Asparaginase-based Regimens Research Articles

Treatment and Prognosis of Newly Diagnosed Advanced-Stage Extranodal Natural Killer/T-Cell Lymphoma: A Single-Center Real-World Study across Two Decades

Introduction: Although there is now a consensus on asparaginase-based chemotherapy regimens in the treatment of advanced-stage extranodal natural killer/T-cell lymphomas (ENKTCLs), patient survival in the real-world setting is still not optimistic according to previous literature reports, and the optimal chemotherapeutic regimens and integration of different therapeutic methods under the concept of combined-modality treatment still need to be further explored and verified. Methods: Newly diagnosed stage Ⅲ/Ⅳ ENKTCL patients from Chinese National Cancer Center in the last two decades were retrospectively collected and analyzed. Overall survival (OS) and progression-free survival (PFS) were determined as primary endpoints. Log-rank tests and Cox proportional hazard models were performed to test for survival differences between subgroups and examine the univariable and multivariable associations. Results: The study included 83 newly diagnosed stage Ⅲ/Ⅳ ENKTCL patients and reported a median OS of 26.07 months and an estimated 5-year OS of 41.3% with a median follow-up of 82.13 months. First-line asparaginase-based regimens compared to non-asparaginase-based regimens significantly prolonged PFS (p = 0.007; HR = 0.48, p = 0.020) and showed a tendency to improve OS (p = 0.064; HR = 0.74, p = 0.359). Gemcitabine-based regimens also exhibited a trend toward improved PFS (p = 0.048; HR = 0.59, p = 0.164) and OS (p = 0.008; HR = 0.67, p = 0.282) compared to non-gemcitabine-based ones. The asparaginase and gemcitabine combinations yielded a 5-year OS of 55.0% and led to significantly superior PFS (p = 0.020; HR = 0.40, p = 0.022) and slightly better OS (p = 0.054; HR = 0.79, p = 0.495) compared to the remaining regimens. First-line combined-modality treatment integrating chemotherapy and radiotherapy improved PFS (p = 0.051) and OS (p = 0.036) compared to chemotherapy alone. Four autologous hematopoietic stem cell transplantation recipients reached a median OS of 58.34 months. Conclusion: Asparaginase and gemcitabine alone brought a favorable impact on PFS and OS; and the asparaginase and gemcitabine combination chemotherapy yielded the optimal efficacy, response duration, and survival outcomes. Combined-modality treatment including potent chemotherapy supplemented by radiotherapy and/or consolidative transplantation could improve prognosis in newly diagnosed advanced-stage ENKTCLs.

High-dose extended-field radiotherapy plus chemotherapy improved survival in extranodal NK/T-cell lymphoma in a real-life setting: results from the multicenter T-Cell Brazil Project

Extranodal natural-killer/T-cell lymphoma (ENKTL) is a rare and aggressive Epstein-Barr virus related mature T-cell and natural-killer malignancy. Although highly prevalent in South America, few studies covering data from this geographic location have been published. Therefore, this study aims to report clinical characteristics, prognostic factors, and outcomes in a multicenter cohort of ENKTL patients from Brazil. This retrospective, observational and multicenter study included 98 ENKTL patients treated during two decades in Brazil. Data were extracted from the T-Cell Brazil Project database. In our cohort, 59/98 patients (60.2%) were male, with a median age of 50 years. Sixty-two patients (63.3%) had B-symptoms, 26/98 (26.5%) had Eastern Cooperative Oncology Group scale ≥ 2; 16/98 (16.3%) presented extranasal disease and 34.7% (34/98) were advanced-stage (Ann Arbor/Cotswolds III/IV). The median follow-up for the whole cohort was 49 months, with an estimated 2-year overall survival (OS) and progression-free survival (PFS) of 51.1% and 17.7%, respectively. In early-stage disease (IE/IIE), the median OS was 21.8 months for patients treated with concurrent radiotherapy plus chemotherapy (CCRT-VIPD [etoposide/vp-16, ifosfamide, cisplatin and dexamethasone), 16.2 months for sequential chemoradiotherapy (SCRT) followed by asparaginase-based regimens, and 56.7 months for SCRT followed by CHOP-like (cyclophosphamide, doxorrubicin, vincristine and prednisone) treatments, p = 0.211. CCRT was associated with higher rates of early-mortality, hematological toxicity, and mucositis. Median OS was 8.2 months for patients with advanced-stage disease receiving regimens containing asparaginase compared to 3.2 months for anthracycline-based therapy, p = 0.851. Chemo-radiotherapy (CRT) regimens demonstrated better OS (p = 0.001) and PFS (p = 0.007) than chemotherapy alone. Multivariate analysis revealed anemia, relapsed/refractory (R/R) disease and radiotherapy omission as poor outcome predictors for OS. Lymphopenia and radiotherapy omission adversely affected PFS. Concerning progression of disease within 24-months (POD-24), clinical stage III/IV was a poor outcome predictor. In this real-life Brazilian cohort, ENKTL presented dismal outcomes. Radiation therapy was an independent factor for increased OS and PFS, but CCRT regimens were associated with higher toxicities. Polychemotherapy based on anti-multi drug resistant agents was not associated with survival benefit in either early or advanced-stage disease in our patient cohort.

