Recent advances of CAR-T in the management of haematological malignancies

Start Date: 22th October, 2020 Thursday

Start Time:7PM HKT

Duration:150 minutes



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Prof. David L. PORTER

Jodi Fisher-Horowitz Professor, Leukemia Care Excellence

Perelman School of Medicine and Abramson Cancer Center

Prof. Peter BADER

Head of Stem Cell Transplantation and Immunology, Department of Pediatrics and Adolescent Medicine

Goethe University, Frankfurt

Prof. KWONG Yok Lam

Chair professor, Department of Medicine,

University of Hong Kong

Prof. LI Chi Kong

Professor; Chief, Division of Haematology/Oncology/BMT, Department of Paediatrics

The Chinese University of Hong Kong

Dr. LAW Man Fai

Associate Consultant, Department of Medicine,

Prince of Wales Hospital

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KYMRIAH® is indicated for the treatment of:1
- Adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy
- Paediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukaemia (ALL) that is refractory, in relapse post-transplant or in second or later relapse
Reference: 1 Kymriah® Hong Kong Package Insert. 2019.

Kymriah® Important note: Before prescribing, consult full prescribing information. Presentation: Cell suspension for infusion in 1-3 bags for intravenous use (tisagenlecleucel). Indications: Paediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukaemia (ALL) that is refractory, in relapse post-transplant or in second or later relapse.Adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy. Dosage:  Kymriah is intended for autologous use only. Paediatric and young adult B-cell ALL patients: For patients 50 kg and below, 0.2 to 5 x 106 CAR-positive viable T cells/kg body weight. For patients above 50 kg: 0.1 to 2.5 x 108 CAR-positive viable T cells (non-weight based). Adult DLBCL patients: 0.6 to 6 x 108 CAR-positive viable T cells (non-weight based). Administration: Refer to full package insert. Special Population: Paediatric population: For B-cell ALL, no formal studies have been performed in paediatric patients below 3 years of age. For DLBCL, the safety and efficacy of Kymriah in children and adolescents below 18 years of age have not yet been established. No data are available. Elderly: For B-cell ALL, the safety and efficacy of Kymriah in this population have not been established. For DLBCL, no dose adjustment is required in patients over 65 years of age. Contraindications: Hypersensitivity to tisagenlecleucel or to any of the excipi-ents. Contraindications of the lymphodepleting chemotherapy must be considered.  Warnings/Precautions: Reasons to delay treatment: Delay infusion if a patient has unresolved serious adverse reactions (especially pulmonary reactions, cardiac reactions or hypotension) from preceding chemotherapies/active uncontrolled infection/active graft-versus-host disease (GVHD)/significant clinical worsening of leukaemia burden or lymphoma following lymphodepleting chemother-apy. Blood, organ, tissue and cell donation: Patients treated with Kymriah should not donate blood, organs, tissues and cells for transplantation. ¨Active CNS leukaemia or lymphoma: Limited experience of use of Kymriah in patients with active CNS leukaemia and active CNS lymphoma. Risk and benefit of Kymriah has not been established in these populations. Cytokine release syndrome: Occurring in almost all cases between 1 to 10 days (median onset 3 days) after Kymriah infusion. The median time to resolution of cytokine release syndrome is 7 days.Neurological adverse reactions: Patients should be monitored for neurological events. In case of neurological events, patients should be diagnostically worked up and managed depending on the underlying pathophysiology and in accordance with local standard of care. ¨Infections: Patients should be monitored for signs and symptoms of infection and treated appropriately. As appropriate, prophylactic antibiotics should be administered and surveillance testing should be employed prior to and during treatment with Kymriah. Febrile neutropenia: infection should be evaluated and managed appropriately with broad-spectrum antibiotics, fluids and other supportive care, as medically indicated. Prolonged cytopenias: Prolonged neutropenia has been associated with increased risk of infection. Myeloid growth factors, particularly GM-CSF, have the potential to worsen cytokine release syndrome symptoms and are not recommended during the first 3 weeks after Kymriah infusion or until cytokine release syndrome has resolved. Secondary malignancies: Patients treated with Kymriah may develop secondary malignancies or recurrence of their cancer. They should be monitored life-long for secondary malignancies. Hypogammaglobulinaemia: Immunoglobulin levels should be monitored after treatment with Kymriah. In patients with low immunoglobulin levels pre-emptive measures such as infection precautions, antibiotic prophylaxis and immunoglobulin replacement should be taken. Tumour lysis syndrome (TLS): Patients with elevated uric acid or high tumour burden should receive allopurinol, or an alternative prophylaxis, prior to Kymriah infusion. Signs and symptoms of TLS should be monitored. Concomitant disease: Patients with a history of active CNS disorder or inadequate renal, hepatic, pulmonary or cardiac function were excluded from