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.     

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.     

A comprehensive review of lenalidomide therapy for B-cell non-Hodgkin lymphoma

Lenalidomide is an oral non-chemotherapy immunomodulator with direct and indirect effects on non-Hodgkin lymphoma (NHL) cells and with single-agent activity in relapsed/refractory aggressive and indolent B-cell NHL, including mantle cell lymphoma (MCL), diffuse large B-cell lymphoma, and follicular lymphoma. Based on the pivotal phase II MCL-001 trial of lenalidomide in heavily pretreated patients with relapsed/refractory MCL, lenalidomide was approved by the US Food and Drug Administration for the treatment of relapsed/refractory MCL after failure of two prior therapies, one of which includes bortezomib, at a recommended starting dose of 25 mg on days 1–21 of each 28-day cycle. Lenalidomide enhanced the survival benefit in combination with rituximab in preclinical models, prompting clinical evaluation of the lenalidomide–rituximab (R2) combination. In phase II trials, lenalidomide 20 mg on days 1–21 in combination with different standard-dose rituximab schedules exhibited promising activity in both first-line and relapsed/refractory disease across multiple B-cell NHL subtypes. The feasibility of combining lenalidomide with immunochemotherapy, including R-CHOP and rituximab–bendamustine, has been demonstrated in phase I/II trials. These latter regimens are currently being evaluated in ongoing phase II and III trials. The role of lenalidomide monotherapy and R2 in maintenance therapy is also being examined. Based on available evidence, a comprehensive review of lenalidomide in all treatment phases of B-cell NHL—relapsed/refractory disease, first-line, and maintenance—is presented here.     

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。     

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.     

Maintenance therapy in lymphoma

As treatment regimens have emerged that increase the proportion of patients with lymphoma achieving responses to therapy, maintenance regimens have followed to provide means for improving progression-free survival and overall survival for responders. An ideal maintenance regimen would have limited toxicity, be easy to administer, and demonstrate a survival benefit over administration of the same agent in the relapsed disease setting. Numerous phase II and randomized trials are now maturing that examine the benefits of maintenance therapies for indolent and aggressive lymphomas. We provide a comprehensive review of existing data describing the shortcomings and benefits of interferon maintenance and rituximab maintenance therapies for patients with non-Hodgkin lymphoma (NHL). Notably, rituximab maintenance has demonstrated benefits for patients with follicular lymphoma after CVP (cyclophosphamide/vincristine/prednisone) induction therapy and after rituximab-containing chemotherapy combinations at relapse. Benefits have also been demonstrated in diffuse large B-cell lymphoma after CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) induction but not after R-CHOP (rituximab plus CHOP) induction. Randomized trials in patients with mantle cell lymphoma demonstrate a benefit for rituximab maintenance after R-FCM (fludarabine/cyclophosphamide/mitoxantrone plus rituximab) chemoimmunotherapy but not after single-agent rituximab. Further studies are needed to characterize the benefits of other agents in maintenance therapy and other strategies for maintaining remissions for patients with NHL.     

Maintenance therapy following induction chemoimmunotherapy in patients with diffuse large B-cell lymphoma: current perspective

BackgroundMaintenance therapy has proven efficacy in indolent non-Hodgkin lymphoma (NHL), yet its role in diffuse large B-cell lymphoma (DLBCL) is an area of ongoing investigation. While DLBCL is potentially curable, >30% of patients relapse following front-line therapy and have a poor prognosis, especially those with refractory disease. Maintenance therapy holds promise to maintain response post-induction.Patients and methodsKeyword searches were carried out in PubMed and congress abstracts of ‘diffuse large B-cell lymphoma’ and ‘maintenance’ and focused on phase II/III studies of maintenance following front-line induction.ResultsAlthough used in indolent forms of NHL, studies of maintenance therapy with rituximab in patients with DLBCL responding to front-line R-CHOP (rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone) have not improved efficacy and are not recommended. Targeted agents enzastaurin and everolimus reported results from the phase III studies PRELUDE and PILLAR-2, respectively, both of which showed no proven maintenance benefit following front-line chemoimmunotherapy induction. Overall, the reported efficacy results with these agents in the maintenance setting do not outweigh the risks. Lenalidomide for maintenance has been reported in three studies. Results from two phase II trials on lenalidomide maintenance revealed positive outcomes in higher-risk patients following induction, resulting in improved progression-free survival in relapsed DLBCL patients who were ineligible for transplantation. First analysis from the phase III REMARC trial showed a significant improvement in progression-free survival for lenalidomide versus placebo, with no difference in overall survival, following front-line R-CHOP induction in elderly patients.ConclusionsBased on currently available studies of DLBCL maintenance therapies, initial results in front-line, as well as the relapsed setting, with immunomodulators such as lenalidomide show promise for further research to identify appropriate patients who would most benefit. Overall, this review of maintenance studies underscores the need for additional analyses of patient subtypes, clinical risk status, and molecular profiles, with careful consideration of study end points.     

