TREATMENT PATTERNS AND OUTCOMES IN PATIENTS WITH MACROPHAGE ACTIVATION SYNDROME SECONDARY TO STILL'S DISEASE TREATED WITH EMAPALUMAB

Edward M. Behrens, MD

Joseph Lee Hollander Chair in Pediatric Rheumatology Chief, Division of Rheumatology The Children's Hospital of Philadelphia Perelman School of Medicine at The University of Pennsylvania

Background


• · Hemophagocytic lymphohistiocytosis (HLH) is a rare, frequently fatal, hyperinflammatory syndrome characterized by pathologic immune dysregulation that results in the overproduction of proinflammatory cytokines such as interferon gamma (IFN γ ) 1,2
• · Macrophage activation syndrome (MAS), a form of secondary HLH (sHLH), is a life-threatening complication of rheumatologic disease, typically systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD) 3,4
• · Emapalumab is a fully human anti-IFN γ monoclonal antibody that binds to and neutralizes the biological activity of IFN γ 5
• · Emapalumab is indicated in the United States (US) for the treatment of adults and children with primary HLH with refractory, recurrent, or progressive disease, or intolerance to conventional HLH therapy 6,7
REAL-HLH: Study Objectives and Design


• · The REAL-HLH study assessed clinical and demographic characteristics and real-world treatment patterns and outcomes in patients treated with emapalumab in the US
• · This presentation focuses on emapalumab treatment patterns and outcomes in patients with MAS secondary to Still's disease (sJIA/AOSD) treated in a real-world clinical setting

STUDY DESIGN

• · Retrospective chart review study conducted across 33 US hospitals to identify patients treated with ≥ 1 dose of emapalumab between November 20, 2018, and October 31, 2021

DATA EXTRACTION

• · Data were extracted from time of emapalumab initiation to end of data availability, death of patient, or end of study (December 31, 2021), whichever occurred first

STUDY OUTCOMES

• · Time to normalization of laboratory parameters
• · Proportion of transplant-eligible patients who received transplant
• · Changes in glucocorticoid dosing over time
• · Survival (overall and at 12 months from emapalumab initiation)
Demographics and Clinical Characteristics of Patients with Still's Disease (n = 10)


• · Ten of 105 (9.5%) study patients presented with Still's disease (sJIA = 9; AOSD = 1)
• · Most patients were female (8/10; 80%) and White (6/10; 60.0%)
• · Median (range) age at HLH diagnosis was 2.5 (1.0-22.0) years
• · The patient with AOSD was 22 years of age
Laboratory Parameter Values at Emapalumab Initiation


HLH-related Therapies Used Prior to or Concurrently with Emapalumab


• · Emapalumab was initiated mostly for treating refractory (4/10; 40%), recurrent (3/10; 30%), or progressive (2/10; 20%) disease
Emapalumab Treatment Duration and Dosing

Time to Initiation of Emapalumab and Duration of Treatment

Emapalumab Dosing


Change in Glucocorticoid Dose Over Time


Time to First Normalization of Laboratory Parameters from Emapalumab Initiation



Median time to first normalization of laboratory parameters ranged from 7 to 51 days


Time to Achieving Defined Laboratory Criteria from Emapalumab Initiation


• · Median time to achieving defined laboratory criteria ranged from 7 to 29.0 days
• · Median (range) number of laboratory parameters for which criteria were achieved was 5.0 (3-5)

Overall Survival from Emapalumab Initiation


• · Median (range) duration of follow-up from emapalumab initiation was 387.5 (29-900) days
• · Overall survival and 12-month survival probability from emapalumab initiation was 90% (9/10)
• · One patient died due to uncontrolled disseminated adenoviremia, unrelated to the clinical condition for which emapalumab was used (investigator determined)
Emapalumab Treatment as a Bridge to HSCT


Limitations


• · As with other retrospective chart review studies, data may not be uniformly available across all treatment centers; therefore, there is a risk of missing or incomplete information
• · Given that emapalumab is indicated as second-line treatment, there is a risk of bias towards patients with poor prognosis
• · Other limitations include an inability to comprehensively evaluate treatment response due to data gaps (limited availability and lack of uniformity in the timing of assessment of laboratory values, no visual analog scale etc.)
• · Safety-related data were not collected or evaluated
• · Given the limited sample size of the study, results may not be generalizable beyond the study patients
Conclusions


• · This is the first study to report real-world treatment patterns and outcomes among patients with MAS secondary to Still's disease who received treatment with emapalumab
• · Glucocorticoid dose reduced by approximately 32% from week 1 of emapalumab initiation to week 8
• · Overall survival and 12-month survival probability from emapalumab initiation was 90.0%
Phase II Open label trial of Emapalumab in MAS

• · 14 Patients enrolled
• · 6 mg/kg of Emapalumab given on day 0, followed by approx twice weekly 3 mg/kg for 28 days
• · Patients needed to have an inadequate response to steroids as determine by physicians to be enrolled.

