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Southampton Clinical Trials Unit News

New treatment regime can improve survival for patients with a rare blood cancer

Published: 27 January 2021
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An international trial, run in the UK by researchers at the CRUK Southampton Clinical Trials Unit (SCTU), has found that an intensive combination of chemotherapy and immunotherapy can dramatically improve survival for some patients with a rare blood cancer that typically have a very poor outlook.

The MARIETTA study* is the largest ever clinical trial looking at the best way to treat secondary central nervous system lymphoma (SCNSL) and results could help contribute to a change in international guidelines on how to treat people the disease. The UK part of the trial was funded by Cancer Research UK’s Stand Up to Cancer campaign and the results are published in Lancet Haematology**.

SCNSL is a rare but potentially lethal cancer that can occur in patients with diffuse large B-cell lymphoma, a type of aggressive blood cancer, if it spreads to the brain or spine. Treatment for this cancer hasn’t been well defined but previous smaller-scale trials have suggested high dose chemotherapy may be effective.

Because SCNSL is so rare, there’s not enough patients in the UK for a clinical trial, so it’s been difficult to develop and test treatments.

For the MARIETTA study, the international research group IELSG*** cast their net over a much wider area. Led by Dr Kate Cwynarski from University College London Hospital and managed by the SCTU at the University of Southampton’s Centre for Cancer Immunology in the UK, and by Professor Andres Ferreri in Milan, Italy (managed internationally by IESLG), the trial assessed 75 patients across 24 centres in four countries. Researchers believe that data gathered from a large number of patients with a wide geographical spread will mean the results are likely to be applicable to many patients with SCNSL.

Kelly Cozens, from the CRUK Southampton Clinical Trials Unit and Senior Trial Manager for the MARIETTA study in the UK, said: “We were delighted to run the UK part of the MARIETTA study. This is a rare type of blood cancer and by working with our international partners we were able to recruit enough patients to carry out the largest study of its kind into treatment for this disease, and we are pleased to see the benefits this new treatment regime can have.”

Patients on the trial received a combination of chemotherapy and immunotherapy drugs in treatment regimens known as MATRIX**** and RICE*****. Treatment included three courses of MATRIX followed by three courses of RICE, before a stem cell transplant using cells taken from the patients themselves. Some patients on the trial also received a chemotherapy called R-CHOP before MATRIX-RICE if their cancer was life-threatening and had extensively spread to the spine or brain.

75 patients were assessed: 32 (43%) patients were initially diagnosed when their lymphoma had already spread to their brain or spine and had not received treatment, and 43 (57%) had previously been treated for lymphoma and the disease had spread after their cancer came back.

The trial achieved its measure of success, and MATRIX-RICE treatment prevented the cancer from worsening in 42 (58%) of the patients for at least one year after registering onto the trial. 100% of the patients who had the stem cell transplant had not seen their cancer worsen a year after registering onto the trial.

Whilst the MATRIX-RICE treatment was effective, those whose lymphoma had spread to the brain or spine when first diagnosed responded far better than those who had been treated for lymphoma already. In those patients, 2-year progression free survival****** was reported to be 71%, which has never been achieved before. Researchers say these results are extremely impressive because they are similar to those who have lymphoma that hasn’t spread to the brain or spine*******.

When patients were followed up at a median of 29 months after starting the trial, 32 did not have any worsening of their cancer and were still alive, with a 2-year progression free survival of 46% of patients, which increased to 83% for patients who received the transplant.

Overall, 56% experienced a serious adverse event********, the most common being febrile neutropenia (fever and lower than normal levels of neutrophils, a type of white blood cell) and infections; and 95% of patients recovered, and four patients died due to infections.

The MARIETTA study suggests that this treatment programme could dramatically improve survival for patients with SCNSL, whilst highlighting the need to take into account whether patients had been treated prior to developing SCNSL. As the largest trial of its kind, it could help contribute to a consensus on how to treat these patients in the UK and around the world.

