Interim data from the study evaluating the investigational chemotherapy-free R2 combination regimen, presented at ASCO and expanded data presented at ICML
Results showed clinical activity across indolent non-Hodgkin lymphomas, marginal zone and follicular histologies, as well as responses in poor risk patient subpopulations including early relapsing patients and patients who were refractory to multiple lines of therapy
The MAGNIFY study continues to evaluate the clinical activity of 12 cycles of R2 combination therapy followed by randomization to either 18 cycles of R2 maintenance or 18 cycles of rituximab monotherapy, in patients with relapsed or refractory follicular lymphoma (FL), marginal zone lymphoma (MZL) or mantle cell lymphoma (MCL). Approximately 500 patients are planned to be enrolled in the study. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), overall response rate (ORR), complete response (CR), improvement of response (IOR), duration of response (DOR) and duration of complete response (DOCR), time to next lymphoma treatment (TTNLT), time to histological transformation (TTHT), safety and exploratory quality of life measures. Enrollment in the MAGNIFY study is ongoing.
"Interim data from the MAGNIFY study continue to show the clinical
potential for the R2 combination across a broad range of
At ASCO, interim data were presented from an analysis of a subset of
patients from the MAGNIFY study with relapsed or refractory FL (n=160)
with early relapse (ER, n=52) and double-refractory (DR, n=50) disease.
Most common grade 3 or 4 adverse events observed in the study for all FL patients, DR patients and ER patients, respectively, were neutropenia (29%, 42%, 37%), fatigue (6%, 4%, 8%), leukopenia (5%, 8%, 10%), thrombocytopenia (4%, 8%, 4%) and lymphopenia (3%, 6%, 4%).
Data being presented at ICML in a separate analysis focused on patients with MZL (n=38), including nodal MZL (n=18), splenic MZL (n=10) and mucosa-associated lymphoid tissue (MALT) lymphoma (n=10). At a median follow-up of 13.8 months from initiation of therapy with the R2 combination, evaluable patients with MZL (n=32) achieved an ORR of 66% with a CR/CRu rate of 44%. Evaluable nodal MZL patients (n=14) had an ORR of 57% with a CR/CRu rate of 57%. Evaluable splenic MZL patients (n=8) had an ORR of 63% with a CR of 25%; and evaluable MALT patients (n=10) had an ORR of 80% with a CR/CRu rate of 40%. Median duration of response was not reached for any group.
The most common grade 3 or 4 adverse events observed in patients with MZL were neutropenia (32%), thrombocytopenia (16%) and leukopenia (11%).
"The chemotherapy-free combination of lenalidomide and rituximab, with
complementary mechanisms of action that are thought to enhance antibody
dependent cellular cytotoxicity, continues to show encouraging activity
and a tolerable safety profile in indolent lymphomas, and particularly
in difficult-to-treat patient subsets," said
MAGNIFY (NCT01996865) is a phase IIIb, multicenter, open-label study of patients with grades 1-3b or transformed FL, MZL, or MCL who received ≥1 prior therapy and had stage I-IV, measurable disease. Approximately 500 patients are planned for enrollment in 12 cycles of R2 induction, with a projected 314 patients with ≥SD after induction randomized (1:1) to two maintenance arms. Induction included oral lenalidomide 20 mg/day, days 1-21 per 28-day cycle (d1-21/28) plus intravenous rituximab 375 mg/m2, days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 3, 5, 7, 9, and 11 (28-day cycles). Patients are then randomized to maintenance lenalidomide 10 mg/day, d1-21/28, cycles 13-30, plus rituximab 375 mg/m2, day 1 of cycles 13, 15, 17, 19, 21, 23, 25, 27, and 29 (R2, Arm A), or rituximab alone (same schedule, Arm B). Patients receiving R2 maintenance after 18 cycles may continue maintenance lenalidomide monotherapy 10 mg/day, d1-21/28 (per patient and/or investigator discretion), until disease progression as tolerated. Patients will be followed for ≥5 years after the last patient initiates induction therapy.
About Follicular and Marginal Zone Lymphomas
FL is the most common indolent (slow-growing) form of NHL, accounting for approximately 22% of all B-cell Non-Hodgkin lymphoma (NHL) patients. Most patients present with advanced disease usually when lymphoma-related symptoms appear (e.g., nodal disease, B symptoms, cytopenia) and receive systemic chemoimmunotherapy. While FL patients are generally responsive to initial treatment, the disease course is characterized by recurrent relapses over time with shorter remission periods. MZL are a heterogeneous group of indolent lymphomas that account for 8% of all NHL. While often treated like FL, MZL has important differences in clinical presentation and pathogenesis. Patients with MZL have historically been grouped within studies of mixed indolent NHL histologies, and large studies are lacking to validate appropriate treatment for MZL patients.
REVLIMID was granted Orphan Drug Designation for the treatment of
extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue
REVLIMID is not approved for combination use with rituximab for any purpose or for the treatment of follicular lymphoma or marginal zone lymphoma.
REVLIMID® (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of patients with multiple myeloma (MM)
REVLIMID is indicated as maintenance therapy in patients with MM following autologous hematopoietic stem cell transplantation (auto-HSCT)
REVLIMID® is indicated for the treatment of patients with transfusion-dependent anemia due to low-or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities
REVLIMID® is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib
REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials
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 REVLIMID REMS® program).
Information about the REVLIMID 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
Allergic Reactions: REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide
WARNINGS AND PRECAUTIONS
Embryo-Fetal Toxicity: See Boxed WARNINGS
REVLIMID REMS® Program: See Boxed WARNINGS: Prescribers and pharmacies must be certified with the REVLIMID 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. MM: Patients taking REVLIMID/dex or REVLIMID maintenance therapy should have their complete blood counts (CBC) assessed every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days thereafter. MDS: 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 dose reduction. Please see the Boxed WARNINGS for further information. MCL: Patients taking REVLIMID for MCL should have their CBCs monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction
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 patient's underlying risks. 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, an increase of hematologic plus solid tumor SPM, notably AML and MDS, have been observed. Monitor patients for the development of SPM. Take into account both the potential benefit of REVLIMID and risk of SPM when considering treatment
Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with REVLIMID/dex. 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
Allergic Reactions: Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) 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. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose; risk-benefit of treatment should be evaluated in patients with lactose intolerance
Tumor Lysis Syndrome (TLS): Fatal instances of TLS have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken
Tumor Flare Reaction (TFR): TFR has occurred during investigational use of lenalidomide for CLL and lymphoma. Monitoring and evaluation for TFR is recommended in patients with MCL. 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 start of REVLIMID treatment and during therapy
Mantle Cell Lymphoma
Periodic monitoring of digoxin plasma levels is recommended due to increased Cmax and AUC with concomitant REVLIMID therapy. Patients taking concomitant therapies such as erythropoietin stimulating agents or estrogen containing therapies may have an increased risk of thrombosis. It is not known whether there is an interaction between dex and warfarin. Close monitoring of PT and INR is recommended in patients with MM taking concomitant warfarin
USE IN SPECIFIC POPULATIONS:
Please see full Prescribing Information, including Boxed WARNINGS.
This press release contains forward-looking statements, which are
generally statements that are not historical facts. Forward-looking
statements can be identified by the words "expects," "anticipates,"
"believes," "intends," "estimates," "plans," "will," "outlook" and
similar expressions. Forward-looking statements are based on
management's current plans, estimates, assumptions and projections, and
speak only as of the date they are made.
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