For example, in one phase III trial, 410 patients with previously untreated CD20-positive FL received either IV rituximab or subcutaneous rituximab with hyaluronidase. The overall response rate at the end of treatment was 84.9% in the IV group and 84.4% in the subcutaneous group.
Full Answer
Do 90 min rituximab infusions affect infusion-related reactions in follicular lymphoma?
This phase III, multicenter, single-arm trial investigated the impact of 90 min rituximab infusions on infusion-related reactions (IRRs) in patients with untreated diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Patients received six or eight cycles of rituximab plus cyclophospham …
Is lenalidomide plus rituximab effective in the treatment of refractory fl/MZL?
The AUGMENT study met its primary end point; lenalidomide plus rituximab demonstrated statistically significant and clinically relevant superiority in PFS over placebo plus rituximab in patients with relapsed or refractory indolent FL/MZL who are considered appropriate for rituximab monotherapy.
How long does a rituximab infusion last?
A total of 425 patients received the first rituximab infusion per standard guidelines; median duration 240 min. Patients who did not experience grade ≥ 3 IRRs received subsequent infusions over 90 min (363 patients). A total of 303 patients received ≥ 6 cycles of rituximab.
Can the dose of rituximab be reduced?
The dose of rituximab could not be reduced; if rituximab was discontinued because of toxicity, lenalidomide or placebo was continued as per protocol. Lenalidomide was held and restarted at the next lower dose (5-mg increments) if the event resolved to a lower grade or discontinued as specified in the protocol.
What is the success rate of rituximab?
Rituximab with bendamustine (Treanda, Cephalon) was studied in a phase 2 trial in patients with relapsed disease. This combination was found to be very effective, with an ORR of 92%.
How long does it take for immune system to recover after rituximab?
Immune reconstitution starts usually after six months with recovery to normal between nine to twelve months. Extended rituximab treatment results in a prolonged recovery of B-cells without an increase of clinically relevant infections.
How quickly does rituximab work on lymphoma?
Patients treated with Rituxan may notice an early response within 8 weeks of treatment, but this is generally transient and due to the glucocorticoid pre-medication given alongside the Rituxan infusion.
How do you know if rituximab is working?
Rituximab works by lowering the number of these B-cells, to reduce inflammation, pain, swelling and joint damage. If rituximab works for you, you'll probably notice an improvement in your symptoms 8-16 weeks after you start treatment.
How will I feel after rituximab infusion?
After a Rituxan (rituximab) infusion you may experience certain side effects or adverse reactions that make you feel unwell. Rituxan affects different people in different ways, but the more common side effects include: Fever (high temperature), muscle aches, headaches and chills, which are signs of infection.
Is rituximab chemotherapy or immunotherapy?
Rituxan (rituximab) is a monoclonal antibody medication that treats different types of blood cancer. Rituxan is also an immunotherapy medication, meaning it helps make the immune system better at fighting cancer.
What is the difference between Rituxan and rituximab?
Rituxan is the trade name for rituximab. In some cases, health care professionals may use the trade name rituxan when referring to the generic drug name rituximab. Drug type: Rituximab is a monoclonal antibody. (For more detail, see "How this drug works" section below).
How long can you stay on Rituxan?
Rituxan can provide up to 6 months of symptom improvement from 1 course of treatment (2 infusions given 2 weeks apart). Be sure to talk with your doctor to find out if starting and continuing treatment with Rituxan is right for you.
What is the success rate of immunotherapy for lymphoma?
Lymphoma Statistics90%Non-Hodgkin lymphoma60%10-year overall relative survival rate for patients with Non-Hodgkin lymphoma590kNewly diagnosed patients each year globally
How long does it take for Rituxan to work on autoimmune disease?
It works for several months to reduce inflammation and improve your symptoms. If you respond well to rituximab you will probably feel better within four to six weeks. The effects of rituximab usually last for between six and nine months.
What steroid is given with Rituxan?
Rituxan for diffuse large B-cell lymphoma. Also for this use, Rituxan is used with the medications cyclophosphamide, doxorubicin, vincristine, and prednisone, or with other chemotherapy drugs called anthracyclines.
What happens when you have no B-cells?