Clinical Outcomes, Prognostic Factors and Therapeutic Management in Extranodal Natural-Killer/T-Cell Lymphoma, Nasal-Type (ENKTL-NT) - Results of the Multicenter T-Cell Brazil Project

Introduction: Extranodal natural-killer/T-cell lymphoma, nasal-type (ENKTL-NT) is an aggressive, angiocentric, and extensively necrotic malignancy, universally associated with Epstein-Barr virus (EBV) infection. Although highly prevalent in South America, few studies involving cohorts from this region have been published. Brazil is the largest and most populous country in South America, but Brazilian data on ENKTL-NT are extremely scare. In order to fill this gap, the current study aims to describe clinical and laboratory characteristics, assess clinical outcomes, determine predictors of survival and compare responses between different therapeutic modalities applied in a multicenter cohort of Brazilian patients with ENKTL-NT. Methods: This is a retrospective, observational and multicenter study, involving 98 patients with ENKTL-NT diagnosed and treated at 20 different Brazilian institutions between January 2000 and December 2021. Endpoints included overall response rate (ORR), overall survival (OS) and progression-free survival (PFS). Survival curves were constructed using the Kaplan-Meier method and the Log-Rank test was used to assess the relationship between variables and outcomes. Univariate analysis was performed using the semi-parametric Cox test and multivariate analysis by Cox regression method or proportional ratios model. The results were presented in hazard ratio (HR) and 95% confidence interval (95% CI) and a p-value ≤ 0.05 was considered statistically significant. Results: The median age was 50 years (IqR 40-58) and 60.2% (59/98) were male. Sixty-three percent (62/98) had B-symptoms, 26.5% (26/98) had ECOG ≥ 2, 16.3% (16/98) had extranasal disease, 34.7% had advanced-stage III/IV, and 30.2% (29/98) had high-risk PINK score [Table 1A]. Table 1B summarizes the main therapeutic modalities, responses and associated adverse event profile among the 89/98 patients undergoing up-front treatment. With a median follow-up of 49.0 months (95% CI: 35.8-62.3), the estimated 2-year OS and PFS were 51.1% (95% CI: 40.4-61.6) and 17.7% (95% CI: 4.5-30.8), respectively. Among early-stage disease (IE/IIE) patients, the estimated 2-year OS were 81.3% (95% CI: 64.8-97.7) for SCRT (sequential chemoradiotherapy) followed by CHOP-like, 53.2% (95% CI: 29.3-77.1) for CCRT (concurrent chemoradiotherapy) followed by VIPD, and 50.5% (95% CI:21.4-79.5) for SCRT followed by asparaginase-based regimens, p=0.221 [Figure 1B]. CCRT-VIPD was associated with higher early-mortality (p=0.034), and higher rates of neutropenia (p=0.075), febrile neutropenia (p=0.043) and mucositis (p<0.001) [Table 1B]. Among advanced-stage (III/IV) disease, the estimated 2-year OS were 37.0% (95% CI: 8.9-65.0) for asparaginase-based regimens and 33.0% (95% CI: 1.9-68.5) for anthracycline-based regimens, p=0.851 [Figure 1C]. Chemoradiotherapy (CRT) was associated with benefit for OS (p=0.001) and PFS (p=0.007) compared to chemotherapy alone [Figure 1D and 1E]. In multivariate analysis, anemia (HR 2.052, p=0.038), lymphopenia [HR 3.600, p=0.012], advanced- stage disease (III/IV) [HR 3.101, p=0.007], bone marrow infiltration [HR 5.406, p=0.034] and omission of RT in up-front therapy [HR 2.791, p=0.023] were independent factors associated with decreased survival. Conclusion: High-dose EF-RT proved to be the cornerstone for the treatment of early-stage ENKTL-NT, and omission of this therapeutic modality was associated with decreased OS and PFS in Brazilian patients. In our real-life study, CCRT-VIPD regimen was poorly tolerated, and surprinsingly protocols based on anti-MDR agents were not associated with increased survival either in early- or advanced-stage disease. We also found that anemia, lymphopenia, advanced-stage (III/IV) and bone marrow involvement were independent predictors associated with poor clinical outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CLINICAL OUTCOMES, PROGNOSTIC FACTORS AND THERAPEUTIC MANAGEMENT IN EXTRANODAL NATURAL-KILLER/T-CELL LYMPHOMA, NASAL-TYPE (ENKTL-NT) – RESULTS OF THE MULTICENTER T-CELL BRAZIL PROJECT

