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

Abstract

IntroductionExtranodal natural killer (NK)/T-cell lymphoma, nasal type, is a rare and severe malignancy. It is more frequent in Asia and Central/South America than in Europe and North America. It is thought to arise from NK cells or, occasionally, from a subset of ␥␦ or ␣␤ cytotoxic T cells, and shows a tight association with Epstein-Barr virus (EBV). It is classically characterized by a cytoplasmic CD3 ⑀ phenotype, with no surface CD3 or T-cell receptor expression, no T-cell receptor gene rearrangements, an activated cytotoxic profile with perforin, granzyme B, and TIA-1 expression, and frequent CD56 expression. [1][2][3] Extranodal NK/T-cell lymphoma is usually diagnosed in adults, with a median age in the fifth decade. The nasal cavity or other parts of the upper aerodigestive tract are primarily involved, but some cases occur at extranasal sites. The term "nasal-type" is used in the World Health Organization classification to describe forms arising both in the nasal cavity and in extranasal sites. 3,4 Because disease incidence is rare even in prevalent areas, there has been no randomized controlled trial, and most treatment protocols are consensus-guided. 5 Localized NK/T-cell lymphomas often respond to radiotherapy 6,7 or to concurrent radiation and chemotherapy, 8 but relapse is common. Chemotherapy protocols used for lymphomas of other histologic subtypes are poorly effective, at least in part, because of frequent multidrug resistance gene expression by tumor cells. 9 Patients with disseminated or relapsing disease have a very poor outcome, 4,10,11 and there is no standard management for relapsed or refractory disease. We and others, in small retrospective studies, 12-16 have observed very good response and survival rates in patients treated with L-asparaginase, a drug with an original antitumoral mechanism not affected by MDR. NK cells lack asparagine synthase activity, and asparaginase has been shown to induce apoptosis of tumoral NK cells in vitro. 17 These findings provided the rationale for this open-label phase 2 study of an L-asparaginase-containing regimen for patients with relapsed and/or refractory extranodal NK/T-cell lymphoma. We chose to combine L-asparaginase with methotrexate, a drug insensitive to the multidrug resistance pathway, because of its well-known synergistic effect with asparaginase in acute lymphoblastic leukemia and its ability to prevent central nervous system involvement. Dexamethasone was added because T-cell lymphomas are usually sensitive to corticosteroids and dexamethasone For personal use only. on May 12, 2018. by guest www.bloodjournal.org From seems to be associated with a lower risk of thrombosis when given with L-asparaginase. 18 Methods PatientsThe patients were at least 18 years of age, with relapsed or refractory extranodal NK/T-cell lymphoma. Eligibility criteria included biopsyproven diagnosis of NK/T-cell lymphoma, nasal-type, irrespective of the anatomic site. Malignant cells in all cases had a CD3⑀ ϩ , CD20 Ϫ phenotype, a cytotoxic profile, and evidence of E...

Current and future management of NK/T-cell lymphoma based on clinical trials

“…These factors make conducting a prospective clinical trial for this population difficult. To overcome these problems, most studies selected a setting of multinational clinical trials [12][13][14], although this set-up might generate some practical problems due to differences in health insurance systems in the participating countries. Some recent studies have enrolled both patients with newly diagnosed stage IV and those with relapsed or refractory disease into first-line treatment [12,14].…”

“…A French group conducted a multicenter phase II study of AspaMetDex (L-asparaginase, methotrexate, and dexamethasone) chemotherapy for relapsed or refractory ENKL [13]. This regimen was selected based on the promising results of their pilot study [57].…”

“…This review will focus on the evidence from prospective clinical trials for ENKL and discuss the most recommended management at present and future directions for the better management of ENKL. methodology used in lymphoma diagnosis (e.g., the availability of anti-CD56 antibodies that can be used for formalin-fixed paraffin-embedded material), and incorporating central pathology review into trials [10,13,14].…”

A phase 2 study of methotrexate, etoposide, dexamethasone, and pegaspargase chemotherapy for newly diagnosed, relapsed, or refractory extranodal natural killer/T‐cell lymphoma, nasal type: a multicenter trial in Northwest China

“…A phase 2 study that evaluated the efficacy and safety of SMILE therapy showed an excellent antitumor activity for patients with relapsed or refractory NKTCL, with an ORR of 77% and a 1‐year OS of 79% or 25%, respectively, and with a 3‐year OS of 50% 22, 52. Phase 2 studies of l ‐asparaginase, methotrexate, and dexamethasone, IMEP, and gemcitabine‐pegaspargase‐cisplatin‐dexamethasone also reported ORRs of 77%, 43%, and 88%, respectively 26, 53, 54…”

“…Asian and non‐Asian patients also experienced other non‐hematologic events such as hyperbilirubinemia and fibrinogenemia 19, 21, 22, 24, 25. These adverse events are frequently accompanied by hypersensitivity to l ‐asparaginase 21, 22, 26, 27. This enzyme is a key component of chemotherapy because of the selective inability of transformed lymphocytes to synthesize asparagine 28.…”