Overview
For a detailed explanation of the treatment for fHLH, see Canna & Marsh [2020] and Jordan et al [2011] (full text).
Given the complexity of fHLH diagnosis and treatment, management should be coordinated by or in consultation with a multidisciplinary team of specialists with expertise in fHLH, including specialists from hematology/oncology, bone marrow and stem cell transplantation, immunology, rheumatology, infectious diseases, critical care, neurology, nephrology, pathology, and medical genetics.
Chemoimmunotherapy. The Histiocyte Society HLH-94 and HLH-2004 protocols have substantially increased the survival for individuals with HLH, including those with fHLH. Use of the HLH-94 protocol resulted in a 54% five-year probability of survival following treatment with etoposide and dexamethasone, delayed cyclosporine, and intrathecal (IT) methotrexate for individuals with central nervous system (CNS) involvement, followed by hematopoietic stem cell transplantation (HSCT) [Trottestam et al 2011]. Nevertheless, 29% of affected individuals died before HSCT, and 19% developed late neurologic sequelae. To reduce pretransplant mortality and neurologic complications, the HLH-2004 protocol added up-front cyclosporine and included IT corticosteroids. Although use of the HLH-2004 protocol resulted in a five-year estimated survival of 62%, neither treatment modification significantly improved overall outcome [Bergsten et al 2017]. Therefore, the HLH-94 protocol remains the current standard of care in most centers.
For individuals with relapsed/refractory fHLH, data are limited on the utility of specific salvage therapies.
These less-than-perfect outcomes of older treatment regimens prompted investigation of alternative therapeutic strategies. Toward this end, a recent report describes 27 individuals with relapsed/refractory fHLH treated with dexamethasone, the IFN-gamma neutralizing antibody emapalumab, and, when needed, other agents [Locatelli et al 2020]. Sixty-three percent of participants exhibited reduction in the signs of active disease with 70.4% proceeding to HSCT.
Allogeneic HSCT. Cure for fHLH can only be obtained via allogeneic HSCT, which generally requires prior chemoimmunotherapy (usually with steroids and etoposide-based chemotherapy regimens such as the HLH-94 protocol) to dampen inflammation.
HLA typing and initiation of the stem cell donor search should be started as soon as fHLH is suspected. HSCT should be undertaken in children with molecularly confirmed fHLH as early in life as is feasible, both for symptomatic children who have achieved clinical remission of active disease (or as close to remission of active disease as possible) following treatment with chemoimmunotherapy as well as presymptomatic children who have not yet experienced a flare of active inflammation (usually identified based on a positive family history of fHLH) [Lucchini et al 2018].
In the past, fully myeloablative conditioning regimens containing busulfan and cyclophosphamide were associated with exceptionally high risks of toxicities and mortality in individuals with fHLH. Although reduced-intensity conditioning regimens containing alemtuzumab, fludarabine, and melphalan (which have come into favor over the last decade), are associated with reduced toxicities and improved overall survival, they are associated with high rates of mixed chimerism and secondary graft failure [Marsh et al 2011, Allen et al 2018].
Experience with reduced toxicity myeloablative conditioning approaches is growing and results appear promising [Richards et al 2018, Contreras et al 2020, Felber et al 2020, Naik et al 2020, Chandra et al 2021, Goode et al 2021]. A recent comparison found that survival with sustained engraftment was higher and toxicity lower for patients treated with reduced toxicity myeloablative regimens containing either (1) busulfan and fludarabine or (2) fludarabine, melphalan, and thiotepa, when compared to reduced-intensity conditioning regimens containing alemtuzumab, fludarabine, and melphalan, or fully myeloablative conditioning regimens containing busulfan and cyclophosphamide [Marsh et al 2022].
Management of neurologic manifestations, respiratory dysfunction, GI tract manifestations, renal impairment, and other system dysfunctions is per standard of care by primary care health care providers or specialty clinicians.