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.     

Evolving Strategies for the Treatment of Chronic Lymphocytic Leukemia in the Upfront Setting

Chronic lymphocytic leukemia (CLL) is a disease of marked clinical heterogeneity, and while some patients have a normal life expectancy, others develop rapidly progressive disease shortly after diagnosis. The current standard for upfront treatment of CLL is chemoimmunotherapy for younger fit patients, FCR (fludarabine, cyclophosphamide, and rituximab) being the prototype. For older patients, BR (bendamustine and rituximab) exhibits excellent activity with decreased toxicity. For the frailest patients, CD20 monoclonal antibodies with or without chlorambucil have proven to be efficacious. The novel oral kinase inhibitors ibrutinib and idelalisib are FDA-approved in the relapsed/refractory setting, and ibrutinib is approved upfront for those with del(17p). These drugs have produced long-term durable responses in the relapsed/refractory setting, and studies are underway using these as single agent upfront or in combination with both chemotherapy and monoclonal antibodies. Here, we review standard upfront therapies and new agents and combinations that are on the horizon for CLL.     

PI3K signaling pathway in normal B cells and indolent B-cell malignancies

In chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphomas (NHLs), B-cell receptor signaling leads to activation of the phosphatidylinositol 3-kinase (PI3K) pathway. Idelalisib, a PI3Kδ inhibitor was approved in 2014 by the US Food and Drug Administration (FDA) in combination with rituximab for the treatment of patients with CLL for whom single-agent rituximab would be considered appropriate and as a single agent for patients with relapsed small lymphocytic lymphoma (SLL) and relapsed follicular lymphoma (FL). Following its approval, several trials investigating various PI3Kδ inhibitors as single agents or in combination with chemoimmunotherapy or other molecular targeted agents in CLL and indolent NHL (iNHL) have uncovered some severe autoimmune related toxicities. This review discusses and summarizes the biologic basis and the clinical experience of the PI3Kδ inhibitors in indolent B-cell malignancies.     

Rituximab: a benchmark in the development of chemotherapy-free treatment strategies for follicular lymphomas

BackgroundWith the introduction of the anti-CD20 antibody rituximab, the outcome of patients with follicular lymphoma (FL) has greatly improved over the last two decades. First-line prolonged rituximab monotherapy is effective, achieving long-term remission and prolonged failure-free survival in some patients. Additionally, rituximab has been shown to synergize with chemotherapeutic and novel targeted agents alike with measurable gains in duration of response. As such, rituximab has made its mark in the treatment of FL and remains a valid agent despite the availability of newer monoclonal antibodies. This review summarizes the evolving role of rituximab as the first available anti-CD20 monoclonal antibody, emphasizing its clear activity as a single agent and in combination with chemotherapy or molecular targeted agents, and setting the standard for the development of new anti-CD20 monoclonal antibodies.ConclusionWe provide data that support the ongoing use of rituximab as a therapeutic partner for novel agents in future clinical trials exploring chemotherapy-free alternatives.     

Novel agents in chronic lymphocytic leukemia: efficacy and tolerability of new therapies

Alkylating agents and purine analogues have been the mainstays of therapy for chronic lymphocytic leukemia (CLL) for decades. The past decade witnessed the general clinical use of monoclonal antibodies such as rituximab and alemtuzumab, both as single agents and in combination regimens with cytotoxic drugs, for previously untreated and relapsed CLL. First-line chemoimmunotherapy regimens combining rituximab and purine analogues have greatly improved initial response rates and progression-free survival. Despite these advances in first-line therapy, patients with CLL invariably experience relapse and often acquire high-risk chromosomal abnormalities, such as del(11q22) and del(17p13), which result in resistance to current therapies. Patients who are refractory to fludarabine-based therapy have a median survival of <1 year. Therefore, new agents with novel mechanisms of action are needed for the treatment of patients with relapsed CLL, particularly for patients with high-risk genetic features. Recent clinical studies have examined the tolerability and efficacy of several novel agents in relapsed CLL: (1) the alkylator bendamustine, (2) the cyclin-dependent kinase inhibitor flavopiridol, (3) the immunomodulating drug lenalidomide, (4) the bcl-2 antisense oligonucleotide oblimersen, and (5) the Bcl-2 small-molecule inhibitor obatoclax. While these agents have demonstrated exciting clinical activity against genetically high-risk CLL, they have also induced toxicities that have not been commonly observed with previous CLL therapies. The most notable toxicities have been tumor lysis syndrome and tumor flare, which are potentially serious or even fatal complications of these new therapies. Thus, further studies are needed to define these agents' biologic mechanism(s) of action, clinical activity, and safety.     

