Efficacy and Safety of a Pegasparaginase-Based Chemotherapy Regimen vs an L-asparaginase–Based Chemotherapy Regimen for Newly Diagnosed Advanced Extranodal Natural Killer/T-Cell Lymphoma

Abstract

IMPORTANCEThe L-asparaginase-based SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide) chemotherapy regimen has shown higher response rates and survival benefit over an anthracycline-containing regimen. However, the safety profile was not satisfied. A well-tolerated regimen with promising efficacy is lacking.OBJECTIVE To compare the efficacy and safety of the DDGP (dexamethasone, cisplatin, gemcitabine, and pegaspargase) regimen with the SMILE regimen in newly diagnosed advanced-stage (III/IV) extranodal natural killer/T-cell lymphoma (ENKL). DESIGN, SETTING, AND PARTICIPANTSThis was an open-label, multicenter, randomized clinical trial that took place across 12 participating hospitals in China from January 2011 to February 2019. Patients were eligible if they were 14 to 70 years old with newly diagnosed ENKL in stages III/IV and had an Eastern Cooperative Oncology Group performance status of 0 to 2. Eligible patients were evenly randomized to either the DDGP or SMILE group.INTERVENTIONS Patients in each group were treated with the assigned regimen every 21 days for 6 cycles. MAIN OUTCOMES AND MEASURESThe primary end point was progression-free survival (PFS), and secondary end points included overall response rate and overall survival (OS). The adverse events between the DDGP and SMILE groups were compared. RESULTS Among the 87 randomized patients, 80 received treatment (40 in the DDGP group and 40 in the SMILE group); the median (IQR) age was 43 (12) years, and 51 (64%) were male. The baseline characteristics were similar between the groups. At a median follow-up of 41.5 months, the median PFS was not reached in the DDGP group vs 6.8 months in the SMILE group (HR, 0.42; 95% CI, 0.23-0.77; P = .004), and the median OS was not reached in the DDGP group vs 75.2 months in the SMILE group (HR, 0.41; 95% CI, 0.19-0.89, P = .02). The PFS rate at 3 years and OS rate at 5 years were higher in the DDGP group vs the SMILE group (3-year PFS, 56.6% vs 41.8%; 5-year OS, 74.3% vs 51.7%). The overall response rate was higher in the DDGP group than in the SMILE group (90.0% vs 60.0%; P = .002). Grade 3 and 4 hematologic toxic effects were more frequently reported in the SMILE group vs the DDGP group (leukopenia, 85.0% vs 62.5%; neutropenia, 85.0% vs 65.0%). CONCLUSIONS AND RELEVANCEIn this randomized clinical trial, the DDGP regimen showed promising preliminary results for patients with newly diagnosed local advanced ENKL. A confirmation trial based on larger population is warranted.

Mesothelioma cancer cells are glutamine addicted and glutamine restriction reduces YAP1 signaling to attenuate tumor formation

“…Asparaginase converts asparagine and glutamine to aspartate and glutamate, respectively, thereby decreasing plasma concentrations of asparagine and glutamine which ultimately reduces glutamine availability to the cancer cells 56 . Recent studies support the use of asparaginase and asparaginase derivatives as cancer therapeutics 9,10,52,57,58 . Mesothelioma is a highly aggressive and treatment‐resistant cancer, and our findings suggest that asparaginase‐dependent glutamine depletion may be a useful mesothelioma treatment strategy.…”

Treatment of extranodal NK/T-cell lymphoma: From past to future

“…41.8%, P = 0.004) and 5-year OS (74.3% vs . 51.7%, P = 0.02) in the DDGP arm were significantly higher than those in the SMILE arm ( 130 ). L-Asp-based CT was inferior to PEG-Asp-based CT, at least in part due to the long L-Asp dosing interval between two courses of CT.…”

“…In another recent randomized controlled study, 80 newly diagnosed ENKTCL patients were assigned to the DDGP (dexamethasone, cisplatin, gemcitabine, and PEG-Asp, repeated at 3-week intervals) arm or the SMILE (dexamethasone, methotrexate, ifosfamide, etoposide, and L-Asp, L-Asp given at 3-week intervals on days 3 to 9) arm. The results showed that the 3-year PFS (56.6% vs. 41.8%, P = 0.004) and 5-year OS (74.3% vs. 51.7%, P = 0.02) in the DDGP arm were significantly higher than those in the SMILE arm (130). L-Asp-based CT was inferior to PEG-Asp-based CT, at least in part due to the long L-Asp dosing interval between two courses of CT.…”

“…In today’s view, aggressive CT is unnecessary for ENKTCL. Mild regimens, such as P-GemOx (GELOX) and DDGP, have equal or better efficacy and a more favorable safety profile than aggressive regimens ( 50 , 69 , 70 , 130 , 143 ). Given the trend towards more simplified CT, the feasibility of concurrent CRT should be reevaluated.…”

Emerging predictive biomarkers for novel therapeutics in peripheral T-cell and natural killer/T-cell lymphoma

“…In NKTCL, L-asparaginase-containing treatment regimens such as SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide) ( 81 , 82 ), P-GEMOX (pegaspargase, gemcitabine, and oxaliplatin) ( 83 ), DDGP (dexamethasone, cisplatin, gemcitabine, and pegaspargase) ( 84 ), and AspaMetDex (pegaspargase, methotrexate, and dexamethasone) ( 85 ) have been regarded as the preferred first-line therapy for advanced disease ( 67 ). Similar to PTCL, the role of hematopoietic stem cell transplant in NKTCL is highly controversial ( 29 , 86 ).…”