Rituximab in lymphoma: a systematic review and consensus practice guideline from Cancer Care Ontario

Rituximab is the first antibody-based therapy approved in cancer. The role of this treatment for non-Hodgkin's lymphoma has evolved significantly since its introduction. We aimed to systematically review the literature on rituximab in non-Hodgkin's lymphoma and provide consensus guidelines as to the rational use of this agent. Validated methodology from the Cancer Care Ontario Program in Evidence-Based Care was applied. A comprehensive literature search was completed by reviewers from the Hematology Disease Site Group of Cancer Care Ontario. Data were abstracted from randomized controlled trials of rituximab-containing regimens for patients with non-Hodgkin's lymphoma. Twenty-three randomized controlled trials (RCTs) of rituximab-based therapy were analyzed. Consistent and clinically important benefits in progression-free and overall survival and were seen in the following settings: (1) addition of rituximab to combination chemotherapy for initial treatment of diffuse large B-cell lymphoma and other aggressive B-cell lymphomas; (2) addition of rituximab to combination chemotherapy for initial and subsequent treatment of follicular lymphoma and other indolent B-cell lymphomas; and (3) use of rituximab alone as extended maintenance therapy in patients with indolent B-cell lymphomas who have responded to initial treatment. The consensus opinion of the Hematology Disease Site Group is that rituximab is recommended for these indications.     

Primary cutaneous B-cell lymphoma: classification and treatment

PURPOSE OF REVIEW: There has been confusion and debate regarding the definition, terminology, and optimal treatment of the different types of primary cutaneous B-cell lymphomas. This review presents the new World Health Organization-European Organization for the Research and Treatment of Cancer classification for cutaneous lymphomas; describes clinicopathologic, immunophenotypic, and genetic features of the different types of cutaneous B-cell lymphomas in this classification; and discusses current views on treatment of these lymphomas. RECENT FINDINGS: The three main types of cutaneous B-cell lymphomas in this new classification are primary cutaneous marginal zone B-cell lymphoma, primary cutaneous follicle center lymphoma, and primary cutaneous large B-cell lymphoma (leg type). Primary cutaneous marginal zone B-cell and primary cutaneous follicle center lymphoma are indolent types with an excellent prognosis that should be treated primarily with nonaggressive therapies. Primary cutaneous large B-cell lymphoma (leg type) is an aggressive lymphoma that should be treated primarily with aggressive chemotherapy. SUMMARY: The World Health Organization-European Organization for the Research and Treatment of Cancer classification will contribute to uniform diagnosis, management, and treatment of patients with cutaneous B-cell lymphoma and will prevent patients with indolent types of the disease from being treated inappropriately with systemic chemotherapy.     

New developments in immunotherapy for non-Hodgkin’s lymphoma

The clinical development of immunotherapy with rituximab (chimeric anti-CD20 monoclonal antibody) has markedly affected the treatment approach for patients with B-cell non-Hodgkin’s lymphoma (NHL). Rituximab was initially evaluated in relapsed indolent lymphoma and has substantial activity in this setting both alone and in combination with chemotherapy. Ongoing efforts in indolent NHL are seeking to optimize the dose and schedule of rituximab through ‘maintenance’ strategies exploring chemotherapyrituximab combinations and the use of other biologic agents or antibodies that may enhance activity when employed together with rituximab. Other studies in indolent NHL suggest that radiolabeled anti-CD20 antibodies (such as I-131 tositumomab and Y-90 ibritumomab tiuxetan) may be useful in relapsed and refractory disease and have potential utility as part of initial treatment as well. In diffuse large B-cell lymphoma, the addition of rituximab to CHOP chemotherapy can improve survival, though benefits are more limited in mantle cell lymphoma. Further studies of unlabeled and radiolabeled immunotherapies are ongoing in order to optimize their use for maximal clinical benefit.     

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.     

