Consolidative Radiotherapy After Autologous Stem Cell Transplantation for Relapsed or Refractory Diffuse Large B-cell Lymphoma

Introduction

We evaluated the role of consolidative radiotherapy (RT) for patients undergoing high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) for relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

利妥昔单抗和挽救性自体造血干细胞移植治疗失败的原发性CD5+弥漫大B细胞淋巴瘤经验分享

目的 分析原发性CD5+弥漫大B细胞淋巴瘤(DLBCL)的特点及其特殊性.方法 对1例初诊时病理漏检CD5的原发性CD5+ DLBCL患者的诊疗过程进行总结,并复习相关文献.结果 本例初诊和复发均按照NCCN指南推荐进行,分别选用含有利妥昔单抗的标准剂量一线、二线化疗方案.并在二次复发时行挽救性自体造血干细胞移植,仍无法阻止病情进展,最终在移植后1 a内死亡.结论 原发性CD5+ DLBCL预后差,加入利妥昔单抗的化疗方案治疗不能改善其生存,挽救性自体造血干细胞移植亦无法改善其预后.     

原发性中枢神经系统淋巴瘤治疗进展

原发性中枢神经系统淋巴瘤（PCNSL）恶性度高,预后较差。PCNSL目前无标准治疗方案,单纯手术或单纯放疗效果较差,以氨甲喋呤（HD-MTX）为基础的综合治疗可改善患者生存率。综合化疗后的放疗以全脑放疗为首选,但放疗可导致老年患者神经毒性。化疗后自体干细胞移植及靶向药物可改善患者预后,并可降低神经毒性发生率。     

Durable Survival Outcomes in Primary and Secondary Central Nervous System Lymphoma After High-dose Chemotherapy and Autologous Stem Cell Transplantation Using a Thiotepa,Busulfan, and Cyclophosphamide Conditioning Regimen

BackgroundHigh-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has been investigated in patients with primary central nervous system lymphoma (PCNSL) and non-Hodgkin lymphoma (NHL) with CNS involvement and has shown promising results.Patients and MethodsA retrospective analysis was performed of 48 consecutive patients who had undergone HDC/ASCT with TBC (thiotepa, busulfan, cyclophosphamide) conditioning for PCNSL (27 patients), secondary CNS lymphoma (SCNSL) (8 patients), or relapsed disease with CNS involvement (13 patients) from July 2006 to December 2017. Of the 27 patients with PCNSL, 21 had undergone ASCT at first complete remission (CR1).ResultsThe 2-year progression-free survival (PFS) rate was 80.5% (95% confidence interval [CI], 69.9-92.9) and the 2-year overall survival (OS) rate was 80.1% (95% CI, 69.2%-92.7%) among all patients. The 2-year PFS and OS rate for patients with PCNSL in CR1 was 95.2% (95% CI, 86.6%-100%) and 95.2% (95% CI, 86.6%-100%), respectively. On univariate analysis of the patients with PCNSL, ASCT in CR1 was the only variable statistically significant for outcome (P = .007 for PFS; P = .008 for OS). Among patients with SCNSL or CNS relapse, the 2-year PFS and OS rate were comparable at 75.9% (95% CI, 59.5%-96.8%) and 75.3% (95% CI, 58.6%-98.6%), respectively. The most common side effects were febrile neutropenia (89.6%; of which 66.7% had an infectious etiology identified), nausea/vomiting (85.4%), diarrhea (93.8%), mucositis (89.6%), and electrolyte abnormalities (89.6%). Four patients (8.3%) died of treatment-related overwhelming infection; of these patients, 3 had SCNSL.ConclusionHDC and ASCT using TBC conditioning for both PCNSL and secondary CNS NHL appears to have encouraging long-term efficacy with manageable side effects.     

Successful Management of Natalizumab-Associated Primary Central Nervous System Lymphoma through Autologous Stem Cell Transplant

Natalizumab is used as a second-line treatment for multiple sclerosis (MS). Some reports have linked natalizumab to primary central nervous system lymphoma (PCNSL), although few have described its management. A 45-year-old woman with Balo’s Concentric Sclerosis presented dizziness, vertigo accompanied by dysarthria, weakness on the left side and blurred vision to the right eye after the fourth dose of natalizumab. Magnetic resonance imaging (MRI) and a brain biopsy confirmed the diagnosis of PCNSL. The patient received modified PCNSL chemotherapy (MATRix protocol) followed by high-dose chemotherapy (HDC) supported by an autologous hematopoietic stem cell transplant (ASCT) as a consolidation therapy. Thirty months later, she is still in complete remission of her PCNSL and MS. In this case, whole brain radiotherapy was excluded because it may be associated with an increased risk of neurotoxicity in MS. ASCT was preferred because it has been shown to prevent disability progression in less advanced MS stages. Our patient is the second to receive an ASCT in this context and this option of treatment should be the preferred if the patient is eligible.     

