ASH Clinical News ACN_5.2_digital | Page 28

On Location 2018 ASH Annual Meeting Algorithm Built on Big Data Improves Prognostic Accuracy Over Existing MDS Models Using machine learning, researchers were able to develop a prognostic model that predicted survival among patients with myelodysplastic syndromes (MDS) and was more accurate than existing, “gold- standard” prognostic tools, according to a study presented at the 2018 ASH Annual Meeting. “All treatment guidelines are driven by risk, which means that if we get the risk wrong, we get the treatment wrong,” said lead study author Aziz Nazha, MD, of the Cleveland Clinic. “Improving and personalizing our prognostic models is extremely important and can help patients understand their disease and what they can expect during their journey.” The survival estimates provided by the International Prognostic Scoring System (IPSS) and IPSS-Revised (IPPS- R) systems “are all over the place … and underestimate the heterogeneity of MDS,” Dr. Nazha said. “So, for us, the question became, ‘Can we build a model that can provide a personalized prediction specific for a given patient?’” To develop this tool, a collaborative team from Cleveland Clinic and Mu- nich Leukemia Laboratory developed a REVLIMID [lenalidomide] capsules, for oral use Other Toxicities in MM For other Grade 3/4 toxicities judged to be related to REVLIMID, hold treatment and restart at the physician’s discretion at next lower dose level when toxicity has resolved to ≤ Grade 2. Starting Dose Adjustment for Renal Impairment in MM: [See Dosage and Administration (2.4)]. 2.4 Starting Dose for Renal Impairment in MM The recommendations for starting doses for patients with renal impairment are shown in the following Table 3: Starting Dose Adjustments for Patients with Renal Impairment Renal Function Dose in REVLIMID Dose in REVLIMID (Cockcroft-Gault) Combination Therapy Maintenance Therapy for MM Following Auto-HSCT CLcr 30 to 60 mL/min 10 mg once daily 5 mg once daily CLcr < 30 mL/min 15 mg every other day 2.5 mg once daily (not requiring dialysis) 5 mg once daily. On 2.5 mg once daily. On CLcr < 30 mL/min (requiring dialysis) dialysis days, administer dialysis days, administer the dose following dialysis. the dose following dialysis. REVLIMID Combination Therapy for MM: For CLcr of 30 to 60 mL/min, consider escalating the dose to 15 mg after 2 cycles if the patient tolerates the 10 mg dose of lenalidomide without dose-limiting toxicity. REVLIMID Maintenance Therapy Following Auto-HSCT for MM: Base subsequent REVLIMID dose increase or decrease on individual patient treatment tolerance [see Dosage and Administration (2.1)]. 4 CONTRAINDICATIONS 4.1 Pregnancy REVLIMID can cause fetal harm when administered to a pregnant female. Limb abnormalities were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis. This effect was seen at all doses tested. Due to the results of this developmental monkey study, and lenalidomide’s structural similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in females who are pregnant [see Boxed Warning]. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.1, 5.2), Use in Special Populations (8.1,8.3)]. 4.2 Severe Hypersensitivity Reactions REVLIMID is contraindicated in patients who have demonstrated severe 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 Cosmos Communications 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 1 Q1 Q2