February 2024

Lara C. Pullen, PhD

Results from a contemporary standard-of-care study of patients with primary hemophagocytic lymphohistiocytosis (pHLH) reveal that firstline etoposide-based therapy is more effective than previously reported. The study by Svea Böhm, MD, assistant physician at the University Medical Center Eppendorf in Hamburg, Germany, and colleagues provides a benchmark for the evaluation of new treatment regimens. The authors recently published their findings in Blood.¹

The international registry study included 88 patients with pHLH who were treated with standard-of-care protocols in a multicenter setting from 2016 to 2021. Of the 88 patients, 63 had biallelic disease-causing mutation in an FHL gene. The cohort also included 12 patients who, because of an affected sibling with pHLH or partial albinism, were diagnosed before the onset of symptoms and remained asymptomatic until hematopoietic cell transplantation (HCT). Of the 76 symptomatic patients, 93% (n=71) fulfilled HLH-2004 criteria, three presented with isolated central nervous system (CNS)-HLH, and two had CNS-HLH with partial systemic activity.

Of the 76 symptomatic patients, 10 did not receive major HLH-directed treatment and instead were treated with combination intravenous immunoglobulin, steroids, and cyclosporin A (n=8) or infliximab only (n=1) or had spontaneous resolution without HLH-directed treatment (n=1). The remainder of the symptomatic patients (n=66) received major HLH-directed drugs (etoposide, alemtuzumab, antithymocyte globulin, emapalumab, ruxolitinib). Approximately one-third (29%) of patients who received major HLH-directed drugs also received salvage therapy, defined as application of at least one additional major drug. HCT was performed in 85% of patients.

The investigators found that not only was survival higher than documented in previous studies (91% compared with 79%-83%), but there were substantial survival improvements in the HCT phase of treatment in the current study relative to previous etoposide-based treatment studies (88% overall survival compared with historical data of 66%-71%). They found no difference in survival between patients who received HCT within three months of diagnosis and those who received HCT later than three months. The authors noted that one of the limitations of the study was that, as with any registry study, they could include reporting bias.

“By documenting a 76% three-year survival for etoposide-based therapy (compared to 59% in previous studies), our findings underline the value of this well-known drug in pHLH,” said Stephen Ehl, MD, director of the Centre for Chronic Immunodeficiency at the University of Freiburg in Germany and corresponding author for the study. “The results provide a contemporary standard-of-care benchmark for studies evaluating novel treatment approaches to pHLH. They also provide reassurance to physicians in countries with limited access to novel drugs for this disease, who have been made insecure by the fact that these drugs have been studied in comparison to the historical etoposide data.”

Dr. Ehl was pleasantly surprised by the higher three-year survival with etoposide-based protocols. “Although it was known that etoposide can induce remission of hyperinflammation in a large proportion of patients with pHLH and that more recent conditioning protocols led to better outcome of HCT in this disease, the number of 59% survival (achieved in the HLH-2004 study²) was in everybody’s mind,” said Dr. Ehl. “It was quoted in many papers and served as a reference for evaluation of new treatments.”

The current study also confirmed the excellent prognosis (100%) of pHLH if it is diagnosed before the onset of symptoms. Dr. Ehl therefore emphasized the potential benefit of newborn screening and explained that, while highly sensitive and specific immunologic tests can diagnose pHLH in a child within 48 hours, the tests require experienced personnel and are not available in all countries.

“The key issue is not a more rapid diagnosis of the child. The vision should be to identify the genetically predisposed child before they develop HLH,” Dr. Ehl said. He also supports the advancement of newborn screening using genetic testing of the newborn screening card.