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。     

滤泡性淋巴瘤治疗中的疑惑和应对策略

 【摘要】 在过去的5年中,滤泡性淋巴瘤的治疗发生了很大的变化。很多抗肿瘤新药应用到一线治疗和维持治疗中,对于复发难治的滤泡性淋巴瘤的治疗策略也有了新的改变。尽管在国际上能够看到这些新的进展,但临床上仍有很多问题有待解决。本文对利妥昔单抗应用的有效性和安全性进行了讨论,对复发难治的滤泡性淋巴瘤的治疗策略进行了整理和展望,并对近年来开展的新药临床试验进行了介绍。     

Biological Therapy Doublets: Pairing Rituximab with Interferon, Lenalidomide, and Other Biological Agents in Patients with Follicular Lymphoma

Rituximab (R) is a monoclonal antibody with high therapeutic efficacy in low-grade CD20+ lymphoma. The combination of R with chemotherapy is the most common treatment option for patients with follicular lymphoma (FL). The efficacy of R has also been shown to be augmented, when used in combinations with biologicals such as interferon-alpha-2a (IFN), bortezomib, or lenalidomide. The best combination of these drugs are not well defined and a better understanding of pharmacokinetics and timing of drugs relative to the rituximab infusion is crucial. Other new targeted agents, such as inhibitors of BTK and PI3Kdelta, have also been promising in FL. Translational research questions should be added to clinical trial protocols to increase the knowledge on how the tumor microenvironment and the host immune system affect the response to the different drugs and combinations with the aim of a more individualized therapy.     

Targeted therapy for chronic lymphocytic leukemia

The introduction of targeted agents such as the monoclonal antibodies rituximab (anti-CD20) and alemtuzumab (anti-CD52) has brought about a remarkable change in the therapy of chronic lymphocytic leukemia (CLL). Although it is unclear whether overall survival has been improved, the incorporation of these monoclonal antibodies into chemoimmunotherapy regimens has dramatically improved complete response rates and progression-free survival in patients with both newly-diagnosed and relapsed CLL. The success of rituximab and alemtuzumab has spurred the development of other monoclonal antibodies targeting distinct proteins and epitopes on the surface of CLL cells and an exciting array of novel immunotherapeutics. The judicious use of these agents provides the opportunity to develop risk-adapted therapeutic strategies to optimize responses and quality of life in patients with CLL.     

Recommendations for the use of yttrium-90 ibritumomab tiuxetan in malignant lymphoma

Radioimmunotherapy (RIT) with Yttrium-90 (90Y) ibritumomab tiuxetan (Zevalin) combines the tumor targeting attributes of a monoclonal antibody against the CD20 antigen and the pure beta-radiation of 90Y. High efficacy and a favorable safety profile have been demonstrated in Phase II and III clinical trials enrolling patients with CD20+ B-cell non-Hodgkin lymphoma (B-NHL). On the basis of these results, 90Y-ibritumomab tiuxetan was approved in the United States for the treatment of patients with follicular lymphoma (FL) or transformed B-NHL. In the European Union its use was restricted to FL, refractory to or relapsed after rituximab. There are a number of important clinical trials currently evaluating 90Y-ibritumomab tiuxetan in other subtypes of lymphoma such as diffuse large-cell and mantle-cell lymphoma, as consolidation therapy or as part of myeloablative regimens. In light of the constantly increasing clinical experience with RIT, clinicians face the challenge of how to best integrate this promising new treatment option into existing established treatment algorithms. By incorporating the most recent data in this rapidly developing field, this review article focuses on current recommendations for the use of 90Y-ibritumomab tiuxetan in patients with malignant lymphoma, outlines future perspectives, and provides practical recommendations for patient management.     

