In an oral abstract presented today we talked about the immune health of lymphoma survivors in a population study of a large population of diffuse large B-cell lymphoma patients in California. We know that as treatments for lymphoma have improved we have a large and increasing number of lymphoma survivors in the US and although we have learned a lot about psychological effects, cardiovascular effects, pulmonary effects etc. in these survivors, little is known about their immune health and that is what we were interested in studying.

What did you look at?

Because lymphoma and its treatments can all affect the immune system we wanted to look at survivorship specifically. So we turned to the California Cancer Registry which is California’s state-wide population cancer surveillance programme run by the California Department of Health. We identified a large group of diffuse large B-cell lymphoma survivors, over 21,000 patients, who were diagnosed as adults and who had survived at least one year after diagnosis. Then we linked their records to state-wide discharge databases and mined all that data for infectious diseases and autoimmune conditions that those patients were diagnosed with in 1-10 years after cancer diagnosis in the survivorship period.

What did you find?

Interestingly we performed four different comparisons: we compared lymphoma patients to survivors of breast cancer, prostate cancer, head and neck cancers and melanoma. In each case we looked at incident rate ratios so we estimated these using a Poisson regression analysis. In each comparison, surprisingly, we found similar diagnoses coming up as top scoring hits. Some of these are already known associations with lymphoma, for example autoimmune cytopenias like autoimmune haemolytic anaemia and thrombocytopenia, as well as deficiencies in  humoural immunity which likely represents persistent hypogammaglobulinemia and Sjögren's syndrome which is an autoimmune condition affecting salivary glands and tear glands.

We also found, interestingly, a high incidence of viral and fungal pneumonias in all four comparisons, up to nine-fold increased in the lymphoma survivors compared to the comparator arms. We also found increased rates of meningitis in several of the comparisons suggesting that lymphoma survivors are at increased risk for many of these serious infections during the survivorship period. The only diagnoses we found to be of higher incidence in the comparator arms, in the breast, prostate, melanoma or head and neck cancer survivors, were ones that were already associated with those diseases. For example vitiligo, which is an autoimmune disease directed against melanocytes in the skin, was much more common amongst the melanoma survivors and cervicitis and endocervicitis was much more common amongst breast cancer survivors, likely related to the fact that they take hormonal therapies.

What can we do with this information?

This work has a lot of implications. It’s a beginning point, we’d like to know what features of patients’ disease and treatments really contribute the most to these altered risks. Potentially in the future to modify how we manage patients but certainly to determine how we track patients during survivorship, what we tell them about their risks and how we follow them and diagnose them for these conditions.

And you were looking at mantle cell lymphoma patients as well?

In this population-based study we were looking at diffuse large B-cell lymphoma patients but to validate these results we are planning a large Stanford-based study of lymphoma survivors to look at prevalence and incidence of immune related conditions. In that study in which we hope to gain a much more comprehensive look at the immune system of lymphoma patients and how that influences diagnoses during survivorship we are planning to collect peripheral blood samples from all these lymphoma survivors and immunophenotype them using single cell mass cytometry.

So as a pilot study to look at the feasibility of this question, of this approach, we took a cohort of eleven mantle cell lymphoma patients who had been uniformly treated with induction chemotherapy and stem cell transplant as well as a vaccine manoeuvre as part of a clinical trial. We looked at their peripheral blood during survivorship, and this was medium term survivorship, on average they were 2.5 years out from the end of treatment and they had no evidence of disease at the time. So we took their blood and performed a large immune profiling experiment using single cell mass cytometry and about 37 markers that delineate cell subtypes and also cell functions and compared to these eleven age-matched healthy controls to look for repeated immunophenotypical alterations. In that analysis, even in the small cohort of patients, we found consistent alterations, especially in T-cell phenotypes, with skewing towards more CD4 cells compared to CD8 cells, skewing within the CD4 cells towards more memory phenotypes and also we see markers of expression that suggest more antigen experience, possibly exhausted T-cells, which would certainly influence the potential for autoimmune diseases and infections in the future and suggests that these patients may have some level of impaired immunity compared to the age-matched controls.