Without B-cells, your body would not be as effective at fighting off a number of common bacteria and viruses; and you would lack the long-lasting "memory antibody" function that is typical after recovering from an infection or after being immunized against a specific infectious invader.
What are clinical trial efficacy results?
Clinical trial efficacy results can be summarised in several different ways: HRs, differences in event rates (proportions) at a specific time point, or differences in medians. They each indicate different aspects of the effect of a treatment.
What is the best treatment for follicular lymphoma?
Rituximab chemotherapy and obinutuzumab chemotherapy are effective treatments for patients with previously untreated follicular lymphoma.
What is FL treatment?
Follicular lymphoma (FL) is one of the most common subtypes of non-Hodgkin lymphoma worldwide. Improved survival outcomes with rituximab-based therapy in clinical trials led to the establishment of rituximab-based immunochemotherapy as standard of care for first-line (1L) treatment of FL. In the GALLIUM trial, obinutuzumab-based immunochemotherapy demonstrated improved progression-free survival (PFS), prolonged time-to-next antilymphoma treatment (TTNT) and comparable overall survival (OS) compared with rituximab-based immunochemotherapy as 1L treatment for FL. Using GALLIUM as an example, this article aims to explain how improved outcomes in 1L treatment of FL have changed the landscape for the design and interpretation of future trials. As approved therapies for 1L FL already achieve good responses, it is becoming more difficult to design trials that demonstrate further treatment benefits with the currently accepted primary endpoints. New endpoints are needed to reflect the long remission times, low relapse rates, and impact of subsequent therapies in FL. PFS is used as a primary efficacy endpoint in registrational clinical trials for indolent malignancies like FL, where improvement in OS is not always observed due to the large number of patients and long study duration required to demonstrate a clear survival benefit. However, there are limitations to using PFS as the primary endpoint. Other potential endpoints, including TTNT, progression of disease within 2 years, response rate, and minimal residual disease status are explored.
Does obinutuzumab cause cell death?
Nonclinical studies have shown that obinutuzumab mediates superior induction of direct cell death and effector cell-mediated, antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis, together with reduced CD20 internalisation, compared with the type I CD20 antibodies rituximab and ofatumumab [14, 15]. The GALLIUM trial was designed to show the superiority of obinutuzumab over rituximab in 1L FL. Overall, 1202 patients were randomised 1:1 to receive obinutuzumab-based or rituximab-based immunochemotherapy (with CHOP, CVP or bendamustine) as induction treatment, and those exhibiting a response continued with the same antibody as maintenance treatment for up to 2 years. Details of the trial have been published previously [16, 17]. Investigator-assessed PFS was the primary endpoint, with a target HR of 0.74, and, at the time of the primary analysis, the observed HR was 0.66 with 95% CI 0.51–0.85 (p= 0.001; Fig. Fig.1)1) [17]. Similarly, in later analyses after a median 76.5 months of follow-up, the HR was 0.76, 95% CI 0.62–0.92 (p= 0.0043) [18]. This is the only trial to date that compares obinutuzumab-based versus rituximab-based immunochemotherapy in patients with FL.
Does Rituximab maintenance improve PFS?
Two years of rituximab maintenance was subsequently found to improve PFS in patients responding to induction immunochemotherapy [3, 11]. The PRIMA trial compared rituximab maintenance with observation in patients who had responded to induction with immuno-chemotherapy [3, 12]. The final analysis of PRIMA, performed after a median of 9 years of follow-up, demonstrated the clinically relevant long-term benefit of rituximab maintenance on PFS in patients who had responded to induction with immunochemotherapy [12]. Rituximab maintenance led to a significant improvement in PFS compared with observation [10.5 vs. 4.1 years, hazard ratio (HR) 0.61; 95% confidence interval (CI) 0.52–0.73], but there was no evidence of a difference in OS (HR 1.04; 95% CI 0.77–1.40), and the 10-year OS rate was approximately 80% in both arms. A 2017 individual patient data meta-analysis showed that rituximab maintenance improved OS versus observation in patients with FL [13], although this analysis included heterogeneous trials in the relapsed setting, with and without rituximab induction therapy.
Is PFS a primary endpoint?