Extranodal natural-killer / T-cell lymphoma, nasal-type (ENKTL-NT) is an aggressive, angiocentric, and extensively necrotic malignancy, universally associated with Epstein-Barr virus (EBV) infection. Although highly prevalent in South America, few studies involving cohorts from this region have been published. Brazil is the largest and most populous country in South America, but Brazilian data on ENKTL-NT are extremely scare. In order to fill this gap, the current study aims to describe clinical and laboratory characteristics, assess clinical outcomes, determine predictors of survival and compare responses between different therapeutic modalities applied in a multicenter cohort of Brazilian patients with ENKTL-NT. This is a retrospective, observational and multicenter study, involving 98 patients with ENKTL-NT diagnosed and treated at 20 different Brazilian institutions between January 2000 and December 2021. Endpoints included overall response rate (ORR), overall survival (OS) and progression-free survival (PFS). Survival curves were constructed using the Kaplan-Meier method and the Log-Rank test was used to assess the relationship between variables and outcomes. Univariate analysis was performed using the semi-parametric Cox test and multivariate analysis by Cox regression method or proportional ratios model. The median age was 50 years (IqR 40-58) and 60.2% (59 / 98) were male. Sixty-three percent (62 / 98) had B-symptoms, 26.5% (26 / 98) had ECOG ≥ 2, 16.3% (16 / 98) had extranasal disease, 34.7% had advanced-stage III / IV, and 30.2% (29 / 98) had high-risk PINK score. With a median follow-up of 49.0 months (95% CI: 35.8-62.3), the estimated 2-year OS and PFS were 51.1% (95% CI: 40.4-61.6) and 17.7% (95% CI: 4.5-30.8), respectively. Among early-stage disease (IE / IIE) patients, the estimated 2-year OS were 81.3% (95% CI: 64.8-97.7) for SCRT (sequential chemoradiotherapy) followed by CHOP-like, 53.2% (95% CI: 29.3-77.1) for CCRT (concurrent chemoradiotherapy) followed by VIPD, and 50.5% (95% CI:21.4-79.5) for SCRT followed by asparaginase-based regimens, p = 0.221. CCRT-VIPD was associated with higher early-mortality (p = 0.034), and higher rates of neutropenia (p = 0.075), febrile neutropenia (p = 0.043) and mucositis (p < 0.001). Among advanced-stage (III / IV) disease, the estimated 2-year OS were 37.0% (95% CI: 8.9-65.0) for asparaginase-based regimens and 33.0% (95% CI: 1.9-68.5) for anthracycline-based regimens, p = 0.851. Chemoradiotherapy (CRT) was associated with benefit for OS (p = 0.001) and PFS (p = 0.007) compared to chemotherapy alone. In multivariate analysis, anemia (HR 2.052, p = 0.038), lymphopenia [HR 3.600, p = 0.012], advanced- stage disease (III / IV) [HR 3.101, p = 0.007], bone marrow infiltration [HR 5.406, p = 0.034] and omission of RT in up-front therapy [HR 2.791, p = 0.023] were independent factors associated with decreased survival. High-dose EF-RT proved to be the cornerstone for the treatment of early-stage ENKTL-NT, and omission of this therapeutic modality was associated with decreased OS and PFS in Brazilian patients. In our real-life study, CCRT-VIPD regimen was poorly tolerated, and surprinsingly protocols based on anti-MDR agents were not associated with increased survival either in early- or advanced-stage disease. We also found that anemia, lymphopenia, advanced-stage (III/IV) and bone marrow involvement were independent predictors associated with poor clinical outcomes.

