4. DISCUSSION
HLH/MAS is an hyperinflammatory syndrome which typically consists on hyperactivation of cytotoxic T and natural killer (NK) cells and macrophages, leading to a massive cytokine production, lymphohistiocytic tissue infiltration and immune-mediated multiorgan failure7,9. CAR-T related HLH is rare, with severe and fulminant cases occurring in approximately 1% of patients receiving this treatment. However, this complication is associated with high mortality rates and a prompt diagnosis and early management is mandatory7.
Given its hyperinflammatory nature, it is considered that CRS and HLH/MAS might belong to a similar spectrum of systemic disorders, which makes HLH/MAS diagnosis difficult, especially in the context of CRS7. The traditional diagnosis criteria for secondary HLH/MAS such as HLH-200410 and H-Score11 are not specific, and Neelapu et al. have proposed new criteria for CAR-T related HLH/MAS, considering it is crucial to promptly diagnose this complication7. Both our patients met criteria of CAR-T related HLH/MAS according to Neelapu et al, with the second patient showing an optimal response to treatment due to its early management.
Distinction between this entity and malignancy-triggered HLH/MAS can be challenging and their management should be different. Currently, there are no generally accepted criteria for malignancy-triggered HLH/MAS9. In Case 1, the presence of previous HLH/MAS at lymphoma diagnosis challenged even more this differential diagnosis. However, detection of CAR-T cells in PB and a lymph node biopsy and the paradoxical response observed in the PET-CT allowed a more specific diagnosis and management in our patient.
So far, very little has been published on CAR-T associated HLH/MAS and no formal guidelines for its management exist. Most authors recommend anti-IL6 therapy and steroids, adding etoposide if no improvement after 48h7, 16, as etoposide selectively deletes activated T cells and suppresses inflammatory cytokine production9.
Anakinra, a recombinant IL-1 receptor antagonist is an emerging treatment for CAR-T associated HLH/MAS16, and was used in our patients. Recent reports and preclinical studies suggest that there may be a benefit in combining Anakinra with other anti-inflammatory agents17, 18. However, due to the variability of these studies, the ideal dose schedule for this drug in HLH/MAS is still to be determined19.
Monoclonal antibodies may have a potential role in the management of this condition in the near future7. Emapalumab, an anti-IFN-gamma has been approved by the FDA for patients with refractory primary HLH/MAS and a phase two clinical trial to evaluate its efficacy in secondary HLH/MAS is undergoing, with promising interim results20. However, there is still no formal indication of Emapalumab in secondary HLH/MAS21, 22.
In conclusion, CAR-T cell related HLH/MAS is an unusual manifestation of severe CRS after CAR-T cell therapy, with poor prognosis, high mortality rates and a challenging diagnosis. The establishment of specific diagnosis criteria is essential for a prompt identification of patients suffering from this complication in whom any delay in treatment can be fatal. Also, the combination of diagnosis techniques for CAR-T cell follow-up allows a more precise diagnosis and more accurate distinction between CAR-T cell related or malignancy associated HLH/MAS, therefore granting a better targeted treatment. However, further studies are needed to provide better preventive and treatment strategies to improve the outcome of these patients.