Secondary Hemophagocytic Lymphohistiocytosis: Do We Really Need Chemotherapeutics for All Patients?

Abstract

Because of the acute and life-threatening course of the hemophagocytic lymphohistiocytosis (HLH) syndrome, International Histiocyte Society guidelines recommend chemoimmune therapy for the treatment of both primary and secondary HLH (sHLH). To manage children with sHLH, instead of HLH-2004 protocol we considered less immunosuppressive/cytotoxic approach. We assessed 12 children who fulfilled the diagnostic criteria for sHLH between January 2009 and March 2015. Multivariate Cox regression analysis showed that ferritin levels (hazard ratio=1.02, P=0.006), pediatric logistic organ dysfunction scores (hazard ratio=1.01, P=0.001) were the predictors of the survival. The hospital survival was 83% for patients with sHLH who were treated with less immunosuppressive therapy. In conclusion initiation of HLH-specific therapy for the patients with hyperferritinemia-associated sHLH should be delayed while awaiting resolution of systemic inflammation with less immunosuppressive therapy.

Efficient management of secondary haemophagocytic lymphohistiocytosis with intravenous steroids and γ-immunoglobulin infusions

“…Remission rate was quite high (76%) with a 30-d mortality rate of 15%. Similar remission rates were reported recently in two small retrospective studies from United States and Turkey in patients with sHLH by using a personalized diagnostic and less immunosuppressive and cytotoxic treatment approach which included treatment with anakinra, cyclosporine, IVIG and steroids[33,42]. In this context, it is worthy to state that the use of anakinra as a treatment option has already been described with favourable results in small studies[43] while on the other hand, IVIG has been proved effective in at least a subgroup of adults with sHLH when started at the beginning of the macrophage activation process, during the ferritin run-up to peak values[44].…”

“…During the period of the study (January 2010 - June 2018) the guidelines in use for the treatment of HLH, whether primary or secondary, included an initial 8 wk of chemo-immune therapy[5]. However, several investigators –including us[24,41] - questioned whether it is rationale all these patients with sHLH, particularly those with infections- or sepsis-associated haemophagocytosis, to receive intense immunosuppressive treatment[33,42,44,49-51]. Indeed, there are several reports for patients with sHLH who treated successfully after the administration of less immunosuppressive and less cytotoxic treatment modalities outside the HLH-2004 protocol including primarily anti-inflammatory agents and IVIG[24,33,41-44,49-51].…”

“…Indeed, there are several reports for patients with sHLH who treated successfully after the administration of less immunosuppressive and less cytotoxic treatment modalities outside the HLH-2004 protocol including primarily anti-inflammatory agents and IVIG[24,33,41-44,49-51]. In this regard, although the grade of evidence in support of the latter intervention in a recent review was moderate[52] (level of evidence 3: obtained from well-designed non-experimental descriptive studies, such as comparative studies, correlation studies and case studies), the use of IVIG seems to be safe and effective as first-line treatment in a number of studies avoiding in parallel unnecessary toxicity[24,33,41,42,44,50,53-57]. Taking into account our preliminary results[24,41] as well as the abovementioned uncertainties we chose to treat our adult patients outside the HLH-2004 protocol with less cytotoxic agents as the vast majority of them (74%) suffered from underlying serious infections.…”

From febrile pancytopenia to hemophagocytic lymphohistiocytosis-associated organ dysfunction

“…The intensivist calls the rheumatologist who believes the presentation is consistent with adult onset stills disease (the adult form of systemic juvenile arthritis)-related MAS. She starts the patient on corticosteroids and Anakinra [ 10 – 12 ]. Other laboratory testing is sent to rule out Systemic Lupus Erythematosis, Sarcoidosis, Scleroderma, Sjogren’s, and Kawasaki’s disease [ 1 , 2 ].…”

“…The intensivist treats shock, AKI, and ARDS in this patient who also has hepatobiliary dysfunction and disseminated intravascular coagulation. The patient is treated with plasma exchange (if AKI and thrombocytopenia are present), IVIG, and Anakinra [ 4 , 12 , 13 ]. An exhaustive search ensues for bacteria including mycoplasma, rickettsia, legionella, chlamydia, brucella, and borrelia; fungi and parasites including histoplasmosis, babesia, leishmaniasis, pneumocystis, aspergillus, toxoplasmosis, cryptococcus, and candida, and viruses including EBV, CMV, HSV, HIV, HHV8, HHV6, parvovirus, adenovirus, and influenza so that appropriate anti-microbial therapy can be used [ 1 , 2 ].…”