Clinical guidance for two rare immune conditions revealed

A global clinical analysis has revealed 95% of children with two rare inborn immune conditions were effectively treated for lymphoma, when therapy occurred early.

Professor Stuart Tangye

03 December 2020

An international study co-led by researchers at the Garvan Institute of Medical Research has provided new guidance for the clinical treatment of two rare inherited immune disorders.

Researchers combined global data on the two conditions, caused by variants of the genes CD27 and CD70, and diagnosed mostly in children. Their study revealed that those affected were predisposed to lymphoma, a cancer originating from immune cells, but also that the cancer was successfully treated in 95% of patients when they underwent a stem cell transplant shortly after diagnosis.

Published in the journal Blood, the analysis compiles the largest ever cohort of patients with CD27 or CD70 deficiency and provides new insights to guide monitoring and treatment.

“Our study highlights that immune defects, such as CD27 and CD70 deficiencies, should be considered by clinicians as a potential underlying cause when children present with cancer, especially when they have a history of recurrent infections,” says Professor Stuart Tangye, Leader of Garvan’s Immunity and Inflammation Research Theme and co-senior author of the study.

Rare condition with severe impact

CD27 or CD70 deficiencies are rare, but have a significant impact on individuals affected, who have imbalanced immune responses and suffer from recurring bacterial and viral infections.

“A significant health challenge for patients is infection with a common virus called Epstein-Barr virus, which their impaired immune system cannot control. This causes severe disease, including a greatly increased risk of lymphoma, which can be fatal in ~30% of cases,” says Professor Tangye. “However, the low case numbers have so far prevented a consensus on the treatment strategy.”

To better understand CD27 and CD70 deficiencies, 20 leading research centres around the world, led by researchers at St. Anna Children's Cancer Research Institute (Austria), the Willem-Alexander Children’s Hospital (The Netherlands), and the Garvan Institute (Australia), combined their patient data. Together, the current study reports in-depth clinical history and immunological profile of 49 patients with genetic variants in CD27 or CD70, the largest cohort identified to date.

New insights through global collaboration

The new analysis revealed a marked predisposition to lymphoma in both CD27 and CD70 deficient patients – 36% of CD27-deficient patients and 56% of CD70-deficient patients developed lymphoma.

However, in 18 of 19 patients who received a stem cell transplant shortly after diagnosis, the cancer was effectively treated. They were also cancer-free after an average follow-up of two years.

The findings suggest that for children with severe Epstein-Barr virus-associated disease, or lymphoma, genetic investigation of CD27 and CD70 could be beneficial. The researchers say a diagnosis could optimise clinical management and, crucially, support the timely decision of a stem cell transplant.

Restoring balance to the immune system

The study further revealed that 43% of patients suffered from autoinflammation, an aberrant inflammatory reaction affecting the body’s own tissues. This suggests that CD27 and CD70 have a regulatory role in fine-tuning immune responses, the researchers say.

Patients with CD27/CD70 deficiencies had reduced levels of both T and B cells in their blood. Those with CD27 deficiency also produced lower levels of cytokines, which are involved in immune signalling, and altered T cells.

“While developing a disease of the immune system can be devastating, not to mention fatal, we are fortunate that we can essentially replace an individuals’ immune system through the process of a stem cell transplant,” says Professor Tangye.

“Our study of these patients provides new mechanistic insight into why stem cell transplants were effective treatments. It shows that the root cause of susceptibility to lymphoma lay exclusively in the cells that comprise the immune system and replacing genetically-defective immune cells with cells from a healthy donor not only treated the cancer but also restored immunity against infections.”

“This study demonstrates the power of combining global expertise to improve clinical advice for rare inherited immune disorders,” he adds. “We hope this new analysis can make a life-changing difference for affected individuals in future.”

 In Australia, this research was supported by a Susan and John Freeman Cancer Research Grant (Cancer Council NSW) and the National Health and Medical Research Council (1127157).

The study was carried out in collaboration with the Inborn Errors Working Party of the European Society for Immunodeficiencies (ESID) and the European Society for Bone and Marrow Transplantation (EBMT).

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