The treatment of ENKTCL- NT employs chemotherapy plus, where indicated, radiotherapy. Early chemotherapies relied on CHOP (i.e. cyclophosphamide, an anthracycline (primarily adriamycin), vincristine, and prednisolone) or chop-like regimens. These were only marginally successful because, as it was later discovered, the malignant<unk>  cells in ENKTCL-NT over-express multidrug resistance protein 1. This protein exports various molecules, including anthracyclines and vincristine, from its parent cells and thereby renders these cells resistant to adriamycin and vincristine and therefore to CHOP and CHOP-like regimens. Subsequent studies discovered that L-asparaginase <unk>  cells do not express L-asaraginase) and, to a lesser extent, platinum-based antineoplastic drugs (e.g.carboplatin) were active on theses cells. Accordingly, several chemotherapeutic regimens were tested and found to give much better results than previous regimens. However, these regimens have bot undergone phase 3 clinical trials that examine their effectiveness relative to other regimens. The following regimens are recommended by many studies and the European Society for Medical Oncology Clinical Practice guidelines or National Comprehensive Cancer Network: * Localized stage I and 2 diseases are treated with a combination of local radiation followed by DeVIC (dexamethasone, etopoxide, ifosfamide, and carboplatin). Five-year progression-free and overall survival rates with this regimen are 70-72% and 61-63%, respectively. An alternative regimen, termed CCRT-VIDL, combines cisplatin plus radiation followed by etopoxide, ifosfamide, cisplatin, and dexamethasone to give complete response and 5 overall survival rates of 87 and 73%, respectively. * Patients who have a partial response or relapse on this regimen are treated with the SMILE regimen (see below). * Disseminated stage III and IV disease are treated with SMILE, i.e. dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide. The regimen obtains complete response and 5 year overall survival rates of 45 and 47%, respectively. In the United States, pegaspartase is used in place of L-asparaginase. * Patients that have a complete or partial response to this regimen may then treated with an autologous stem-cell transplantation regimen, palliative chemotherapy, and/or experimental drugs. Experimental drugs There are numerous regimens that use non-chemotherapeutic agents to target specific elements known or thought to be involved in the survival of the malignant cells in a significant percentage of ENKTCL-NT cases. The targets should be determined as overexpressed or present in the malignant tissues of each case before treatment. The targets, therapeutic agents, and some phase 1 clinical trials (testing for appropriate dosages, safety, and side effects) and/or phase 2 clinical trials (testing for efficacy and safety) include: * PD1: Program death-ligand 1 (PD-L1) is commonly overexpressed in ENKTCL-NT as an apparent result of EBV infection. Pembrolizumab and Nivolumab are monoclonal antibody preparations that bind to the programmed cell death 1 receptor on lymphocytes thereby blocking the action of PD-L1 in suppressing the anti-cancer actions of these cells. Seven patients with refractory or relapsed ENKTCL-NT had either complete (5 patients) or partial (2 patients) responses to Pembrolizumab and three patients with relapsed ENKTCL-NT had had either complete (2 patients) or partial (1 patient) responses to Nivolumab. A clinical study sponsored by the Memorial Sloan Kettering Cancer Center in New York City is recruiting individuals to study the effects of Pembrolizumab in patients with early-stage ENKTCL-NT; a phase I/II clinical study sponsored by the Abramson Cancer Center of the University of Pennsylvania in Philadelphia is recruiting individuals to examine the effects of Pembrolizumab in individuals with relapsed or refractory ENKTCL-NA; and a clinical phase 2 study sponsored by the University of Hong Kong is recruiting individuals to examine the effects of Pembrolizmab on ENKTCL-NT. * CD30: The malignant cells in ~40% of ENKTCL-NT cases express the surface membrane protein, CD30. Two case reports have indicated that the CD30-targeted monoclonal antibody (which is conjugated to the cytoxic/antineoplastic agent auristatin E, brentuximab vedotin, was helpful in treating relapsed ENKTCL-NT. A not-yet-recruiting study estimated to be finished by Sept., 2018 examines the effects of brentuxixmab vedotin on EBV-positive, CD30-positive lymphomas. * CD38: CD38 is almost always expressed in the malignant cells of ENkTCL-NT. One patient with this disease, after relapsing following each of two chemotherapy courses, had a complete remission when treated with a cytotoxic antibody directed at CD38, Daratumumab. A phase 2 clinical study on the effects of Daratumumab on ENTCL-NT sponsored by Janssen Research & Development, LLC is recruiting patients in China, South Korea, and Taiwan. * EBV antigens: EBV-infected cells express the viral LMP1 and LMP2 proteins on their surface membranes and therefore are potential targets for attack by cytotoxic T cells (CTL). Studies have used CTL that have been engineered to attack and kill LMP1 and/or LMP2 expressing cells. Eleven patients with refractory or relapsed ENKTCL-NT were treated with their own CTL that had been engineered to kill LMP1/2-expressing cells. Nine patients had durable (>4 years) remissions, 1 patient had a complete remission which lasted only 9 months, and 2 patients show no response to the treatment. In a second study, 8 patients with localized and two with advanced disease who were in complete remission after chemotherapy (with or without radiation treatment) were given their own CTL that had been engineered to kill LMP1/2-bearing cells. One patient relapsed after 32 months while the remaining 7 patients had progression-free and overall survivals of 100 and 90%, respectively. A phase I clinical trial sponsored by Baylor College of Medicine, the Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and the Methodist Hospital System is recruiting individuals to test the effects of donor CTL engineered to kill cells bearing LMP1/2, ARF, and/or EBNA-1 viral antigens. A phase 2 clinical study sponsored by ViGenCell Inc. is being conducted at the Catholic University of Korea to test the effects of CTL engineered to kill EBV-infected cells on patients that are in complete remission following chemotherapy (±radiation treatment) but at high risk for recurrent disease. Patients will receive the CTL or placebo (i.e. peripheral blood mononuclear cells). The study, which begins recruitment in late Feb., 2019, seeks to determine if the CTL treatment prolongs remissions. * Bcl-2 proteins: Bcl-2 proteins are a family of proteins that regulate cellular apoptosis. Venetoclax (also termed ABT-199) is a small-molecule drug that indirectly promotes the activation of two apoptosis-inducing proteins, Bcl-2-associated X protein and Bcl-2 homologous antagonist killer thereby promoting cell death. It is approved for the treatment of chronic lymphocytic leukemia. Venetoclax is currently recruiting patients for a phase 2 clinical trial sponsored by the City of Hope Medical Center and the National Cancer Institute to evaluate its effects on refractory and recurrent ENKTCL-NT. Small molecule inhibitors of JAK3 (e.g. tofacitinib), JAK1/JAK2 (e.g. AZD1480), STAT3 (e.g. WP1066), and DDX3X (e.g. RK-33) are being study in pre-clinical in vitro experiments as potential inhibitors of malignant<unk> /T cell proliferation and survival. They are in further studies to test them as potential therapeutic agents in ENKTCL-NT patients that have activating mutations or overexpression of the cited targets.
Extranodal NK/T-cell lymphoma, nasal type
Pediatric-type follicular lymphoma
Indolent lymphoma
Pleomorphic T-cell lymphoma
Mature T-cell lymphoma
Primary mediastinal B-cell lymphoma
Nodular lymphocyte predominant Hodgkin lymphoma
T cell/histiocyte-rich large B-cell lymphoma