Real World Outcomes for T- and NK-cell lymphomas in England using National Cancer Registration and Analysis Service Data ( ODR2021_180 )

The Data will be used for the purpose of a research project: Real World Outcomes for T- and NK-cell lymphomas in England using National Cancer Registration and Analysis Service Data (ODR2021_180).

The Data will be used to answer the following questions:

• Address current gaps in knowledge about the occurrence and natural history of T and NK cell lymphomas.

• Improve understanding of why these diseases develop.

• Overcome challenges related to the small number of cases available for research.

• Use high quality, routinely collected NCRAS data from Public Health England to identify when, where, and in whom T and NK cell lymphoma cases occurred in England (2013–2020).

• Analyse outcomes for affected individuals, including survival and disease progression.

• Identify inequalities in diagnosis and survival based on age, sex, and treatment information from SACT, RTDS, and HES datasets.

• Generate insights that support earlier diagnosis, better outcomes, and improved quality of life for patients with these rare lymphomas.

No data will flow to NHS England for the purposes of this Data Sharing Agreement (DSA).

NHS England will provide access to the relevant records from the NDRS Systemic Anti-Cancer Therapy Dataset (SACT), NDRS Linked Cancer Waiting Times (Treatments only), NDRS Linked HES Outpatient, NDRS Cancer Registrations, NDRS National Radiotherapy Dataset (RTDS), NDRS Linked DIDs, NDRS Linked HES APC to Nottingham University Hospitals NHS Trust. The Data will contain no direct identifying data items. The Data will be pseudonymised and individuals cannot be reidentified through linkage with other data in the possession of the recipient.

The Data will not be transferred to any other location.

The Data will be stored on servers at Nottingham University Hospitals NHS Trust.

The Data will be accessed onsite at the premises of Nottingham University Hospitals NHS Trust and will be accessed by authorised personnel via remote access.

The Controller(s) must confirm and provide evidence upon audit by NHS England that access via any remote device complies with the data security obligations within this DSA and the Data Sharing Framework Contract.

For remote access:

• Remote access will only be from secure locations situated within the territory of use (as further restricted elsewhere within the DSA if so done) stated within this DSA.

• Access controls granting users the minimum level of access required are in place.

• Remote access is only via secure connections (e.g., VPNs or secure protocols) to protect data.

• Multifactor authentication (MFA) is required for remote access.

• Device security, including up-to-date software and operating systems, antivirus software, and enabled firewalls are utilised for the remote access.

• All remote access is undertaken within the scope of the organisation’s DSPT (or other security arrangements as per this DSA) and complies with the organisation’s remote access policy.

The above applies in addition to any condition set out elsewhere within the DSA (e.g. who may carry out processing, and for what purpose).

The Data will not be linked with any other data outside of this agreement.

The outputs of the research will be

• Reports of findings to the research team and collaborators, produced at key project milestones, including completion of subtype specific analyses and prior to each manuscript submission.

• Submissions to peer reviewed journals, including:

• Two manuscripts already published,

• One currently under review,

• One further manuscript planned for submission on completion of remaining analyses.

• Presentations to clinical and academic stakeholders, including haematology research groups and NCRAS affiliated collaborators.

• Presentations at appropriate national and international conferences, such as haematology, oncology, epidemiology, and cancer registry meetings.

• A population level analytic dataset describing incidence, treatment patterns, survival outcomes, co morbidities, and inequalities across T and NK cell lymphoma subtypes, to be used as a resource for future health research (not publicly released; used within project governance constraints).

• Evidence summaries highlighting disparities in incidence and survival by deprivation, ethnicity, and region, supporting future health policy and service planning.

The outputs will not contain NHS England Data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset(s) from which the information was derived.

The main benefits of this research are expected to:

• Enhance evidence generated from clinical trials, which are performed in selected patient populations.

• Provide additional data on outcomes (e.g., longer follow-up of progression-free survival and overall survival) than clinical trials.

• Supplement data required by regulatory agencies, alleviating barriers to uptake of new medicines.

• Be systematically analysed to identify ways to improve disease management.

T- and NK-cell lymphomas are a heterogeneous group of diseases that are aggressive and generally associated with poor prognosis.

The rarity and heterogeneity of patients with specific subtypes of T- and NK-cell lymphomas severely limits the ability to make conclusions regarding the optimal treatment for most of these diseases.

The more common subtypes are thought to have 5-year overall survival (OS) rates between 15-30%, with patients with relapsed or refractory disease having dismal prognoses. The management of limited stage disease and the use of autologous or stem cell transplantation (SCT) remains controversial despite therapies being both toxic and expensive.

Despite these problems, there have been therapeutic breakthroughs with marked improvement in survival for the specific subtypes extra nodal NTK-cell lymphoma (NKTL), using asparginase based treatment and Anaplastic Large Cell Lymphoma (ALCL), using the immunoconjugate brentuximab vedotin in combination with chemotherapy. These data was obtained in multi-centre early phase trials with small patient numbers (NKTL) and one very large randomised international clinical trial conducted internationally.

