We read with great interest the article by Kramer et al. [
] on the haematological adverse effects associated with immune checkpoint inhibitors (ICIs). The authors have extensively discussed several rare but clinically significant hematological adverse effects that may also prove to be fatal in some cases. The adverse effect that drew our attention, in particular, is haemophagocytic lymphohistiocytosis (HLH). HLH is a potentially fatal clinical syndrome that results from a severe, uncontrolled hyperinflammatory state, which may be triggered by several causes such as infection, malignancy, drugs and so on [
- Kramer R.
- Zaremba A.
- Moreira A.
- et al.
Hematological immune related adverse events after treatment with immune checkpoint inhibitors.
Eur J Canc. 2021 Apr; 147: 170-181
]. Patients may have a non-specific clinical picture that includes, but is not limited to, a triad of fever, cytopenias and hepatosplenomegaly, but atypical or overlapping presentations are common [
- Janka G.E.
- Lehmberg K.
Hemophagocytic lymphohistiocytosis: pathogenesis and treatment.
Hematol Am Soc Hematol Educ Prog. 2013; 2013: 605-611
]. ICIs are known to be associated with several immune-related adverse events (irAEs) including HLH or ICI-related HLH (ICI-HLH). The underlying mechanism proposed in this regard is the inhibition of cytotoxic T-cell activity by ICIs, which results in a pathologic hyperinflammatory state [
- Birndt S.
- Schenk T.
- Heinevetter B.
- et al.
Hemophagocytic lymphohistiocytosis in adults: collaborative analysis of 137 cases of a nationwide German registry.
J Canc Res Clin Oncol. 2020; 146: 1065-1077
]. The authors determined the frequency of HLH to be 2 of 50 (4%) in their study cohort. However, the real magnitude of occurrence of ICI-HLH is unknown as it is a poorly understood clinical phenomenon and existing data majorly come from isolated case reports.
- Kalmuk J.
- Puchalla J.
- Feng G.
- Giri A.
- Kaczmar J.
Pembrolizumab-induced hemophagocytic lymphohistiocytosis: an immunotherapeutic challenge.
Canc Head Neck. 2020; 5: 3
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- Hematological immune related adverse events after treatment with immune checkpoint inhibitors.Eur J Canc. 2021 Apr; 147: 170-181
- Hemophagocytic lymphohistiocytosis: pathogenesis and treatment.Hematol Am Soc Hematol Educ Prog. 2013; 2013: 605-611
- Hemophagocytic lymphohistiocytosis in adults: collaborative analysis of 137 cases of a nationwide German registry.J Canc Res Clin Oncol. 2020; 146: 1065-1077
- Pembrolizumab-induced hemophagocytic lymphohistiocytosis: an immunotherapeutic challenge.Canc Head Neck. 2020; 5: 3
Published online: June 18, 2021
Accepted: April 27, 2021
Received: April 22, 2021
© 2021 Elsevier Ltd. All rights reserved.
ScienceDirectAccess this article on ScienceDirect
- Hematological immune related adverse events after treatment with immune checkpoint inhibitorsEuropean Journal of CancerVol. 147
- PreviewWith the increasing use of checkpoint inhibitors, rare immune-related adverse events (irAE) are being identified. Haematological irAE (hem-irAE) are difficult to treat and have shown high mortality rates. In order to improve side-effect management for these potentially life-threatening events, we analysed frequency, severity and outcomes.
- Response to letter entitled: ‘Re: Hematological immune related adverse events after treatment with immune checkpoint inhibitors’European Journal of CancerVol. 153
- PreviewCheckpoint inhibitor–induced haemophagocytic histiocytosis (HLH) is an important side-effect with a challenging therapy and high mortality rate. Thus, we agree that it is critical to raise awareness to the condition, which allows early detection and treatment. It is also essential to gather data on these events to establish best practice. Case reports are an important tool to identify signals for further investigation of such rare events as has been the case for cardiomyositis , which triggered an US Food and Drug Administration (FDA) initiative.