Three patients in the UK have become the first in Europe to receive CAR T-cell therapy for light chain amyloidosis (AL).
AL is a rare but serious haematological malignancy and without treatment, the condition can lead to organ failure and be life-threatening. There is currently no cure.
The current standard treatment for AL is chemotherapy. While often effective, it can cause significant side-effects, and the impact on patients’ quality-of-life during prolonged treatment can be considerable.
Moreover, there is no current established standard-of-care for patients with relapsed/refractory AL, highlighting the urgent need for new options. Although the introduction of daratumumab combined with bortezomib, cyclophosphamide, and dexamethasone as frontline therapy has significantly improved outcomes, a subset of patients fail to achieve adequate responses or relapse, posing a therapeutic challenge.
CAR T-cell therapy targets proteins such as B-cell maturation antigen (BCMA), which are present on the abnormal plasma cells producing amyloid-forming protein in AL. Given the demonstrated efficacy of CAR T-cell therapy in multiple myeloma (MM), in which abnormal plasma cells also express BCMA, its potential application in AL is under active investigation. If successful, CAR T-cell therapy could offer AL patients a single treatment with a high and lasting response rate. By suppressing the abnormal cells at their source, it may also give damaged organs a better chance to recover.
A recent real-world cohort study in the US found that commercial BCMA CAR T-cell therapy was associated with encouraging haematologic response rates and a manageable safety profile in patients with systemic AL, including those with advanced cardiac involvement.
University College London Hospitals (UCLH) has now opened an early-phase study for this patient group, the first in Europe. The ALARIC trial, which was developed within the UK Myeloma Research Alliance (London, UK) and supported by the National Institute for Health and Care Research UCLH Biomedical Research Centre, aims to treat at least 12 patients over the next two years and will also shortly open in Leeds. Three patients have already been treated at UCLH.
Prof Lydia Lee, UCLH Consultant Haematologist who is also Associate Professor at University College London (UCL) and principal investigator of the study, said for patients with relapsed or refractory AL, treatment options are extremely limited, and their disease is likely to progress.
“CAR T-cell therapy has transformed outcomes in multiple myeloma and we are hopeful it could have a similarly significant impact in amyloidosis. This trial is an important first step in evaluating whether we can safely and effectively use this highly targeted therapy to eliminate the cells that drive this disease.”
Chief investigator of the study Prof Ashutosh Wechalekar, Professor of Medicine and Haematology, UCL, and Consultant Haematologist, UCLH and the Royal Free London NHS Trust (UK), acknowledged that this is a phase I study, so the first priority is safety.
“However, the scientific rationale is strong. The abnormal plasma cells in amyloidosis express the same target protein that we successfully treat in myeloma. If we can interrupt the disease process at its source, we may be able not only to control the condition, but also to improve patients’ quality-of-life.”
AL: Diagnosis tips
AL is a rare illness and can be challenging to diagnose. According to Dr John Quinn, Consultant Haematologist, Beaumont Hospital, Dublin, there is typically one AL case for every 10–15 MM cases.
It can be a difficult diagnosis to make because the symptoms of AL are non-specific and often subtle, so a patient can see a number of doctors before a diagnosis is made. This means the disease can be at an advanced stage and if there is cardiac involvement, then it becomes more difficult to manage and has a poorer outlook.
The main organs affected in AL are the heart, kidneys, liver, and nervous system. The symptoms that people develop tend to reflect the organs involved. The most common symptoms that Dr Quinn reports seeing would be shortness of breath and fatigue, particularly if the heart is involved, and lower limb swelling if the kidneys and/or heart are involved. Numbness and tingling in the peripheries can also happen if there is nervous system involvement. Gut upset and diarrhoea can also occur. Patients can also get tongue enlargement and occasionally can experience easy bruising.
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