Transplant Related Outcomes in Patients with Hemophagocytic Lymphohistiocytosis Treated with Emapalumab As a Bridge to Hematopoietic Stem Cell Transplantation: The Real-HLH Study

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hyperinflammatory syndrome characterized by overactivation of proinflammatory cytokines, predominately interferon gamma (IFNγ). Current treatment is aimed at achieving clinical stability and symptom resolution, ahead of Hematopoietic Stem Cell Transplantation (HSCT), the only definitive cure especially for patients (pts) with primary HLH (pHLH). In non-refractory forms of secondary HLH, the disease gets resolved when the underlying triggering event is adequately managed. Emapalumab, an anti-IFNγ monoclonal antibody, approved by the FDA for pts with pHLH with refractory, recurrent, or progressive disease or intolerance to conventional therapy, has been used to successfully bridge pts to transplant. The REAL-HLH study assessed clinical and demographic characteristics, real-world treatment patterns and outcomes in pts with HLH treated with emapalumab.

Methods: A retrospective medical chart review across 33 US hospitals identified pts treated with ≥1 dose of emapalumab between November 20, 2018, and October 31, 2021. Pt data was extracted from time of emapalumab initiation to end of data availability, death, or study end (December 31, 2021). Data from the subset of pts with HLH who received their 1^st transplant following emapalumab treatment are presented.

Results: Overall, 35/98 (35.7%) pts treated for HLH in the study cohort received their 1^st transplant following emapalumab treatment. The majority met the pHLH classification criteria at diagnosis** (29/35^‡; 82.9%), were male (22/35; 62.9%), and non-white (18/35; 51.4%). Median (Interquartile range [IQR]) age at HSCT was 2 (1,11) years. Median (IQR) duration of conditioning was 10 (7,12) days with melphalan/reduced intensity-based regimens (17/35; 48.6%) being the most common conditioning regimen. Emapalumab was administered during conditioning in 10/35 (35%) and post-conditioning in 8/35 (22.9%). Median (range) cumulative treatment dose of emapalumab during conditioning was 22.5 (75-170) mg/kg. Most pts received bone marrow product (24/35; 68.6%) and were matched with an unrelated donor (23/35; 65.7%). Overall, 30/35 (85.7%) pts had available data for evaluation of engraftment^¶, of these, 24/30 (80%) achieved engraftment without graft failure^†, need for a 2^nd transplant or stem cell boost. Median (IQR) time to engraftment was 16.1 (9, 29) days. Mixed chimerism occurred in 13/35 (37.1%) pts and 3/13 (23.1%) of pts had ≤25% (i.e. lowest level) of donor chimerism by day 100. Graft-versus-host (GVHD) occurred in 19/35 (54.3%) of pts (Acute [n=13; 5/13 had Grade 3 or 4] and chronic [n=6]). Median (IQR) duration of follow-up from transplant was 342 (169, 498) days. Overall survival rate was 74.3% (26/35; pHLH=22/29 (75.9%)), 12-month survival probability from transplant was 73.4% (pHLH=75.1%), and intervention free survival^†† was 60% (21/35; pHLH= 17/29 (58.6%)).

Conclusion: This study reported transplant-related outcomes in the real-world among pts with HLH who received their 1^st transplant following emapalumab treatment. Overall, 85.7% of pts with evaluable data achieved engraftment and 74.3% of pts survived.

**Patients (pts) were classified as presenting with pHLH if they lacked evidence of underlying malignancy, rheumatologic, or metabolic disease and met at least 1 of 3 criteria: (a) Presence of a known genetic mutation associated with pHLH (a biallelic mutation for PRF1, UNC13D, STX11, STXBP2, RAB27A, LYST, or AP3B1, or a monoallelic mutation for SH2D1A or XIAP); (b) met ≥5 of 8 HLH-2004 diagnostic criteria; and (c) had family history of HLH.

^‡6 pts were classified as presenting with secondary HLH. Of these, 2 pts had no identifiable underlying disease; 2 pts had underlying rheumatologic disease (sJIA/MAS (n=1) and diffuse myositis (n=1)); 1 pt had underlying malignancy disease (EBV/NK T Cell lymphoma); and 1 pt had Heme oxygenase 1 deficiency with episodes of chronic MAS.

^¶Donor engraftment defined as three consecutive days with ANC > 500/mcl (sustained >20 x 10⁹/L platelets and hemoglobin >80g/L, free of transfusion requirements)

^†Primary graft failure defined as no evidence of hematologic recovery within 6 weeks of HSCT (ANC <500/ mcl, Hb <80 g/L and PLT <20 ×10⁹ /L)

^††Defined as survival without experiencing primary graft failure, receiving a second transplant or cellular product