Outcomes of HTLV-1 Carriers with Diffuse Large B-Cell Lymphoma: A Single-Center Retrospective Matched Cohort Study

BackgroundThe human T-cell lymphotropic virus type 1 (HTLV-1) is associated with aggressive diseases, such as adult T-cell leukemia/lymphoma (ATLL). However, less is known on the impact of HTLV-1 infection in non-ATLL hematologic malignancies. We aimed to investigate if HTLV-1 carriers with diffuse large B-cell lymphoma (DLBCL) have worse survival outcomes than non-HTLV-1 carriers.Materials and MethodsWe performed a single-center retrospective cohort study by matching HTLV-1 carriers to non-carriers based on age, sex, Ann Arbor stage, and year of diagnosis. Our outcomes of interest were overall survival (OS) and progression-free survival (PFS). The Kaplan-Meier method was used to estimate OS and PFS between carriers and non-carriers. We fitted multivariate Cox regression models to assess the mortality and recurrence/disease progression risk of HTLV-1 infection.ResultsA total of 188 patients, 66 with HTLV-1 infection and 122 without HTLV-1, were included in the study. HTLV-1 carriers had higher extranodal involvement than non-carriers (47% vs. 27%, P = .010). With a median follow-up of 78 months (95% CI: 41-90 months), HTLV-1 carriers had a similar 5 year OS (41% vs. 42%, P = .940) and PFS (34% vs. 32%, P = .691) compared to non-carriers. In the multivariate Cox analysis, HTLV-1 infection was not associated with worse OS (aHR: 0.98, 95% CI: 0.64-1.50) or PFS (aHR: 0.90, 95% CI: 0.60-1.34).ConclusionHTLV-1 carriers with DLBCL did not have worse survival outcomes compared to non-carriers. Our results suggest that clinicians should follow standard guidelines for DLBCL management on HTLV-1 seropositive patients.     

Clinical Outcomes of RTOG 9310 Protocol for Primary Central Nervous System Lymphoma: Single-Center Experience with 87 Patients

The Radiation Therapy Oncology Group (RTOG) 9310 protocol clinical trial established high-dose methotrexate (HDMTX) as the standard for primary central nervous system lymphoma (PCNSL). We aimed to investigate the RTOG 9310 protocol’s PCNSL outcomes by examining progression-free survival (PFS) and overall survival (OS) rates and determining the influential factors. Between 2007 and 2020, 87 patients were histopathologically diagnosed with PCNSL and treated with the RTOG 9310 protocol. All received HDMTX 2.5 g/m² and vincristine 1.4 mg/m²/day for 1 day during weeks 1, 3, 5, 7, and 9, and procarbazine 100 mg/m²/day for 1 day during weeks 1, 5, and 9. Dexamethasone was administered on a standard tapering schedule from the first week to the sixth week. Whole brain radiotherapy (WBRT), consisting of 45 Gy for patients with less than a complete response to the chemotherapy or 36 Gy for complete responders, was started 1 week after the last dose of chemotherapy was administered. Within three weeks of the completion of WBRT, patients received two courses of cytarabine, which were separated by 3–4 weeks. Clinical, radiological, and histopathological characteristics were retrospectively reviewed. All patients completed five HDMTX cycles and a mean follow-up of 60.2 (range, 6–150) months. Twenty-eight (32.2%) patients experienced recurrence during follow-up. The mean time to recurrence was 21.8 months, while the mean PFS was 104.3 (95% confidence interval (CI), 90.6–118.0) months. Eleven (12.6%) patients died; the mean OS was 132.1 (95% CI, 122.2–141.9) months. The 3- and 5-year survival rates were 92.0% and 87.4%, respectively. One patient experienced acute renal failure, while the remainder tolerated any cytotoxic side effects. On multivariate analysis, the Eastern Cooperative Oncology Group performance score ≤ 2; the International Extranodal Lymphoma Study Group low-risk status; XBP-1, p53, and c-Myc negativity; homogenous enhancement; gross total resection, independently correlated with long PFS and OS. The RTOG 9310 protocol is effective for PCNSL and features good outcomes.     

