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Successful Treatment of Macrophage Activation Syndrome in Chronic Lymphoproliferative Disorder of Natural Killer Cells with Cyclophosphamide

Introduction: 

Chronic natural killer (NK) cell lymphoproliferative disorders comprise a rare subgroup of diseases characterized by proliferation of NK cells with expression of CD3-/CD16+ or CD56+ on flow cytometry. Clinically, these patients present with cytopenias as well as fatigue and B symptoms. The diagnosis can be challenging due to frequent lack of a unique clonal marker. Chronic NK cell lymphoproliferative disorder can be differentiated from NK cell leukemia based on the absence of chronic EBV infection. Macrophage activation syndrome (MAS) can occur in the setting of hematologic malignancies. Due to the rarity of this diagnosis, there are no randomized controlled trials to determine the optimal therapy. We report the case of an elderly gentleman whom we diagnosed with chronic NK cell lymphoproliferative disorder, complicated by transfusion-dependent autoimmune hemolytic anemia, and MAS, and who was successfully treated with oral cyclophosphamide.

Case Report: 

In March 2014, a 75 year old Caucasian male, who was otherwise in good health, had a syncopal episode. Two months earlier, he had reported dyspnea on exertion and cough. He was diagnosed with bronchitis and these symptoms resolved with a course of antibiotics. Cardiac work-up was unremarkable. Complete blood count demonstrated white blood count of 16.8K with 84% lymphocytes, with hemoglobin of 7.8g/dL and platelets of 264K. Lactate dehydrogenase (LDH) was elevated at 615 IU/L, haptoglobin was undetectable, total bilirubin was mildly elevated at 1.5mg/dL and a Coomb's assay was negative. The patient had adequate iron stores with 50% saturation and erythropoietin level was 76.7ug/L. CT of the abdomen/pelvis demonstrated mild splenomegaly of 14cm. CT scan also revealed numerous thoracic-spine soft lesions. Bone marrow biopsy revealed a hypercellular marrow with appropriate trilineage hematopoiesis, erythroid hyperplasia and increased lymphocytes which were CD2+ CD7+ CD16+ and CD 56 negative cells as well as negative for T and B cell markers. This lymphocyte population was identified as NK cells and comprised 16% of his cells. The patient's transfusion dependence did not decrease despite oral prednisone. He transferred to our university medical center. Repeat flow cytometry after one month on prednisone demonstrated an increase to 70% of the lymphocytes. Further, there was a high suspicion for macrophage activation syndrome given his ferritin of 7,358ng/mL, triglycerides of 290mg/dL and interleukin-2 receptor of 7,250pg/mL. There was no evidence of active hemophagocytosis on the bone marrow biopsy. He continued on prednisone 60mg daily, and started on cyclophosphamide 50mg daily. His clinical course over the next several months was complicated by recurrent fevers, night sweats, mental status changes, and hyponatremia. Sepsis was ruled out as a cause of his fevers and his mental status changes were attributed to be secondary to hyponatremia and MAS. Work-up of his hyponatremia revealed syndrome of inappropriate antidiuretic hormone secretion (SIADH). After 2 months of treatment, his sodium level and mental status normalized. His cyclophosphamide was increased to 100mg daily and maintained at that dose. He was then tapered off prednisone. This patient's B symptoms of fevers and night sweats abated after several months of this therapy, and his transfusion dependence and underlying MAS resolved. The patient has been maintained on cyclophosphamide 100mg for 11 months and has shown resolution of his lymphocytosis and normalization of his blood counts.

Discussion: 

Chronic lymphoproliferative disorders of NK cells continue to be a difficult group of diseases to recognize. Moreover, this case was further complicated by MAS based on elevated interleukine-2 receptor, triglycerides and ferritin levels in the setting of B-symptoms and liver enzyme elevations. This constellation of factors has not been previously described in the literature. Due to lack of clonal markers in NK cells, the diagnosis is frequently made by exclusion. The patient has done very well on oral cyclophosphamide and prednisone alone. We present this case to increase provider awareness and hopefully allow for improved diagnosis and treatment options in the future.

Disclosures No relevant conflicts of interest to declare.