warnings and cautions
5 WARNINGS AND PRECAUTIONS Thrombosis and Thromboembolic Events : Evaluate the risk factors for thrombosis prior to and after LENMEDLY infusion. Consider prophylaxis with anti-thrombotic agents prior to treatment with LENMELDY. ( 5.1 ) Encephalitis : Monitor children for signs or symptoms of encephalitis after treatment with LENMELDY. ( 5.2 ) Serious Infection : Monitor children for serious infection after myeloablative conditioning and LENMELDY infusion. ( 5.3 ) Veno-occlusive Disease : Monitor children for signs and symptoms of VOD including liver function tests in all patients during the first month after LENMELDY infusion. Consider prophylaxis for VOD. ( 5.4 ) Delayed Platelet Engraftment : Monitor children for thrombocytopenia and bleeding until platelet recovery is achieved. ( 5.5 ) Risk of Neutrophil Engraftment Failure : Monitor absolute neutrophil counts (ANC) after LENMELDY infusion. If neutrophil engraftment does not occur, administer rescue cells. ( 5.6 ) Risk of Insertional Oncogenesis: Monitor children for hematologic malignancies annually after treatment with LENMELDY. ( 5.7 ) Risk of Hypersensitivity Reactions : Monitor for hypersensitivity reactions during infusion. ( 5.8 ) 5.1 Thrombosis and Thromboembolic Events Treatment with LENMELDY may increase the risk of thrombosis and thromboembolic events. A child with PSEJ MLD died after experiencing a left hemisphere cerebral infarction secondary to a thrombotic event in a large blood vessel approximately one year after treatment with LENMELDY. Prior to the cerebral infarction, the child’s D-dimer was elevated (82 nmol/L, normal range: 1.5 - 4.2). Additional clinical findings included a minor elevation of liver enzymes. The etiology of the cerebral infarction was unclear but attribution to LENMELDY cannot be ruled out. No other events related to cerebral infarction have been reported during the clinical development of LENMELDY. Some children received anti-thrombotic prophylaxis [ see Clinical Trials Experience (6.1) ]. Evaluate the risk factors for thrombosis prior to and after LENMELDY infusion according to best clinical practice. 5.2 Encephalitis Treatment with LENMELDY may increase the risk of encephalitis. A child with ESEJ MLD developed a serious event of encephalitis after treatment with LENMELDY. At the time of treatment, GMFC-MLD was Level 1 (able to walk independently with impaired gait). One month after treatment, the child experienced subacute neurological deterioration, with asthenia, hypotonia, cognitive and behavioral problems, vomiting, and swallowing disturbance. The child was afebrile, blood and CSF cultures were negative for bacterial infection, a large viral panel was negative and all routine laboratory tests were normal. The child was treated with plasmapheresis, immunoglobulin and rituximab leading to clinical improvement. Five months after onset of symptoms the child had reached GMFC-MLD Level 4 (walking not possible; able to sit without support and locomotion possible, or unable to sit without support but locomotion is possible). The child was subsequently treated with eculizumab and tocilizumab. The etiology of this event is unclear but attribution to LENMELDY cannot be ruled out. Treatment with LENMELDY may trigger a relapsing-remitting pattern of disease progression. No other events related to encephalitis have been reported during the clinical development of LENMELDY. Monitor children for signs or symptoms of encephalitis after LENMELDY treatment. 5.3 Serious Infection In the period between start of conditioning and within one year after LENMELDY treatment, severe Grade 3 infections occurred in 39% of all children (21% bacterial, 5% viral, 5% bacterial and viral or bacterial and fungal, and 8% unspecified). The most common Grade 3 infections were device related infections (18%) (including two events of sepsis), respiratory tract infections (including 1 Grade 3 event of pneumonia) (8%), and gastroenteritis/enteritis (8%). Grade 3 febrile neutropenia developed within 1 month after LENMELDY infusion in 82% of children. In the event of febrile neutropenia, monitor for signs and symptoms of infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated. Monitor children for signs and symptoms of infection after myeloablative conditioning and LENMELDY infusion and treat appropriately. Administer prophylactic antimicrobials according to best clinical practice. 5.4 Veno-occlusive Disease Three children (8%) treated in clinical trials of LENMELDY developed veno-occlusive disease (VOD), with one Grade 4 SAE and two Grade 3 AEs. None of these three events met Hy’s Law criteria. Monitor children for signs and symptoms of VOD including liver function tests in all children during the first month after LENMELDY infusion. Consider prophylaxis for VOD with anti-thrombotic agents based on risk factors for VOD and best clinical practice. 5.5 Delayed Platelet Engraftment Delayed platelet engraftment has been observed with LENMELDY treatment [ see Adverse Reactions (6.1) ]. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in children with prolonged thrombocytopenia. In clinical trials of LENMELDY, 4 (10%) children had delayed platelet engraftment after day 60 (range day 67-109), with 3 children requiring platelet transfusions until engraftment occurred. All children treated with LENMELDY received transfusion support with platelets according to best clinical practice. Inform children of the risk of bleeding until platelet recovery has been achieved. Monitor children for thrombocytopenia and bleeding. 5.6 Neutrophil Engraftment Failure There is a potential risk of neutrophil engraftment failure after treatment with LENMELDY. In clinical trials of LENMELDY, no cases of neutrophil engraftment failure have been reported. Neutrophil engraftment failure is defined as failure to achieve three consecutive absolute neutrophil counts (ANC) ≥ 500 cells/microliter obtained on different days by Day 60 after infusion of LENMELDY. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a child treated with LENMELDY, provide rescue treatment with the unmanipulated back-up collection of CD34 + cells [ see Preparation before LENMELDY Infusion (2.2) ]. 5.7 Insertional Oncogenesis There is a potential risk of LVV-mediated insertional oncogenesis after treatment with LENMELDY. In clinical trials of LENMELDY, no cases of insertional oncogenesis have been reported. Children treated with LENMELDY may develop hematologic malignancies and should be monitored lifelong. Monitor for hematologic malignancies with a complete blood count (with differential) annually and integration site analysis as warranted for at least 15 years after treatment with LENMELDY. In the event that a malignancy occurs, contact Orchard Therapeutics at 1-888-878-0185 for reporting and to obtain instructions on collection of samples for testing. 5.8 Hypersensitivity Reactions There is a potential risk of allergic reactions in children treated with LENMELDY. The dimethyl sulfoxide (DMSO) in LENMELDY may cause hypersensitivity reactions, including anaphylaxis which is potentially life-threatening and requires immediate intervention. Hypersensitivity including anaphylaxis can occur in children with and without prior exposure to DSMO. In clinical trials of LENMELDY, no cases of hypersensitivity reactions have been reported. 5.9 Anti-retroviral Use Children should not take prophylactic HIV anti-retroviral medications for at least one month prior to mobilization, or for the expected duration of time needed for the elimination of the medications. Anti-retroviral medications may interfere with the manufacturing of LENMELDY. [ see Drug Interactions (7.2) ]. If a child requires anti-retrovirals for HIV prophylaxis, initiation of LENMELDY treatment should be delayed until confirmation of a negative test for HIV. 5.10 Interference with Serology Testing Children who have received LENMELDY are likely to test positive by polymerase chain reaction (PCR) assays for HIV due to LVV provirus insertion resulting in a false-positive test for HIV. Therefore, children who have received LENMELDY should not be screened for HIV infection using a PCR-based assay.