There are several limitations to using PFS as a primary endpoint in clinical trials of FL. In lymphoma, progression is generally defined using either Cheson 2007 [29] or Lugano 2014 criteria [30], both of which have a subjective element. Progression assessment may also be influenced by the size and location of the target lesions, and the timing of the assessment. Several other considerations apply to using PFS as a primary endpoint, particularly what its clinical value is to patients and clinicians when the trial cannot show a benefit on OS and only an improvement in PFS, and whether this is complemented by other benefits such as improvements in health-related quality of life and/or cost savings due to lower costs associated with the management of disease progression. For example, a trial might show that PFS is improved using combination immunochemotherapy compared to rituximab monotherapy, but if most patients survive for many years on both arms and 30% never need additional chemotherapy [31], the advantage of PFS might be less clear cut to patients and payers.
Is rituximab used for FL?
Clinical trials of the type I anti-CD20 antibody rituximab in the early-2000s showed a significant improvement in patient outcomes that led to rituximab-based immunochemotherapy becoming the standard of care for 1L treatment of FL. Rituximab with chemotherapy was shown to prolong overall survival (OS) when given as induction therapy, and to delay the time to disease progression when rituximab was used as maintenance therapy [2, 3]. Obinutuzumab, a type II anti-CD20 antibody, in combination with chemotherapy was granted approval in 2017 by the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and many other agencies for the 1L treatment of FL. Approval was based on the results of the multicentre, randomised, Phase III, GALLIUM trial, which demonstrated improved progression-free survival (PFS) with obinutuzumab-based immunochemotherapy compared with rituximab-based immunochemotherapy in this patient population [4].
How many infusions of rituximab?
The choice of the rituximab schedule took into consideration studies showing that extended dosing of rituximab with four additional infusions (total eight infusions) further improves efficacy with acceptable toxicity, which has led to the approval of four or eight doses of rituximab in certain countries, including the United States. The totality of published studies showed that extended dosing (ie, additional doses of rituximab beyond standard four weekly infusions) further improves benefit in a manner that is independent of the number or schedule of extended rituximab dosing (ie, four or more doses; every 1, 2, 3, or 6 months; Hainsworth JD, et al: J Clin Oncol 23:1088-1095, 2005; Piro LD, et al: Ann Oncol 10:655-661, 1999). 18, 32, 33 Lenalidomide 20 mg was chosen based on published studies indicating that the combination of lenalidomide 20 mg with rituximab is well tolerated and active in relapsed/refractory indolent non-Hodgkin lymphoma. 23, 35 In a previous study, 25 mg lenalidomide in combination with rituximab was not tolerated because of grade 3 tumor lysis syndrome in two out of four patients. 23
How many patients have had a serious adverse event with lenalidomide plus rituximab?
With lenalidomide plus rituximab, 45 patients (26%) had at least one serious adverse event versus 25 (14%) with placebo plus rituximab (Appendix Table A7, online only). Pneumonia was the most common serious adverse event, occurring in five patients (3%) in each group. Deep vein thrombosis occurred in three patients (2%) in the lenalidomide plus rituximab and one patient (1%) in the placebo plus rituximab groups; only one incidence (lenalidomide plus rituximab group) was a serious adverse event. Antiplatelet and anticoagulant medication use is listed in Appendix Table A8 (online only). Second primary cancers were reported in six patients (3%) in the lenalidomide plus rituximab group and 10 patients (6%) with placebo plus rituximab (Appendix Table A9, online only). Two patients died of second primary cancers (both placebo plus rituximab arm).
How long does lenalidomide last?
The hypothesized median progression-free survival (PFS) for lenalidomide plus rituximab was 17.6 months, on the basis of a reasonable risk reduction (hazard ratio [HR] = 0.0625) from a median PFS expected of rituximab monotherapy (11 months). In single-arm studies of lenalidomide plus rituximab in previously treated settings, the median PFS has ranged from approximately 12 months to 24 months, making 17.6 months a reasonable assumption. We hypothesized that median PFS for placebo plus rituximab would be 11 months, on the basis of previous results of rituximab monotherapy.
What is the best treatment for FL?
