck, and thymus hyperplasia, widespread frosted glass density, interstitial clarification, and acinar nodules were detected in the upper lobes of both lungs.

There was no malignant cell infiltration in bone marrow aspiration. An incisional biopsy of skin lesion was performed. On immunohistochemical stains, the neoplastic cells were strongly and diffusely positive for CD1a, langerin, and S100. Based on histomorphologic features and immunohistochemistry, a final diagnosis of multisystem LCH was rendered (Figure 2).

Figure 2.

Histopathology of Langerhans cell histiocytosis.

DAL-HX 90 group C protocol was given, consisting of etoposide (5 mg/kg/weekly for 6 weeks), vinblastine (0.2 mg/kg/wk for 6 weeks), and prednisolone (40 mg/m²/d as a 4-week course, then tapered off over 2 more weeks). At the end of the induction treatment, skin lesions reappeared and new lytic lesions developed in the left femur and right tibia. Treatment was augmented by adding methotrexate (16 mg/kg/wk) to the maintenance treatment of the protocol. At the 42nd week of maintenance therapy, second relapse was determined. Chemotherapy protocol was switched to COP protocol (cyclophosphamide 600 mg/m²; vincristine 1.4 mg/m²; prednisolone 1 mg/kg/d). After 2 cycles of COP treatment, the patient had not achieved remission. He was treated according to the LCH III chemotherapy protocol, consisting of prednisone (40 mg/m²/d as a 4-week course, then gradually decreased over 2 more weeks), vinblastine IV (6 mg /m²/wk for 6 weeks) as initial treatment and 6-mercaptopurine (50 mg/m² by mouth daily until the end of month 12), prednisone (40 mg/m²/d in 3 doses daily days 1–5 every 3 weeks until the end of month 12), and vinblastine IV (6 mg/m²/d, day 1 every 3 weeks until end of month 12) as continuation therapy.

At the 34th week of continuation therapy, the patient presented with severe hypoalbuminemia, pancytopenia, skin rashes, and hepatosplenomegaly. Skin biopsy revealed relapsed LCH. Cytarabine (100 mg/m^2/d) and cladribine (5 mg/m²/d) were given. After 3 cycles, he experienced severe and prolonged myelosuppression for 2 months duration. During the prolonged myelosuppression period, the signs of disease were exacerbated. Cyclosporine (12 mg/kg/d) and prednisolone (1 mg/kg/d) together with IV immunoglobulin replacement therapy were started. The clinical findings regressed gradually in the first month of CSA therapy and treatment was tapered off at 12 months. The patient has been followed up with durable remission for 5 years without any further treatment.

Discussion

Cyclosporine provided prolonged remission in our patient with multiple-relapsed and progressive LCH with no adverse effects during or after CSA therapy. There are limited data regarding CSA treatment for refractory LCH in the literature. Mahmoud et al.⁴ reported that CSA was effective in three newly diagnosed untreated infants with multisystem LCH. All patients achieved partial remission with CSA alone at 2 months. Complete response in all cases was obtained by adding steroids and/or vinblastine. Aricò et al.⁵ assessed the role of CSA as a second-line therapy in children with LCH who had been previously treated with vinblastine and/or etoposide but who were either refractory or had reactivation of disseminated disease. A total of 12 patients were pretreated with chemotherapy including vinblastine and/or etoposide or steroid and received oral CSA (12 mg/kg/d) as a second-line therapy. CSA treatment was found to be associated with clinical response in 8 of 12 patients; however, only 3 patients had a complete response. Five patients had partial response and 3 patients experienced disease reactivation requiring additional CSA courses after a favorable response to the first course. However, experience with CSA treatment in young children is limited.

Severe side effects have not been reported so far. Aricò et al.⁵ reported hypertrichosis and hypertension requiring transient treatment. Our patient experienced hypertrichosis during CSA treatment that disappeared after tapering. Körholz et al.⁶ reported a 4-year-old boy with severe LCH who failed to respond to conventional treatment showed a delayed response to a combination of CSA, VP16, and prednisone. Minkov et al.⁷ evaluated the effectiveness of CSA in multisystem LCH. A total of 10 patients received CSA as a single agent and 16 in combination with vinblastine, etoposide, prednisolone, and/or antithymocyte globulin. Complete response was observed only in 1 patient and partial response was observed in 3 patients receiving only cyclosporine treatment. The authors suggest that CSA combined with other agents appeared to have a slightly better effect than did CSA alone. In addition, they suggested that CSA has limited value in high-risk patients with progressive disease, especially if they have been heavily pretreated. Inconsistent with that, our patient was heavily pretreated with multiple drugs, and complete remission was obtained with CSA and steroid. Similarly, Zeller et al.⁸ reported a 4-month-old girl diagnosed with multisystem LCH with life-threatening pulmonary involvement. She did not respond to conventional therapy, pulmonary involvement progressed, and CSA treatment was given. There was an improvement in her condition during the first week of CSA therapy and the respiratory situation stabilized. Due to disease activation, 6-mercaptopurine and methotrexate were added to the treatment at 9 months. The authors used CSA treatment for 3.5 years, which is the longest duration reported in the literature.⁸ CSA was tapered off at 12 months in our case. Multisystem LCH seems to involve both expansion of the local population of Langerhans cells and cytokine-mediated activation or proliferation of histiocytes and lymphocytes in tissues, so immunosuppressive treatment such as CSA might be efficacious treatment even in relapsed and refractory LCH after cladribine and cytarabine therapy.

In conclusion, we report an infant diagnosed with multisystem LCH refractory to multimodal therapy who was treated successfully with cyclosporine treatment. Cyclosporine might be an effective alternative drug as nonmyelosuppressive rescue therapy in multiple relapsed-refractory LCH that has not achieved remission with cladribine and cytarabine therapy.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Derya Özyörük

References

Emile

Abla

Fraitag

, et al. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood 2016; 127: 2672–2681.

Zinn

Chakraborty

Allen

. Langerhans cell histiocytosis: emerging insights and clinical implications. Oncol J 2016; 30: 122–139.

Fureu

Katz

. The effect of cyclosporin on epidermal cells: i: cyclosporine inhibits accessory cell functions of epidermal Langerhans cells in vitro. J Immunol 1988; 140: 4139–4143.

Mahmoud

Wang

Murphy

. Cyclosporine therapy for advanced Langerhans cell histiocytosis. Blood 1991; 77: 721–725.

Aricò

Colella

Conter

, et al. Cyclosporine therapy for refractory Langerhans cell histiocytosis. Med Pediatr Oncol 1995; 25: 12–16.

Körholz

Janssen

Göbel

. Treatment of relapsed Langerhans cell histiocytosis by cyclosporine A combined with etoposide and prednisone. Pediatr Hematol Oncol 1997; 14: 443–449.

Minkov

Grois

Broadbent

, et al. Cyclosporine A therapy for multisystem Langerhans cell histiocytosis. Med Pediatr Oncol 1999; 33: 482–485.

Zeller

Storm-Mathisen

Smevik

, et al. Multisystem Langerhans-cell histiocytosis with life-threatening pulmonary involvement: good response to cyclosporine A. Med Pediatr Oncol 2000; 35: 438–442.