Update in indolent non-Hodgkin lymphoma (NHL): paradigm for Waldenström's macroglobulinemia (WM)

Indolent non-Hodgkin lymphomas are characterized by a low proliferation, but relapses are frequent. The gold standard treatment at diagnosis is still unknown. Careful watchful waiting is appropriate in asymptomatic patients with low tumor burden. In symptomatic patients that require treatment, chemoimmunotherapy with rituximab in association with chlorambucil, CVP, CHOP, fludarabine-containing regimens or bendamustine is recommended. Maintenance treatment with rituximab after induction is effective and safe and determines an improvement of progression-free survival respect observation; also, radioimmunotherapy consolidation is effective. High-dose chemotherapy with autologous stem cell transplantation is useful in relapsed/refractory patients. Knowledge on biology and pathogenesis of lymphoma represents the basis for the introduction of targeted therapy. New drugs such as bortezomib, lenalidomide, humanized monoclonal antibody anti-CD20 or anti-CD22 are tested in relapse and front-line patterns, with encouraging results. These therapeutic approaches improved the outcome of indolent lymphoma's patients and may represent a paradigm for the treatment of Waldenström's macroglobulinemia.     

套细胞淋巴瘤治疗方案的选择和建议

套细胞淋巴瘤的治疗近年来受到广泛重视。以R—HyperCVAD为代表的多药联合方案大大提高了套细胞淋巴瘤的疗效和生存率。新的抗肿瘤药物和靶向药物包括硼替佐米、苯达莫司汀和来那度胺等已经被应用到新的方案中,开阔了该肿瘤治疗的新视野。文章在介绍套细胞淋巴瘤治疗新进展的同时,对临床上常见的疑惑和问题给予了分析和解答。     

惰性淋巴瘤治疗进展

惰性淋巴瘤诊断时多为晚期,一般认为常规化疗不能治愈。随着新的化疗药物以及免疫靶向治疗抗CD20单克隆抗体利妥昔的广泛用于惰性淋巴瘤治疗,研究结果显示了利妥昔单药治疗复发/难治性惰性淋巴瘤的突出疗效;利妥昔单药或与化疗联合用于惰性淋巴瘤的一线诱导治疗以及维持治疗的显著效果,并可获得分子学缓解,使得惰性淋巴瘤的有效率和长期生存得到了明显改善。     

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。     

Assessing the Effectiveness of Treatment Sequences for Older Patients With High-risk Follicular Lymphoma With a Multistate Model

BackgroundDisease progression within < 2 years of initial chemoimmunotherapy and patient age > 60 years have been associated with poor overall survival (OS) in follicular lymphoma (FL). No standard treatment exists for these high-risk patients, and the effectiveness of sequential therapies remains unclear.Patients and MethodsWe studied the course of FL with first-, second-, and third-line treatment. Using large population-based data, we identified 5234 patients with FL diagnosed in 2000 to 2009. Of these patients, 71% had received second-line therapy < 2 years, and 29% had received no therapy after first-line therapy, with a median OS of < 3 years. Treatment included rituximab, R-CVP (rituximab, cyclophosphamide, vincristine), R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine), R-Other (other rituximab-containing), and other regimens. The Aalen-Johansen estimator and Cox proportional hazards models were used to quantify the outcomes and assess the effects of the clinical and sociodemographic factors.ResultsR-CHOP demonstrated the most favorable 5-year OS among first- (71%), second- (55%), and third-line (61%) therapies. First-line R-CHOP improved OS (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.50-0.64) and reduced the mortality risks after first-line (HR, 0.60; 95% CI, 0.47-0.77), second-line (HR, 0.40; 95% CI, 0.29-0.53), and third-line (HR, 0.63; 95% CI, 0.53-0.76) treatments. B-symptoms, being married, and histologic grade 1/2 were associated with the use of earlier second-line therapy. Early progression from second- to third-line therapy was associated with poor OS. The repeated use of R-CHOP or R-CVP as first- and second-line treatment yielded high 2-year mortality rates (R-CHOP + R-CHOP, 17.3%; R-CVP + R-CVP, 21.1%).ConclusionOur multistate approach assessed the effect of sequential therapy on the immediate and subsequent treatment-line outcomes. We found that R-CHOP in any line improved OS for patients with high-risk FL.     

