- Clinical Data
REVLIMID® (lenalidomide) in combination with a rituximab product is indicated for the treatment of adult patients with previously treated follicular lymphoma (FL). REVLIMID in combination with a rituximab product is indicated for the treatment of adult patients with previously treated marginal zone lymphoma (MZL). REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials.
PHASE III AUGMENT TRIAL OVERVIEW
REVLIMID® (lenalidomide) + rituximab (R2) vs rituximab in previously treated follicular and marginal zone lymphoma1
A Treatment Option for Previously Treated Follicular Lymphoma
Dr Lori Leslie, hematologist-oncologist at the John Theurer Cancer Center, reviews the Phase III AUGMENT trial and R2 as a treatment option.
View Video Transcript
[Non KOL Voiceover talent]
REVLIMID (lenalidomide) in combination with a rituximab product is indicated for the treatment of adult patients with previously treated follicular lymphoma or marginal zone lymphoma.
REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials.
REVLIMID has a Boxed Warning for embryo-fetal toxicity, hematologic toxicity, and venous and arterial thromboembolism.
Please see additional Important Safety Information for REVLIMID at the end of this video.
My name’s Lori Leslie. I’m a hematologist-oncologist at the John Theurer Cancer Center in Hackensack, New Jersey, where I run the indolent B cell non-Hodgkins lymphoma program and clinically see all lymphomas and chronic lymphocytic leukemia.
I am here today to share with you some information about the R2 regimen in previously treated follicular lymphoma and marginal zone lymphoma.
THE ADVENT OF R2
Currently, when we look at the regimens for previously treated follicular lymphoma, approved second-line options include rituximab monotherapy and regimens containing chemotherapy. REVLIMID plus rituximab, referred to as R2, is an option to consider when thinking about non-chemotherapy-containing regimens.
In May 2019, R2 was approved for treatment of previously treated follicular lymphoma. In general, there is no single standard of care in relapsed/refractory follicular lymphoma; however, R2 is an approved option to consider.
AUGMENT: Pivotal Phase III Trial
The FDA approved R2 as a combination immunotherapy supported by the results of the AUGMENT trial.
A total of 358 patients with previously treated follicular or marginal zone lymphoma were randomized 1 to 1 to R2 or rituximab plus placebo for a total of 12 treatment cycles. The dosing information for REVLIMID and rituximab is shown on your screen.
Highlights of the baseline patient characteristics are presented here. Patients had received at least 2 prior doses of rituximab, but none of the patients were rituximab refractory.
The primary endpoint of the trial was progression-free survival. Secondary and exploratory endpoints included overall survival, PFS2, and time to next anti-lymphoma treatment.
R2 DEMONSTRATED SIGNIFICANT IMPROVEMENT IN PFS
In the intention-to-treat population, the primary endpoint of progression-free survival was statistically superior in the R2 group. At a median follow-up of 28.3 months, median PFS was 39.4 months with R2 versus 14.1 months with rituximab. This is an approximate 2.8-time improvement in median PFS.
The progression-free survival benefit persisted beyond the end of the treatment period.
In the follicular lymphoma population, the median progression-free survival was 39.4 months with R2 and 13.9 months with rituximab alone.
Additional secondary and exploratory efficacy analyses were conducted in the follicular lymphoma subgroup, including overall survival.
These follicular lymphoma subgroup data were analyzed for exploratory purposes and should be interpreted with caution.
CONSIDER R2 AS EARLY AS SECOND LINE
Other exploratory analyses were conducted, including PFS2 and the time until the patients needed their next anti-lymphoma treatment.
Due to the multiple relapses that patients typically experience in follicular lymphoma, it may be helpful to consider the entire course of disease when selecting treatment regimens for patients.
ESTABLISHED SAFETY PROFILE
When considering a long-term treatment strategy for follicular lymphoma, it’s also important to consider potential adverse reactions.
In the AUGMENT trial, neutropenia was the most commonly reported adverse reaction with R2 and was observed in 58% of patients, including 50% who had Grade 3 or 4 reactions. Incidences of Grade 3 or 4 neutropenia resolved in a median of 9 days. 3 percent of patients who received R2 vs less than 1 percent of patients who received rituximab experienced febrile neutropenia.
Other commonly reported adverse reactions were diarrhea, constipation, cough, fatigue, rash, pyrexia, leukopenia, and pruritus.
In AUGMENT, patients in the R2 arm received an average of 11.2 cycles of treatment with appropriate growth factor support, dose modifications, and/or interruptions. The dose reductions and dose interruptions are shown on your screen.
Overall, 71% of patients receiving R2 completed all 12 cycles of treatment vs 62% receiving rituximab plus placebo, and the most common reasons for discontinuation were progressive disease, adverse events, or withdrawal from the trial.
Thanks for watching. I hope you found this information helpful. Here’s some Important Safety Information to keep in mind when considering this treatment option.
[Non KOL Voiceover talent]
Important Safety Information
WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM
Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the Lenalidomide REMS program.
Information about the Lenalidomide REMS program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436.
Hematologic Toxicity (Neutropenia and Thrombocytopenia)
REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q MDS had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors.
Venous and Arterial Thromboembolism
REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with MM who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks.
Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to the fetus.
Severe Hypersensitivity Reactions: REVLIMID is contraindicated in patients who have demonstrated severe hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide.
WARNINGS AND PRECAUTIONS
Embryo-Fetal Toxicity: See Boxed WARNINGS
- Females of Reproductive Potential: See Boxed WARNINGS.
- Males: Lenalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 4 weeks after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm.