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.     

Autologous Stem-Cell Transplantation for Primary Central Nervous System Lymphoma: Systematic Review and Meta-analysis

Background

Primary central nervous system lymphoma (PCNSL) is an aggressive form of non-Hodgkin lymphoma. Methotrexate is first-line chemotherapy. Autologous stem-cell transplantation (ASCT) is increasingly used as an alternative consolidative treatment to whole-brain radiotherapy.

Disparities in Utilization of Autologous Stem Cell Transplantation as Consolidative Therapy for Multiple Myeloma: A Single Institution Retrospective Review

BackgroundMost guidelines recommend induction therapy followed by autologous hematopoietic cell transplantation. A Surveillance, Epidemiology, and End Results–Medicare database analysis from 2000 to 2011 noted a lower use of HCT and bortezomib among Black patients, despite adjusting for care barriers, and this practice was associated with a poorer outcome. The goal of this study was to evaluate patterns of acceptance of HCT as consolidative therapy for MM.MethodsCox proportional hazards model was used to investigate the association between the survival time of the patients (overall survival) and age of the diagnosis, race, socioeconomic status, disease cytogenetic, and initial induction regimens. A total of 194 patients with a confirmed diagnosis of MM who were referred for HCT between January 1, 2009, and June 30, 2019, were included in this study. Patients who received autologous stem cell transplant for relapsed MM were excluded.ResultsWe found that income category was not significantly associated with overall survival, time to transplant or transplant-/relapse-related mortality. High-risk cytogenetic was significantly associated with shorter overall survival, higher transplant-related mortality and relapse-related mortality (P < .002). The use of aggressive induction choices was associated with poorer transplant outcomes (P = .02). Time to transplant tended to be shorter in African American compared with other ethnic groups (P = .07).ConclusionThere was no significant difference in the use rate of the HCT between Caucasians and AA patients with MM. Further comparative studies of MM induction therapy and access to clinical trials in African Americans and other racial minorities are warranted.     

High-dose Thiotepa,Busulfan, Cyclophosphamide,and Autologous Stem Cell Transplantation as Upfront Consolidation for Systemic Non-Hodgkin Lymphoma With Synchronous Central Nervous System Involvement

IntroductionSynchronous involvement of the central nervous system (CNS) at the diagnosis of systemic non-Hodgkin lymphoma (NHL) is associated with an increased risk for relapse despite complete remission to initial therapy. High-dose chemotherapy with a CNS-directed conditioning regimen followed by autologous stem cell transplantation (ASCT) holds promise as a consolidative approach.Patients and MethodsWe conducted a retrospective analysis of all patients with systemic B-cell NHL and synchronous CNS involvement who received upfront consolidation with high-dose chemotherapy with thiotepa, busulfan, cyclophosphamide, and ASCT while in first complete remission between July 2008 and June 2016 at 2 partner academic institutions.ResultsTwenty patients were identified through the transplant database. The median age at diagnosis was 53 years (range, 37-65 years). The majority had diffuse large B-cell lymphoma histology (n = 17; 85%). The sites of CNS involvement were parenchymal (n = 12; 60%) and leptomeningeal disease (n = 9; 45%). All patients received systemic and CNS-directed therapy prior to transplant, with the most common approaches being R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone) (n = 13; 65%) and high-dose intravenous methotrexate (n = 16; 80%), respectively. With a median follow up of 4.4 years after ASCT (range, 2 months-8.5 years), the Kaplan-Meier estimates of 4-year progression-free and overall survival were 77% (95% confidence interval, 48%-91%) and 82% (95% confidence interval, 54%-94%), respectively.ConclusionCNS-directed high-dose chemotherapy and ASCT provides durable remission for patients with synchronous aggressive lymphoma and should be strongly considered as consolidative therapy for eligible patients with systemic NHL with CNS involvement in first complete remission.     