There are several treatment options, none considered curative, for patients with relapsed/refractory FL and MZL, including chemotherapy plus anti-CD20 monoclonal antibodies and targeted agents such as phosphatidylinositol 3-kinase inhibitors. Treatment choice is often based on duration of response to prior therapies, types of prior therapies, and patient comorbidities. 3, 17 Rituximab monotherapy is a treatment option in patients who had previously responded to rituximab, on the basis of observations that frequent responses can occur with rituximab retreatment. 18, 19 Rituximab monotherapy was commonly used in the second-line treatment of FL (25% to 47% of patients) according to studies in the United States and Europe. 20 - 22 Lenalidomide plus rituximab combination showed clinical activity in patients with previously treated indolent NHL in a key phase II study 23 and others 24, 25 demonstrating overall response rates of 65% to 77%, complete response (CR) rates of 35% to 41%, and median progression-free survival (PFS)/time to progression of 1 to 2 years. Recently, the lenalidomide plus rituximab combination also showed clinical activity in a phase III study of advanced untreated FL. 26 The AUGMENT trial ( ClinicalTrials.gov identifier: NCT01938001) prospectively compared efficacy and safety of lenalidomide plus rituximab to placebo plus rituximab (a standard of care, among several) in patients with relapsed or refractory indolent NHL who are appropriate for rituximab monotherapy (Appendix Table A1, online only).
What is lenalidomide used for?
Lenalidomide is an immunomodulatory (IMiD) drug that binds to the cereblon E3 ubiquitin ligase complex, resulting in ubiquitination of the transcription factors Aiolos and Ikaros, leading to antilymphoma effects. 9, 10 Preclinically, lenalidomide restored the response of tumor-infiltrating lymphocytes in autologous T-cell conjugates 11 and increased natural killer cell count and function in peripheral blood and natural killer cell lines. 12, 13 Adding lenalidomide to rituximab enhanced antibody-dependent cell-mediated cytotoxicity, immune synapse formation, monocyte-mediated killing, and direct cytotoxicity against FL cells. 11, 14 - 16
What is a MZL grade?
Eligible patients had MZL or FL (grades 1 to 3a ) requiring treatment per investigator assessment; at least one prior chemotherapy, immunotherapy, or chemoimmunotherapy and two or more previous doses of rituximab; and relapsed, refractory, or progressive disease and not rituximab-refractory disease. Patients with neuropathy grade greater than one were excluded. Additional eligibility criteria are in the Appendix (online only).
How often do you have to do follow up on PD?
For patients who completed treatment or discontinued treatment for reasons other than PD or relapse, overall survival and second malignancies were assessed every 6 months, and follow-up computed tomography or magnetic resonance imaging scans occurred every year. For patients who discontinued treatment because of PD or relapse, overall survival, subsequent antilymphoma therapies, and second malignancies were assessed every 6 months.
How many deaths were reported in the rituximab trial?
Adverse events that occurred during the treatment period and resulted in death (grade 5 events) were reported in 4 patients (1%) in the rituximab–lenalidomide group and in 5 patients (1%) in the rituximab–chemotherapy group. Among the patients who received at least one dose of trial treatment, 37 deaths were reported in the rituximab–lenalidomide group (with 23 of the deaths attributed by the investigators to lymphoma) as compared with 29 deaths reported in the rituximab–chemotherapy group (with 10 of the deaths attributed by the investigators to lymphoma). The death of 1 patient in each group was assessed as being related to the trial treatment (see the Results section in the Supplementary Appendix ).
What is the grade of CD20?
Patients were eligible for inclusion in the trial if they had histologically confirmed, CD20-positive follicular lymphoma (grade 1 to 3a); were assessed as being in need of treatment according to Groupe d’Étude des Lymphomes Folliculaires (GELF) criteria 2,22; and had received no previous systemic treatment for lymphoma. Additional eligibility criteria, information regarding GELF criteria, and details of the trial methods are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.
What is the median dose intensity of lenalidomide?
