Can targeted therapy improve outcome in Epstein–Barr virus-negative aggressive natural killer cell leukemia: A case report

INTRODUCTION

Aggressive natural killer cell leukemia (ANKL) is a rare hematological malignancy, with only a few cases reported in the literature.^[1] The overall median survival is estimated to be less than 2 months.^[2] Moreover, Epstein–Barr virus (EBV)-negative ANKL is a rarity, with only a few being EBV-negative.^[3] The diagnosis of this disease poses difficulty, and treatment is challenging. This article aims to report a rare EBV-negative ANKL patient successfully managed with an unconventional regimen.

CASE REPORT

The patient is a 27-year-old male with no previously known comorbidities. He presented initially with a fever of 1-week duration, loss of appetite and 14 kg weight loss over 2 months. His physical examination revealed mild pallor, icterus, hepatomegaly (4 cm), and massive splenomegaly (10 cm below the left subcostal margin). No skin lesions were seen, and no palpable lymph nodes were noted. His laboratory investigations are given in Table 1.

Bone marrow (BM) revealed the presence of few atypical lymphocytes. Flow cytometry (BM aspirate) showed abnormal lymphocytes, gated at 13% of all leucocytes, showing moderate expression of CD16, CD38, CD2, and CD45 and moderate to dim CD56. These lymphocytes showed dim expression of CD7 and CD117, variable cytoplasmic CD3, and were negative for surface CD3, T-cell receptor (TCR) alpha beta and TCR gamma delta, CD4, CD8, and CD5. Myeloid markers CD13, CD33, CD64, and markers for blastic plasmacytoid dendritic cell neoplasm CD123 were also negative. Immaturity markers, including HLA-DR, CD10, CD1a, CD34, and Tdt, were negative [Figure 1]. BM biopsy revealed interstitial infiltration of CD56 and CD2-positive atypical lymphocytes with no expression of Tdt.

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Figure 1:

Representative flow cytometry plots showing moderate expression of CD45 and CD38; moderate to dim CD56, dim CD7 and CD117; positive for cytoplasmic CD3 and negative for surface CD3, TdT, CD34, CD33, CD123, and myeloperoxidase.

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Based on findings of BM biopsy, flow cytometry, negative Epstein–Barr encoding region – in situ hybridization, and EBV deoxyribonucleic acid, a diagnosis of EBV-negative natural killer (NK) cell leukemia/lymphoma was made. The modified SMILE (dexamethasone, methotrexate, ifosfamide, etoposide, and L-asparaginase) regimen was started as first-line therapy. A contrast-enhanced computed tomography (CECT) done after two cycles of the SMILE regimen showed disease progression. There was an increase in the size of the liver and spleen, with compression of the left kidney. The retroperitoneal lymph node enlargement was also evident. In view of the progressive disease, the CHOP treatment regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) was started. However, the disease response to this regimen was also not satisfactory, and disease progression was noted in CECT after the first cycle of the CHOP regimen. Due to the rapid progression of the disease with conventional treatment, it was decided to use daratumumab (anti-CD38 monoclonal antibody) along with CHOP regimen. The patient received eight cycles of the CHOP regimen and six cycles of daratumumab. The patient attained complete remission, with regression of hepatosplenomegaly, lymphadenopathy, and normal hematological and biochemical investigations at the end of the regimen. BM flow cytometry was negative for measurable residual disease. The patient has survived for more than 24 months after diagnosis and is presently on follow-up on maintenance daratumumab, awaiting allogenic hematopoietic stem cell transplant.

DISCUSSION

ANKL is a rare yet fulminant hematological malignancy of mature NK cells. It usually affects the younger age group; however, EBV-negative ANKL tends to occur in the elderly with a median age of 63 years.^[3] The commonly involved sites are BM, peripheral blood, liver, and spleen. The usual clinical features are fever, hepatomegaly with hepatic dysfunction, hemophagocytosis, and disseminated intravascular coagulation. The disease has a rapidly progressive course spanning over weeks or sometimes months. The diagnosis of ANKL is challenging and sometimes delayed due to non-specific clinical features and the presence of fewer tumor cells in peripheral blood or BM.

Etiologically, ANKL has been associated with EBV. However, EBV-negative ANKL is also a well-recognized entity with a debatable prognosis.^[3,4] The present case was also EBV negative but had immunophenotypic markers of mature NK cells such as CD56, CD7, and CD2. Other CD56-positive hematolymphoid neoplasms were excluded to confirm the diagnosis.

Due to the rarity and aggressive nature of the disease, there is no high degree of evidence to formulate a most effective chemotherapeutic regimen. L-asparaginase-based regimens are usually first-line therapy. Other regimen includes CHOP (with anthracycline and vincristine) and hemophagocytic lymphohistiocytosis-04 (containing dexamethasone and etoposide). Targeted therapy with a monoclonal antibody against CD38 (Daratumumab) has been utilized with gleaming prospect, but still is not standard of care.^[5,6]

In the present case, daratumumab was utilized as a salvage therapy for progressive disease under the SMILE and CHOP regimen. The combination of daratumumab with the CHOP regimen resulted in excellent disease remission.

CONCLUSION

A rare case of EBV-negative ANKL is presented here. Despite the poor prognosis of the disease and the patient being refractory to two standard treatment regimens, the addition of daratumumab resulted in disease remission and increased survival of the patient. Hence, further studies are warranted for targeted therapy in fulminant diseases like ANKL.