De Benedetti F, Grom AA, Brogan PA, Bracaglia C, Pardeo M, Marucci G, Eleftheriou D, Papadopoulou C, Schulert GS, Quartier P, Antón J, Laveille C, Frederiksen R, Asnaghi V, Ballabio M, Jacqmin P, de Min C. Efficacy and safety of emapalumab in macrophage activation syndrome. Ann Rheum Dis. 2023 Jun;82(6):857-865. PMID: 37001971; PMCID: PMC10314091.


Emapalumab seems efficacious in MAS



Ferritin, platelets, liver enzymes, and LDH all improve in 1-2 weeks

IFNg biology shows rapid improvement on emapalumab


Conclusions


• · Emapalumab has significant real world use experience as well as clinical trial evidence for SJIA-MAS
• · Placebo controlled data, either as primary treatment or withdrawal, is lacking
• · The fundamental biology and the existing data support the notion that this therapy may be an important part of the armamentarium in refractory disease

REAL-HLH Study Group (Investigators)

Dr. Allyson Hays [CHILDREN'S MERCY HOSPITALS AND CLINICS]

Dr. Anand Tandra [FRANCISCAN HEALTH]

Dr. Anish Ray [COOK CHILDREN'S MEDICAL CENTER]

Dr. Arun Panigrahi

[UC DAVIS MEDICAL CENTER]

Dr. Ashley Hinson [CAROLINAS MEDICAL CENTER]

Dr. Ashley Baker

[UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER]

Dr. Blachy Davila Saldana [CHILDREN'S NATIONAL MEDICAL CENTER]

Dr. Brant Ward [CHILDREN'S HOSPITAL OF RICHMOND AT VCU]

Dr. Carl Allen [TEXAS CHILDREN'S HOSPITAL]

Drs. Deepika Bhatla & Lauren Draper [ST. LOUIS UNIVERSITY]

Dr. Diaz Gidvani [METHODIST CHILDREN'S HOSPITAL]

Dr. Edward Behrens [CHILDREN'S HOSPITAL OF PHILADELPHIA]

Dr. Hilary Haines [CHILDREN'S HOSPITAL OF ALABAMA]

Dr. Jennifer Rothman [DUKE UNIVERSITY MEDICAL CENTER]

Dr. Joanna Weinstein [ANN AND ROBERT H. LURIE CHILDREN'S HOSPITAL]

Dr. John Carter

[OREGON HEALTH AND SCIENCE UNIVERSITY]

Dr. May Chien [LUCILE PACKARD CHILDREN'S HOSPITAL AT STANFORD UNIVERSITY]

Dr. Michael Henry

[PHOENIX CHILDREN'S HOSPITAL]

Dr. Michael Isakoff [CONNECTICUT CHILDREN'S MEDICAL CENTER]

Dr. Michael Jordan [CINCINNATI CHILDREN'S HOSPITAL MEDICAL CENTER]

Dr. Michelle Hermiston

[UCSF MEDICAL CENTER]

Dr. Mona Riskalla [UNIVERSITY OF MINNESOTA MEDICAL CENTER]

Dr. Nicholas Gloude

[RADY CHILDREN'S HOSPITAL]

Dr. Prakesh Satwani [NEW YORK PRESBYTERIAN HOSPITAL]

Dr. Rabi Hanna [CLEVELAND CLINIC]

Dr. Renee Modica

[UF HEALTH SHANDS HOSPITAL]

Dr. Robert Cooper

[BELLFLOWER MEDICAL CENTER]

Dr. Sachit Patel [UNIVERSITY OF NEBRASKA MEDICAL CENTER]

Dr. Shanmuganathan Chandrakasan [CHILDREN'S HEALTHCARE OF ATLANTA]

Dr. Sima Bhatt [WASHINGTON UNIVERSITY]

Dr. Stefanos Intzes [PROVIDENCE SACRED HEART MEDICAL CENTER & CHILDREN'S HOSPITAL]

Dr. Susmita Sarangi [GEORGETOWN UNIVERSITY HOSPITAL-MEDSTAR]

Dr. Taizo Nakano [CHILDREN'S HOSPITAL COLORADO]



Appendix



Laboratory Parameter Values at Time Closest to Emapalumab Initiation: Still's disease (n = 10)