Treatment of NonHodgkin’s lymphomas with rituximab in Slovene patients

The introduction of rituximab into the treatment of patients with NonHodgkin’s lymphomas has changed the long-term prognosis of patients with CD20 positive B cell lymphomas, especially follicular and diffuse large B-cell lymphomas (DLBCLs). The addition of rituximab to chemotherapy improves the overall response rate, prolongs the response duration and the overall survival both in patients with follicular and other indolent CD20 positive lymphomas, and DLBCLs. Maintenance treatment with rituximab in patients with indolent lymphomas further prolongs the remission duration, and some of the studies have also shown survival benefit. However, the maintenance therapy in aggressive lymphomas most probably gives no further improvement in patients, who have received rituximab already in the induction treatment. Rituximab has been used at the Institute of Oncology Ljubljana since 1998. In the period from 2004 to 2006, we have treated 340 patients with rituximab either as a single agent or in combination with chemotherapy. Our treatment group included 46.8% of patients with DLBCLs and 19.4% with follicular lymphomas. In majority of the patients, rituximab was given as the first-line treatment (54.4%), while 26.2% of patients received it as the second-line treatment and 19.4% of patients as the third or subsequent line of treatment. Among patients with indolent lymphomas, just 15% received rituximab as the first-line treatment. On the other hand, 75.9% of patients with aggressive lymphomas were treated with rituximab for newly diagnosed disease. About 67.4% of patients were treated with R–CHOP combination, while the others received different rituximab–chemotherapy combinations. The overall response rate regardless of the histological type of lymphoma was 78.8%, and the highest response rate was achieved in patients with aggressive follicular lymphomas (91.7%). The highest overall response rate was observed when rituximab was given as the first-line treatment in all lymphoma types except the mantle cell lymphoma (66.6% overall response rate for the first-line treatment versus 73.7% overall response rate for the second-line treatment). In 75% of patients regardless of the histological type of lymphoma, the response lasted more than 12 months; the median response duration has not been reached yet. In patients receiving rituximab as the first-line treatment, the median response duration also has not been reached yet, while for the second-line treatment, it was 25 months and for the third or subsequent line, 24 months. The longest disease-free survival was observed in patients with DLBCLs. The overall survival rate of all patients regardless of the type of lymphoma was 75% 26 months after the beginning of the treatment, and the median overall survival has not been reached yet. When analyzed by the lines of treatment—the median overall survival has not been reached in any line. The longest overall survival was observed in patients with indolent follicular lymphomas. The treatment results with rituximab at the Institute of Oncology Ljubljana are comparable to the results of larger randomized trials. According to the beneficial influence of rituximab on the long-term prognosis of patients with CD20 positive lymphomas, it became the standard of treatment in these patients.     

GM1 expression of non-Hodgkin's lymphoma determines susceptibility to rituximab treatment

Immunotherapy with rituximab alone or in conjunction with chemotherapy has significantly improved the treatment outcome of B-cell lymphoma patients. Nevertheless, a subpopulation of patients does not respond to rituximab. The reason for treatment failure as well as the exact mechanism of action is still uncertain. The function of rituximab has long been associated with the partitioning of CD20 molecules to lipid microdomains. We now show that the extent of CD20 recruitment to lipid rafts correlates with response to rituximab. In addition, expression of the raft-associated sphingolipid GM1 on lymphoma cells is associated with the susceptibility of lymphoma cells to rituximab. Furthermore, we show substantially different GM1 expression in various primary non-Hodgkin's lymphomas. Whereas chronic lymphocytic leukemia (CLL) cells have a low GM1 expression, marginal zone lymphoma cells exhibit much higher levels. Differences were not only detected among various lymphoma subgroups but also within one lymphoma subtype. Interestingly, whereas CLL cells from patients with high GM1 expression responded to rituximab, patients with low GM1 expressing CLL cells did not. These data show the importance of membrane microdomains in the effect of rituximab and may offer a predictive factor for the responsiveness of lymphoma cells to rituximab.     

Role of CD20 Monoclonal Antibodies in Previously Untreated Chronic Lymphocytic Leukemia

Monoclonal antibodies (MoAbs) directed against the CD20 antigen on B cells have dramatically altered the treatment landscape for patients with chronic lymphocytic leukemia (CLL). Rituximab, a chimeric mouse/human MoAb, was the first antibody to be approved for the treatment of indolent B-cell lymphomas. Although single-agent, standard-dose rituximab has limited activity as first-line therapy for patients with CLL, it has synergistic therapeutic activity when combined with chemotherapy. Indeed, chemoimmunotherapy with combined fludarabine (F), cyclophosphamide (C), and rituximab was shown to improve both progression-free and overall survival in a randomized phase III clinical trial compared with FC in previously untreated patients with CLL. In this article, we review important clinical trials that have incorporated rituximab with other agents for treatment-naive patients with CLL. We also highlight second- and third-generation CD20 MoAbs approved or in development for the treatment of CLL.     

