Celgene Corporation
Dec 8, 2014
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REVLIMID® (Lenalidomide) Single-Agent and Combination Studies in Mantle Cell Lymphoma (MCL) Presented at ASH

Results of MCL-002 (SPRINT) study demonstrated significantly longer progression-free survival for lenalidomide compared to investigators' choice in relapsed/refractory MCL

Combination of lenalidomide plus rituximab demonstrated 84.2% response rate in previously untreated MCL

SAN FRANCISCO--(BUSINESS WIRE)-- Celgene Corporation (NASDAQ:CELG) today announced results from studies of REVLIMID® (lenalidomide) and the combination of lenalidomide plus rituximab in patients with mantle cell lymphoma (MCL), which were presented during the 56th American Society of Hematology annual meeting.

The SPRINT study, a multicenter, open-label, phase II randomized trial compared lenalidomide with investigators' choice (IC) in patients with relapsed/refractory (MCL) (MCL-002 SPRINT). In the study, presented by Dr. Mark Trneny, 250 patients were randomized 2:1 to receive either lenalidomide (n=170) or single agent cytarabine, rituximab, gemcitabine, fludarabine or chlorambucil (n=84).

"The SPRINT study provided the first head-to-head, randomized, controlled study of single-agent lenalidomide compared with a range of single-agent comparators in previously-treated MCL," said Dr. Trneny. "The study demonstrated a statistically significant reduction in the risk of disease progression or death for lenalidomide over investigator's choice in patients with relapsed/refractory MCL."

At a median follow-up of 15.9 months, median progression-free survival, the primary endpoint of the study, was 8.7 months for patients receiving lenalidomide compared with 5.2 months for IC. This equated to a risk reduction of 39% (HR 0.61 [95% CI, 0.44-0.84]; p=0.004) for patients receiving lenalidomide. Median overall survival for patients receiving lenalidomide was 27.8 months vs 21.2 months. The overall response rate (ORR) for patients in the lenalidomide arm was 40% (68/170), with a complete response (CR) rate of 5% (8/170) compared with an ORR of 11% (9/84) and CR of 0% (0/84) for IC. Median duration of response for lenalidomide and IC, respectively, was 16 and 10.4 months.

The most common grade 3/4 adverse events (AEs) were neutropenia (lenalidomide 44% vs IC 34%) thrombocytopenia (18% vs 28%), anemia (8% vs 7%) and leukopenia (8% vs 11%). Tumor flare reaction occurred in lenalidomide patients only (10%; 2% grade ≥3); one patient in each arm experienced tumor lysis syndrome. Invasive second primary malignancies were identified in 4% and 5% of lenalidomide and IC treated patients, respectively.

Lenalidomide plus Rituxan (R2) Combination

In a separate multi-center phase II study, presented by Dr. Jia Ruan, 38 patients with previously untreated MCL were enrolled at four centers and received lenalidomide (20 mg daily on days 1-21 of a 28-day cycle for 12 cycles) plus standard dose rituximab weekly during cycle one, then once every other cycle for a total of 9 doses. A maintenance phase followed, starting at cycle 13, where patients received lenalidomide (15 mg daily on days 1-21 of a 28-day cycle) with rituximab maintenance every other cycle until disease progression. The primary objective of the study was to evaluate overall response rate (ORR).

At a median follow-up of 24 months, 36 patients are evaluable for response. Two patients were inevaluable - one withdrew consent, and one was intolerant of tumor flare. The ORR for all patients was 84.2% (95% CI, .687-.94) with a 52.6% CR rate (95% CI, .358-.69). Median time to objective response was 2.8 months, with median time to CR achieved at 11 months. Thirty (79%) patients remain on study without evidence of disease progression, including 24 who have completed induction and are now in maintenance. Six evaluable patients had disease progression - three with primary refractory disease, three progressed following initial responses (one CR with PFS of 18 months, two PRs with PFS at 14 and 25 months, respectively).

Grade 3-4 hematologic toxicities included neutropenia (47% in total, 42% with induction, 24% with maintenance), thrombocytopenia (13%) and anemia (8%). Grade 3-4 non-hematologic toxicities including rash (26%), tumor flare (11%), serum sickness associated with rituximab (8%) and fatigue (8%), were reported during induction phase only. Grade 1-2 infections including URI (34%), UTI (16%), sinusitis (11%) and bronchitis (8%) were reported during both induction and maintenance. One patient developed grade 3 cholangitis from cholecystitis requiring cholecystectomy. Secondary malignancy was reported in an 86 year-old patient who developed melanoma in-situ and Merkel cell carcinoma following 18 months of therapy.

The combination of REVLIMID plus rituximab is not indicated for the treatment of MCL in any country.