Professor Gareth Griffiths, Director of the CRUK Southampton Clinical Trials Unit, said: “The MARIETTA trial was conducted in a very rare cancer patient group, and although trials in more common cancers usually involve hundreds or thousands of patients, in rarer cancers this is just isn’t possible. This trial has shown clear evidence that this new treatment regime can improve survival for some patients with lymphoma that has spread to the brain and spinal cord. This is a cancer where patients typically have a very poor prognosis, but we hope this study could have a real impact on patients’ lives in the future.”

Maureen Brewster, a patient who took part in the trial, said: “I was diagnosed with a brain tumour in 2016 after originally having lymphoma in 2011, and feel incredibly grateful to have been on the MARIETTA trial. Being on the trial meant that my health and treatment course was closely monitored. I also had the opportunity to try out a new treatment course that, at the end of the day, means I’m still alive and have since been able to return to work and enjoy life.”

Dr Kate Cwynarski, a consultant haematologist at University College London Hospital and one of the lead researchers for the trial, said: “The MARIETTA trial has meant patients who may have had just months to live are alive and living well years after being diagnosed. It is incredible to be able to sign DVLA forms for many of my patients treated with this approach, as you can’t drive until you have been clear of treatment for two years and are well, which really brought home the impact this study has had.”

Michelle Mitchell, chief executive of Cancer Research UK, said: “We are dedicated to improving outcomes for all cancer patients, but it can be incredibly difficult to make progress and develop new treatments for rare cancers. As we’ve seen during the COVID-19 pandemic, international collaboration is needed to tackle research challenges that can’t be faced alone, and the MARIETTA trial is a great example of this.”

The MARIETTA trial was supported in the UK by Adienne Pharma and Biotech who supplied the drug thiotepa, part of the MATRIX treatment, free of charge for patients on the study.

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Trial funded by Cancer Research UK's Stand Up To Cancer campaign

Notes for editors

*The MARIETTA study (IESLG-42) is an international trial that took place in the United Kingdom, Italy, Switzerland and the Netherlands. The UK centres were managed by the Cancer Research UK Southampton Clinical Trials Unit based at the University of Southampton’s Centre for Cancer Immunology, and the international centres by the International Extranodal Lymphoma Studies Group (IESLG).

**Ferreri, A. J. M. et al. (2021) MATRIX-RICE therapy and autologous transplant in diffuse large B-cell lymphoma with CNS involvement: a phase II trial of the international extranodal lymphoma study group. Lancet Haematology.

*** IELSG is the International Extranodal Lymphoma Studies Group

****MATRIX treatment consisted of: Rituximab, day 0; methotrexate, day 1; cytarabine, days 2 and 3; thiotepa, day 4. In the UK, the trial was supported by Adienne Pharma and Biotech who supplied thiotepa without charge.

*****RICE treatment consisted of: Rituximab, day 1; etoposide, days 1-2-3; ifosfamide, day 2; carboplatin, day 2.

******Progression-free survival (PFS): the time from treatment to when the cancer begins to progress again, or until death from any cause.

*******Vitolo U, Trneny M, Belada D, et al. Obinutuzumab or Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Previously Untreated Diffuse Large B-Cell Lymphoma. J Clin Oncol 2017; 35(31): 3529-37.

********Serious adverse events are side effects from treatment that: result in death, require hospitalisation, are life-threatening, result in persistent or significant disability/incapacity, a congenital anomaly/birth defect or medically important condition, or requires intervention to prevent permanente impairment or damage.

About the CRUK Southampton Clinical Trials Unit

The Southampton Clinical Trials Unit (CTU) is a Cancer Research UK (CRUK) funded CTU with expertise in the design, conduct and analysis of interventional clinical trials. The CTU is based within the University of Southampton’s Centre for Cancer Immunology with offices at the University Hospital Southampton NHS Foundation Trust Southampton General Hospital site. ( www.southampton.ac.uk/ctu/index.page )

About the University of Southampton

The University of Southampton is among the top 90 institutions globally (QS World University Rankings 2021) and top 15 in the UK (The Times and The Sunday Times Good University Guide 2021). As a founding member of the Russell Group, we are committed to using our knowledge to help shape economic, cultural and intellectual decisions, playing a part in researching solutions to national and global issues. ( www.southampton.ac.uk )

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