Successful treatment of gastrointestinal follicular lymphoma with rituxan and combination chemotherapy

The clinical course of follicular lymphoma (FL) is well known. Although it is a chemosensitive disease, thereby allowing substantial palliation, recurrence is the rule; only a small subset who presents with limited stage disease is cured. Multiple attempts have been made over the past two decades to improve the survival of patients with FL, and a large number of phase III trials have been reported. These have included a variety of different therapeutic interventions, such as combination chemotherapy, recombinant interferons, new cytotoxic drugs, and immunologic agents. Most studies have not demonstrated that the use of a particular therapy convincingly prolongs survival. Follicular lymphoma cells express CD20 and are associated in most cases with the t(14:18) chromosomal translocation. Rituximab is a chimeric monoclonal antibody directed against the B-cell CD20 antigen, which has been utilized for the therapy of B-cell non-Hodgkin's lymphoma. Rituximab was shown to be active in FL, and studies of its effectiveness in combination with cytotoxic chemotherapy to increase the response rate are forthcoming.     

The role of fludarabine in the treatment of follicular and mantle cell lymphoma

Advanced-stage follicular lymphoma (FL) and mantle cell lymphoma (MCL) cannot be cured using conventional chemotherapy. Fludarabine, the most widely used purine analog, exhibits a particularly high level of activity against small lymphocytic lymphoma and chronic lymphocytic leukemia (CLL). Numerous studies have investigated the efficacy of fludarabine as a single agent or in combination with other cytostatic compounds in the treatment of FL and MCL. Hematologic toxicity is the most commonly observed adverse event in patients treated with fludarabine, but serious infectious complications are relatively rare. Fludarabine monotherapy has proven to be particularly effective in the treatment of FL; however, complete responses (CRs) are observed in only approximately 20-40% of all cases. In contrast, combinations containing fludarabine and anthracyclines or alkylating agents have yielded superior response rates and longer periods of progression-free survival (PFS), and the addition of the anti-CD20 antibody rituximab appears to yield even better results. In a randomized trial, an immunochemotherapy regimen consisting of a fludarabine-containing combination and rituximab resulted in superior remission and survival rates compared with the fludarabine-containing combination alone. In summary, fludarabine has proven to be a safe and effective agent in the treatment of indolent lymphoma. In particular, combinations containing fludarabine, anthracyclines and/or alkylating agents, and rituximab have yielded remarkable CR and PFS rates. Consequently, current research efforts have focused on the use of fludarabine-containing combinations in the first-line treatment of FL and MCL.     

滤泡淋巴瘤的分子靶向及免疫治疗新进展

滤泡淋巴瘤（follicular lymphoma,FL）为最常见的惰性非霍奇金淋巴瘤（non-Hodgkin lymphoma,NHL）,其5年生存率较高,但多数患者最终会发展成为复发/难治性淋巴瘤。其特点为进展缓慢,且晚期较难治愈。因此,治疗策略目标为高疗效及低毒性。基于各种新型药物的不断出现,FL患者的预后得到改善。目前的临床研究结果中,具有良好活性的分子靶向药物包括BTK抑制剂、PI3K抑制剂、Bcl-2抑制剂、EZH2抑制剂等。此外,免疫调节药物,如来那度胺、GA101、CAR-T、PD-1、抗体-药物结合物以及双特异性抗体等均显示出较好的治疗效果,为改善FL患者的预后提供新的可能。免疫治疗需考虑药物不良反应,以选择合适方式减轻毒性。本文就FL免疫治疗及分子靶向治疗的新进展进行综述。      

Integration of molecular testing for the personalized management of patients with diffuse large B-cell lymphoma and follicular lymphoma

Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the most common forms of aggressive and indolent lymphoma, respectively. The majority of patients are cured by standard R-CHOP immunochemotherapy, but 30%–40% of DLBCL and 20% of FL patients relapse or are refractory (R/R). DLBCL and FL are phenotypically and genetically hereterogenous B-cell neoplasms. To date, the diagnosis of DLBCL and FL has been based on morphology, immunophenotyping and cytogenetics. However, next-generation sequencing (NGS) is widening our understanding of the genetic basis of the B-cell lymphomas. In this review we will discuss how integrating the NGS-based characterization of somatic gene mutations with diagnostic or prognostic value in DLBCL and FL could help refine B-cell lymphoma classification as part of a multidisciplinary pathology work-up. We will also discuss how molecular testing can identify candidates for clinical trials with targeted therapies and help predict therapeutic outcome to currently available treatments, including chimeric antigen receptor T-cell, as well as explore the application of circulating cell-free DNA, a non-invasive method for patient monitoring. We conclude that molecular analyses can drive improvements in patient outcomes due to an increased understanding of the different pathogenic pathways affected by each DLBCL subtype and indolent FL vs R/R FL.     