Precision medicine in follicular lymphoma: Focus on predictive biomarkers

Current care for patients with follicular lymphoma (FL) offers most of them long-term survival. Improving it further will require careful patient selection. This review focuses on predictive biomarkers (ie, those whose outcome correlations depend on the treatment strategy) in FL, because awareness of what patient subsets benefit most or least from each therapy will help in this task. The first part of this review aims to summarize what biomarkers are predictive in FL, the magnitude of the effect and the quality of the evidence. We find predictive biomarkers in the setting of (a) indication of active treatment, (b) front-line induction (use of anthracyline-based regimens, CHOP vs bendamustine, addition of rituximab), (c) post-(front-line)induction (rituximab maintenance, radioimmunotherapy), and (d) relapse (hematopoietic stem cell transplant) and targeted agents. The second part of this review discusses the challenges of precision medicine in FL, including (a) cost, (b) clinical relevance considerations, and (c) difficulties over the broad implementation of biomarkers. We then provide our view on what biomarkers may become used in the next few years. We conclude by underscoring the importance of assessing the potential predictiveness of available biomarkers to improve patient care but also that there is a long road ahead before reaching their broad implementation due to remaining scientific, technological, and economic hurdles.     

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.     

Maintenance therapy in nonsmall‐cell lung cancer

Systemic chemotherapy with platinum‐based regimens provides modest improvements in survival and quality of life for patients with advanced‐stage nonsmall‐cell lung cancer (NSCLC). Extended first‐line chemotherapy with combination regimens for more than 4 to 6 cycles is not recommended because of cumulative toxicities and lack of proven advantage in survival with the increased duration of therapy. The early use of an anticancer agent as maintenance therapy after disease stabilization or maximal response with platinum‐based regimens is, therefore, being recognized as a new treatment paradigm in NSCLC. Maintenance therapy can extend first‐line treatment and provide an acceptable balance between efficacy and toxicity. The essential prerequisites for maintenance therapy include good tolerability, ability to administer extended cycles of therapy without cumulative toxicity, and an increase in the duration of progression‐free survival. Pemetrexed has recently been shown to improve the median PFS in the maintenance setting. Molecularly targeted therapies with cytostatic properties and documented tolerability also have the potential to be effective as maintenance therapy to maintain tumor regression after an initial response to chemotherapy. Consequently, the role of erlotinib and other molecular targeted agents in this treatment setting is under active investigation in ongoing phase 3 trials. This could potentially establish a new standard on the clinical utility of molecular targeted agents as maintenance therapy for patients with advanced‐stage NSCLC. Cancer 2009. © 2009 American Cancer Society.     

SOHO State of the Art Updates and Next Questions | Management of Most Difficult Cases of Chronic Lymphocytic Leukemia: Relapse After Both BTK and BCL2 Inhibition and Richter Transformation

The introduction of targeted therapies in chronic lymphocytic leukemia (CLL) has ushered in a new era in which patients achieve better control of their disease, survive longer, and experience fewer toxicities than before. Despite this progress, a subgroup of patients with CLL will develop resistance to both Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 inhibitors. In addition, a subgroup of CLL cases will transform into aggressive lymphoma – called Richter transformation – either before or during targeted therapy. These two subgroups of patients have a poor prognosis, and available therapies lead to long-term remission in only a minority of patients. In this paper, two cases are presented that are reflective of these difficult scenarios. In the first case, a patient with CLL, complex karyotype, del 17p, and a mutation in TP53 experiences progression after ibrutinib, venetoclax, bendamustine, rituximab, and idelalisib. In the second case, a patient with CLL and del 17p develops a Richter transformation to diffuse large B-cell lymphoma after treatment with obinutuzumab, chlorambucil, ibrutinib, venetoclax, and idelalisib. The aggressive lymphoma is refractory to chemoimmunotherapy, and she expires. The literature pertaining to these two scenarios is reviewed, including the role of available targeted therapies, chemoimmunotherapy, and hematopoietic cell transplantation. Emerging novel therapies, including reversible BTK inhibitors and CAR T cell therapy, are discussed.     