原发中枢神经系统生殖细胞瘤诊治

原发中枢神经系统生殖细胞肿瘤(primary central nervous system germ cell tumors,CNS GCTs)好发于儿童青少年和年轻成人。主要位于松果体和鞍上区。病理上分为胚组织瘤(germinoma)和非胚组织瘤(Nongerminoma,NGGCT),后者包括畸胎瘤、胚胎癌、内胚窦瘤和绒毛膜上皮癌。治疗前明确病理诊断对治疗方案的选择非常重要。肿瘤标记物AFP和β-HCG的检测有助于鉴别诊断。胚组织瘤主要采用放射治疗,对儿童患者可通过联合化疗减少放疗的剂量和范围。非胚组织瘤对放疗敏感性较差,需要化疗、放疗或手术等综合治疗改善生存率。CNSGCTs具有侵袭性和转移性的行为,不合适单纯采用立体定向伽玛射线(伽玛刀)治疗。针对CNSGCTs的生物学特点,采用减少不良反应保证疗效的综合治疗已取得较好的结果,值得进一步研究。     

原发性中枢神经系统淋巴瘤的临床诊治分析

[目的]探讨免疫正常的原发性中枢神经系统淋巴瘤（PCNSL）的生物学行为和临床特征．以帮助临床合理的诊断、治疗及对预后的判断。[方法]31例PCNSL经病理证实,其中27例为原发性脑淋巴瘤（PBL）;4例原发性眼淋巴瘤,回顾性分析其临床特征、诊断方法及治疗效果。在活检或手术后,患者主要以放化疗综合治疗为主。化疗以CHOP和MTX＋Arac方案为主;全脑放疗40Gy～44Gy,局部肿瘤缩野放疗加量11Gv～25．4Gy。对眼部淋巴瘤放疗25．2Gy～30Gy。[结果]PCNSL发病率明显上升。全组病人均为免疫正常者。发病中位年龄56岁（14～83岁）,≥60岁占48．2％。脑多发者22例（81．5％）。脑立体定向活检确诊20例（1次性成功率90％）,手术确诊7例。B细胞淋巴瘤占93．6％,T细胞淋巴瘤占6．4％。有4例患者在外院曾误诊65天～7个月。全组PBL1、3、5年生存率分别为68．2％、52．3％和29％。全组中位生存时间37个月。[结论]PCNSL常发生在中老年人,B细胞来源为主。PBL临床和影像学很难与其他CNS肿瘤相区别,易误诊。对PBL疑似病人,脑立体定向活检可提高诊断效率。化放疗综合治疗可提高疗效。≥60岁者预后不良。     

High-dose Therapy and Autologous Hematopoietic Cell Transplantation as Consolidation Treatment for Primary Effusion Lymphoma

BackgroundPrimary effusion lymphoma (PEL) is a rare type of non-Hodgkin lymphoma. The limited disease-free survival after chemotherapy has resulted in a poor prognosis. The outcomes data for high-dose therapy followed by autologous hematopoietic cell transplantation (auto-HCT) for PEL are limited owing to the rarity of the disease.Patients and MethodsThe present study included 9 patients with PEL from 2 major academic centers. Of these patients, 4 had received auto-HCT after high-dose therapy. Of the 9 patients, 8 (89%) had immunodeficiency (7 with human immunodeficiency virus seropositivity; 1, a solid organ transplant recipient) at the diagnosis. Human herpesvirus-8 by immunohistochemistry was positive in 8 patients. Anthracycline-based combination chemotherapy was used as first-line treatment in 7 patients; 4 underwent auto-HCT after attaining first complete remission.ResultsThe median follow-up of the surviving patients was 25 months (95% confidence interval [CI], 8%-29%). The 2-year progression-free and overall survival for the 8 patients who had received treatment was 58% (95% CI, 22%-95%) and 73% (95% CI, 41%-100%), respectively. The 2-year progression-free and overall survival for the patients who had received auto-HCT was 50% (95% CI, 1%-99%) and 75% (95% CI, 33%-100%), respectively. Of the 4 auto-HCT recipients, all had been in first complete remission at the time of autografting. The cumulative incidence of relapse was 50% (95% CI, 19%-100%). No deaths were attributable to auto-HCT at 2 years after autografting.ConclusionDespite the small sample size, our data have shown that consolidative auto-HCT is safe and effective and should be considered for eligible patients with PEL after demonstration of an objective response to induction chemotherapy. However, the high relapse rate remains a concern and warrants the development of new strategies to mitigate post-transplantation relapse.     