滤泡淋巴瘤治疗研究进展

滤泡淋巴瘤（FL）是起源于滤泡生发中心的惰性非霍奇金淋巴瘤。第58届美国血液学会（ASH）年会上,多篇研究报道了FL治疗的最新进展。 GA101联合化疗、苯达莫司汀（BR）联合90Y替伊莫单抗（90YIT）治疗中晚期FL的临床试验结果鼓舞人心;自体造血干细胞移植与非清髓同种异基因造血干细胞移植（allo-SCT）序贯治疗给复发、难治的FL患者带来更好的疗效,PI3K抑制剂、bcl-2抑制剂、抗体-药物共轭物等新药接连涌现,复发、难治FL的治疗效果和缓解程度不断提高。     

Proteasome inhibition with bortezomib: a new therapeutic strategy for non-Hodgkin's lymphoma

The incidence of non-Hodgkin's lymphoma (NHL) has markedly increased in the US and other westernized countries in recent years and presents a considerable clinical challenge. NHL is divided into subtypes that follow an aggressive or indolent course. Follicular lymphoma (FL), the most common indolent subtype, and mantle cell lymphoma (MCL), an aggressive subtype that accounts for approximately 5% of cases, are generally incurable. MCL has a relatively poor prognosis, with a median survival of 3-4 years. Despite improving response rates with new agents and regimens, the lack of demonstrated improvement in overall survival in many subtypes supports the development of novel approaches, such as proteasome inhibition. Bortezomib is the first proteasome inhibitor to be evaluated in human studies. It has already been approved as second-line treatment in multiple myeloma and is now under active investigation in NHL. The US FDA has granted bortezomib fast-track designation for relapsed and refractory MCL. In vitro and in vivo studies have demonstrated single-agent activity against various lymphoid tumors, and additive or synergistic effects in combination with other agents, including standard chemotherapy drugs employed in NHL. Phase 2 clinical trials indicate that bortezomib is well tolerated and active in several NHL subtypes, with response rates of 18-60% in FL and 39-56% in MCL. A number of combination trials are currently underway with a range of standard agents. Bortezomib has the potential to play a significant role throughout the NHL treatment algorithm in the future.     

滤泡性淋巴瘤新药研究进展

 滤泡性淋巴瘤（FL）是一种起源于B淋巴细胞的非霍奇金淋巴瘤（NHL）,临床自然病程较长,表现惰性,初始治疗后易复发,传统的治疗方案多难以治愈。因此选择合适的治疗方案是延长患者生存时间的关键。利妥昔单抗、放射免疫治疗、苯达莫司汀等已应用于FL的治疗。一些具有前景的新药如ofatumumab、epratuzumab、雷利度胺、硼替佐米、ABT-263等目前正在进行临床试验,这些新药将会为FL的治疗增加更多的选择。     

Recent progress in the treatment of malignant lymphoma

The present state of the art and developments in the treatment for Hodgkin's disease (HD), follicular lymphoma (FL), MALT lymphoma, and aggressive non-Hodgkin's lymphoma are reviewed. Four courses of ABVD therapy (ABVd therapy in Japan) followed by involved-field irradiation (IFRT), and 6 to 8 courses of ABVD (ABVd in Japan) are the current state art of the therapy for early stage HD and advanced stage HD, respectively. High-dose chemotherapy with autologous hematopoietic stem cell transplantation (auto-HSCT) is also the state of the art for refractory or relapsed HD within 1 year after complete remission (CR) produced by polychemotherapy. The prognosis of the patients with 3 or more International Prognostic Scores (IPS) is poor. New intensified polychemotherapy or auto-HSCT as up-front setting is under randomized phase III clinical trial in Europe and the USA. There is no state of the art therapy for indolent lymphoma including FL, or MALT. Promising results were reported from clinical studies using new anti-lymphoma drugs such as rituximab, iibritumomab, or purine analogs (cladribine and fludarabine), and auto-HSCT with effectively purged stem cells or allogeneic HSCT. These therapeutic strategies hold a possibility of cure for indolent lymphomas. Antibiotic treatment for Helicobacter pylori-positive localized gastric MALT lymphoma is the state of the art therapy. However, there is no standard therapy for advanced stage MALT lymphoma. Risk adapted therapy using the International Prognostic Index is essential for the treatment of aggressive NHL. Three courses of CHOP followed by IFRT for localized aggressive NHL and 8 courses of CHOP for the low-risk group of advanced stage aggressive NHL are the state of the art therapies, respectively. High-dose chemotherapy with auto-HSCT is also the state of the art for sensitive relapse patients with aggressive NHL. Although some clinical studies suggested that high-dose chemotherapy with auto-HSCT as up-front setting for high-intermediate or high-risk group aggressive NHL is more effective than conventional chemotherapy, the efficacy remains to be determined. The development of new therapeutic strategies with combined use of molecular targeting drugs such as rituximab, or new anti-lymphoma drugs such as purine analogs, and HSCT is desired for more effective therapy for refractory lymphomas.     