Intrathecal Central Nervous System Prophylaxis in Patients With Diffuse Large B-cell Lymphoma at an Academic Healthcare System

Introduction

Intrathecal chemoprophylaxis is often administered to patients with diffuse large B-cell lymphoma (DLBCL) to lower the rates of central nervous system (CNS) relapse, although its benefit has not been well-described. Prognostic models, including the CNS-International Prognostic Index (IPI), have been developed to aid in identifying patients at highest risk for CNS relapse.

Autologous Stem Cell Transplantation in Central Nervous System Lymphoma: A Multicenter Retrospective Series and a Review of the Literature

BackgroundCentral nervous system (CNS) lymphoma is associated with poor outcomes. Autologous stem cell transplantation (ASCT) has been reported to improve outcomes when used as a consolidation strategy in primary CNS lymphoma (PCNSL) and as a salvage strategy in patients with disease relapse limited to the CNS. Herein, we describe our experience of using ASCT in PCNSL and secondary CNS lymphoma (SCNSL).Patients and MethodsWe evaluated clinical outcomes of 18 patients from 2 major academic centers with a median age of 55 (range, 46-72) years. Thirteen patients had PCNSL and 5 patients had SCNSL. Most of the cases were in the first (CR1) or second (CR2) complete remission (CR1 = 7, CR2 = 7) at the time of ASCT. Carmustine with thiotepa (n = 12, 67%) was the most commonly prescribed preparative regimen.ResultsThe median follow-up from ASCT for surviving patients was 12 (range, 0.9-115) months. The 2-year progression-free survival (PFS) and overall survival (OS) were 74% (95% confidence interval [CI], 48%-99%) and 80% (95% CI, 55%-100%), respectively. Two-year non-relapse mortality was 0%. The 2-year cumulative incidence of relapse/progression was 27% (95% CI, 10%-72%). In subgroup analysis of PCNSL patients, 2-year PFS, OS, and relapse were 71% (95% CI, 38%-100%), 71% (95% CI, 38%-100%), and 29% (95% CI, 9%-92%), respectively.ConclusionIn this retrospective study of patients with CNS lymphoma, consolidation with ASCT after high-dose methotrexate-based chemotherapy is safe and effective in reducing disease relapse.     

Allogeneic Hematopoietic Cell Transplantation for Richter Syndrome: A Single-Center Experience

Background

Recent studies have shown dismal outcomes when chronic lymphocytic leukemia progresses to Richter syndrome after patients receive ibrutinib, with a median overall survival ranging from 2.6 to 3.5 months. Published data on efficacy of allogeneic hematopoietic cell transplantation in Richter syndrome are limited to single-center case series and registry data.

Oncologic Outcomes of Cytoreductive Nephrectomy in Synchronous Metastatic Renal-Cell Carcinoma: A Single-Center Experience

Purpose

To evaluate the prognostic role of cytoreductive nephrectomy (CN) in patients with synchronous metastatic renal-cell carcinoma (mRCC).

Implication of Rituximab Infusion Reactions on Clinical Outcomes in Patients With Diffuse Large B-cell Lymphoma: A Single Institution Experience