Antibodies for the treatment of diffuse large cell lymphoma

The development of monoclonal antibodies has significantly affected the therapy of B-cell non-Hodgkin's lymphomas (NHLs). Rituximab, a chimeric monoclonal antibody directed against the CD20 antigen, has activity in both indolent and aggressive B-cell lymphomas. Perhaps the greatest change has occurred in first-line therapy of advanced stage, diffuse large cell lymphoma (DLCL), where rituximab combined with conventional chemotherapy has improved both overall survival (OS) and progression-free survival (PFS) over combination chemotherapy alone. Further studies are needed assessing the role of rituximab in salvage therapy, as part of the conditioning regimen prior to autologous stem cell transplant, and as maintenance therapy for large cell lymphoma. Several novel monoclonal antibodies are in development and may also be active in DLCL. These agents may be most promising when combined with either chemotherapy or with rituximab. This review will summarize the use of rituximab in the therapy of diffuse large B-cell lymphoma and briefly describe antibodies in development.     

ASH Update 2013: chronic lymphocytic leukemia and indolent lymphoma

At the annual meeting of the American Society of Hematology 2013, the focus in the field of chronic lymphocytic leukemia (CLL) and indolent lymphomas was again dominated by compelling data generated in clinical trials exploring the use of novel drugs targeting the B-cell receptor pathway. The results observed in early trials, e.g., with the Bruton’s tyrosine kinase inhibitor ibrutinib (formerly PCI-32765) and PI3Kδ inhibitor idelalisib (formerly CAL-101) have been consolidated. In view of these data, new clinical standards have been set up for the treatment of relapsed/refractory CLL. However, with the presentation of several randomized trials new standards concerning the use of immunochemotherapy are being suggested underscoring the importance of immunochemotherapeutic strategies despite the upcoming era of tyrosine kinase inhibitor treatment of CLL and indolent lymphoma.     

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)     

Spotlight on Rituximab in Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia

Rituximab is an anti-CD20 monoclonal antibody that has demonstrated efficacy in patients with various lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin’s lymphoma (NHL) and B-cell chronic lymphocytic leukemia (CLL). While the optimal use of the drug in many clinical settings has yet to be clarified, two pivotal trials have established rituximab as a viable treatment option in patients with relapsed or refractory indolent NHL, and as a standard first-line treatment option when combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy in elderly patients with diffuse large B-cell lymphoma (the most common type of aggressive NHL). The former was a noncomparative trial in relapsed indolent NHL (follicular and small lymphocytic subtypes) with clinical responses achieved in about half of patients treated with rituximab 375 mg/m² intravenously once weekly for 4 weeks, which was similar to some of the most encouraging results reported with traditional chemotherapeutic agents. The latter was a randomized comparison of eight cycles of CHOP plus rituximab 375 mg/m² intravenously (one dose per cycle) versus CHOP alone in previously untreated elderly patients (60 to 80 years of age) with diffuse large B-cell lymphoma. In this pivotal trial, 2-year event-free and overall survival were significantly higher with rituximab plus CHOP, and there was no increase in clinically significant adverse effects compared with CHOP alone. Treatment with rituximab is generally well tolerated, particularly in terms of adverse hematological effects and serious or opportunistic infections relative to standard chemotherapy. Infusion-related reactions occur in the majority of patients treated with rituximab; these are usually mild to moderate flu-like symptoms that decrease in frequency with subsequent infusions. In approximately 10% of patients, however, severe infusion-related reactions develop (e.g. bronchospasm, hypotension). These reactions are usually reversible with appropriate interventions and supportive care but there have been rare reports of fatalities. Conclusion: Clinical trials with rituximab indicate that the drug has broad application to B-cell malignancies, although further clarification is needed to determine its optimal use in many of these clinical settings. Importantly, rituximab in combination with CHOP chemotherapy has emerged as a new treatment standard for previously untreated diffuse large B-cell lymphoma, at least in elderly patients. Compared with conventional chemotherapy, rituximab is associated with markedly reduced hematological events such as severe neutropenia, as well as associated infections. Rituximab may be particularly suitable for elderly patients or those with poor performance status, and its tolerability profile facilitates its use in combination with cytotoxic drugs.     