Controversies in multiple myeloma: Evidence-based update

The US Food and Drug Administration (FDA) approved 10 new drugs for the treatment of multiple myeloma (MM) over the last two decades. The influx of new anti-myeloma agents with high efficacy and acceptable tolerability add complexity to the clinical decision-making process. First, treatment of smoldering multiple myeloma (SMM) remains investigational to date, although a randomized trial showed a survival gain in high-risk patients receiving lenalidomide. Second, in newly diagnosed MM, the majority of contemporary induction regimens have been studied in single-arm trials or compared to an older regimen, which complicates evidence-based treatment selection. Third, the role of consolidation chemotherapy followed by autologous stem cell transplant (ASCT) needs to be revisited in the context of highly effective agents, as newer regimens— such as carfilzomib, lenalidomide, and dexamethasone—are able to achieve extremely deep responses equivalent to or exceeding those seen after conventional induction and ASCT. Fourth, risks and benefits of maintenance therapy should also be redefined and individualized, as long-term survival and safety data accumulate. Here we selected four clinical settings where controversies exist, reviewed evidences behind conflicting treatment strategies, and asked myeloma experts to discuss evidence-based recommendations.     

Innovations in chemotherapy for metastatic colorectal cancer: an update of recent clinical trials

It has been estimated that cancer of the colon and rectum (CRC) would be diagnosed in 153,760 men and women in the U.S. alone in 2007. Approximately one in five patients has metastatic CRC (mCRC) at diagnosis, which, at best, is associated with a 5-year survival rate of just 10.3%. Oxaliplatin- and irinotecan-based combination regimens are standard first-line therapies for mCRC. Recent studies suggest that survival outcomes can possibly be further improved by adding biologic agents to chemotherapy. Novel treatment strategies are being investigated to optimize the opportunity for patients to receive and benefit from the increasing number of available active agents and to further improve the efficacy, safety, and tolerability of multiagent therapy. These include switching therapy before progression, maintenance therapy, and chemotherapy-free intervals. Recent innovations in chemotherapy for mCRC are reviewed, with a focus on emerging data that may significantly improve both survival and quality of life for patients with CRC in the future.     

Diffuse large B-cell lymphoma: new targets and novel therapies

Newer, more effective and non-cytotoxic therapies are an unmet need for patients with diffuse large B-cell lymphoma (DLBCL) and other B-cell malignancies. Recently approved agents include polatuzumab with bendamustine and rituximab, selinexor, and tafasitamab plus lenalidomide. Three CAR-T cell products are currently approved by the FDA, with others in clinical trials. Additional agents in development include bispecific antibodies and antibody drug conjugates. Combinations of targeted therapies should lead to further improvement in the outcome of patients with B-cell malignancies.Subject terms: Drug development, Lymphoma     

Bendamustine

Alkylating agents form the basis of most combination treatment regimens for low‐grade lymphoproliferative disorders. Bendamustine is a unique alkylating agent that has distinctive preclinical activity in cell lines resistant to other alkylators. Furthermore, clinical activity has been demonstrated in patients with alkylating agent resistant disease. Recently, larger studies have been organized to study the clinical effects of bendamustine further. In indolent B‐cell non‐Hodgkin lymphoma that is resistant to rituximab, bendamustine induced a remission in 77% of patients. Myelosuppression was identified as the most common toxicity. In 2 studies of similar populations of patients, the combination of bendamustine and rituximab induced remission 90% of patients with a median progression‐free survival of 23‐24 months. The overall remission rate was 59% in a prospective, randomized study of untreated patients with chronic lymphocytic leukemia, which was significantly greater than the rate of 26% in the chlorambucil control arm (P < 0.001). Combined with rituximab, bendamustine induces a remission in 67% of patients with relapsed or refractory chronic lymphocytic leukemia. Bendamustine is an active agent for the treatment of low‐grade lymphoproliferative disorders and more study is needed to determine which dose and schedule is optimal, and which patients will derive the greatest benefit from its use. Cancer 2009. © 2008 American Cancer Society.