How do you approach diagnosis and treatment of HLH/MAS following CAR T-cell therapy?

I maintain that immune effector cell associated hyperinflammatory syndrome is NOT HLH. Most patients post CAR-T cell therapy fulfill the criteria for HLH even if they don’t have hyperinflammatory syndrome, so it makes diagnosis very challenging. Many patients with this “HLH-like” hyperinflammatory syndrome respond to IL6 or IL1 inhibitors—which I have found almost uniformly ineffective in true HLH, although they can be helpful in MAS. More research is needed to better define this syndrome and how it should be treated. Currently, patients usually receive steroids, cytokine inhibitors (tocilizumab, anakinra, ruxolitinib) with efforts to control the syndrome without having to resort to cytotoxic therapies that will also eliminate the CAR T-cells.

In pediatrics, I have always believed that secondary HLH/MAS is the most severe end of the spectrum of hyperinflammatory syndromes and most of the manifestations are due to the release of proinflammatory cytokines (although increased levels of anti-inflammatory IL10 is usually seen as well). The cytokines are released from activated T-Cells which in turn activate macrophages to release more cytokines establishing a feedback loop.

The cytokine release syndrome following CAR-T and blinatumomab also has activated T-Cells (obviously) but indeed usually responds to drugs such as tocilizumab. Although a few case reports of the success of tocilizumab in treating HLH can be found in the literature, it does not seem to be the successful therapy initially hoped for, and ruxolitinib in our hands or Interferon antibodies have proved to be better salvage options.

In general, in CAR-T cell therapy, dexamethasone has usually only been used if the more targeted inhibitors/antibodies such as tocilizumab fail.