Is There a Best Initial Treatment for a New Patient With Low Grade Follicular Lymphoma

The treatment landscape for newly diagnosed follicular lymphoma (FL) has dramatically changed over the past decade, first with the advent of rituximab and then with the activity of old and new drugs, like bendamustine and lenalidomide, in this disease. The efficacy and tolerability of rituximab has led to a paradigm shift for the management of patients with low volume FL for many oncologists. Despite the lack of a survival benefit seen with this approach, many now use this single agent in patients who had historically been observed. Likewise, its use as maintenance therapy following successful front-line induction therapy of patients with symptomatic FL, with either rituximab alone or specific chemoimmunotherapy regimens, has improved remission duration and widely been adopted. As newer chemoimmunotherapy regimens, like bendamustine and rituximab, have superior outcomes with improved tolerability, upfront treatment options are redefined and questions emerge: whom do maintenance strategies benefit, and what is the optimal sequencing of therapies? Finally, as newer targeted and potentially better tolerated therapies demonstrate efficacy in the relapsed setting, their use, both in combination with and in place of chemotherapy, is being explored. The promising regimen of lenalidomide with rituximab is being compared with chemoimmunotherapy in a randomized fashion. Cure remains elusive, however, in advanced stage disease and so safety and tolerability, in addition to efficacy, remain important endpoints.     

Considerations with newer regimens for indolent non-Hodgkin lymphoma

Follicular lymphoma (FL) is considered incurable with current therapies and shows a pattern of multiple remissions and repeated relapses. After demonstrations of significant improvements in clinical outcomes with the addition of rituximab to chemotherapy regimens including alkylating agents and anthracyclines, rituximab-containing chemoimmunotherapy strategies have become central to the management of FL. More recently, novel cytotoxic agents such as bendamustine and pixantrone, that circumvent some of the limitations of conventional chemotherapeutic agents, have been developed and are being clinically investigated. These novel agents are showing promising clinical activity alone and in combination with rituximab in indolent lymphomas. In order to further improve the therapeutic index for patients with FL, rituximab is being combined with novel biologic agents such as immunomodulatory cytokines and monoclonal antibodies targeting CD80 and CD22. This article provides a review of newer chemoimmunotherapy strategies in the management of patients with FL.     

滤泡性淋巴瘤的预后分层和治疗进展

滤泡性淋巴瘤(Follicular lymphoma,FL)是非霍奇金淋巴瘤(Non-Hodgkin's lymphoma,NHL)中发病率仅次于弥漫大B细胞淋巴瘤的常见B细胞淋巴瘤。FL属于惰性淋巴瘤,尽管该疾病进展缓慢但并不能治愈,且由于复发及进展,严重影响着患者的生存。近年来,针对FL的“无化疗”方案疗效确切且毒性较低,新型免疫治疗和靶向药物也显示较好疗效,受到研究者的广泛关注。为进一步加深临床医生对FL治疗新进展的认识,本文对FL的分层及治疗进展进行综述。     

Phase II study of tazemetostat for relapsed or refractory B-cell non-Hodgkin lymphoma with EZH2 mutation in Japan

