Refractory Extranodal Nasal NK/T-Cell Lymphoma with CNS Involvement Treated with Radiotherapy and Pralatrexate: Case Report
Authors: Enrique Rico 
Published: October 2019

Abstract
Introduction
Peripheral T-Cell Lymphoma represents a clinically and biologically heterogeneous group of Non-Hodgkin's lymphomas. One uncommon subtype is extranodal nasal natural killer (NK)/T-cell lymphoma (ENKL) type which occur worldwide, with a strong geographic predilection for Asian, Central and South American populations from Mexico, Peru, Argentina and Brazil, constituting 5% to 15% of lymphomas in these countries1. The clinical course is aggressive, and the prognosis is poor mainly due to the expression of P-glycoprotein, which actively exports several anticancer agents outside the lymphoma cells2,3. However, in recent years, novel therapeutic approaches improved the response to therapy and survival2. Based on this recent progress, nowadays this subtype is categorized as a lymphoma with intermediate prognosis, but the overall treatment results are not satisfactory4. This report represents the first Mexican case of relapsed ENKL refractory to multiple lines of treatment with successful response to radiotherapy, followed by pralatrexate as monotherapy.
Case
The patient is male, 30 years old with history of nasal congestion for 1 year, refractory to treatment. Who presented with B symptoms, nasal voice and mild malar edema. Imaging by PET showed SUV max of 13.8 in ethmoid, maxillar and sphenoid sinuses with mucosal thickening and septum fracture. Biopsy confirmed ENKL and immunochemistry was positive for CD3, CD20 and CD55.
The initial treatment was made with 3 cycles of CHOEP, followed by 2 cycles of MTX + vorinostat + folinic acid; consolidation therapy with radiotherapy 25 sessions with 50 Gy and 4 cycles of VIPD. Control PET showed tumor reduction of 78% and 3 months later was negative, biopsy was also negative. Three months later presented headache and walking abnormalities. PET showed CNS tumor. Radiotherapy was initiated with whole brain plus sequential focal radiation boost in 20 sessions with 20 Gy; consolidation therapy with 2 cycles of 6 weeks with pralatrexate at 30 mg/m2. The diffusion weighted whole body imaging showed no signs of tumoral activity at any site.
Discussion
The nose and paranasal area including the upper aerodigestive tract are the most commonly affected sites of origin for ENKL, followed by skin and gastrointestinal tract1. In this case initially the patient presented nasal and paranasal disease. The most important issue considering the treatment of ENKL is the expression of P-glycoprotein, which mediates multi-drug resistance. Therefore, CHOP or other anthracycline based chemotherapy usually are not effective for ENKL3. For localized disease, radiotherapy together with chemotherapy is the standard approach. In disseminated ENKL, systemic chemotherapy remains the mainstay of treatment2. However, in recent years, novel agents have been identified for the treatment of ENKL. Chemotherapeutic agents not affected by P-glycoprotein, such as methotrexate4. This is why treatment with pralatrexate was initiated in this patient, representing the first experience in Mexico using pralatrexate on a patient with ENKL. The patient previously was heavily treated and with very poor prognosis due to CNS involvement, additional to the scarce therapeutic options and difficult access to health care system in Mexico. The patient showed favorable and rapid response to therapy. Currently the patient is in remission and waiting for bone marrow transplant. Pralatrexate appears to be a promising agent for consolidation therapy or as bridge therapy for those patients that will undergo on bone marrow transplant. Suzuki R. Pathogenesis and treatment of extranodal natural killer/T-cell lymphoma. Semin Hematol 2014; 51: 42-51Tse E, Kwong YL. How I treat NK/T-cell lymphomas. Blood 201320; 121: 4997-5005Egashira M, Kawamata N, Sugimoto K, Oshimi K. P-glycoprotein expression on normal and abnormally expanded natural killer cells and inhibition of P-glycoprotein function by cyclosporine A and its analogue, PSC833. Blood 1999; 93: 599-606Jaccard A, Gachard N, Marin B, et al; GELA and GOELAMS Intergroup. Efficacy of L-asparaginase with methotrexate and dexamethasone (AspaMetDex regimen) in patients with refractory or relapsing extranodal NK/T-cell lymphoma, a phase 2 study. Blood 2011; 117: 1834-1839

Disclosures
Enrique: Alexion: Speakers Bureau; Janssen: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Mundipharma: Other: Subsidies for the costs of travel to the ASH annual meeting; Bristol-Myers Squibb: Speakers Bureau.