Treatment of fludarabine‐refractory chronic lymphocytic leukemia

The development of resistance to purine analogs defines a poor‐risk subset of patients with chronic lymphocytic leukemia (CLL). Although in recent years chemoimmunotherapeutic combinations such as fludarabine, cyclophosphamide, and rituximab have induced response rates of 95% in previously untreated patients and increased the rates of failure‐free survival, CLL remains incurable for many patients because of a lack of disease response or the development of refractoriness to fludarabine. Fludarabine‐refractory disease is defined as CLL that does not respond to fludarabine or that recurs within 6 months of treatment with a fludarabine‐containing regimen. The natural course of the disease is associated with poor survival. Salvage therapeutic strategies include alemtuzumab‐containing regimens, targeted agents, and allogeneic stem cell transplantation. Single‐agent alemtuzumab induces response in up to 40% of patients with fludarabine‐refractory CLL, but responses are not durable, and the median survival is approximately 1 to 2 years. Alemtuzumab is also combined with fludarabine, cyclophosphamide, and/or rituximab, and other agents such as lenalidomide and flavopiridol, as well as targeted agents, and used in fludarabine‐refractory CLL. Cumulative evidence suggests that allogeneic stem cell transplantation is an efficacious therapeutic strategy for patients who do not respond to fludarabine or who develop disease recurrence within 12 months after purine analog treatment. In conclusion, chemoimmunotherapy regimens that include alemtuzumab and/or rituximab and allogeneic stem cell transplantation improve the prognosis of this disease, but there is a continued need for novel, more effective therapies. Cancer 2009. © 2009 American Cancer Society.     

New aspects of the treatment of chronic lymphocytic leukemia

Progress in the understanding of the biology of chronic lymphocytic leukemia and in the development of new and effective therapies has generated a shift in treatment paradigms within only a few years. Traditional chemotherapy agents such as alkylators or nucleoside analogs are rapidly being replaced by combination regimens. Combinations of monoclonal antibodies with chemotherapy agents (chemoimmunotherapy) have proved especially powerful, almost doubling clinical complete response rates compared with chemotherapy alone. In addition to an increase in the number of responders, eradication of residual disease and achievement of molecular responses have become possible, leading to novel treatment concepts including consolidation and maintenance. New therapeutic agents and vaccines are in development and are being evaluated in clinical trials. Cytogenetic-molecular characterization has begun to be tailored into treatment considerations and it is hoped that the combination of molecular biology with effective therapies will lead to risk-adapted strategies and improved survival.     

Immunotherapy for non-Hodgkin's lymphoma: monoclonal antibodies and vaccines.

Advances in the development of monoclonal antibodies have led to new agents rapidly incorporated into standard lymphoma therapy. The characteristics of the target antigen and the properties of the antibody including interaction with the host immune system have been found to correlate with outcome. Antibodies targeting the CD20 antigen on B cells have been most widely used, led by the chimeric antibody rituximab, now used in nearly all types of B-cell non-Hodgkin's lymphoma (NHL). New antibodies targeting CD20 with augmented complement or Fc receptor binding are now being evaluated and will eventually have to be compared with rituximab. Challenges to these new antibodies include the nearly universal use of rituximab early in NHL therapy, and its increasing use as maintenance therapy. It is not clear what the activity of these antibodies will be in rituximab-refractory patients. New antibodies targeting antigens such as CD40 and CD80 are also being tested alone and in combination with rituximab. Vaccine trials using patient-specific immunization with immunoglobulin idiotype (Ig-Id present on the surface of most B-cell NHL) isolated by molecular rescue or by cell hybridization techniques are also nearing completion. These approaches attempt to actively induce specific humoral or cellular immune responses to the Ig-Id by attaching the protein to a carrier protein and the use of an immunologic adjuvant such as granulocyte macrophage colony-stimulating factor. Prior rituximab appears to delay humoral responses to the idiotype but may still allow cellular responses. The incorporation of all these approaches into optimal NHL therapy remains a challenge.     

Rituximab

CHOP has been the standard chemotherapy for aggressive non-Hodgkin's lymphoma (NHL). However, indolent NHL remains largely an incurable diseases, with nearly static overall survival, and only 40% of patients with aggressive NHL are cured by CHOP. Monoclonal antibodies are an exciting advance in the treatment of lymphoma. Rituximab is a mouse/human chimeric monoclonal antibody that targets the CD20 antigen found on the surface of malignant and normal cells of the B-cell lineage, but not on primitive stem cells or mature plasma cells. Rituximab is safe and well-tolerated, and exhibit little cross-resistance with conventional chemotherapeutic agents. Clinical trials with rituximab indicate that the drug has broad application to NHL, although further clarification is needed to determine its optimal use in many of these clinical settings. In indolent NHL, rituximab has shown useful response rates, both as first-line therapy in relapsed disease. In aggressive lymphomas, diffuse large B-cell lymphoma is the most common form, the addition of rituximab to CHOP chemotherapy significantly lengthens disease-free and overall survival compared to CHOP alone as first line therapy, at least in elderly patients. These included combination with chemotherapy, prolonged or increased dosing regimens, and maintenance therapy, in which rituximab is administered to patients in remission to eliminate minimal residual disease and reduce the risk of relapse. Rituximab in vivo purging and maintenance is also being evaluated in autologous transplantation setting. Newer agents, including radiolabelled antibodies, Immunotoxin-linked antibodies and antibodies against novel target antigens are being tested in on-going clinical trial.     

