CLINICAL NEWS hematopoietic cell transplantation for a variety of underlying malignancies . Patients had received a median of two prior regimens ( range = 1-3 regimens ). Mouth and skin were the most frequently involved organs , and 36 patients ( 85 %) had evidence of cGVHD in two or more organs .
Based on results from the phase I , dosefinding portion of the study , patients received ibrutinib 420 mg daily until cGVHD progression . At last follow-up , 12 patients ( 29 %) were still receiving ibrutinib , and 30 ( 71 %) had discontinued treatment ( most commonly due to adverse events [ AEs ; n = 14 ], cGVHD progression [ n = 5 ], or patient decision [ n = 6 ]). Treatment duration ranged from 5.6 to 24.9 months for the 12 patients who continued treatment .
Response was assessed according to the National Institutes of Health ’ s cGVHD criteria every 12 weeks .
At a median follow-up of 13.9 months ( range = 0.5-24.9 months ), 28 patients responded to treatment , for an overall response rate ( ORR ) of 67 percent , including :
• 9 patients with a complete response ( 21 %)
• 19 patients with a partial response ( 45 %)
• 7 patients with stable disease ( 17 %)
• 2 patients with progressive disease ( 5 %)
REVLIMID ® [ lenalidomide ] capsules , for oral use 4.2 Allergic Reactions
REVLIMID is contraindicated in patients who have demonstrated hypersensitivity ( e . g ., angioedema , Stevens-Johnson syndrome , toxic epidermal necrolysis ) to lenalidomide [ see Warnings and Precautions ( 5.8 )].
5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity
REVLIMID is a thalidomide analogue and is contraindicated for use during pregnancy . Thalidomide is a known human teratogen that causes life-threatening human birth defects or embryo-fetal death [ see Use in Specific Populations ( 8.1 )]. An embryo-fetal development study in monkeys 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 .
REVLIMID is only available through the REVLIMID REMS program [ see Warnings and Precautions ( 5.2 )].
Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy , during therapy , during dose interruptions and for at least 4 weeks after completing therapy .
Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control , beginning 4 weeks prior to initiating treatment with REVLIMID , during therapy , during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy .
Two negative pregnancy tests must be obtained prior to initiating therapy . The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing REVLIMID therapy and then weekly during the first month , then monthly thereafter in females with regular menstrual cycles or every 2 weeks in females with irregular menstrual cycles [ see Use in Specific Populations ( 8.3 )].
Males Lenalidomide is present in the semen of patients receiving the drug . Therefore , 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 [ see Use in Specific Populations ( 8.3 )].
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 .
5.2 REVLIMID REMS Program
Because of the embryo-fetal risk [ see Warnings and Precautions ( 5.1 )], REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy ( REMS ), the REVLIMID REMS program .
Required components of the REVLIMID REMS program include the following :
• Prescribers must be certified with the REVLIMID REMS program by enrolling and complying with the REMS requirements .
• Patients must sign a Patient-Physician agreement form and comply with the REMS requirements . In particular , female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [ see Use in Specific Populations ( 8.3 )] and males must comply with contraception requirements [ see Use in Specific Populations ( 8.3 )].
• Pharmacies must be certified with the REVLIMID REMS program , must only dispense to patients who are authorized to receive REVLIMID and comply with REMS requirements .
Further information about the REVLIMID REMS program is available at www . celgeneriskmanagement . com or by telephone at 1-888-423-5436 .
5.3 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 medication that may increase risk of bleeding . Patients taking REVLIMID should have their complete blood counts assessed periodically as described below [ see Dosage and Administration 2.1 ].
Patients taking REVLIMID in combination with dexamethasone or as REVLIMID maintenance therapy for MM should have their complete blood counts ( CBC ) assessed every 7 days ( weekly ) for the first 2 cycles , on
Days 1 and 15 of Cycle 3 , and every 28 days ( 4 weeks ) thereafter . A dose interruption and / or dose reduction may be required [ see Dosage and Administration ( 2.1 )]. In the MM maintenance therapy trials , Grade 3 or 4 neutropenia was reported in up to 59 % of REVLIMID-treated patients and Grade 3 or 4 thrombocytopenia in up to 38 % of REVLIMID-treated patients [ see Adverse Reactions ( 6.1 )].
5.4 Venous and Arterial Thromboembolism
Venous thromboembolic events ( VTE [ DVT and PE ]) and arterial thromboembolic events ( ATE , myocardial infarction and stroke ) are increased in patients treated with REVLIMID .
A significantly increased risk of DVT ( 7.4 %) and of PE ( 3.7 %) occurred in patients with MM after at least one prior therapy who were treated with REVLIMID and dexamethasone therapy compared to patients treated in the placebo and dexamethasone group ( 3.1 % and 0.9 %) in clinical trials with varying use of anticoagulant therapies . In the newly diagnosed multiple myeloma ( NDMM ) study in which nearly all patients received antithrombotic prophylaxis , DVT was reported as a serious adverse reaction ( 3.6 %, 2.0 %, and 1.7 %) in the Rd Continuous , Rd18 , and MPT Arms , respectively . The frequency of serious adverse reactions of PE was similar between the Rd Continuous , Rd18 , and MPT Arms ( 3.8 %, 2.8 %, and 3.7 %, respectively ) [ see Boxed Warning and Adverse Reactions ( 6.1 )].
Myocardial infarction ( 1.7 %) and stroke ( CVA ) ( 2.3 %) are increased in patients with MM after at least one prior therapy who were treated with REVLIMID and dexamethasone therapy compared to patients treated with placebo and dexamethasone ( 0.6 %, and 0.9 %) in clinical trials . In the NDMM study , myocardial infarction ( including acute ) was reported as a serious adverse reaction ( 2.3 %, 0.6 %, and 1.1 %) in the Rd Continuous , Rd18 , and MPT Arms , respectively . The frequency of serious adverse reactions of CVA was similar between the Rd Continuous , Rd18 , and MPT Arms ( 0.8 %, 0.6 %, and 0.6 %, respectively ) [ see Adverse Reactions ( 6.1 )].
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 ( Standardized MedDRA Query Embolic and Thrombotic events ) occurred in patients with refractory and relapsed MM who were treated with REVLIMID and dexamethasone compared to 8.3 % thrombosis in patients treated with placebo and dexamethasone . The median time to first thrombosis event was 2.8 months . In the NDMM study in which nearly all patients received antithrombotic prophylaxis , the overall frequency of thrombotic events was 17.4 % in patients in the combined Rd Continuous and Rd18 Arms , and was 11.6 % in the MPT Arm . The median time to first thrombosis event was 4.3 months in the combined Rd Continuous and Rd18 Arms .
Thromboprophylaxis is recommended . The regimen of thromboprophylaxis should be based on an assessment of the patient ’ s underlying risks . Instruct patients to report immediately any signs and symptoms suggestive of thrombotic events . ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision in patients receiving REVLIMID [ see Drug Interactions ( 7.2 )].
5.5 Increased Mortality in Patients with CLL
In a prospective randomized ( 1:1 ) clinical trial in the first line treatment of patients with chronic lymphocytic leukemia , 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 the risk of death . The trial was halted for safety in July 2013 .
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 .
5.6 Second Primary Malignancies
In clinical trials in patients with MM receiving REVLIMID , an increase of hematologic plus solid tumor second primary malignancies ( SPM ) notably AML and MDS have been observed . An increase in hematologic SPM including AML and MDS occurred in 5.3 % of patients with NDMM receiving REVLIMID in combination with oral melphalan compared with 1.3 % of patients receiving melphalan without REVLIMID . The frequency