Title: Tisagenlecleucel-T for previously treated B-cell acute lymphoblastic leukaemia in people aged 3 to 25 at initial diagnosis [ID1167]
Funder: Department of Health and Social Care

Abstract: To appraise the clinical and cost effectiveness of tisagenlecleucel-T within its marketing authorisation for treating relapsed or refractory B-cell acute lymphoblastic leukaemia..

Lay abstract: Acute lymphoblastic leukaemia (ALL) is a cancer of lymphocyte-producing cells. Lymphocytes are white blood cells that are vital for the body's immune system. In ALL there is an excess production of immature lymphocyte- precursor cells, called lymphoblasts or blast cells, in the bone marrow. This affects the production of normal blood cells and there is a reduction in the numbers of red cells, white cells and platelets in the blood. ALL can be classified into 3 groups based on immunophenotyping: B-precursor ALL (also known as precursor-B-cell ALL), mature B-cell ALL and T-cell ALL.(1) B-cell ALL is characterised by the presence of cytoplasmic immunoglobulins and CD10, CD19, CD22 and CD79a expression. A specific chromosomal abnormality known as the ‘Philadelphia chromosome’ is present in 3-7% of paediatric and young adults with ALL.(2) ALL is most common in children, adolescents and young adults, with 68% of cases diagnosed in people aged under 25 years. A second increase in incidence is observed in people aged over 60 years. In England, 654 people were diagnosed with ALL, and 201 people died from ALL, in 2014.(3) The aim of treatment in ALL is to achieve a cure. Treatment can take up to 3 years to complete and is generally divided into 3 phases; induction phase, consolidation and maintenance. The choice of chemotherapy regimen can depend on the phase and although selection of drugs, dose schedules and treatment duration may differ slightly between different subtypes of ALL, the basic treatment principles remain similar. During induction, newly diagnosed ALL in children and adults is generally treated with chemotherapy combinations including vincristine, an anthracycline and asparaginase. NICE technology appraisal guidance 408 recommends pegaspargase (a polyethylene glycol conjugate of E. coli-derived L-asparaginase) as part of antineoplastic combination therapy, as an option for treating ALL in children, young people and adults when they have untreated newly diagnosed disease. Targeted therapy with tyrosine kinase inhibitors (such as imatinib and dasatinib; no longer available through the Cancer Drugs Fund for the treatment of ALL) can be used for treating Philadelphia-chromosome-positive ALL. During the consolidation phase, intensified chemotherapy is used, which may include high dose methotrexate with mercaptopurine, high dose asparaginase or a repeat of the induction therapy. During the maintenance phase, low dose chemotherapy is used, which typically consists of weekly methotrexate and daily mercaptopurine for an extended period of time to prevent relapse. For high risk ALL, stem cell transplantation and chemotherapy are both considered first line treatment options.(4) Initial treatment is not effective in approximately 45% of people with newly diagnosed B-cell ALL. The overall survival rate at 5 years is approximately 10%.(5) Adults with relapsed or refractory B-cell ALL may have combination chemotherapy and for most people this would be fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) with idarubicin (FLAG-IDA). Clofarabine is sometimes used, but its marketing authorisation is only for children. It is available in England through the Cancer Drugs Fund (at the time the draft scope was written) for people with relapsed or refractory ALL ‘with intent to use the treatment to bridge to bone marrow transplant. Adults with Philadelphia-chromosome-positive disease can have FLAG-based therapy with tyrosine kinase inhibitors or tyrosine kinase inhibitors alone. In adults with relapsed or refractory disease, NICE technology appraisals recommend: • blinatumomab for Philadelphia-chromosome-negative precursor B-cell ALL (technology appraisal guidance 450) • ponatinib for Philadelphia-chromosome-positive ALL with T315I gene mutation or for whom dasatinib or imatinib cannot be used (technology appraisal guidance 451). Other treatment options may include stem cell transplantation if a suitable donor can be found, or best supportive care (including palliative care). There is currently no NICE guidance on treating relapsed or refractory ALL in people who are younger than 18 years old. For people aged 18 to 21, the above NICE technology appraisal guidance applies. Possible treatment options for people who are younger than 18 years old may include FLAG. Clofarabine has a marketing authorisation in the UK as a treatment for ALL ‘in paediatric patients who have relapsed or are refractory after receiving at least two prior regimens and where there is no other treatment option anticipated to result in a durable response’. The safety and efficacy of clofarabine have been assessed in studies of patients aged 21 years and younger at initial diagnosis. It is available in England through the Cancer Drugs Fund (at the time the draft scope was written) for people with relapsed or refractory ALL ‘with intent to use the treatment to bridge to bone marrow transplant’. Stem cell transplantation (SCT) may be an option for children who relapse early or who have multiple relapses. References: 1. Eden T (2017) Acute Lymphoblastic Leukaemia. In: Warrell DA, Cox TM, Firth JD, editors. Oxford Textbook of Medicine. UK: Oxford University Press [accessed November 2017]. 2. National Comprehensive Cancer Network (2017) NCCN Clinical Practice Guidelines in Oncology: Acute Lymphoblastic Leukaemia. Version 1. 3. Cancer Research UK (2016) Acute lymphoblastic leukaemia (ALL) incidence statistics [accessed November 2017]. 4. Macmillan Cancer Support (2016) Treatment overview for acute lymphoblastic leukaemia [accessed November 2017]. 5. Oriol A, Vives S, Hernández-Rivas JM et al. (2010) Outcome after relapse of acute lymphoblastic leukemia in adult patients included in four consecutive risk-adapted trials by the PETHEMA Study Group. Haematologica 95(4):589–96.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS