Written in Blood
Weighing the Risks and Benefits of Nivolumab in Patients With Hodgkin Lymphoma Undergoing AlloHCT
For patients with Hodgkin lymphoma ( HL ), allogeneic hematopoietic cell transplantation ( alloHCT ) can induce longterm disease control ; however , relapse is common and rates of 3-year progressionfree survival ( PFS ) range from 20 to 60 percent – suggesting a need for new treatment agents .
In May 2016 , the U . S . Food and Drug Administration ( FDA ) approved nivolumab ( a programmed death receptor-1 [ PD-1 ] blocking antibody ) for the treatment of patients with relapsed classical HL . The drug carries a warning , though , about complications in patients who have undergone alloHCT , based on reports of transplant-related deaths and hyper-acute and severe-acute graft-versushost disease ( GVHD ) following nivolumab treatment . The FDA also required that the drug ’ s manufacturers conduct a postmarketing study to assess the safety of nivolumab in these patients .
Charles Herbaux , MD , from the Department of Hematology at the Hospital Center Regional University De Lille in France , and co-authors published results from a retrospective study of patients with HL ( median age = 33 years ; range = 20-48 years ) who were treated with both alloHCT and nivolumab , finding a high overall response rate ( 95 %; 95 % CI 74-100 ) and an
REVLIMID ® [ lenalidomide ] capsules , for oral use
slightly lower body weight gains during gestation when bred to male offspring . As with thalidomide , the rat model may not adequately address the full spectrum of potential human embryo-fetal developmental effects for lenalidomide .
Following daily oral administration of lenalidomide from Gestation Day 7 through Gestation Day 20 in pregnant rabbits , fetal plasma lenalidomide concentrations were approximately 20-40 % of the maternal C max . Following a single oral dose to pregnant rats , lenalidomide was detected in fetal plasma and tissues ; concentrations of radioactivity in fetal tissues were generally lower than those in maternal tissues . These data indicated that lenalidomide crossed the placenta .
8.2 Lactation Risk Summary
There is no information regarding the presence of lenalidomide in human milk , the effects of REVLIMID on the breastfed infant , or the effects of REVLIMID on milk production . Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants from REVLIMID , advise women not to breastfeed during treatment with REVLIMID .
8.3 Females and Males of Reproductive Potential Pregnancy Testing
REVLIMID can cause fetal harm when administered during pregnancy [ see Use in Specific Populations ( 8.1 )]. Verify the pregnancy status of females of reproductive potential prior to initiating REVLIMID therapy and during therapy . Advise females of reproductive potential that they must avoid pregnancy 4 weeks before therapy , while taking REVLIMID , during dose interruptions and for at least 4 weeks after completing therapy .
Females of reproductive potential must have 2 negative pregnancy tests before initiating REVLIMID . The first test should be performed within 10-14 days , and the second test within 24 hours prior to prescribing REVLIMID . Once treatment has started and during dose interruptions , pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use , then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles . If menstrual cycles are irregular , the pregnancy testing should occur every 2 weeks . Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding . REVLIMID treatment must be discontinued during this evaluation .
Contraception
Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously : one highly effective form of contraception – tubal ligation , IUD , hormonal ( birth control pills , injections , hormonal patches , vaginal rings , or implants ), or partner ’ s vasectomy , and 1 additional effective contraceptive method – male latex or synthetic condom , diaphragm , or cervical cap . Contraception must begin 4 weeks prior to initiating treatment with REVLIMID , during therapy , during dose interruptions , and continuing for 4 weeks following discontinuation of REVLIMID therapy . Reliable contraception is indicated even where there has been a history of infertility , unless due to hysterectomy . Females of reproductive potential should be referred to a qualified provider of contraceptive methods , if needed .
Males Lenalidomide is present in the semen of males who take REVLIMID . 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 .
8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients . 8.5 Geriatric Use
MM Maintenance Therapy : Overall , 10 % ( 106 / 1018 ) of patients were 65 years of age or older , while no patients were over 75 years of age . Grade 3 or 4 AEs were higher in the REVLIMID arm ( more than 5 % higher ) in the patients 65 years of age or older versus younger patients . The frequency of Grade 3 or 4 AEs in the Blood and Lymphatic System Disorders were higher in the REVLIMID arm ( more than 5 % higher ) in the patients 65 years of age or older versus younger patients . There were not a sufficient number of patients 65 years of age or older in REVLIMID maintenance studies who experienced either a serious AE , or discontinued therapy due to an AE to determine whether elderly patients respond relative to safety differently from younger patients .
Since elderly patients are more likely to have decreased renal function , care should be taken in dose selection . Monitor renal function .
8.6 Renal Impairment
Adjust the starting dose of REVLIMID based on the creatinine clearance value and for patients on dialysis [ see Dosage and Administration ( 2.4 )].
10 OVERDOSAGE
There is no specific experience in the management of lenalidomide overdose in patients with MM , MDS , or MCL . In dose-ranging studies in healthy subjects , some were exposed to up to 200 mg ( administered 100 mg BID ) and in single-dose studies , some subjects were exposed to up to 400 mg . Pruritus , urticaria , rash , and elevated liver transaminases were the primary reported AEs . In clinical trials , the dose-limiting toxicity was neutropenia and thrombocytopenia .
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis , Mutagenesis , Impairment of Fertility Carcinogenicity studies with lenalidomide have not been conducted .
Lenalidomide was not mutagenic in the bacterial reverse mutation assay ( Ames test ) and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes , or mutations at the thymidine kinase ( tk ) locus of mouse lymphoma L5178Y cells . Lenalidomide did not increase morphological transformation in Syrian Hamster Embryo assay or induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats .
A fertility and early embryonic development study in rats , with administration of lenalidomide up to 500 mg / kg ( approximately 200 times the human dose of 25 mg , based on body surface area ) produced no parental toxicity and no adverse effects on fertility .
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved Patient labeling ( Medication Guide )
Embryo-Fetal Toxicity Advise patients that REVLIMID is contraindicated in pregnancy [ see Boxed Warning and Contraindications ( 4.1 )]. REVLIMID is a thalidomide analog and can cause serious birth defects or death to a developing baby [ see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.1 )].
• Advise females of reproductive potential that they must avoid pregnancy while taking REVLIMID and for at least 4 weeks after completing therapy .
• Initiate REVLIMID treatment in females of reproductive potential only following a negative pregnancy test .
• Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use 2 different forms of contraception including at least 1 highly effective form , simultaneously during REVLIMID therapy , during dose interruption and for 4 weeks after she has completely finished taking REVLIMID . Highly effective forms of contraception other than tubal ligation include IUD and hormonal ( birth control pills , injections , patch or implants ) and a partner ’ s vasectomy . Additional effective contraceptive methods include latex or synthetic condom , diaphragm and cervical cap .
• Instruct patient to immediately stop taking REVLIMID and contact her healthcare provider if she becomes pregnant while taking this drug , if she misses her menstrual period , or experiences unusual menstrual bleeding , if she stops taking birth control , or if she thinks FOR ANY REASON that she may be pregnant .
• Advise patient that if her healthcare provider is not available , she should call Celgene Customer Care Center at 1-888-423-5436 [ see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.3 )].
• Advise males to 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 .
• Advise male patients taking REVLIMID that they must not donate sperm [ see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.3 )].
• All patients must be instructed to not donate blood while taking REVLIMID , during dose interruptions and for 4 weeks following discontinuation of REVLIMID [ see Warnings and Precautions ( 5.1 )].