Tazemetostat is a selective, reversible, small-molecule inhibitor of the histone methyltransferase enzyme, enhancer of zest homolog 2 (EZH2). In this multicenter, open-label, phase II study, we assessed the efficacy and safety of tazemetostat in Japanese patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma harboring the EZH2 mutation. Tazemetostat (800 mg twice daily) was given orally (28-day cycle) until disease progression or unacceptable toxicity. Among the 20 eligible patients, 17 were enrolled in cohort 1 (follicular lymphoma [FL]), and three were enrolled in cohort 2 (diffuse large B-cell lymphoma). At data cut-off, the objective response rate in cohort 1 was 76.5%, including six patients (35.3%) with complete response and seven patients (41.2%) with partial response (PR). All three patients in cohort 2 achieved PR. In cohort 1, median progression-free survival (PFS) was not reached at the median follow-up of 12.9 months. The estimated PFS rate at 12 and 15 months was 94.1% and 73.2%, respectively. The most common grade 3 treatment-emergent adverse event (TEAE) was lymphopenia (n = 2). Grade 4 TEAEs included hypertriglyceridemia and pneumonia aspiration (n = 1 each), which were not related to tazemetostat. Treatment-emergent adverse events leading to study drug discontinuation were reported in four of the 20 patients, indicating that the safety profile of tazemetostat was acceptable and manageable. Tazemetostat 800 mg twice daily showed encouraging efficacy in patients with R/R EZH2 mutation-positive FL with a manageable safety profile in the overall population. Thus, tazemetostat could be a potential treatment for R/R EZH2 mutation-positive FL.     

Rituximab therapy in malignant lymphoma

Rituximab is the first monoclonal antibody to have been registered for the treatment of B-cell lymphomas. Randomized studies have demonstrated its activity in follicular lymphoma (FL), mantle cell lymphoma and diffuse large B-cell lymphoma (DLBCL) in untreated or relapsing patients. Non-comparative studies have shown an activity in all other lymphomas. Because of its high activity and low toxicity ratio, rituximab has transformed the outcome of patients with B-cell lymphoma. A combination of rituximab plus chemotherapy, rituximab+cyclophosphamide+doxorubicin+vincristine+prednisolone (R-CHOP), has the highest efficacy ever described with any chemotherapy in DLBCL and FL. Some patients are refractory to rituximab but the precise mechanisms of this refractoriness are not understood.     

滤泡淋巴瘤治疗进展:第56届美国血液学会年会报道

滤泡淋巴瘤(FL)是一种起源于滤泡生发中心的惰性非霍奇金淋巴瘤(NHL).在2014年12月召开的第56届美国血液学会年会上,多篇研究报道了FL治疗的最新进展.放疗在早期FL的疗效依旧被肯定,GA101联合化疗治疗中晚期FL的临床试验结果亦鼓舞人心;利妥昔单抗年代造血干细胞移植仍给复发难治的FL患者带来更优的缓解,BTK、PI3K抑制剂等新药随着相应临床试验的进展也树立了治疗复发难治FL的新路标.     

利妥昔单抗时代滤泡性淋巴瘤移植治疗的现状及前景

 滤泡性淋巴瘤（FL）是来源于滤泡生发中心的B细胞淋巴瘤。作为最常见的惰性淋巴瘤,FL总体预后较好,但其转归又具有异质性。利妥昔单抗的应用改善了疾病的疗效和预后。对于复发、难治患者,尤其是前期接受过含利妥昔单抗的一线方案治疗者,移植治疗是其重要选择。与传统清髓性预处理方案相比,减低强度预处理（RIC）方案降低了非复发死亡（NRM）率,扩展了可接受异基因移植的患者选择,但移植后复发率偏高是其主要缺陷。移植后应用供体淋巴细胞输注治疗可以减少和治疗疾病复发。未来,移植策略改进和新药应用会为FL治疗带来新的思路和机会。     

Primary duodenal follicular lymphoma successfully treated with rituximab

Non-Hodgkin’s lymphoma (NHL) of the gastrointestinal (GI) tract is the most common extranodal lymphoma, accounting for approximately 40% of all extranodal NHLs. Initial treatment of duodenal lymphoma includes surgery, chemotherapy and radiotherapy, alone or in combination. Here, we present a case of stage I primary duodenal follicular lymphoma (FL) showing a complete response after rituximab therapy. Rituximab alone can be an effective alternative treatment for duodenal FL.     