the studies. These patients require special attention. Prior bone marrow transplant: Not recommended that patients receive Kymriah within 4 months of undergoing an allogeneic stem cell transplant (SCT) because of the poten-tial risk of Kymriah worsening GVHD. Leukapheresis for Kymriah manufacturing should be performed at least 12 weeks after allogeneic SCT. Patients seropositive for HBV, HCV and HIV: No experience with manufacturing Kymriah for patients testing positive for HBV, HCV and HIV. Leukapheresis material from these patients will not be accepted for Kymriah manufacturing. Screening for HBV, HCV and HIV must be performed. Prior treatment with anti-CD19 therapy: Limited experi-ence with Kymriah in patients exposed to prior CD19-directed therapy. Kymriah is not recommended if the patient has relapsed with CD19-negative leukaemia after prior anti-CD19 therapy. Interference with serological testing: Some commer-cial HIV nucleic acid tests may give a false positive result. Content of dextran 40 and dimethyl sulfoxide (DMSO): These excipients are known to possibly cause anaphylactic reaction following parenteral administration. Patients not previously exposed to dextran and DMSO should be observed closely during the first minutes of the infusion period. Women of childbearing potential: Pregnancy status for females of child-bearing age should be verified prior to starting treatment with Kymriah. Kymriah is not recommended in women of childbearing potential not using contraception. Pregnancy: No data from the use of Kymriah in pregnant women. No animal studies have been conducted with Kymriah to assess whether it can cause foetal harm when administered to a pregnant woman. It is not known whether Kymriah has the potential to be transferred to the foetus via the placenta and could cause foetal toxicity, including B-cell lymphocytopenia. Kymriah is not recommended during pregnancy. Pregnant women who have received Kymriah may have hypogammaglobulinaemia. Assessment of immunoglobulin levels is indicated in newborns of mothers treated with Kymriah. Breast-feeding: It is unknown whether Kymriah cells are excreted in human milk. A risk to the breast-fed infant cannot be excluded. Women who are breast-feeding should be advised of the potential risk to the breast-fed infant. Fertility: No data on the effect of Kymriah on fertility. Effects of Kymriah on male and female fertility have not been evaluated in animal studies Interactions: No pharmacokinetic or pharmacodynamic drug interaction studies with tisagenlecleucel have been performed. The co-administration of agents known to inhibit T-cell function has not been formally studied. Administration of low-dose steroids as per the cytokine release syndrome treatment algorithm does not impact the expansion and persistence of CAR-T cells. The co-administration of agents known to stimulate T-cell function has not been investigated and the effects are unknown. Live vaccines: The safety of immunisation with live viral vaccines during or following Kymriah treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during Kymriah treatment, and until immune recovery following treatment with Kymriah. Adverse reactions: Very common (>10%): Infections-pathogen unspecified, viral infections, bacterial infections, fungal infections, febrile neutropenia, leukopenia, lymphopenia, anaemia, thrombocytopenia, cytokine release syndrome, hypogammaglob-ulinaemia, decreased appetite, hypokalaemia, hypophosphataemia, hypocalcaemia, hypomagnesaemia, hypoalbuminaemia, hyperuricaemia, hyperglycaemia, delirium, anxiety, sleep disorder, headache, encephalopathy, dizziness, tachycardia, hypotension, hypertension, cough, hypoxia, dyspnoea, pulmonary oedema, pleural effusion, tachypnoea, diarrhoea, nausea, vomiting, constipation, abdominal pain, rash, back pain, myalgia, arthralgia, acute kidney injury, pyrexia, fatigue, oedema, pain, chills, haemoglobin decreased, lymphocyte count decreased, white blood cell count decreased, neutrophil count decreased, platelet count decreased, aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased, international normalised ratio increased, weight decreased Common (1 to 10%): Disseminated intravascular coagulation, coagulopathy, histiocytosis haematophagic, pancytopenia, graft-versus-host disease, fluid overload, hypermagnesaemia, hyponatraemia, hyperphosphataemia, tumour lysis syndrome, tremor, peripheral neuropathy, speech disorders, seizure, cerebral haemorrhage, neuralgia, ischaemic cerebral infarction, cardiac failure, arrhyth-mia, cardiac arrest, capillary leak syndrome, flushing, epistaxis, lung infiltration, dry mouth, mouth haemorrhage, stomatitis, abdominal distension, ascites, abdominal compartment syndrome, hyperbilirubinaemia, pruritus, erythema, night sweats, petechiae, hyperhidrosis, asthenia, influenza-like illness, multiple organ dysfunction syndrome, activated partial thromboplastin time prolonged, blood fibrinogen decreased, serum ferritin increased, blood alkaline phosphatase increased, fibrin D dimer increased, prothrombin time prolonged Packs and prices: Ethylene vinyl acetate (EVA) infusion bag with polyvinyl chloride (PVC) tubing and a luer spike interconnector closed by a luer-lock cap containing either 10–30 mL (50 mL bags) or 30–50 mL (250 mL bags) cell dispersion. Legal classification: P1S1S3 Reference: EMA Sep 2018