Successful Treatment of Macrophage Activation Syndrome and Symptom of Inappropriate Anti- Diuretic Hormone in Chronic Natural Killer Cell Lymphoproliferative Disorder with Cyclophosphamide

Case Report

Ann Hematol Oncol. 2018; 5(4): 1205.

Successful Treatment of Macrophage Activation Syndrome and Symptom of Inappropriate Anti- Diuretic Hormone in Chronic Natural Killer Cell Lymphoproliferative Disorder with Cyclophosphamide

Sarkissian S1*, Siaghai PJ2, Mkhikian H2, Jeyakuma D1 and Rezk S2

1Department of Hematology and Oncology, University of California, USA

2Department of Pathology, University of California, USA

*Corresponding author: Sarkissian S, Department of Hematology and Oncology, University of California at Irvine, USA

Received: May 03, 2018; Accepted: May 30, 2018; Published: June 12, 2018


Chronic natural killer (NK) cell lympho proliferative disorders (LPD) are very rare indolent hematologic disorder. Less than 100 cases have been reported world-wide. The disease is characterized by proliferation of NK cells, that have a CD3-, CD16+, CD56+ flow cytometry signature, and a non-rearranged T-cell receptor γ. Patients can present with cytopenias, macrophage activation syndrome and constitutional symptoms. Differentiation from malignant NK disorders such as aggressive natural killer cell leukemia’s and extra nodal NK/Tcell lymphoma, nasal type, is crucial.

We report the case of an elderly gentleman who presented with a several months history of leukopenia and constitutional symptoms. Diagnostic work-up revealed a Comb’s negative hemolytic anemia, SIADH, macrophage activation syndrome, hyper cellular bone marrow, splenomegaly and extra-nodal disease. His flow cytometry signatures showed a unique CD2+ CD3- CD7+ CD16+ and CD56dim lymphocyte population, which comprised 16% of the total lymphocyte population. T-cell receptor gene γ rearrangement as well as B-cell markers was negative. The patient was refractory to corticosteroid and IVIG therapy. After several months of therapy with oral cyclophosphamide, he showed a robust response with improvement in his symptoms and resolution of his transfusion dependence

Chronic NKLPD is a rare disease and poses a diagnostic and treatment challenge for hematologists. The lack of a clonally marker and indolent nature of the disease make diagnosis very elusive and challenging. While some studies suggest clinical utility of unique molecular and flow cytometry features, the entity remains a diagnosis of exclusion. A lack of randomized clinical trials and biomarkers makes therapeutic decision-making contingent on short case series publications.

Keywords: Macrophage activation syndrome; Chronic natural killer; Cell lymphoproliferative disorder cyclophosphamide


Large granular lymphocytes (LGL) are cytotoxic lymphocytes that play an important role in the innate immune system. Disorders of large granular lymphocytes can be either reactive to an underlying malignancy or autoimmune disease, or a primary clonal disorder. Reactive processes are polyclonal, while malignant processes are monoclonal. In the clonal disorder, the lymphocyte population has a T-cell receptor gene rearrangement in either the α/β orγ/δ configuration. Clonal T- LGL and reactive chronic LGL are defined by a chronic, 6-month, proliferation of LGL cells. T-cell LGL has a CD3+ CD4- CD8+ CD45- CD56± CD57+ phenotype. Chronic NKLPD, has a CD3- CD8+ CD16+ CD56+ CD57- phenotype. Natural killer cell neoplasms lack the T-cell receptor gene rearrangement. The distinction between the 2 entities can be made via flow cytometry and T-cell receptor gene rearrangement. In the setting of an un-rearranged T-cell receptor, diagnosis is made via exclusion [1-11].

In 2008, the World Health Organization, WHO, distinguished 3 different LGL disorders, T-cell LGL, Chronic NKLPD, aggressive NK/T cell leukemia/lymphoma (ANKL) (of which, extra-nodal NK/Tcell leukemia/lymphoma, nasal type, is an entity). Clinical distinction between chronic NKLPD and T-cell LGL can be challenging as they have relatively similar clinical presentation. Mutations in the STAT3 gene have been shown to be a common marker of pathogenesis. While there is no universally validated clonal marker, CD94 (hi)/HLADR+ lymphocyte positivity and lack of Killer Cell Immunoglobulin Receptor (KIR3DL1) expression have been proposed. Given the rarity of chronic natural killer cell lymphoproliferative disorder, only a few case series have been published. The largest registry study, published by the French, showed the following: The presence of constitutional symptoms (30%), autoimmune disease (24%, splenomegaly (14%), recurrent infections (14%), neuropathy (3%). 13% and 11% had a reported prior solid malignancy or hematologic malignancy, respectively. 15% had an autoimmune cytopenia and 51% had a reported neutropenia [12-25].

Given the rarity of Chronic NK cell Lymphoproliferative Disorder, there are no randomized trials helping direct the ideal mode of therapy. Much of the information has been extrapolated from treatment of LGL. Anecdotal data suggests that corticosteroids, cyclophosphamide, and methotrexate may prove to be efficacious. If there is a driver disease such as another neoplasm, infection, or autoimmune disease then the primary disease should be targeted as well. We report the case of a patient with unexplained constitutional symptoms, cytopenias, macrophage activation syndrome, and SIADH who we treated with cyclophosphamide [26-29].

Case Presentation

A 75 years old Caucasian gentleman, who was otherwise in good health, presented to his PCP with complaints of dyspnea on exertion and a dry cough. He was treated for bronchitis with a course of antibiotics with resolution of the cough but without improvement in his respiratory symptoms. Two months later, the patient had a syncopal episode, with work-up revealing a leukocytosis with 16,800 leukocytes (84% Lymphocytes), hemoglobin of 7.8 g/dL and platelets of 264. Further work-up revealed that he had a lactate dehydrogenize of 873 IU/L (91-180), haptoglobin 6.0 ng/mL (16-200), total bilirubin of 1.5 mg/dL (0.1 -1.0) and a negative Coomb’s test. Erythropoietin level was elevated at 76.7 ug/L. Peripheral smear showed numerous large atypical appearing lymphocytes with azurophilic granules suspicious for LGL (Figure 1,2 and 3). There was a high suspicion for macrophage activation syndrome given his Ferritin of 7,358 ng/ mL, triglycerides of 290 mg/dL (‹150) and an elevated Interleukin-2 receptor of 7,250 pg/mL (‹1,032 pg/mL). Viral studies were negative for CMV, EBV and HHV-8. Computed tomography of the abdomen showed a 14 cm spleen, as well as numerous thoracic spine lesions. He underwent a bone marrow biopsy, revealing a hyper cellular marrow with appropriate trilineage hematopoiesis, erythroid hyperplasia and increased natural killer cell-like cells (Figure 4,5 and 6). There was no evidence of active hemophagocytosis on the bone marrow biopsy. Flow Cytometry showed that 70% of the lymphocytes were CD2+, CD7+, CD16+ while negative for CD 3,5,4,8, and 57 (Figure 2 and 3).