2012-12-11 23:30:16 -
Celgene International Sàrl, a subsidiary of Celgene Corporation (NASDAQ.
CELG), announced results from several studies evaluating combination treatment with REVLIMID ® (lenalidomide) and antibody therapy in non-Hodgkin lymphoma (NHL). The data were presented at the 54 th Annual Meeting of the American Society of Hematology (ASH) in Atlanta, GA.
The presented data included two Phase II trials on the combination of lenalidomide with R-CHOP, a Phase I/II trial evaluating the combination of lenalidomide and ofatumumab, and a Phase II trial analyzing the combination of lenalidomide and rituximab.
First, a Phase II trial (abstract #689) evaluated lenalidomide in combination with R-CHOP (rituximab-CHOP) in patients with aggressive B-cell lymphomas, including diffuse large B-cell lymphoma and follicular lymphoma. Treatment resulted in an overall response rate (ORR) of
98% and one-year progression-free survival (PFS) rate of 73%. Grade ≥3 hematological toxicities were thrombocytopenia (40%), neutropenia (89%), and anemia (19%). Non-hematological side effects of grade 3 or higher included febrile neutropenia (10%), pneumonia (4%), sepsis (2%), venous thrombosis (2%), fatigue (6%), and dehydration (6%).
Another Phase II trial (abstract #3668) evaluated the clinical activity of lenalidomide as maintenance therapy following R-CHOP in patients with diffuse large B-cell lymphoma who achieved a complete response to the chemotherapy regimen. At a median follow up of 24 months, patients who received maintenance lenalidomide achieved a median two-year PFS rate of 92%, compared with 83% for patients treated with lenalidomide plus rituximab as maintenance; overall survival rates were 92% and 77%, respectively. Grade ≥3 toxicities include neutropenia (25%), fatigue (15%), hypothyroidism (5%), deep-vein thrombosis (3%), and rash (3%).
A phase I/II trial (abstract #3692) evaluated lenalidomide in combination with ofatumumab in patients with relapsed/refractory B-cell NHL. Patients in this trial with follicular lymphoma demonstrated an ORR of 83% and a one-year PFS of 67%. Overall, grade 4 neutropenia occurred in 24% (9/37) of patients, and one case occurred for each of grade 4 bacteremia, grade 4 deep vein thrombosis, stroke, and acute renal failure.
Lastly, final results of a Phase II trial (abstract #901) evaluated lenalidomide plus rituximab in patients with advanced stage, untreated indolent NHL, with an ORR of 90%. In the study, the estimated three-year PFS was 78%. Grade ≥3 neutropenia occurred in 41% of patients, and thrombocytopenia in 6% of patients. The most common grade ≥3 non-hematologic toxicities included muscle pain (8%), rash (7%), and fatigue (5%), thrombosis (3%) and other pulmonary events (4%). Five patients developed neutropenic fever.
These data are from investigational studies. REVLIMID ® is not approved for use in patients with non-Hodgkin lymphoma.
REVLIMID is an IMiDs ® compound. REVLIMID and other IMiDs continue to be evaluated in over 300 clinical trials worldwide.
The IMiDs pipeline is covered by a comprehensive intellectual property estate of issued and pending patent applications in the US, EU and other regions, including composition-of- matter and use patents.
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.
Marketing Authorization Applications are currently being evaluated in a number of other countries.
Since 1998, Celgene continues to be a pioneer in creating environments in which patients can benefit from our disease-altering therapies safely. As a result, hundreds of thousands of patients worldwide have accessed the clinical benefits of our therapies through our performance-based risk management programs including, S.T.E.P.S. ® , RevAssist ® and RevMate ® , which form the foundation of our commitment to patient safety.
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.
Important Safety Information
WARNING: FETAL RISK, HEMATOLOGIC TOXICITY, and DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM
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 death to a developing baby. In women of childbearing potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Women of childbearing potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid fetal exposure to lenalidomide, REVLIMID is only available under a restricted distribution program called “RevAssist ® .”
Information about the RevAssist program is available at www.REVLIMID.com : cts.businesswire.com/ct/CT?id=smartlink&url=http%3A%2F%2Fwww ..
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. (see DOSAGE and ADMINISTRATION)
DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM
REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with MM who were treated with REVLIMID and dexamethasone therapy. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolic events. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors.