BackgroundThe addition of the anti-CD20 monoclonal antibody rituximab to chemotherapy for diffuse large B-cell lymphoma (DLBCL) has led to improvements in progression-free survival and overall survival, although the exact mechanism of rituximab is not known. Rituximab administration often results in transient, non–life-threatening infusion reactions (IRs). We report a retrospective cohort of patients with DLBCL who received rituximab to determine the significance of IRs on clinical outcomes.Patients and MethodsWe identified and analyzed a retrospective cohort of 229 patients with DLBCL. They were stratified into 2 cohorts; those who did and did not have an IR. Univariate and multivariate analyses were performed to evaluate the prognostic significance of rituximab-related IRs relative to DLBCL subtype, International Prognostic Index score, c-Myc translocations or amplifications, chemotherapy regimen, and Ki-67 proliferative index.ResultsBaseline characteristics did not differ significantly between the 2 groups. Rituximab was included as initial treatment in all patients. Patients with an IR had a significantly higher overall survival (hazard ratio, 0.26; 95% confidence interval, 0.07-0.95) at 5 years. In addition, subgroup analysis showed a significantly higher progression-free survival in patients with the germinal center subtype of disease and c-Myc alterations who had a rituximab-related IR (log-rank P < .0001).ConclusionsThe presence of a rituximab-related IR is associated with a better overall survival in patients with DLBCL. Although limited by the small sample size and retrospective nature, these results provide rationale for further investigation into the mechanism of action of rituximab in order to optimize the efficacy of CD20 monoclonal antibodies.     

Primary Dural Diffuse Large B-cell Lymphoma: A Comprehensive Review of Survival and Treatment Outcomes

Primary dural diffuse large B-cell lymphoma (PD-DLBCL) is a rare and aggressive B-cell non-Hodgkin lymphoma that can present in intracranial or intraspinal locations. Although the optimal management is unknown, PD-DLBCL therapy is often mirrored after primary central nervous system lymphoma therapy and aggressive treatment with a high dose methotrexate-based regimen is frequently used. Our comprehensive, retrospective study of 24 reported cases of PD-DLBCL provide the most complete analysis of this rare disease including data on biology, treatment outcomes, and survival. Our findings demonstrate good outcomes following induction treatment with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), suggesting that these cases can be treated as DLBCL rather than primary central nervous system lymphoma, obviating the need for more aggressive and toxic approaches. The durable responses following R-CHOP also confirm that PD-DLBCL is not protected by the blood brain barrier.     

Prognostic Values of Various Clinical Factors and GeneticSubtypes for Diffuse Large B-cell lymphoma Patients: ARetrospective Analysis of 227 Cases

Aim: To analyze the significance of different clinical factors for prognostic prediction in diffuse large B-celllymphoma (DLBCL) patients. Methods: Two hundred and twenty-seven DLBCL patients were retrospectivelyreviewed. Patients were managed with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)regimen or rituximab plus the CHOP (RCHOP) regimen. Results: Lactate dehydrogenase (LDH), β2-microglobulin (β2-M), B symptoms, Ann Arbor stage and genetic subtypes were statistically relevant in predictingthe prognosis of the overall survival (OS). In the CHOP group, the OS in patients with germinal center B-celllike(GCB)(76.2%) was significantly higher than that of the non-GCB group (51.9%, P=0.032). With RCHOPmanagement, there was no statistical difference in OS between the GCB (88.4%) and non-GCB groups (81.9%,P=0.288). Conclusion: Elevated LDH and β2-M levels, positive B symptoms, Ann Arbor stage III/IV, and primarynodal lymphoma indicate an unfavorable prognosis of DLBCL patients. Patients with GCB-like DLBCL have abetter prognosis than those with non-GCB when treated with the CHOP regimen. The RCHOP treatment withthe addition of rituximab can improve the prognosis of patients with DLBCL.     

A Multi-Institutional Validation of the Prognostic Value of the Neutrophil-to-Lymphocyte Ratio in Patients With Diffuse Large B-Cell Lymphoma: A Study From The Latin American Group of Lymphoproliferative Disorders (GELL)

