Title: Zanubrutinib for waldenstrom's macroglobulinaemia [ID1427]
Funder: Department of Health and Social Care

Abstract: Waldenström’s macroglobulinaemia is a type of non-Hodgkin’s lymphoma. Lymphomas are cancers of the lymphatic system, which is a part of the immune system. Lymphomas are divided into two types: Hodgkin’s lymphoma and non-Hodgkin’s lymphoma. Non-Hodgkin’s lymphomas can be categorised according to their grade (how fast they grow) or cell type affected (B-cell or T-cell), as well as by their clinical features. Lymphoplasmacytic lymphomas are a group of rare low grade (slow growing or indolent) non-Hodgkin’s lymphomas. The most common of these is Waldenström’s macroglobulinaemia[1]. Waldenström’s macroglobulinaemia is caused by abnormal B cells which produce too much immunoglobulin M (IgM). Overproduction of IgM can reduce red blood cell levels, causing anaemia and fatigue[2]. IgM molecules also cluster together, which can thicken the blood (hyperviscosity). This reduces blood flow through capillaries which can cause headaches, a lack of concentration, breathlessness, poor circulation in the organs and limbs, and an increased risk of stroke[2]. IgM may react against the body, causing inflammatory conditions such as nerve damage (neuropathy)[3]. Cryoglobulinaemia can result when IgM forms immune complexes upon cold exposure, causing kidney damage and ulceration of the skin[4]. In rare cases Waldenström’s macroglobulinaemia cells can infiltrate the central nervous system (CNS), resulting in Bing-Neel syndrome[5]._x000D_ _x000D_ Waldenström’s macroglobulinaemia is more common in men and mainly affects people 65 years and older[6]. Waldenström’s macroglobulinaemia is incurable and the median life expectancy is 5 years[7]. In 2017, there were 353 newly diagnosed cases of Waldenström’s macroglobulinaemia registered in England[8]. In 2018-19, there were a total of 5,384 hospital episodes with a primary diagnosis of Waldenström’s macroglobulinaemia in England[9]._x000D_ _x000D_ There is no established standard of care for Waldenström’s macroglobulinaemia in England. The British Committee for Standards in Haematology (BCSH) guidelines recommend treatment with a combination regimen with rituximab and either cladribine, bendamustine, dexamethasone (plus cyclophosphamide) or fludarabine (with or without cyclophosphamide)[7]. Chlorambucil monotherapy is also recommended for those people who cannot tolerate other treatments. Choice of treatment usually depends on a variety of clinical factors including grade of disease, kidney function, co-morbidities and whether a person is able to have stem cell transplantation[7]. Patients treated with existing treatments generally have a partial response which lasts for a time before the disease relapses. More recently, mutations in the MYD88 gene have been found to confer a better prognosis and greater response to Bruton’s tyrosine kinase (BTK) inhibitors. Around 90% of people with Waldenström’s macroglobulinaemia have a MYD88 mutation[10]._x000D_ _x000D_ Ibrutinib monotherapy is recommended for use in the Cancer Drugs Fund as an option for treating Waldenström’s macroglobulinaemia in adults who have had at least one prior therapy (NICE technology appraisal 491)._x000D_ _x000D_ References_x000D_ _x000D_ 1. Lymphoma Action. Lymphoplasmacytic lymphoma and Waldenström’s macroglobulinaemia. Accessed October 2020._x000D_ _x000D_ 2. American Cancer Society. Signs and Symptoms of Waldenstrom Macroglobulinemia. Accessed October 2020_x000D_ _x000D_ 3. MedlinePlus. Waldenström macroglobulinemia. Accessed October 2020_x000D_ _x000D_ 4. Leukemia & Lymphoma Society (2012). Waldenström Macroglobulinemia Facts_x000D_ _x000D_ 5. Castillo J J et al. (2019) Ibrutinib for the treatment of Bing-Neel syndrome: a multicenter study. Blood 133(4):299-305_x000D_ _x000D_ 6. WMUK. (2018) What is WM? Accessed October 2020_x000D_ _x000D_ 7. Owen, R et al. (2014) Guidelines on the diagnosis and management of Waldenström macroglobulinaemia. British Journal of Haematology, 165:316-33._x000D_ _x000D_ 8. Office of National Statistics (2019), Cancer Statistics Registrations, England, 2017 dataset. https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/datasets/cancerregistrationstatisticscancerregistrationstatisticsengland_x000D_ _x000D_ 9. NHS Digital (2019) Hospital Admitted Patient Care Activity 2018-19. Accessed July 2020_x000D_ _x000D_ 10. Baron, M et al. (2019) How Recent Advances in Biology of Waldenström’s Macroglobulinemia May Affect Therapy Strategy. Current Oncology Reports, 21:27

Lay abstract: To appraise the clinical and cost effectiveness of zanubrutinib within its marketing authorisation for treating Waldenström’s macroglobulinaemia.

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