INDICATIONS
Gamifant (emapalumab-lzsg) is an interferon gamma (IFNγ)-neutralizing antibody indicated for the treatment of adult and pediatric (newborn and older) patients with:
- Primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent, or progressive disease or intolerance with conventional HLH therapy.
- HLH/macrophage activation syndrome (MAS) in known or suspected Still’s disease, including systemic Juvenile Idiopathic Arthritis (sJIA), with an inadequate response or intolerance to glucocorticoids, or with recurrent MAS.
IMPORTANT SAFETY INFORMATION
Infections
Gamifant may increase the risk of fatal and serious infections with pathogens including mycobacteria, herpes zoster virus... and histoplasma capsulatum. Do not administer Gamifant in patients with these infections until appropriate treatment has been initiated.
INDICATIONS
Gamifant (emapalumab-lzsg) is an interferon gamma (IFNγ)-neutralizing antibody indicated for the treatment of adult and pediatric (newborn and older) patients with:
- Primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent, or progressive disease or intolerance with conventional HLH therapy.
- HLH/macrophage activation syndrome (MAS) in known or suspected Still’s disease, including systemic Juvenile Idiopathic Arthritis (sJIA), with an inadequate response or intolerance to glucocorticoids, or with recurrent MAS.
IMPORTANT SAFETY INFORMATION
Infections
Gamifant may increase the risk of fatal and serious infections with pathogens including mycobacteria, herpes zoster virus, and histoplasma capsulatum. Do not administer Gamifant in patients with these infections until appropriate treatment has been initiated.
In patients with primary HLH receiving Gamifant in clinical trials, serious infections such as sepsis, pneumonia, bacteremia, disseminated histoplasmosis, necrotizing fasciitis, viral infections, and perforated appendicitis were observed in 32% of patients.
In patients with HLH/MAS in Still’s disease receiving Gamifant in clinical trials, serious infections such as pneumonia, cytomegalovirus infection, cytomegalovirus infection reactivation, and sepsis were observed in 13% of patients.
Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating Gamifant. Administer tuberculosis prophylaxis to patients at risk for tuberculosis or known to have a positive purified protein derivative (PPD) test result.
Consider prophylaxis for herpes zoster, Pneumocystis jirovecii, and fungal infection while receiving Gamifant. Employ surveillance testing during treatment with Gamifant.
Closely monitor patients receiving Gamifant for signs or symptoms of infection, promptly initiate a complete diagnostic workup appropriate for an immunocompromised patient, and initiate appropriate antimicrobial therapy.
Increased Risk of Infection With Use of Live Vaccines
Do not administer live or live attenuated vaccines to patients receiving Gamifant and for at least 4 weeks after the last dose of Gamifant. The safety of immunization with live vaccines during or following Gamifant therapy has not been studied.
Infusion-Related Reactions
Infusion-related reactions in patients with primary HLH, including drug eruption, pyrexia, rash, erythema, and hyperhidrosis, were reported with Gamifant treatment in 27% of patients. In one-third of these patients, the infusion-related reaction occurred during the first infusion.
Infusion-related reactions in patients with HLH/MAS in Still’s disease, including pyrexia, headache, paresthesia, bone pain, pruritic rash, and peripheral coldness, were reported with Gamifant treatment in 13% of patients. Infusion-related reactions were reported as mild in 8% of patients and as moderate in 5% of patients.
Monitor patients for infusion-related reactions, which can be severe. Interrupt the infusion for infusion reactions and institute appropriate medical management before continuing infusion at a slower rate.
Adverse Reactions
Primary HLH
Serious adverse reactions were reported in 53% of patients. The most common serious adverse reactions (≥3%) included infections, gastrointestinal hemorrhage, and multiple organ dysfunction. Fatal adverse reactions occurred in 2 (6%) of patients and included septic shock and gastrointestinal hemorrhage.
The most common adverse reactions were (≥10%) for Gamifant included infection (56%), hypertension (41%), infusion-related reactions (27%), pyrexia (24%), hypokalemia (15%), constipation (15%), rash (12%), abdominal pain (12%), CMV infection (12%), diarrhea (12%), lymphocytosis (12%), cough (12%), irritability (12%), tachycardia (12%), and tachypnea (12%).
HLH/MAS
Serious adverse reactions were reported in 12 patients (31%), with the most common serious adverse reaction being pneumonia (5%). Fatal adverse reactions occurred in two patients (5%) and included multiple organ dysfunction and circulatory shock.
The most common adverse reactions (≥10%) for Gamifant included viral infection (44%), rash (21%), anemia (18%), leukopenia (15%), thrombosis (15%), bacterial infections (13%), headache (13%), hyperglycemia (13%), infusion-related reactions (13%), abdominal pain (10%), hypertension (10%), pyrexia (10%), and thrombocytopenia (10%).
References
- Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood. 2011;118(15):4041-4052. doi:10.1182/blood-2011-03-278127
- Zhang K, Filipovich AH, Johnson J, et al. Hemophagocytic lymphohistiocytosis, familial. March 22, 2006. Updated September 30, 2021. Accessed July 29, 2024. https://www.ncbi.nlm.nih.gov/books/NBK1444/?report=classic
- Locatelli F, Jordan MB, Allen C, et al. Emapalumab in children with primary hemophagocytic lymphohistiocytosis. N Engl J Med. 2020;382(19):1811-1822. doi:10.1056/NEJMoa1911326
- Stone JH, McDowell PJ, Jayne DRW, et al. The glucocorticoid toxicity index: measuring change in glucocorticoid toxicity over time. Semin Arthritis Rheum. 2022;55:152010. doi:10.1016/j.semarthrit.2022.152010
- La Rosée P. Alleviating the storm: ruxolitinib in HLH. Blood. 2016;127(13):1626-1627. doi:10.1182/blood-2016-02-697151
- De Benedetti F, Prencipe G, Bracaglia C, Marasco E, Grom AA. Targeting interferon-γ in hyperinflammation: opportunities and challenges. Nat Rev Rheumatol. 2021;17(11):678-691. doi:10.1038/s41584-021-00694-z
- Verkamp B, Zoref-Lorenz A, Francisco B, et al. Early response markers predict survival after etoposide-based therapy of hemophagocytic lymphohistiocytosis. Blood Adv. 2023;7(23):7258-7269. doi:10.1182/bloodadvances.2023010546
- Sepulveda FE, de Saint Basile G. Hemophagocytic syndrome: primary forms and predisposing conditions. Curr Opin Immunol. 2017;49:20-26. doi:10.1016/j.coi.2017.08.004
- Gamifant (emapalumab-lszg) prescribing information. Stockholm, Sweden: Sobi, Inc. 2024.
Getting patients to transplant
For patients with primary hemophagocytic lymphohistiocytosis (HLH), a successful hematopoietic stem cell transplantation (HSCT) is the only cure. Before HSCT can be performed, prompt and effective treatment is necessary to calm hyperinflammatory symptoms.1,2
Primary HLH treatment has 3 main goals:
Stabilize the patient
Subdue hyperinflammation to prevent irreversible organ damage1
Minimize treatment toxicities
Reduce collateral damage of broad-spectrum medications3,4
Prepare for transplant
Condition the patient for HSCT, the only curative treatment for primary HLH1
The treatment landscape
Broadly acting first-line treatment options do not target interferon gamma (IFNγ), a key driver of hyperinflammation in primary HLH. Instead, these conventional therapies seek to control hyperinflammation through broad immune suppression.5,6
Monitoring response to conventional therapy7
At day 7 of treatment with the HLH-94 or HLH-2004 protocols, these 5 key prognostic biomarker tests were identified in a retrospective chart review. This review assessed survival to HSCT or ~1 year if no HSCT was pursued in 89 patients. Consider evaluating biomarker values through serial monitoring.
Study limitations: This was a retrospective chart review that was observational in nature and reflects data outside of a controlled clinical trial with prospective endpoints. Missing data were imputed in several instances. Fifty-seven patients transferred institutions after starting HLH-directed therapy. These data use descriptive statistics to summarize a data set and are not powered to detect between group differences in the outcomes. Causality cannot be established based on these data. Outcomes should be interpreted with caution alongside physician clinical judgment and other relevant lab assessments.
Important prognostic factors to consider within the first week of treatment7
| BIOMARKER | THRESHOLDS AT DAY 7 |
|---|---|
| sCD25/sIL-2Rα | <25% improvement from baseline |
| >17,000 U/mL | |
| Platelet count (PLT) | <25 x 109/L |
| Absolute lymphocyte count (ALC) | <0.35 x 109/L |
| Blood urea nitrogen (BUN) | ≥20 mg/dL |
- *Day 1 was defined as the first day of etoposide administration. Baseline (pretreatment) laboratory markers were defined as the peak pathologic value obtained within 7 days of treatment initiation.
- sCD25 testing is not available at all institutions and may take longer to receive results.
- sCD25=soluble cluster of differentiation 25; sIL-2Rα=soluble interleukin 2 receptor alpha.
Information on sCD25 prognostic utility7
- sCD25 levels and their improvement from baseline were identified as a predictor of pre-HSCT mortality
- The authors concluded that serial sCD25 monitoring should be considered
- Given the lack of rapid sCD25 availability, additional day 7 prognostic markers were assessed
This retrospective study found that7:
Each of the 5 markers were predictive of pre-HSCT mortality
The effect of multiple unfavorable prognostic indicators was additive
Patients with poor prognostic indicators at day 7 demonstrated increased pre-HSCT mortality risk
Early response assessment7
sCD25 improvement from baseline <25%†
sCD25 >17,000 U/mL
PLT <25 x 109/L
ALC <0.35 x 109/L
BUN ≥20 mg/dL
≥3 poor prognostic indicators?
Consider response adaptive therapy
- †sCD25 Improvement: (difference between baseline and day 7 value)/baseline value.
- ‡Analysis presents results from a multi-institutional, retrospective chart review of patients diagnosed with HLH, treated with etoposide-based therapy, and evaluated between 2010 and 2019 at Cincinnati Children’s Hospital Medical Center (CCHMC), Arkansas Children’s Hospital (ACH), or Schneider Children’s Medical Center of Israel (SCMCI).