IntroductionWe aimed at investigating the prognostic role of the neutrophil-to-lymphocyte ratio (NLR) in 2 independent cohorts of Latin American patients with diffuse large B-cell lymphoma (DLBCL) treated with chemoimmunotherapy.Patients and MethodsThe learning cohort was composed of 274 patients and the validation cohort of 323 patients, for a total of 597 patients. An optimal NLR cutoff ≥ 4 was determined using receiver operating characteristic analysis.ResultsIn multivariate models, NLR ≥ 4 was independently associated with lower odds for complete response to chemoimmunotherapy in the learning (odds ratio, 0.46; P = .006) and the validation cohort (odds ratio, 0.49; P = .01), and independently associated with worse survival in the learning (hazard ratio, 1.55; P = .04) and the validation cohort (hazard ratio, 1.80; P = .003).ConclusionsThe adverse prognostic value of NLR ≥ 4 was independent of the International Prognostic Index and the National Comprehensive Cancer Network-International Prognostic Index score. Based on the results of this multi-institutional study, NLR ≥ 4 emerges as an adverse prognostic factor in Latin American patients with DLBCL treated with chemoimmunotherapy.     

Late Relapses After High-dose Chemotherapy and Autologous Stem Cell Transplantation in Patients With Diffuse Large B-cell Lymphoma in the Rituximab Era

BackgroundThe standard of care for diffuse large B-cell lymphoma (DLBCL) relapsing after front-line therapy is high-dose chemotherapy and autologous stem cell transplantation (ASCT). Evidence has suggested that early relapses (ie, within 1 year) after this approach portends exceptionally poor outcomes. However, data examining relapses > 1 year after ASCT for patients with refractory or relapsed DLBCL are limited, in particular, in the rituximab era. We sought to examine the effect of early (≤ 1 year) and late (> 1 year) relapse after ASCT in a single-institution cohort of patients with relapsed and refractory DLBCL treated with chemoimmunotherapy.Materials and MethodsA retrospective analysis was performed on the data from 85 consecutive patients who had undergone ASCT for biopsy-confirmed relapsed or refractory DLBCL from 2001 to 2010 at the University of Rochester Medical Center. All patients had received rituximab as a part of treatment. Of the 85 patients, 35 developed relapse after ASCT. These 35 patients were divided into 2 groups according to the timing of the relapse (≤ 1 year and > 1 year after ASCT).ResultsThe median follow-up period was 6.4 years. For all patients, the overall survival (OS) from post-ASCT relapse was 5.2 years. For the 27 patients developing relapse at ≤ 1 year after ASCT, the median OS was 0.6 year and progression-free survival was 0.4 year. For the 8 patients developing relapse at > 1 year after ASCT, the median OS was 5.9 years and progression-free survival was 2.9 years.ConclusionPatients with relapsed or refractory DLBCL experiencing relapse > 1 year after ASCT had good outcomes. Despite the relative rarity in incidence, a significant risk of relapse of DLBCL after ASCT remains, suggesting the need for continued monitoring because of the possibility of later progression.     

弥漫性大B细胞淋巴瘤中mTOR与MRP1的表达及相关性分析

目的 探讨雷帕霉素靶蛋白（mammalian target of rapamycin, mTOR）与多药耐药相关蛋白1（multidrug resistance protein 1, MRP1）在弥漫性大B细胞淋巴瘤（diffuse large B-cell lymphoma,DLBCL）中的表达及其意义。方法 选择新疆医科大学附属肿瘤医院2010年1月—2013年6月间确诊的DLBCL患者共109例。采用Western blot法检测p-mTOR蛋白的表达;采用RT-PCR方法检测MRP1的表达,分析p-mTOR蛋白与MRP1 mRNA表达之间的相关性;采用Kaplan-Meier法进行生存分析。结果 p-mTOR及MRP1 mRNA在DLBCL中的表达率分别为58.7%、56.9%;p-mTOR、MRP1 mRNA在GCB型DLBCL与non-GCB型DLBCL中的表达差异具有统计学意义（P<0.01）,p-mTOR的表达与MRP1 mRNA的扩增显著相关（P=0.003）。p-mTOR表达阳性组、阴性组患者的3年无进展生存率（progression free survival, PFS）分别为23%、69%,差异具有统计学意义（P=0.003）;MRP1 mRNA扩增阳性组、阴性组患者的3年PFS分别为39%、62%,差异具有统计学意义（P=0.042）。结论 MRP1、mTOR可能参与了DLBCL的发病,MRP1的表达与mTOR信号通路的激活密切相关。     