- Blood Donation: Patients must not donate blood during treatment with REVLIMID and for 4 weeks following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID.
Lenalidomide REMS Program: See Boxed WARNINGS: Prescribers and pharmacies must be certified with the Lenalidomide REMS program by enrolling and complying with the REMS requirements; pharmacies must only dispense to patients who are authorized to receive REVLIMID. Patients must sign a Patient-Physician Agreement Form and comply with REMS requirements; female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements.
Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medications that may increase risk of bleeding. Patients may require a dose interruption and/or dose reduction. Monitor complete blood counts (CBC) in patients taking REVLIMID for FL or MZL weekly for the first 3 weeks of Cycle 1 (28 days), every 2 weeks during Cycles 2-4, and then monthly thereafter.
Venous and Arterial Thromboembolism: See Boxed WARNINGS: Venous thromboembolic events (DVT and PE) and arterial thromboses (MI and CVA) are increased in patients treated with REVLIMID. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended and the regimen should be based on the patient’s underlying risks. Erythropoietin-stimulating agents (ESAs) and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision.
Increased Mortality in Patients With CLL: In a clinical trial in the first-line treatment of patients with CLL, single-agent REVLIMID therapy increased the risk of death as compared to single-agent chlorambucil. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure, occurred more frequently in the REVLIMID arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials.
Second Primary Malignancies (SPM): In clinical trials in patients with MM receiving REVLIMID and in patients with FL or MZL receiving REVLIMID + rituximab therapy, an increase of hematologic plus solid tumor SPM, notably AML, have been observed. In patients with MM, MDS was also observed. Monitor patients for the development of SPM. Take into account both the potential benefit of REVLIMID and risk of SPM when considering treatment.
Increased Mortality With Pembrolizumab: In clinical trials in patients with MM, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with MM with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.
Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with REVLIMID + dexamethasone. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered.
Severe Cutaneous Reactions: Severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. Consider REVLIMID interruption or discontinuation for Grade 2-3 skin rash. Permanently discontinue REVLIMID for Grade 4 rash, exfoliative or bullous rash, or for other severe cutaneous reactions such as SJS, TEN, or DRESS.
Tumor Lysis Syndrome (TLS): Fatal instances of TLS have been reported during treatment with REVLIMID. The patients at risk of TLS are those with high tumor burden prior to treatment. Closely monitor patients at risk and take appropriate preventive approaches.
Tumor Flare Reaction (TFR): TFR has occurred during investigational use of REVLIMID for CLL and lymphoma. Monitoring and evaluation for TFR is recommended in patients with MCL, FL or MZL. Tumor flare may mimic the progression of disease (PD). In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with REVLIMID until TFR resolves to ≤ Grade 1. REVLIMID may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion.
Impaired Stem Cell Mobilization: A decrease in the number of CD34+ cells collected after treatment (>4 cycles) with REVLIMID has been reported. Consider early referral to transplant center to optimize timing of the stem cell collection.
Thyroid Disorders: Both hypothyroidism and hyperthyroidism have been reported. Measure thyroid function before starting REVLIMID treatment and during therapy.
Early Mortality in Patients With MCL: In another MCL study, there was an increase in early deaths (within 20 weeks); 12.9% in the REVLIMID arm versus 7.1% in the control arm. Risk factors for early deaths include high tumor burden, MIPI score at diagnosis, and high WBC at baseline (≥10 x 109/L).
Hypersensitivity: Hypersensitivity, including angioedema, anaphylaxis, and anaphylactic reactions to REVLIMID has been reported. Permanently discontinue REVLIMID for angioedema and anaphylaxis.
Follicular Lymphoma/Marginal Zone Lymphoma
- Fatal adverse reactions occurred in 6 patients (1.5%) receiving REVLIMID + rituximab across both trials. Fatal adverse reactions (1 each) included: cardio-respiratory arrest, arrhythmia, cardiopulmonary failure, multiple organ dysfunction syndrome, sepsis, and acute kidney injury. The most frequent serious adverse reaction that occurred in the REVLIMID + rituximab arm was febrile neutropenia (3.0%).
- Grade 3 and 4 adverse reactions reported in ≥5% of patients treated in the FL/MZL trial with REVLIMID + rituximab were: neutropenia (50%) and leukopenia (7%).
- Adverse reactions reported in ≥15% of patients with FL/MZL treated with REVLIMID + rituximab were: neutropenia (58%), diarrhea (31%), constipation (26%), cough (24%), fatigue (22%), rash (22%), pyrexia (21%), leukopenia (20%), pruritus (20%), upper respiratory tract infections (18%), abdominal pain (18%), anemia (16%), headache (15%), thrombocytopenia (15%).
Periodically monitor digoxin plasma levels due to increased Cmax and AUC with concomitant REVLIMID therapy. Patients taking concomitant therapies such as ESAs or estrogen-containing therapies may have an increased risk of thrombosis. It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is recommended in patients with MM taking concomitant warfarin.
USE IN SPECIFIC POPULATIONS
- PREGNANCY: See Boxed WARNINGS: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. There is a REVLIMID pregnancy exposure registry that monitors pregnancy outcomes in females exposed to REVLIMID during pregnancy as well as female partners of male patients who are exposed to REVLIMID. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to REVLIMID to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436.
- LACTATION: There is no information regarding the presence of lenalidomide in human milk, the effects of REVLIMID on the breastfed infant, or the effects of REVLIMID on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants from REVLIMID, advise female patients not to breastfeed during treatment with REVLIMID.
- RENAL IMPAIRMENT: Adjust the starting dose of REVLIMID based on creatinine clearance value and for patients on dialysis.
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