Marked clinical activity of the proteasome inhibitor bortezomib in patients with follicular and mantle-cell lymphoma

Recent advanced developments in our understanding of cancer cell biology have begun to generate a host of new targets that are proving to be valuable substrates for new drug development. One example includes our ever-increasing understanding of the complex biology surrounding the ubiquitin-proteasome pathway. For years there have been a variety of compounds used in the laboratory that have been shown to inhibit the proteasome, though many of these compounds have proven to be relative non-specific inhibitors of intracellular and proteasome proteases. The recent synthesis of 1 novel inhibitor, bortezomib (formerly known as PS341), has proven to be an effective reversible inhibitor of the chymotryptic protease in the 26S proteasome. Proteasome inhibition represents a new approach for the treatment of many forms of cancer, especially select hematologic malignancies. Bortezomib has been approved by the United States Food and Drug Administration for the treatment of relapsed or refractory multiple myeloma. In addition to myeloma, bortezomib has also shown promising activity in the treatment of select types of non-Hodgkin's lymphomas (NHLs). Several single-agent phase II clinical trials in patients with a host of different NHL histologies have demonstrated that bortezomib has reproducible activity in mantle-cell lymphoma (MCL) and follicular lymphoma (FL), with some suggestion of activity in marginal zone lymphoma. The promising activity in these smaller studies has led to a number of larger multicenter studies with bortezomib in combination with rituximab in MCL, FL, and marginal zone lymphoma. The collective early experience from these studies continues to support the activity of bortezomib in these histologies of NHL. Herein, some of the biologic rationale for using proteasome inhibitors in lymphoma as well as some of the clinical data from these promising studies are discussed.     

A phase 1 dose escalation study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone for untreated follicular lymphoma and other low-grade B-cell lymphomas

BACKGROUND:

Bortezomib has demonstrated efficacy in patients with relapsed B‐cell non‐Hodgkin lymphoma (NHL) both alone and in combination with other agents; however, limited data exist regarding its toxicity in combination with common frontline therapies for indolent NHL. A phase 1 study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone (R‐CHOP) was conducted in patients with untreated follicular lymphoma (FL) and other indolent NHLs.

METHODS:

Nineteen patients, including 10 patients with FL, were enrolled. The median patient age was 59 years (range, 29‐71 years). Seven patients had a FL International Prognostic Index score ≥3. R‐CHOP with the vincristine dose capped at 1.5 mg was administered on a 21‐day cycle for 6 to 8 cycles, and 1 of 3 dose levels of bortezomib (1.0 mg/m² [n = 1], 1.3 mg/m² [n = 6], or 1.6 mg/m² [n = 12]) was administered on days 1 and 8 of each cycle using a Bayesian algorithm for dose escalation.

RESULTS:

The maximum tolerated dose (MTD) of bortezomib with modified R‐CHOP was reached at 1.6 mg/m². Dose‐limiting toxicity was observed in 5 patients (1 patient at a bortezomib dose of 1.0 mg/m², 1 patient at a bortezomib dose of 1.3 mg/m², and 3 patients at a bortezomib dose of 1.6 mg/m²). Neuropathy occurred in 16 patients (84%), including 2 patients (11%) who experienced grade 3 sensory neuropathy. Grade 4 hematologic toxicity occurred in 4 patients. Of 19 evaluable patients, 100% responded, and the complete response rate was 68%. At a median follow‐up of 32 months, the 3‐year progression‐free survival rate was 89.5%.

CONCLUSIONS:

Bortezomib combined with modified R‐CHOP produced high response rates without substantial increases in toxicity. A phase 2 study of R‐CHOP and bortezomib given at this established MTD is currently ongoing. Cancer 2012;3538–3548. © 2012 American Cancer Society.     

HA14-1, a small molecule Bcl-2 antagonist, induces apoptosis and modulates action of selected anticancer drugs in follicular lymphoma B cells

The BCL-2 overexpression is a hallmark of follicular lymphoma (FL). Since patients with FL often suffer from resistant to chemotherapy refractory disease, the development of new regimens is required. Herein, we analyze for the first time the effects of a B-cell lymphoma 2 (Bcl-2) antagonist, HA14-1, alone and in combination with antineoplastic agents commonly used against follicular lymphoma, in human FL cell lines with t(14;18). All cell lines tested were sensitive to HA14-1-induced cytotoxicity and apoptosis, as depicted by morphological changes, SYTO16/PI staining, oligonucleosomal DNA fragmentation and loss of Deltapsi(m). Moreover, HA14-1 significantly enhanced dexamethasone- and doxorubicin-mediated (in schedule independent and dependent manner, respectively), but not vincristine-mediated cytotoxicity and apoptosis.