Genetic Predispositions, Management Strategies, and Clinical Outcomes in Adults with Hemophagocytic Lymphohistiocytosis (HLH) after Reduced-Intensity Conditioning (RIC) Hematopoietic Stem Cell Transplantation (HSCT) at Dana-Farber Cancer Institute

Abstract

Introduction HLH has historically been considered a pediatric disease. There are limited prospective data for adults with HLH, particularly on management during and outcomes after allogeneic HSCT. Following the CTN1204 study of HSCT in pediatric HLH, this retrospective analysis sets a benchmark for adult-onset HLH. Subjects We identified 20 patients, median 45yo (21-72), who underwent RIC HSCT for HLH since 2010. 5 (25%) had a malignancy, 3 (15%) a rheumatologic diagnosis, and 3 (15%) a viral precipitant. Of 17 patients tested, 65% had ≥1 variant in HLH-associated or immunologically-relevant genes. (Table) Initial therapy was largely etoposide/dexamethasone (n=16) or malignancy-directed chemotherapy (n=5), with multiple agents, including alemtuzumab, as salvage/bridging therapy. (Figure 1) 17 patients received alemtuzumab as “pre-conditioning” for HSCT, intentionally stopped median 25 days (19-32) prior to cell infusion. Conditioning was fludarabine/busulfan (n=17) in 7 related and 11 unrelated HSCTs or fludarabine/cyclophosphamide/TBI in 2 haploidentical HSCTs. 50% received PBSCs. HSCT occurred median 8 mos after HLH diagnosis (3-13). Results All patients engrafted neutrophils (median 15.5 days) and platelets (median 19.5 days). Donor leukocyte and T-cell chimerisms were variable (30day 43-100%, 5-100%; 1 yr 67-100%, 40-100%). 2 patients received CD34-selected infusions for cytopenias with full donor chimerism; 2 had DLIs for T-cell chimerism ≤20% to augment sustained remission. There was no correlation between alemtuzumab timing and chimerism. With follow-up of 22 months (3-61), 6mo Grade II-IV acute GvHD was 17%, and 12mo cGvHD was 35%. 2 patients relapsed with DLBCL at 3-4 mos; 1 with concurrent HLH. There were no isolated HLH relapses. Before HSCT, patients experienced 7 viral, 8 bacterial, and 5 fungal infections, plus 3 surgeries. In the year following HSCT, 3 patients had CMV, 1 adenoviral, 1 fungal, and 7 bacterial infections. 3 patients required steroids for hyperinflammatory pulmonary syndromes. 18mo OS was 83% (95% CI, 56-94) which compares favorably with 80% OS on CTN1204 and 57-60% on prior CIBMTR query of HSCT in adults with histiocytic diseases. (Figure 2) (Nikiforow. Tandem Mtg 2014). Conclusions Variants in genes associated with familial HLH and other syndromes of immune dysregulation (e.g., Chediak Higashi, Familial Mediterranean Fever) reflect a significant and under-appreciated predisposition to adult-onset HLH. Infectious complications and need for 2nd cell therapies occur, but overall, RIC HSCT preceded by alemtuzumab therapy is a highly feasible approach in adults.