29例 CD5阳性弥漫大B 细胞淋巴瘤患者的临床预后分析

目的：探讨 CD5阳性弥漫大 B 细胞淋巴瘤的预后影响因素。方法回顾性分析了29例 CD5阳性弥漫大 B 细胞淋巴瘤患者临床资料及随访数据,采用 Kaplan-Meier 法估算患者的生存时间,采用 COX 比例风险模型进行预后影响因素分析。结果29例 CD5阳性弥漫大 B 细胞淋巴瘤患者1、2年无事件生存率分别为483%、255%,中位疾病无进展生存时间为10个月。全组患者1、2、3年总生存率分别为586%、449%、318%,中位总生存时间为19个月。单因素分析结果显示：不同的 Ann Arbor 分期、LDH 水平、IPI评分、结外受累范围、病理分型、利妥昔单抗的使用与否对总生存时间有显著影响（P ＜005）。COX 多因素回归分析结果显示：影响总生存时间的独立预后因素为 Ann Arbor 分期、病理类型及利妥昔单抗的使用与否。结论 CD5表达是 DLBCL 的不良预后因素,病理类型、Ann Arbor 分期及利妥昔单抗的使用是 CD5阳性 DLBCL 影响患者总生存期的独立预后因素。     

Intravenous Methotrexate as Initial Treatment for Primary Central Nervous System Lymphoma: Response to Therapy and Quality of Life of Patients

In anticipation of a consortium study of methotrexate (MTX) therapy provided to patients with primary central nervous system lymphoma (PCNSL) we have provided intravenous MTX without irradiation therapy to 31 non-immunosuppressed individuals. Twenty (65%) achieved complete response and 11 (35%) partial response to therapy. For the 31 patients the median survival was 30.43 months with an actuarial median follow up time of 30.69 months. The 2+ year survival was 63% for all patients and 90% for complete responders. Of 375 drug cycles, grade 3 leukopenia was identified in 3 cycles, mucositis in 6 cycles and delayed drug clearance in 47 cycles. Recurrences included brain (9/20) and/or spinal fluid (2/20). The median Karnofsky scale improved from 40 (10–80) prior to therapy to 90 after treatment. Eleven patients, in complete response for a median of 22+ months after diagnosis were evaluated using 4 instruments that assess Quality of Life Functional Assessment of Cancer Therapy – Brain (FACT-BR) modified, Symptom Questionnaire, Social Adjustment Scale-Self-Report and Problem Solving Inventory. Their psychosocial adjustment, well-being and stress coping abilities were comparable to the normative groups. Further there was no evidence of any MTX-induced, Magnetic Resonance Imaging (MRI)-detected encephalopathy in these individuals and there was preservation of clinical cognition and memory. We conclude that therapy with MTX, without radiation can be used in PCNSL patients without limitations of age or pretreatment Karnofsky scores. Further rates of response and median survival approach those of therapies using multiple drugs and radiation, but with a less likely risk of dementia.     

Academic Centers Compared With Nonacademic Centers for Patients With International Prognostic Index Risk-stratified Diffuse Large B-cell Lymphoma: A Survival Outcomes Analysis

IntroductionDiffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease associated with varying outcomes. The International Prognostic Index (IPI) has been the standard for the baseline prognostic assessment in these patients. The present study aimed to determine the effect of the treatment facility on the overall survival outcomes in patients with DLBCL stratified by IPI risk groups.Materials and MethodsThe National Cancer Database was used to identify patients with a diagnosis of DLBCL from 2004 to 2015. DLBCL was stratified by the IPI risk score from low- to high-risk disease, and the overall survival of those treated at academic centers was compared with that of those treated at nonacademic centers.ResultsTreatment at academic centers was associated with significantly improved overall survival for all patients with DLBCL (108.3 months) compared with those treated at nonacademic centers (74.5 months; P < .001). The median survival for patients with high-risk disease treated at academic centers (33.5 months) was more than twice that of high-risk patients treated at nonacademic centers (14.4 months; P < .001). The median survival for the other risk categories was similarly improved, although less pronounced in the lower IPI score groups. The long-term overall survival for all patients with DLBCL at academic centers was improved at 5 and 10 years (59% and 43% survival, respectively) compared with those treated at nonacademic centers (51% and 35% survival, respectively; P < .001).ConclusionPatients with DLBCL treated at academic centers demonstrated improved survival compared with those treated at nonacademic centers, especially those with high-risk disease. Further investigations into the factors contributing to such disparities are required to help standardize care and improve outcomes.     

