Haemophagocytic lymphohistiocytosis in patients treated with immune checkpoint inhibitors: analysis of WHO global database of individual case safety reports

Abstract

Background Immune checkpoint inhibitor (ICI) use in clinical practice has unravelled a spectrum of immune-related adverse events (irAEs) due to immune system hyper-activation. ICI-related haemophagocytic lymphohistiocytosis (HLH) has been recently outlined in single case reports, raising a concern about the need of increasing our knowledge on this rare yet life threatening ICI haematological toxicity. Methods To determine ICI-related HLH clinical, haematological, and coagulation features, its timing and outcome, concurrent irAEs and concomitant infections, we performed a retrospective observational cross-sectional study and queried VigiBase, the WHO global database of suspected adverse drug reactions (ADRs), on September 30th, 2018. We retrieved the individual case safety reports reporting HLH in association with ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab or durvalumab, gathered in the database starting from the ICIs’ approval dates by the US Food and Drug Administration. The main outcome measures were co-suspected drugs, concurrent irAEs, HLH clinical, haematological and coagulation features, concomitant infections, HLH median time to onset and outcome. Results Among 49′883 ICI-related ADRs collated in VigiBase as of September 30th, 2018, HLH was reported in 38 cases of which 34 (90%) mentioned ICIs as the solely suspected drugs. ICI-related HLH showed clinical, haematological and coagulation features similar to those of HLH with different etiology. Concurrent irAEs occurred in 5 (13%) patients and 6 (16%) reported concomitant viral infections. 31 (82%) cases defined ICI-related HLH outcome, which resolved in 19 (61%) cases. HLH developed a median of 6.7 weeks after initiation of ICI treatment (IQR 2.9–15.4, n = 18, 47%). Conclusions By evaluating the largest cohort of ICI-related HLH cases, we observed that ICI-related HLH arises with a delayed timing with respect to initiation of ICI treatment, and usually presents without other irAEs and concomitant infections. Keeping in mind these findings, clinicians should consider ICIs’ involvement in the onset of HLH whenever they diagnose a disease of this group of syndromes in cancer patients treated with ICIs.

Hemophagocytic lymphohistiocytosis with advanced malignant melanoma accompanied by ipilimumab and nivolumab: A case report and literature review

“…The two previous cases were reported from the Unites States and Germany, and this is the first reported case of irHPS/HLH in an Asian patient receiving combined nivolumab + ipilimumab therapy for malignant melanoma. The interval to onset varies depending on the case, and the reported mean interval is 6.9 weeks, similar to that in the present study 8 …”

“…In one published report, the features of 38 cases of irHPS/HLH extracted from Vigibase, the WHO global database, are described 8 . IrHPS/HLH is uncommon, accounting for less than 0.1% of all adverse reactions, and the median interval to onset was 6.7 weeks, although no detailed characteristics by the causative drug were reported.…”

Lessons to be Learnt from Real-World Studies on Immune-Related Adverse Events with Checkpoint Inhibitors: A Clinical Perspective from Pharmacovigilance

“…Recovered in 71% (data for 36 patients). Overlap with colitis (5.8%), thyroid diseases (4.6%) Raschi et al (2019); FAERS [ 32 ] SLE 0.02% (among rheumatic events) Median TTO = 196 4870 rheumatic events (arthralgia, n = 711), 18 cases of SLE (plus 7 cases of cutaneous SLE), only with anti-PD-1/PD-L1 No anti-TNF drugs/procainamide/hydralazine were recorded among concomitant drugs; overlap in two cases with arthralgia, arthritis and other rheumatic events Davis et al (2019); Vigibase [ 49 ] Hematological toxicities 23% (HLH), 15% (HH), 11% (ITP) Median TTO = 40 for HLH (23 for anti-CTLA-4, 47.5 for anti-PD-1/PD-L1), 50 for HA, 41 for ITP 168 cases (HA = 68, ITP = 57, HLH = 26); HLH mainly with anti-CTLA-4, earlier onset (26), and higher fatality (23%) Overlap only with non-hematologic irAEs (23%) Noseda et al (2019); Vigibase [ 50 ] HLH 26% Median TTO = 46.9 38 cases (0.08% of total events), 90% ICIs as the solely suspected drug), 58% with anti-PD-1/PD-L1. Recovered in 61%.…”

Hematological toxicities in immune checkpoint inhibitors: A pharmacovigilance study from 2014 to 2019

“…Sixth, we did not take combination of chemotherapy into our strategic. Previously, two studies explored the Vigibase to analyze hematological toxicities, describing the median time to onset and outcome, characteristics distribution to some AEs including immune thrombocytopenic purpura, hemolytic anemia, hemophagocytic lymphohistiocytosis, aplastic anemia, and pure red cell aplasia 35,36 ; our study is a more systematic study that extensively characterized the hematological toxicities in total and class‐specific ICIs. Concluding from nearly thirty million records, our results seem to be more stable and convenient and would surely provide valuable evidence for further clinical practice.…”