Rituximab and other emerging antibodies as molecular target-based therapy of lymphoma

Among the monoclonal antibodies (mAbs) under clinical development, anti-CD20 mAbs have been most extensively investigated and have shown definitive clinical activities. Rituximab is a genetically engineered, chimeric anti-CD20 mAb with mouse variable and human constant regions. Consecutive clinical trials conducted in the United States, Europe, and Japan have revealed that rituximab is an effective agent, with acceptable toxicities, in the treatment of indolent and aggressive B-cell non-Hodgkin's lymphomas (B-NHLs). A recent European phase III study in elderly patients with untreated diffuse large B-cell lymphoma suggested that rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) chemotherapy is superior to CHOP chemotherapy alone in terms of complete response rate and event-free and overall survivals. Lymphoma is inherently a radiosensitive tumor. The aim of radioimmunotherapy is to use the mAb to target radiation to lymphoma tissue while minimizing toxicity to normal cells. Clinical trials of ⁹⁰Y-ibritumomab tiuxetan and ¹³¹I-tositumomab showed that they have definitive efficacy in relapsed indolent B-NHL, with acceptable toxicities. A recent comparative study in relapsed indolent B-NHL showed that ⁹⁰Y-ibritumomab tiuxetan produced a higher response rate than rituximab. In addition, BL22, a recombinant anti-CD22 immunotoxin, showed significant efficacy in patients with chemotherapy-resistant hairy cell leukemia. Monoclonal antibodies will have significant roles in the treatment of lymphoid malignancies in the future.     

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.     

Treatment of non-Hodgkin's lymphoma: a look over the past decade

The past decade has seen enormous changes in our understanding of lymphomas with a better classification (World Heath Organization) and identification of better prognostic factors; however, important genetic prognostic factors have not been completely analyzed. The appearance of rituximab and other monoclonal antibodies has completely revolutionized the treatment of this disease. If monoclonal antibodies have activity when used alone, most patients experienced relapse after such a treatment, even after maintenance therapy. The combination of rituximab with chemotherapy has now been shown in several randomized studies to increase the response rate, decrease the relapse rate, and prolong progression-free survival and overall survival. Rituximab plus CHOP (cyclophosphamide/doxorubicin/prednisone/vincristine; R-CHOP) has become the standard for patients with diffuse large B-cell lymphoma. Rituximab chemotherapy, probably with the CHOP regimen, is slowly gaining importance as the standard for patients with follicular lymphoma. Although little is known for other indolent lymphomas and mantle cell lymphoma, progress has been made there, too. Several questions remain for future randomized studies to continue our search toward cure.     

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.     

The use of galiximab in non-Hodgkin lymphoma

Monoclonal antibodies are expanding the therapeutic options for patients with B-cell lymphoma. Despite the antitumor activity of rituximab alone or in combination with systemic chemotherapy against various subtypes of B-cell lymphomas, a significant number of patients relapse or do not respond to initial therapy, stressing the need to identify novel molecular targets. CD80 is a surface glycoprotein and a member of the B7 family of costimulatory molecules. CD80 antigen is expressed in antigen-presenting cells, normal B cells, and various subtypes of B-cell lymphomas. Moreover, CD80 is an important regulator of T-cell activation. In addition, in vitro binding of CD80 by specific monoclonal antibodies (MoAbs) results in growth inhibition and apoptosis of normal and malignant B cells. Galiximab is a primatized MoAb targeting CD80. Preclinical studies had shown significant antitumor activity as a single agent or in combination with rituximab against various B-cell lymphoma cell lines in vitro and in vivo. An initial phase I/II study with galiximab as a single agent in patients with relapsed B-cell lymphoma demonstrated its safety and antitumor activity and had provided a framework for future studies. Interestingly, and in contrast with what had been observed with other biologic agents, the time to best response for the responding patients was delayed, suggesting an alternative mechanism of action other than the traditional antibody-dependent cellular cytotoxicity, apoptosis, and complement-mediated cytotoxicity. Ongoing and future studies are warranted to further evaluate the therapeutic role of galiximab in the treatment of patients with B-cell lymphomas in combination with rituximab or systemic chemotherapy.     