To date, large scale UK/English data regarding delivered therapies, responses to treatment, the use of SCT, and their impact on progression free survival (PFS) and OS for all subtypes of T- and NK-cell lymphoma has never been published. We requested data on these diseases from NCRAS to help describe, on an unbiased population level (i) incidence rates of each specific lymphoma and describe variation in sociodemographics including regional, deprivation, age, sex, and ethnicity, (ii) Describe and analyse delivered lines of therapies for those patient with systemic anti-cancer therapy (SACT) and radiotherapy dataset (RTDS) data available, (iii) the impact of treatment on overall survival, cancer related survival, progression free survival, and time to next treatment, (iv) regional and socio-economic inequality and its relationships with treatments and survival, (v) analysis of all episodes of care prior to and after diagnosis, co-morbidities and linked GP and prescription data.

To date we have published two manuscripts in high impact journals, have another under review at a journal and are completing a fourth, and are as follows:

Publication #1: Ethnicity and socio-economic status affects the incidence and survival of hepatosplenic T-cell lymphoma. Mark J Bishton, Colin J Crooks, Timothy R Card, Joe West. Br J Haematol. 2024 Jun;204(6):2222-2226. doi: 10.1111/bjh.19371. Epub 2024 Feb 29. [impact factor 6.5]

This paper reported the first population-based age-standardised incidence of HSTCL over a contemporary timeframe, reducing bias in reporting socio-economic factors in comparison with prior series. Several of our findings were consistent with prior reports and previously reported smaller studies, again describing diagnosis in the fifth decade, a male predilection, a clear association with IBD and most patients dying within 1 year of diagnosis. Thanks to comparatively large numbers, our series described for the first time a higher incidence in areas with greater deprivation, and more cases than would be expected occurring in patients with non-White ethnicity. Data suggested an increased risk of death in non-White patients, even after adjusting for deprivation, the younger age of diagnosis of non-Whites, and receipt of allogeneic SCT.

Publication #2: Incidence and survival in patients with Enteropathy Associated T-cell lymphoma: nationwide registry studies from England and Denmark. Joe West, Peter Jepsen, Timothy R. Card, Colin J. Crooks, Mark Bishton. Gastroenterology 2023 Oct;165(4):1064-1066.e3. doi: 10.1053/j.gastro.2023.06.003. Epub 2023 Jun 9. [impact factor 33.88]

Enteropathy-associated T-cell lymphoma (EATL) is a rare and highly aggressive T-cell non-Hodgkin lymphoma that is strongly associated with refractory coeliac disease. In a collaboration with colleagues from Denmark we reported in this paper (i) the overall incidence rates of EATL and survival after diagnosis were very similar, (ii) approximately 50% of all cases of EATL have a coexisting diagnosis of coeliac disease and 6%– 8% had coexisting IBD, (iii) people with coeliac disease fare better, as do those who have small-bowel surgery at diagnosis. The best survival rates were found in a small minority of patients with EATL well enough to have both small-bowel surgery and stem cell transplantation.

Publication #3: Incidence and survival of patients with angioimmunoblastic T-cell lymphoma: A nationwide population-based study using English Cancer Registration Data. Submitted to Haematological Oncology journal.

The data confirmed the disease incidence increases dramatically with age and is lower in females. We highlight a higher disease incidence in London compared to other regions of England. We found no benefit for more intensive chemotherapy (CHOEP) compared to CHOP. Patients who received auto-SCT had good survival outcomes, with a median 66.9 months from date of transplant although there is significant residual confounding factors/bias, as these will have been deemed fit enough, and survive long enough, to reach transplant. Several reports have described a relationship between AITL and development of later B-cell lymphoma. We suggest a risk of a secondary lymphoma to be 14.3%, of which the majority are aggressive B-cell lymphoma (7.3%). Outcomes for aggressive B-cell lymphoma appeared very good given the competing risk of death from AITL. We have also confirmed the association of autoimmune haemolytic anaemia and thrombocytopenia with ATL.

Publication #4: Real World Outcomes for adult T-cell leukaemia/lymphoma in England using National Cancer Registration and Analysis Service Data. Work in progress. Planned submission to the British Journal of Haematology.

Adult T-cell leukaemia/lymphoma (ATL) is a rare, aggressive T-cell malignancy that occurs in carriers of the human T-lymphotropic virus type 1 (HTLV-1). Most clinical data is from Japan, an HTLV-1 endemic country, so little is known about current incidence and survival trends in the UK.

This paper will define the first population-based estimates of ATL incidence in England; we have confirmed poor survival outcomes in an unselected population and will highlight how age and black ethnicity negatively impact survival.

Our publications/planned publications have highlighted disparities in terms of deprivation and ethnicity in terms of disease incidence and survival which is clearly important for future health policies. An extension to the DSA is required to both compete these papers and allows us to adequately respond to reviewer’s comments and be able to address their need for any further information.