REVLIMID is approved in combination with dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy in nearly 70 countries, encompassing Europe, the Americas, the Middle-East and Asia, and in combination with dexamethasone for the treatment of patients whose disease has progressed after one therapy in Australia and New Zealand.

REVLIMID is also approved in the United States, Canada, Switzerland, Australia, New Zealand and several Latin American countries, as well as Malaysia and Israel, for transfusion-dependent anaemia due to low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities and in Europe for the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.

In addition, REVLIMID is approved in the United States 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.

U.S. Regulatory Information for REVLIMID®

REVLIMID (lenalidomide) in combination with dexamethasone is indicated for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy

REVLIMID (lenalidomide) 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 (lenalidomide) 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 not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials

Important Safety Information


Embryo-Fetal Toxicity

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 (formerly known as the "RevAssist®"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 dex 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.



Allergic Reactions:


Embryo-Fetal Toxicity:


Because of embryo-fetal risk, REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) the REVLIMID REMS Program (formerly known as the "RevAssist®" Program). Prescribers and pharmacies must be certified with the program and patients must sign an agreement form and comply with the requirements. Further information about the REVLIMID REMS program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436

Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia. MM: Patients taking REVLIMID for MM should have their complete blood counts monitored every 2 weeks for the first 12 weeks and then monthly thereafter. In the pooled MM trials Grade 3 and 4 hematologic toxicities were more frequent in patients treated with the combination of REVLIMID and dex than in patients treated with dexamethasone alone. MCL: Patients taking REVLIMID for MCL should have their complete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients. Grade 3 or 4 thrombocytopenia was reported in 28% of the patients. Patients may require dose interruption and/or dose reduction. See Boxed WARNINGS

Venous and Arterial Thromboembolism: A significantly increased risk of DVT (7.4%) and PE (3.7%) occurred in patients with MM treated with REVLIMID and dex compared to the placebo and dex group (3.1% and 0.9%) in clinical trials with varying use of anticoagulant therapies. Myocardial infarction (1.7%) and stroke (CVA) (2.3%) are increased in patients with MM who were treated with REVLIMID and dex therapy compared with placebo and dex (0.6%, and 0.9%) in clinical trials. 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). In controlled clinical trials that did not use concomitant thromboprophylaxis, 21.5% overall thrombotic events occurred in patients with refractory and relapsed MM who were treated with REVLIMID and dex compared to 8.3% thrombosis in the placebo and dex group. Median time to first thrombosis event was 2.7 months. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision. See Boxed WARNINGS

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. In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08-3.41] consistent with a 92% increase in risk of death. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure occurred more frequently in the REVLIMID treatment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials

Second Primary Malignancies: Patients with MM treated with lenalidomide in studies including melphalan and stem cell transplantation had a higher incidence of second primary malignancies, particularly acute myelogenous leukemia (AML) and Hodgkin lymphoma, compared to patients in the control arms who received similar therapy but did not receive lenalidomide. Monitor patients for the development of second malignancies. Take into account both the potential benefit of lenalidomide and the risk of second primary malignancies when considering treatment with lenalidomide

Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dex. The mechanism of drug-induced hepatotoxicity is unknown. 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 REVLIMID treatment should be evaluated in patients with lactose intolerance

Tumor Lysis Syndrome: Fatal instances of tumor lysis syndrome (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: Tumor flare reaction (TFR) has occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials

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 lenalidomide until TFR resolves to ≤ Grade 1. In the MCL trial, approximately 10% of subjects experienced TFR; all reports were Grade 1 and 2 in severity. All of the events occurred in cycle 1 and one patient developed TFR again in cycle 11. Lenalidomide may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician's discretion. Patients with Grade 1 or 2 TFR may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR


Multiple Myeloma

Myelodysplastic Syndromes

Mantle Cell Lymphoma


Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID. It is not known whether there is an interaction between dex and warfarin. Close monitoring of PT and INR is recommended in MM patients taking concomitant warfarin. Erythropoietic agents, or other agents, that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution after making a benefit-risk assessment in patients receiving REVLIMID


Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436

Nursing Mothers: It is not known whether REVLIMID is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother

Pediatric Use: Safety and effectiveness in pediatric patients below the age of 18 have not been established

Geriatric Use: Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function

Renal Impairment: Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr < 30 mL/min) and in patients on dialysis

Please see full Prescribing Information, including Boxed WARNINGS.

About Celgene

Celgene Corporation, headquartered in Summit, New Jersey, is an integrated global pharmaceutical company engaged primarily in the discovery, development and commercialization of innovative therapies for the treatment of cancer and inflammatory diseases through gene and protein regulation. For more information, please visit www.celgene.com. Follow us on Twitter @Celgene, and on Pinterest and LinkedIn.

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