The median relative dose intensity (the proportion of administered doses relative to planned doses) was 90% for lenalidomide and was greater than 99% for rituximab and for chemotherapy. Vincristine had the lowest median relative dose intensity of all the chemotherapeutic agents. Among the patients who received R-CVP, the relative dose intensity for vincristine was less than 75% in 13% of the patients and was 75% to less than 90% in 17% of the patients. Among the patients who received R-CHOP, the relative dose intensity for vincristine was less than 75% in 16% of the patients and was 75% to less than 90% in 2% of the patients. Although the median relative dose intensity of lenalidomide was 90% over the course of the entire treatment period, the relative dose intensity of lenalidomide in the rituximab–lenalidomide group was less than 75% in 21% of the patients and was 75% to less than 90% in 29% of the patients. A higher percentage of the patients in the rituximab–lenalidomide group than in the rituximab–chemotherapy group had adverse events that led to dose reduction (36% vs. 14%), dose interruption (59% vs. 35%), or early discontinuation of trial treatment (11% vs. 3%), findings that reflected the protocol-specified guidelines on dose modification for the management of toxic effects. Among the patients in the rituximab–lenalidomide group, neutropenia was the most common reason for dose reduction (20% of the patients) and interruption (32%); neutropenia led to early discontinuation of trial treatment in 1% of the patients. A total of 69% of the patients in the rituximab–lenalidomide group and 71% of the patients in the rituximab–chemotherapy group completed 120 weeks of treatment. In the rituximab–lenalidomide group, 76% of the patients completed all 18 cycles of lenalidomide.
What is lenalidomide used for?
Lenalidomide is an immunomodulatory agent that binds the cereblon E3 ubiquitin ligase complex , which results in recruitment, ubiquitination, and degradation of transcription factors Aiolos and Ikaros. 9-11 In malignant lymphoma B cells, this degradation results in up-regulation of interferon-stimulated genes and apoptosis. 11 In T cells, the degradation results in enhanced IL-2 secretion, which leads to T-cell activation, thereby indirectly activating NK cells. 9,10 Combining lenalidomide with rituximab enhances apoptosis and antibody-dependent cell-mediated cytotoxicity of B-cell non-Hodgkin’s lymphoma cells more effectively than monotherapy. 12-16 In addition, lenalidomide repairs defective immune synapses between follicular lymphoma cells and T cells. 17 In phase 2 trials involving patients with previously untreated follicular lymphoma, rituximab plus lenalidomide showed promising activity, with high response rates. 18-21
How long does it take to complete a subgroup analysis of progression-free survival?
Subgroup Analyses of Progression-free Survival and Confirmed or Unconfirmed Complete Response at 120 Weeks.
Is rituximab effective for follicular lymphoma?
Rituximab plus chemotherapy has been shown to be effective in patients with advanced-stage, previously untreated follicular lymphoma; nevertheless, most patients will have a relapse. Combination immunotherapy with lenalidomide and rituximab is an immunomodulatory regimen that has shown promising activity in patients with indolent B-cell non-Hodgkin’s lymphoma.
Does rituximab help with chemotherapy?
Incorporation of rituximab into combination chemotherapy regimens has been shown to significantly improve survival over chemotherapy alone. 28 In the current trial, rituximab in combination with lenalidomide showed results that were similar to those reported with rituximab plus chemotherapy in two randomized phase 3 trials with similar populations. 1,2 In the rituximab–chemotherapy group, the rate of progression-free survival at 3 years was 78% (as assessed by both the independent review committee and the investigators), and the rate of overall survival at 3 years was 94%. These results are consistent with 3-year rates of progression-free survival of 78% (by central assessment) and 73% (by investigator assessment) and an overall survival rate of 92% with rituximab plus chemotherapy in the GALLIUM trial 1 and a 3-year rate of progression-free survival of 75% (by investigator assessment) with rituximab plus chemotherapy in the PRIMA trial. 2,3 The progression-free survival and overall survival results for the rituximab–lenalidomide group were also similar to historical results in two phase 2 trials 19,21; the 3-year progression-free survival rate of 77% reported here was similar to that reported in the Cancer and Leukemia Group B (CALGB) 50803 trial (81%) 21 and in a trial sponsored by M.D. Anderson Cancer Center (79%). 19 A limitation inherent to the current analysis is the limited follow-up time for time-to-event end points. Longer follow-up with more mature survival data will be needed to assess long-term outcomes.