Pregnancy Category X:
- Lenalidomide is contraindicated in pregnant women and women capable of becoming pregnant. Females of childbearing potential may be treated with lenalidomide provided adequate precautions are taken to avoid pregnancy
- REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide
WARNINGS AND PRECAUTIONS:
- REV may cause fetal harm when administered to a pregnant woman
- REVLIMID is an analogue of thalidomide, a known human teratogen that causes life-threatening human birth defects. An embryofetal development study in non-human primates indicates that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy. If REVLIMID is used during pregnancy, it may cause birth defects or death to a developing baby
- Females of childbearing potential must be advised to avoid pregnancy while on REVLIMID. Two effective contraceptive methods must be used by female patients of childbearing potential for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for 4 weeks following discontinuation of REVLIMID therapy
- Male Patients: Clinical data has demonstrated the presence of lenalidomide in human semen. Male patients taking REVLIMID should not donate sperm. Males receiving REVLIMID must always use a latex condom during any sexual contact with females of childbearing potential, even if they have undergone a successful vasectomy
Reproductive Risk and Special Prescribing Requirements (RevAssist Program):
- Because of this potential toxicity and to avoid fetal exposure, REVLIMID is only available under a special restricted distribution program called “RevAssist.” Prescribers and pharmacists registered with the program can prescribe and dispense the product to patients who are registered and meet all the conditions of the RevAssist program
Hematologic Toxicity—Multiple Myeloma:
- REVLIMID can cause significant neutropenia and thrombocytopenia
- 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 studies Grade 3 and 4 hematologic toxicities were more frequent in patients treated with the combination of REVLIMID and dexamethasone than in patients treated with dexamethasone alone
- Patients may require dose interruption and/or dose reduction
Deep Vein Thrombosis and Pulmonary Embolism:
- Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary embolism) have occurred in patients with MM treated with lenalidomide combination therapy and patients with MDS treated with lenalidomide monotherapy
- 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 have been reported during treatment with lenalidomide. The patients at risk of tumor lysis syndrome 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 has occurred during investigational use of lenalidomide for chronic lymphocytic leukemia (CLL) and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. Treatment of CLL or lymphoma with lenalidomide outside of a well-monitored clinical trial is discouraged
- Cases of transient liver laboratory abnormalities (predominantly transaminases) were reported in patients treated with lenalidomide.
Treatment with lenalidomide should be interrupted and restarted once the levels return to baseline. Successful re-challenge without recurrence of liver laboratory elevation was reported in some patients
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
- 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 dexamethasone 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 in MM patients receiving lenalidomide with dexamethasone
USE IN SPECIFIC POPULATIONS:
- It is not known whether REVLIMID is excreted in human milk
- 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
- Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection Monitor renal function
- 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
- In the REVLIMID/dexamethasone treatment group, 269 patients (76%) underwent at least one dose interruption with or without a dose reduction of REVLIMID compared to 199 patients (57%) in the placebo/dexamethasone treatment group
- Of these patients who had one dose interruption with or without a dose reduction, 76% (269/353) vs 57% (199/350), 50% in the REVLIMID/dexamethasone treatment group underwent at least one additional dose interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group
- Most adverse events and Grade 3/4 adverse events were more frequent in MM patients who received the combination of REVLIMID/dexamethasone compared to placebo/dexamethasone
- Grade 3/4 neutropenia occurred in 33.4% vs 3.4%; 2.3% experienced Grade 3/4 febrile neutropenia vs 0%
- Deep vein thrombosis (DVT) was reported as a serious adverse drug reaction (7.4%) or Grade 3/4 (8.2%) compared to 3.1% and 3.4%.
Discontinuations due to DVT were reported at comparable rates between groups
- Pulmonary embolism (PE) was reported as a serious adverse drug reaction (3.7%) or Grade 3/4 (4.0%) compared to 0.9% and 0.9%.
Discontinuations due to PE were reported at comparable rates between groups
- Adverse reactions reported in ≥15% of MM patients (REVLIMID/dexamethasone vs dexamethasone/placebo): fatigue (44% vs 42%), neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (28% vs 23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%), upper respiratory tract infection (25% vs 16%), dyspnea (24% vs 17%), dizziness (23% vs 17%), thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs 7%), weight decreased (20% vs 15%), nasopharyngitis (18% vs 9%), blurred vision (17% vs 11%), anorexia (16% vs 10%), and dysgeusia (15% vs 10%)
- Thrombocytopenia (61.5%; 91/148) and neutropenia (58.8%; 87/148) were the most frequently reported adverse events observed in the del 5q MDS population
- Grade 3 and 4 adverse events reported in ≥ 5% of patients with del 5q MDS were neutropenia (53%), thrombocytopenia (50%), pneumonia (7%), rash (7%), anemia (6%), leukopenia (5%), fatigue (5%), dyspnea (5%), and back pain (5%)
- Other adverse events reported in ≥15% of del 5q MDS patients (REVLIMID): diarrhea (49%), pruritus (42%), rash (36%), fatigue (31%), constipation (24%), nausea (24%), nasopharyngitis (23%), arthralgia (22%), pyrexia (21%), back pain (21%), peripheral edema (20%), cough (20%), dizziness (20%), headache (20%), muscle cramp (18%), dyspnea (17%), pharyngitis (16%), epistaxis (15%), asthenia (15%), upper respiratory tract infection (15%)
DOSAGE AND ADMINISTRATION:
- Treatment is continued or modified based upon clinical and laboratory findings. Dosing modifications are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to REVLIMID
- For other Grade 3 or 4 toxicities judged to be related to REVLIMID, hold treatment and restart at next lower dose level when toxicity has resolved to ≤Grade 2
Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS.
About Non-Hodgkin Lymphoma
Lymphoma is the name for the group of blood cancers that start in the lymphatic system, which is part of the body’s immune system. Lymphomas generally start in the lymph nodes or lymphatic tissue in sites of the body such as the stomach or intestines. They may involve the marrow and the blood in some cases as well. Most people with lymphoma have one of the many different kinds of non-Hodgkin’s lymphoma (NHL) and there are an estimated 360,000 cases of NHL in the U.S. with more than 59,000 new cases diagnosed annually.
About Celgene International Sàrl
Celgene International Sàrl, located in Boudry, in the Canton of Neuchâtel, Switzerland, is a wholly owned subsidiary and international headquarters of Celgene Corporation. 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 the Company's website at www.celgene.com : cts.businesswire.com/ct/CT?id=smartlink&url=http%3A%2F%2Fwww ..
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