Analyse toont reductie overlijdensrisico AML bij gebruik REVLIMID
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Celgene International SÃ rl, een dochteronderneming van Celgene Corporation (NASDAQ: CELG) meldt de resultaten van een retrospectieve analyse ter beoordeling van het risico van acute myeloide leukemie (AML)-progressie en overlijden bij patienten die behandeld werden met REVLIMID (lenalidomide) versus onbehandelde patienten. De met lenalidomide behandelde patienten hadden een lager risico op overlijden, terwijl geen risico van AML-progressie werd waargenomen, ondanks een hogere transfusielast in vergelijking met patienten met myelodysplastische syndromen, die geen lenalidomide ontvangen hadden.
De resultaten werden gepresenteerd op de 53ste jaarvergadering van de Amerikaanse Vereniging voor Hematologie in San Diego.
Engelstalig bericht:
The Study Reported Median Overall Survival of 5.2 Years for Patients Treated with REVLIMID (Lenalidomide) Compared with 3.8 Years for Untreated Patients
Celgene International SÃ rl, a subsidiary of Celgene Corporation (NASDAQ: CELG) announced results from a retrospective analysis to assess the risk of acute myeloid leukemia (AML) progression and death in REVLIMID (lenalidomide)-treated versus untreated patients with red blood cell (RBC) transfusion-dependent patients with IPSS Low or Int-1 risk myelodysplastic syndromes (MDS) with deletion 5q chromosome (with or without additional cytogenetic abnormalities). These results were presented during the 53rd Annual Meeting of the American Society of Hematology in San Diego, CA.
In this retrospective analysis, 295 lenalidomide-treated patients from two Celgene-sponsored multicenter trials, MDS-003 and MDS-004, were compared with 125 untreated patients from an international multi-center MDS Registry with similar baseline characteristics who had received best supportive care only, including erythropoiesis-stimulating agents (ESAs) in some patients. Baseline characteristics of lenalidomide-treated patients were similar to registry patients, except for a higher RBC transfusion burden among lenalidomide-treated patients (median [range] units/8 weeks: 6 [1-25] vs. 2 [1-10]).
The lenalidomide-treated patients benefited from a reduction in risk of death, while no risk of progression to AML was observed, despite a higher transfusion burden at baseline compared with patients from the MDS registry who had not received lenalidomide.
The two- and five-year cumulative overall survival (OS) probabilities were 90% and 54% for patients treated with lenalidomide compared with 74% and 41% for patients not treated with lenalidomide. In addition, the two- and five-year cumulative AML incidences were 7% and 23% for patients treated with lenalidomide compared with 12% and 20% for patients not treated with lenalidomide. The median OS was 5.2 years for patients treated with lenalidomide compared with 3.8 years for patients not treated with lenalidomide, and the median time to AML progression had not been reached for either cohort.
Significant baseline factors associated with an increased risk of AML progression included: complex cytogenetics (greater than or equal to 2, p=0.002); 5–10% bone marrow blasts (p=0.016); and higher transfusion burden (10% increase in risk per unit at baseline, p=0.029). Furthermore, higher hemoglobin (Hgb) levels at baseline were associated with a reduced risk of AML progression (p=0.054). Factors that reduced the risk of death included treatment with lenalidomide (p=0.012); higher baseline Hgb levels (p=0.028); higher baseline platelet counts (p=0.035), and female gender (p=0.002). The risk of death increased as a result of baseline transfusion burden (p=0.037) and age (p<0.001).
About REVLIMID®
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 multiple myeloma (MM) patients who have received at least one prior therapy.
REVLIMID ® (lenalidomide) is indicated for 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 in the United States under a restricted distribution program called “RevAssist®.â€
Information about the RevAssist program is available at www.REVLIMID.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. (see DOSAGE and ADMINISTRATION)
DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM
EXTEND BLACK BOX AROUND THIS PARAGRAPHREVLIMID 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.