Prophylaxis of thromboembolism during therapy with asparaginase in adults with acute lymphoblastic leukaemia.

Prophylaxis of thromboembolism during therapy with asparaginase in adults with acute lymphoblastic leukaemia.

Genomic and Transcriptomic Characterization of Natural Killer T Cell Lymphoma

Natural killer/T cell lymphoma (NKTCL) is an aggressive and heterogeneous entity of non-Hodgkin lymphoma, strongly associated with Epstein-Barr virus (EBV) infection. To identify molecular subtypes of NKTCL based on genomic structural alterations and EBV sequences, we performed multi-omics study on 128 biopsy samples of newly diagnosed NKTCL and defined three prominent subtypes, which differ significantly in cell of origin, EBV gene expression, transcriptional signatures, and responses to asparaginase-based regimens and targeted therapy. Our findings thus identify molecular networks of EBV-associated pathogenesis and suggest potential clinical strategies on NKTCL.

Clinical analyses of 24 patients with primary pulmonary NK/T-cell lymphoma

目的探讨原发性肺NK/T细胞淋巴瘤的临床特点、最佳治疗方案及预后因素，以提高对原发性肺NK/T细胞淋巴瘤的认识。方法回顾性分析2011年4月至2019年5月收治的24例明确诊断为原发性肺NK/T细胞淋巴瘤患者的临床资料，并对其临床特征、治疗及预后进行分析。采用Kaplan-Meier进行生存分析，应用Cox比例风险回归模型确定影响总生存（OS）期和疾病无进展生存（PFS）期的预后因素。结果①入组的24例患者中男16例，女8例，中位年龄为49（4~76）岁。②患者初始症状大多为发热（66.7%）、咳嗽、呼吸困难。主要的胸部影像学表现为单侧（45.8%）或双侧（54.2%）肺部浸润、结节或肿块。③24例患者中20例接受放化疗或造血干细胞移植，4例接受姑息治疗。所有患者的中位OS期为9.5（0.1~26.0）个月，1年OS率为45.8%。以门冬酰胺酶为基础化疗方案的总有效率（ORR）为88.2%。④单因素分析显示，年龄≤60岁患者的OS和PFS显著优于年龄>60岁的患者（P值分别为0.002、0.004），美国东部肿瘤协作组体能状态评分（ECOG评分）≤2分患者的OS和PFS显著优于ECOG评分>2分患者（P值分别为0.042、0.004）。多因素分析显示，年龄>60岁和ECOG评分>2分与不良OS和PFS相关（OS：P值分别为0.024、0.024；PFS：P值分别为0.035、0.024）。结论原发性肺NK/T细胞淋巴瘤罕见且预后差，以门冬酰胺酶为基础的化疗方案疗效显著，年龄>60岁和ECOG评分>2分是患者独立的不良预后因素。

Predictors of Outcomes in Patients with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia at First Relapse in the Era of Tyrosine Kinase Inhibitors

Predictors of Outcomes in Patients with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia at First Relapse in the Era of Tyrosine Kinase Inhibitors

Circulating Low Absolute CD4+ T Cell Counts May Predict Poor Prognosis in Extranodal NK/T-Cell Lymphoma Patients Treating with Pegaspargase-Based Chemotherapy.