Outcomes of Transplant-Eligible Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma After Second-Line Salvage Chemotherapy: The Gustave Roussy Experience

IntroductionAfter failure of frontline therapy, patients with relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL) that does not respond to first-line salvage chemotherapy can be recommended second-line salvage chemotherapy. The available literature in this regard is weak, although many centers routinely offer this type of second-line salvage chemotherapy to their patients.Patients and MethodsThis retrospective study included transplant-eligible patients with RR-DLBCL treated at Gustave Roussy between January 2008 and April 2020. Eligible patients were those who received second-line salvage chemotherapy using R-DHAP or R-ICE in patients who experienced an insufficient partial response, stable disease, or progressive disease in response to first-line salvage chemoimmunotherapy using an alternative regimen.ResultsForty-six RR-DLBCL patients received second-line salvage regimen, which yielded an objective response rate of 33%, median progression-free survival of 2.1 months, and overall survival of 11.4 months. Twelve patients proceeded to autologous stem-cell transplantation (ASCT), of whom 70% remained alive 1 year after ASCT. To explore the impact of transplantation, a multivariate analysis (excluding response to the first-line salvage regimen because this covariate was totally embedded within the transplantation covariate), ASCT was associated with progression-free survival (hazard ratio = 0.16; 95% confidence interval, 0.06-0.42) and overall survival (hazard ratio = 0.27; 95% confidence interval, 0.08-0.88).ConclusionSecond-line salvage chemotherapy with R-DHAP or R-ICE followed by ASCT leads to a favorable outcome in almost one third of patients with RR-DLBCL and offers a median overall survival of approximately 1 year. These data support the administration of second-line salvage chemotherapy followed by ASCT.     

Influence of MTHFR C677T Polymorphism on High-Dose Methotrexate-Related Toxicity in Patients With Primary Central Nervous System Diffuse Large B-Cell Lymphoma

BackgroundPrimary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL) is a relatively rare and aggressive neoplasm. High-dose methotrexate (HD-MTX) is an effective regimen for the treatment of PCNS-DLBCL, but MTX–related toxicity remains a problem. The aim of this analysis study was to investigate the influence of the methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism on HD-MTX–related toxicity in patients with PCNS-DLBCL.Material/MethodsA prospective, observational study was conducted to analyze 148 MTX courses in 32 patients with PCNS-DLBCL.ResultsThe delayed MTX clearance was observed in 53 cycles (35.8%). The patients carrying the homozygous variant genotype had a higher risk of developing nephrotoxicity than those carrying the wild-type genotype (odds ratio [OR] 13.08; 95% confidence interval [CI], 1.65-103.86; P = .002) or heterozygous variant genotype (OR 8.43; 95% CI, 2.31-30.70; P < .001). Significant differences were observed in hepatotoxicity (OR 9.33; 95% CI, 2.54-34.27; P < .001) and hematologic toxicity (OR 3.09; 95% CI, 1.18-8.07; P = .024) in addition to nephrotoxicity between the homozygous variant genotype and the wild-type genotype.ConclusionThe homozygous mutation of C to T at nucleotide 677 increases the risk on HD-MTX–related toxicity. The MTHFR C677T polymorphism can be used to predict HD-MTX–related toxicity for patients with PCNS-DLBCL.