Upfront Autologous Stem Cell Transplantation for Untreated High-Risk Diffuse Large B-Cell Lymphoma in Patients Up to 60 Years of Age

BackgroundAlthough rituximab added to CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) is the standard chemotherapy for untreated DLBCL, its therapeutic effect is limited in younger patients with high-intermediate risk or high-risk disease according to the age-adjusted international prognostic index. In fact, the efficacy and safety of HDT plus rituximab followed by ASCT for such patients remain unclear.Patients and MethodsWe retrospectively investigated the safety and effectiveness of HDT/ASCT in patients with untreated DLBCL. Twenty-two patients, aged 60 years and younger, with untreated DLBCL (classified as high-intermediate [n = 14 (64%)] or high [n = 8 (32%)] risk) underwent upfront HDT/ASCT between January 2004 and December 2008, achieving either a complete response (CR; n = 15 (68%)) or a partial response (PR; n = 7 (32%)).ResultsThe 5-year overall survival rate was 81.0% and the progression-free survival rate was 73.0%, with no significant difference between risk groups based on the international prognostic index. The most common nonhematologic toxicity was febrile neutropenia [n = 9 (41%)]. The cause of all 3 fatalities was exacerbation of the underlying disease, and no treatment-related mortality was observed. No variables with a significant influence on overall survival were identified, but a correlation of the treatment response before transplanation with progression-free survival was suggested (CR vs. PR: 92% vs. 30%, P = .002).ConclusionThese results suggest that adding rituximab to upfront HDT/ASCT is feasible and can improve the outcome in untreated patients with poor-prognosis DLBCL. In the future, upfront HDT/ASCT should be more extensively evaluated in clinical trials.     

Patterns of Utilization and Outcomes of Autologous Stem Cell Transplantation and Chimeric Antigen Receptor T-Cell Therapy in Relapsed or Refractory Diffuse Large B-cell Lymphomas with MYC and BCL2 and/or BCL6 Rearrangements

BackgroundPatients with Diffuse Large Bcell Lymphoma (DLBCL) with MYC and BCL2 and/or BCL6 gene rearrangements [double-hit lymphoma/triple-hit lymphoma (DHL/THL)] have poor prognosis in the relapsed/refractory setting.MethodsWe utilized a real-world deidentified database of DLBCL patients and report patterns of therapy utilization in relapsed/refractory DLBCL. We used log-rank test to compare real-world overall survival (rwOS) among DHL and non-DHL subgroups for CAR Tcell therapy or ASCT respectively, stratified for prior lines of therapy.ResultsOf all 7,877 patients with DLBCL, 367 patients had DHL while 6113 had non-DHL. Second line chemotherapy was administered to 147 DHL patients and 1517 non-DHL. 1393 were excluded, including 934 with unknown DHL/THL status. Approximately 47% received salvage intent chemotherapy in the DHL subgroup, of which 19% patients eventually received ASCT, while 34% received salvage intent chemotherapy in the non-DHL/THL group with 32% receiving ASCT. DHL/THL status negatively influenced median rwOS for patients who underwent ASCT in the second-line while it was associated with numerically inferior but without statistically significant rwOS among patients that underwent CAR Tcell therapy on multivariable analysis.ConclusionrwOS of relapsed DHL/THL is inferior to non-DHL/THL. Fewer patients with DHL/THL were able to proceed with ASCT after salvage chemotherapy compared to non-DHL/THL. ASCT as second-line therapy for relapsed DHL/THL had worse rwOS than for non-DHL/THL, consistent with the natural history of DHL/THL. This difference was not seen for CAR Tcell therapy, which combined with promising results from clinical trials, suggests a greater role for CAR T-cell therapy in relapsed/refractory DHL.     

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.     

Small-Molecule Inhibitors for the Treatment of Diffuse Large B Cell Lymphoma

Purpose of Review

Diffuse large B cell lymphoma (DLBCL) remains the most common non-Hodgkin lymphoma (NHL) in developed countries. Up to 30–40% of patients experience either refractory or relapsed disease following receipt of front-line chemoimmunotherapy, and the majority of these patients will not be cured following receipt of subsequent therapy.

Recent Findings

Small-molecule inhibitors (SMIs) are an attractive class of therapeutics for patients with chemorefractory DLBCL, and early-phase studies with these agents have typically demonstrated prolonged periods of disease control in responding patients without significant toxicity. Later-phase studies have investigated the combination of SMIs with cytotoxic agents in hopes that exposure to SMIs in the treatment course may improve outcomes for patients who would otherwise develop chemorefractory disease.

Summary

SMIs appear to be effective in the treatment of DLBCL. A greater understanding of the molecular features of cases of DLBCL will allow for the more rational and presumably successful utilization of these targeted agents.