Phase I study of LY2469298, an Fc-engineered humanized anti-CD20 antibody, in patients with relapsed or refractory follicular lymphoma

Patients with follicular lymphoma (FL), where position 158 of FcγR-IIIa is heterozygous valine/phenylalanine or homozygous phenylalanine (F-carriers), have natural killer cells with lower binding affinity to IgG than valine homozygote patients. In addition, F-carriers show less efficacy with rituximab treatment than patients homozygous for valine. LY2469298 is a humanized IgG1 monoclonal antibody targeting CD20, with human germline framework regions, and specific amino acid substitutions engineered into the Fc region to increase effector function in antibody-dependent cell-mediated cytotoxicity. This dose-escalation, phase I study was conducted to assess the safety, pharmacokinetics and preliminary efficacy of LY2469298 in Japanese patients with previously treated, CD20-positive FL who had not relapsed or progressed within 120 days of prior rituximab. LY2469298 was administered by intravenous infusion at 100 or 375 mg/m(2) weekly for 4 weeks. Ten patients were enrolled (median age, 60 years); all had previously been treated with rituximab. Nine patients were F-carriers while one was homozygous for valine at position 158 of FcγRIIIa. No patients developed dose-limiting toxicities, and the most frequent adverse events were lymphopenia, pyrexia, leukopenia, chills and neutropenia. Five (50%) of the ten patients responded to LY2469298 treatment (three complete responses, one unconfirmed complete response and one partial response). Serum LY2469298 was eliminated in a biphasic manner and the pharmacokinetic profiles were not different from those in a preceding study in the United States. In conclusion, LY2469298 was well tolerated and clinical activity was observed in FL patients pretreated with rituximab, mostly consisting of F-carriers. Further investigation of FL is warranted.     

Histological and immunophenotypic changes in 59 cases of B-cell non-Hodgkin's lymphoma after rituximab therapy

Rituximab is a chimeric monoclonal antibody that recognizes the CD20 antigen. It has been used to treat B-cell non-Hodgkin lymphoma (B-NHL), but recently rituximab resistance has been a cause for concern. We examined histological and immunohistochemical changes in 59 patients with B-NHL after rituximab therapy. The patients comprised 32 men and 27 women with a median age of 59 years. Pre-rituximab specimens comprised 34 follicular lymphomas (FL), 11 diffuse large B-cell lymphomas (DLBCL), 10 mantle cell lymphomas, two marginal zone B-cell lymphomas (MZBCL), and two chronic lymphocytic leukemias (CLL). CD20 expression in lymphoma cells was evaluated by immunohistochemistry or flow cytometry. Post-rituximab materials were taken a median of 6 months (4 days to 59 months) after rituximab therapy. Sixteen cases (27%) showed loss of CD20 expression with four histological patterns: pattern 1, no remarkable histological change (FL, 5; DLBCL, 3; and CLL, 2); pattern 2, proliferation of plasmacytoid cells (FL, 2; DLBCL, 1; and MZBCL, 1); pattern 3, transformation to classical Hodgkin's lymphoma (FL, 1); and pattern 4, transformation to anaplastic large cell lymphoma-like undifferentiated lymphoma (FL, 1). Loss of CD20 was unrelated to the interval of biopsies, treatment regimen, clinical response, and frequency of rituximab administration. Loss of CD20 within 1 month of rituximab therapy (3/14, 21%) and regain of CD20 (2/7, 29%) were not frequent. CD20-positive relapse with transformation occurred most frequently in cases of early relapse. In conclusion, B-NHL showed various histological and immunophenotypic changes after rituximab therapy, including not only CD20 loss but also proliferation of plasmacytoid cells or transformation to special subtypes of lymphoma. ( Cancer Sci 2009; 100: 54–61)     

Has the time come to leave the "watch-and-wait" strategy in newly diagnosed asymptomatic follicular lymphoma patients?