PurposeExtranodal natural killer/T-cell lymphoma, nasal type (ENKTL) is a rare subtype of non-Hodgkin lymphoma, and asparaginase-based regimens are the best first-line treatments. Data on the role of specific circulating lymphocyte subsets in the progression of ENKTL are limited. The aim of this study was to investigate the clinical correlation and distribution of circulating absolute CD4+ T-cell counts (ACD4Cs) in ENKTL.Materials and MethodsWe retrospectively searched medical records for 70 newly diagnosed ENKTL patients treated with pegaspargase-based regimens. Comparison of ACD4Cs as a continuous parameter in different groups was calculated. Univariate and multivariate analyses were used to assess prognostic factors for overall survival (OS) and progression-free survival (PFS).ResultsStage III/IV, B symptoms, elevated lactate dehydrogenase, monocytopenia, high-intermediate and high risk International Prognostic Index (IPI) and Korean Prognostic Index (KPI), high risk Prognostic Index of Natural Killer Lymphoma (PINK), and lower lymphocytes were significantly associated with low ACD4C at diagnosis. With a median follow-up time of 32 months, patients who had an ACD4C < 0.30×109/L had a worse OS. Median OS was 11 months and median PFS was 5 months in the low ACD4C cohort. There were significant differences in both OS and PFS between the two cohorts. Moreover, multivariate Cox analysis identified ACD4Cs as an independent predictor for OS and PFS.ConclusionLow ACD4Cs were associated with poorer survival and could act as a negative predictor for ENKTL patients treated with asparaginase-based regimens.

A Phase II Study of Methotrexate, Etoposide, Dexamethasone and Pegaspargase Sandwiched with Radiotherapy in the Treatment of Newly Diagnosed, Stage IE to IIE Extranodal Natural-Killer/T-Cell Lymphoma, Nasal-Type

BackgroundA phase II study of methotrexate, etoposide, dexamethasone, and pegaspargase (MESA) sandwiched with radiotherapy for newly diagnosed, stage IE-IIE extranodal natural-killer/T-cell lymphoma, nasal-type (ENKTL) was conducted to explore its clinical efficacy and safety, as well as novel serum biomarkers upon anti-metabolic treatment. MethodsFour cycles of MESA sandwiched with radiotherapy were administered. The primary end point was the overall response rate (ORR). Serum metabolomic profiles were assessed by liquid chromatography-mass spectrometry, with specific metabolites quantified by targeted metabolic analysis. FindingsForty patients were enrolled and the ORR was 92.1% (95%CI, 83.1%–100.0%). The 2-year progression-free survival (PFS) rate was 89.1% and overall survival (OS) rate was 92.0%. Grade 3/4 non-hematologic and hematologic toxicities were observed in 17 (42.5%) and 26 patients (65·0%) during chemotherapy, and in 9 (22.5%) and 0 (0.0%) patients during radiotherapy, respectively. Fifty-six significantly decreased and 59 increased metabolites were identified in ENKTL, as compared to healthy volunteers. A predictive principal components analysis model of asparaginase-associated metabolites, asparaginase-associated metabolic score (AspM), was established, including alanine, aspartate, glutamate, and succinic acid. Patients with high AspM score displayed superior survival and prognostic significance of AspM was validated in a historical cohort of early and advanced-stage ENKTL treated with asparaginase-based regimens. Multivariate analysis confirmed AspM as a prognostic score independent of PINK and PINK combined with Epstein-Barr virus DNA. InterpretationMESA sandwiched with radiotherapy is an effective and safe regimen for early-stage ENKTL. AspM score may be a promising prognostic index of serum metabolites in addition to clinical prognostic index in ENKTL.

Efficacy of combined gemcitabine, oxaliplatin and pegaspargase (P-gemox regimen) in patients with newly diagnosed advanced-stage or relapsed/refractory extranodal NK/T-cell lymphoma.

Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive neoplasm with a poor outcome. Asparaginase-based regimens are recommended for patients with advanced-stage or relapsed/refractory ENKTL. We retrospectively investigated the efficacy and toxicity of combined gemcitabine, oxaliplatin, and pegaspargase (P-gemox) in these patients. A total of 35 patients with newly diagnosed stage III–IV, relapsed or refractory ENKTL were treated with 2 to 8 cycles of P-gemox: gemcitabine (1250 mg/m2) and oxaliplatin (85 mg/m2) injected intravenously and pegaspargase (2500 IU/m2) injected intramuscularly on day 1 and repeated every 2 weeks. Upon completion of treatment, the overall response rate was 80.0%, with a complete response in 51.4% of patients. The 1-, 2- and 3- year progression-free survival rates were 45.0%, 38.6% and 38.6%, and overall survival rates were 76.8%, 64.7% and 64.7%, respectively. Patients who attained a complete response showed better progression-free survival than those without a complete response (p = 0.01). The major adverse effects were hematologic toxicity and liver dysfunction. Grade 3/4 leucopenia and neutropenia occurred in 40.0% of patients. No treatment-related deaths occurred. These results indicate the P-gemox regimen is a safe and effective treatment for patients with newly diagnosed advanced-stage or relapsed/refractory ENKTL. We anticipate future prospective trials will confirm the efficacy.

Combination of gemcitabine, l-asparaginase, and oxaliplatin (GELOX) is superior to EPOCH or CHOP in the treatment of patients with stage IE/IIE extranodal natural killer/T cell lymphoma: a retrospective study in a cohort of 227 patients with long-term follow-up

Optimal treatment strategies for localized extranodal natural killer/T cell lymphoma (ENKTL) have not been fully defined. We retrospectively compared the efficacy and safety of combined gemcitabine, L-asparaginase, and oxaliplatin (GELOX) (n=38), continuous infusion of etoposide, vincristine and doxorubicin, with cyclophosphamide and prednisone (EPOCH) (n=54), or combined cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (n=135) as induction chemotherapy in patients who were newly diagnosed with stage I/II ENKTL. After induction chemotherapy, the complete response (CR) rate and overall response rate (ORR) for the GELOX group were significantly higher than those in the EPOCH group (68.4 vs. 42.6%, P=0.011 for CR and 86.8 vs. 68.5%, P=0.038 for ORR). Both EPOCH and GELOX groups can attain much higher CR rates than CHOP group (CR rate was 31.8%, P<0.05). The 3-year overall survival (OS) and progression-free survival (PFS) rate were significantly better in GELOX group than in EPOCH or CHOP group (87.0 vs. 54.0 vs. 54.0% for OS, P<0.05; 72.0 vs. 50.0 vs. 43.0% for PFS, P<0.05). However, no significant differences were found between EPOCH and CHOP groups in OS or PFS (P=0.765 for OS, and 0.421 for PFS). The safety profiles were acceptable in all three groups. In conclusion, GELOX is superior to EPOCH or CHOP in the treatment of patients with stage I/II ENKTL. Further clinical trials of ENKTL should use asparaginase-based regimens as the standard chemotherapy.

Risk stratification in extranodal natural killer/T-cell lymphoma

Extranodal natural killer/T-cell lymphoma (ENKL), a subtype of natural killer/T-cell malignancies, is a rare subset of lymphomas with significant biological and clinical heterogeneity. The prognosis of ENKL is variable and therapeutic approaches are not well established. The optimal dose, combination, and sequence of radiotherapy and chemotherapy are evolving, as is the role of stem cell transplantation. Radiotherapy is an essential component of therapy for early-stage disease. The clinical course of advanced disease is highly aggressive, with frequent chemotherapy resistance and a poor prognosis. For relapsed disease, asparaginase-based regimens have provided encouraging results and are currently under investigation in the frontline setting. Our article discusses the key aspects of biology, pathogenesis and clinical presentation that contribute to the heterogeneity, and proposes a stratified approach to the treatment of ENKL based on clinical, pathologic and biologic risk factors. Although considerable advances have been made in our understanding of the biology and prognosis of this lymphoma, it remains critical that all patients with a diagnosis of ENKL are enrolled and treated in clinical trials so that optimal therapies can be identified.