Abstract
Patients with extranodal natural killer/T-cell lymphoma (ENKTL), nasal type are benefit from peg-asparaginase, gemcitabine, and methotrexate. Therefore, we conducted a prospective phase II trial using a combination of these drugs as GAD-M regimen in naïve ENKTL patients, simultaneously, explored the combinational mechanism. The GAD-M regimen was administered for 6 cycles sandwiched by radiotherapy for stage I/II and 6 cycles for stage III/IV patients. After 6 cycles, the overall response rate of 36 patients was 91.6%, and the complete remission rate increased to 83.3%. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 74.8% and 77.8%, respectively. The 5-year PFS and OS were 68.3% and 77.8%. No patient suffered from the central nervous system (CNS) relapse. Most patients experienced recoverable liver dysfunction and anemia in this study. The plasma MTX concentration ratio at 12 to 24 hr during the first cycle could be an early predictor of outcomes in ENKTL (PFS, P=0.005; OS, P=0.002). Additionally, we found that high dose MTX (HD-MTX) and gemcitabine had the synergistic effect of ENKTL cell in vitro. Mechanistically, we demonstrated that the combination could lead to obviously apoptosis in ENKTL cell with extremely release of reactive oxygen spices (ROS), which mediated by endoplasmic reticulum stress. In conclusion, the GAD-M regimen could be a new choice to newly diagnosed ENKTL, especially for stage I/II patients. Furthermore, our results showed the synergy effect of HD-MTX with gemcitabine in ENKTL.Clinical Trial RegistrationThis trial was registered at www.clinicaltrials.gov as #NCT01991158.
Highlights
Extranodal NK/T-cell lymphoma (ENKTL) is a highly aggressive lymphoma that has a geographic predilection in Asian and South American populations [1–4]
It has been shown that cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy or CHOP-like regimens were associated with poor outcomes in ENKTL [8] because the multidrug resistance (MDR) P-glycoprotein expressed by ENKTL cells acts as an efflux pump to combat the effects of various drugs, including cyclophosphamide and doxorubicin [9– 11]
A total of 38 patients diagnosed at the Sun Yat-sen University Cancer Center from November 2013 to October 2015 were consecutively considered for this study
Summary
Extranodal NK/T-cell lymphoma (ENKTL) is a highly aggressive lymphoma that has a geographic predilection in Asian and South American populations [1–4]. In China, the incidence of ENKTL is higher and secondary to the diffuse large B-cell lymphoma, accounting for approximately 11% of all lymphomas [5]. Almost 75% of ENKTL cases typically involve the nasal cavities, with the common initial symptoms being nasal obstruction, nasal discharge, and epistaxis; caused by the nasal lesions [6, 7]. They can develop rapidly in any other site such as the nasopharynx, skin, orbits, gastrointestinal tract, testis, and lymph nodes. Regimens incorporating anthracycline-containing chemotherapy have been abandoned as treatments for ENKTL [1, 2, 8]. A series of regimens incorporating peg-asparaginase/ L-asparaginase-based chemotherapy have shown greater efficacy [12–18]. The optimal treatment for ENKTL has not yet been fully defined, and the dilemma regarding which drugs should be combined with peg-asparaginase/Lasparaginase continues to evolve
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