CONTRAINDICATIONS:
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
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:
Fetal Risk:
- 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 should be used during therapy, during therapy interruptions, and for at least 4 weeks after completing therapy
- Male Patients: It is not known whether lenalidomide is present in the semen of patients receiving the drug. Therefore, 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:
- 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
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
Tumour Lysis Syndrome:
- Fatal instances of tumour lysis syndrome have been reported during treatment with lenalidomide. The patients at risk of tumour lysis syndrome are those with high tumour burden prior to treatment. These patients should be monitored closely and appropriate precautions taken
Tumour Flare Reaction:
- Tumour flare reaction has occurred during investigational use of lenalidomide for chronic lymphocytic leukaemia (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
DRUG INTERACTIONS:
- Erythropoietic agents, or other agents, that may increase the risk of thrombosis, such as oestrogen containing therapies, should be used with caution in MM patients receiving lenalidomide with dexamethasone
USE IN SPECIAL POPULATIONS:
Nursing Mothers:
- 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
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 or severe renal impairment (CLcr < 60 mL/min) and in patients on dialysis
ADVERSE REACTIONS:
Multiple Myeloma
- In the REVLIMID/dexamethasone treatment group, 269 patients (76%) underwent at least one dose interruption with or without a dose reduction of REVLIMID compared with 199 patients (57%) in the placebo/dexamethasone treatment group
- Of these patients who had one dose interruption with or without a dose reduction, 50% in the REVLIMID/dexamethasone treatment group underwent at least one additional dose interruption with or without a dose reduction compared with 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 with placebo/dexamethasone
- 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%), diarrhoea (39% vs. 27%), muscle cramp (33% vs. 21%), anaemia (31% vs. 24%), pyrexia (28% vs. 23%), peripheral oedema (26% vs. 21%), nausea (26% vs. 21%), back pain (26% vs. 19%), upper respiratory tract infection (25% vs. 16%), dyspnoea (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%)
Myelodysplastic Syndromes
- 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
- Other adverse events reported in ≥15% of del 5q MDS patients (REVLIMID): diarrhoea (49%), pruritus (42%), rash (36%), fatigue (31%), constipation (24%), nausea (24%), nasopharyngitis (23%), arthralgia (22%), pyrexia (21%), back pain (21%), peripheral oedema (20%), cough (20%), dizziness (20%), headache (20%), muscle cramp (18%), dyspnoea (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 Myelodysplastic Syndromes
Myelodysplastic syndromes (MDS) are a group of hematologic malignancies that affect approximately 300,000 people worldwide. Myelodysplastic syndromes occur when blood cells remain in an immature or “blast” stage within the bone marrow and never develop into mature cells capable of performing their necessary functions. Eventually, the bone marrow may be filled with blast cells suppressing normal cell development. MDS patients must often rely on blood transfusions to manage symptoms of anaemia and fatigue and may develop life-threatening iron overload and/or toxicity from frequent transfusions, thus underscoring the critical need for new therapies targeting the cause of the condition rather than simply managing its symptoms.
About Acute Myeloid Leukaemia
Acute Myeloid Leukaemia (AML) is a cancer of myeloid blood cells that often transforms from MDS upon disease progression. AML is the proliferation of abnormal cells that accumulate in the bone marrow and interfere with all types of normal blood cell production (multi-lineage dysplasia). AML has traditionally been treated with high intensity chemotherapy, which is poorly tolerated by the majority of the patients who are afflicted – the elderly. Many of these patients may go untreated and because they are ineligible for curative therapy, life expectancy is short and often measured in weeks to months.
About Deletion 5q Chromosomal Abnormality
Chromosomal (cytogenetic) abnormalities are detected in more than half of patients with myelodysplastic syndrome (MDS), and involve a deletion in all or part of one or more specific chromosomes. The most common cytogenetic abnormalities in MDS are deletions in the long arm of chromosomes 5, 7, and 20. Another common abnormality is an extra copy of chromosome 8. A deletion involving the 5q chromosome may be involved in 20 percent to 30 percent of all MDS patients. The World Health Organization has also recently identified a unique subset of MDS patients with a “5q- Syndrome” where the only chromosomal abnormality is a specific portion of the 5q chromosome.
About Celgene International SÃ rl
Celgene International Sà rl, 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.
Forward-Looking Statements
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