ABSTRACT: BACKGROUND: Historically, the median overall survival for follicular lymphoma (FL) has been considered to be 9-10 years, and no treatment had ever prolonged this time period. Studies conducted more than 20 years ago demonstrated that treating patients with asymptomatic FL at the onset of the disease did not increase their survival, and that almost 20% of these patients did not need any treatment in the first 10 years of follow-up. Based on these facts, most clinical practice guidelines recommend active surveillance policies for patients with asymptomatic FL. DISCUSSION: The introduction of antiCD-20 monoclonal antibodies, over the last 15 years, has significantly increased the median survival rate to above 14 years. This improvement was achieved before the combination of rituximab and chemotherapy regimens became extensively used in patients with symptomatic disease. Therefore, this increase in survival may currently be more significant. At present, several clinical trials have evaluated low-toxicity therapies that prolong progression-free periods, among which rituximab monotherapy, radioimmunotherapy or the combination of rituximab with bendamustine are the most relevant. Unfortunately, these clinical trials have included only patients with symptomatic FL. The results of a recently reported clinical trial show that treatment with single-agent rituximab prolongs progression-free survival rates, time to new treatment and the quality of life of asymptomatic patients, as compared with the active surveillance strategy. Longer follow-up of these results and data regarding overall survival are awaited before this treatment can be recommended as the standard initial therapy. SUMMARY: There are different therapeutic possibilities for asymptomatic FL patients, but no data are currently available to indicate which option is the best. Patients need to understand the risks and benefits of observation versus treatment before a final decision can be made. For patients who want active treatment the administration of four weekly rituximab doses should be considered.     

What is the role of maintenance rituximab in follicular NHL?

Recent trials have demonstrated improvements in progression-free and overall survival with the inclusion of the chimeric anti-CD20 monoclonal antibody rituximab (Rituxan) in chemotherapy regimens for treatment-naive and relapsed patients with advanced-stage follicular non-Hodgkin's lymphoma (NHL). As rituximab therapy has significant single-agent activity infollicular NHL, is generally well tolerated, and has no dose-limiting or significant hematologic toxicity, a number of approaches evaluating maintenance therapy with extended dosing of rituximab are being tested. Trials have demonstrated prolonged progression-free survival in patients treated with maintenance rituximab using a variety of schedules following treatment with single-agent rituximab, induction or salvage chemotherapy, or salvage therapy with rituximab and chemotherapy combinations. Small increases in neutropenia and infections have been reported with extended rituximab use. Ongoing trials are evaluating the optimal use of rituximab (maintenance vs. retreatment) and the benefit of rituximab maintenance following treatment of therapy-naive patients treated with rituximab-containing chemoimmunotherapy induction regimens. This article discusses the risks and benefits of maintenance rituximab for follicular NHL.     

Enteroviral infection in patients treated with rituximab for non‐Hodgkin lymphoma: a case series and review of the literature

In recent years, anti‐CD20 antibodies have been increasingly used to treat lymphoproliferative and immune disorders. Chronic viral infections are infrequently reported in patients receiving these therapies. Enteroviral infection can cause life‐threatening meningoencephalitis and other systemic chronic syndromes in immune deficient patients. We describe the clinical courses and outcomes of 6 patients from 2 tertiary care institutions who developed chronic enteroviral infection with neurological manifestations, after combined chemoimmunotherapy with rituximab for B‐cell lymphoma. We review the literature that includes 10 sporadic reported cases of chronic enteroviral meningoencephalitis attributed to rituximab therapy. It is a rare disease, and its diagnosis is often elusive. We propose that low immunoglobulin G levels are the main risk factor for developing chronic enteroviral infection and emphasize the need for a high index of suspicion, early diagnosis, and intervention in this iatrogenic and potentially fatal complication.     

Treatment strategies in follicular lymphomas: current status and future perspectives.

Although little progress has been made in the treatment of follicular lymphomas (FL) within the last few decades, several new therapeutic modalities have recently demonstrated promising activity. These include myeloablative therapy followed by autologous stem cell transplantation in younger patients in first remission revealing a significant prolongation of remission duration in three prospective randomized trials, whereas the impact on overall survival still needs to be determined. Adding the anti-CD20 antibody rituximab to conventional chemotherapy resulted in a significant increase in remission rate, remission duration and in two of four currently available prospective randomized studies even in a longer overall survival. A prolongation of remission duration was also seen when rituximab was administered as maintenance after cytoreductive therapy or by prolonged application as a single agent. Radioimmunotherapy (RIT) with radioisotopes coupled to monoclonal antibodies revealed encouraging data in several phase II studies. Prospective randomized studies are warranted, however, to define the impact of RIT on FL therapy. New therapeutic perspectives also emerge from increasing insights into the biology of the disease that unravel molecular targets for novel agents, some of which have entered clinical evaluation already.