MALT lymphomas: pathogenesis can drive treatment

Marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma is an indolent B-cell non-Hodgkin lymphoma arising from the lymphoid tissue at extranodal sites. It is genetically characterized by different, usually mutually exclusive, genetic abnormalities that lead to activation of the nuclear factor kappa B (NF-kappaB) pathway. These lymphomas can arise in any extranodal organ or tissue; however, the stomach--where MALT lymphoma development has been strongly linked to chronic Helicobacter pylori infection--is the most common site. Other microorganisms have been associated with non-gastric MALT lymphomas, but the evidence for such associations is weaker. Treatment aimed at eradicating H pylori infection results in remission of gastric MALT lymphoma in most patients and represents a model of anticancer treatment based on the eradication of the causative factor. Treatment of non-gastric MALT lymphomas is much less well established; either radiotherapy or systemic therapy (with chemotherapy and/or rituximab [Rituxan]) can be effective, while antibiotic therapies (e.g., doxycycline in ocular adnexal lymphomas) should still be considered investigational.     

Differential diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma and other indolent lymphomas,including mantle cell lymphoma

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) accounts for approximately 1% of all lymphomas in our department. In this article, we describe the differential diagnosis of CLL/SLL from other indolent lymphomas, with special reference to follicular lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, and mantle cell lymphoma, although the latter is considered to be aggressive. CLL/SLL often exhibits proliferation centers, similar to follicular lymphoma. Immunohistological examination can easily distinguish these two lymphomas. The most important characteristic of CLL/SLL is CD5 and CD23 positivity. Mantle cell lymphoma is also CD5-positive and there are some CD23-positive cases. Such cases should be carefully distinguished from CLL/SLL. Some marginal zone lymphomas are also positive for CD5 and such cases are often disseminated. Lymphoplasmacytic lymphoma should also be a differential diagnosis for CLL/SLL. It frequently demonstrates MYD88 L265P, which is a key differential finding. By immunohistological examination, the expression of lymphoid enhancer-binding factor 1 is specific for CLL/SLL and can be a good marker in the differential diagnosis.     

Should all patients with indolent lymphoma be treated with rituximab maintenance therapy? An overview of the data

Indolent non-Hodgkin's lymphoma remains a generally incurable malignancy. Administration of the anti-CD20 monoclonal antibody rituximab as a single agent or in combination with chemotherapy has become widely employed in this patient population. Although the addition of maintenance treatment after 1 course of single-agent rituximab prolongs time to progression in patients with indolent non-Hodgkin's lymphoma, a similar "duration of rituximab benefit" is observed when rituximab is administered at the time of relapse. Progression-free survival is clearly improved when rituximab is administered with chemotherapy whether it is given concomitantly, in a maintenance fashion, or both. In fact, the available data show a trend toward survival benefit with these strategies in some settings. Further follow-up will elucidate the effect of maintenance rituximab on long-term outcomes. For now, these initial data suggest that patients with indolent lymphoma might derive significant benefit from these novel therapeutic strategies.     

Maintenance therapy for low-grade lymphomas: has the time come?

PURPOSE OF REVIEW: The introduction of rituximab (MabThera, Rituxan) maintenance treatment has initiated a new era in the management of low-grade non-Hodgkin's lymphomas. RECENT FINDINGS: Five randomized trials have recently reported on rituximab maintenance in the treatment of indolent non-Hodgkin's lymphomas. These trials enrolled patients with follicular, mantle cell and small lymphocytic non-Hodgkin's lymphomas, mostly in relapse. Patients responding to either rituximab monotherapy, chemotherapy alone or rituximab associated with chemotherapy were randomly assigned between observation and rituximab maintenance. Maintenance treatment significantly improved progression-free survival and response duration, and resulted in increased overall survival in two patients. In one trial, rituximab maintenance therapy produced significantly longer progression-free survival compared with rituximab retreatment at disease progression. SUMMARY: Rituximab maintenance therapy has demonstrated an impact on survival in patients with follicular lymphoma. These data justify recommending rituximab maintenance for patients with relapsed follicular lymphoma. Further trials are needed to determine its efficacy in first-line follicular lymphoma and other histological subtypes. The optimal schedule of maintenance therapy has not been established. Although these trials did not report severe adverse drug reactions, information concerning long-term toxicity is scarce, and careful monitoring of patients is therefore recommended.