Pediatric Late-Onset Acute and Chronic Graft-Versus-Host Disease: A Single Center Cohort Study 2007-2017

Abstract

<h3>Objectives</h3> Late acute graft-versus-host-disease (GVHD) in children is not well described. The 2014 NIH Chronic GVHD Consensus Criteria have not been studied in pediatric populations. We examined the incidence, organ involvement, severity by 2014 NIH criteria, and outcomes of late acute GVHD (L-aGVHD), overlap cGVHD, (O-cGVHD) and classic-chronic GVHD (C-cGVHD) in children. <h3>Methods</h3> We retrospectively reviewed 573 children, median age 7 (range 0.1-17.9) years who underwent first allogeneic hematopoietic cell transplant (HCT) at the University of Minnesota (2007-2017). 377 (66%) had a non-malignant disease. Graft sources included bone marrow (47%), peripheral blood (2%) and cord blood (51%). The majority (76%) received myeloablative regimens. GVHD prophylaxis was calcineurin-based (93%), sirolimus-based (2%) or ex vivo T-cell depletion (5%). <h3>Results</h3> While 79 patients (14%; 95%CI: 11–17) developed early onset (ie, ≤ day +100 after HCT) acute GVHD by 3 years, 9 patients had developed L-aGVHD (> day +100; cumulative incidence 2%, 95%CI: 1–3), 16 patients developed O-cGVHD (3%; 95%CI: 1–4) and 6 patients C-cGVHD (1%; 95%CI: 0–2) (Figure 1). Patients with prior grade II–IV early onset acute GVHD had a higher incidence of O-cGVHD or C-cGVHD (8% vs. 3%, p=0.02). No other patients or graft characteristics were associated with the 32 patients with L-aGVHD, O-cGVHD, or C-cGVHD. Skin was the most common involved organ at GVHD diagnosis across all the GVHD subtypes (Figure 2). No cases with joint or genitourinary chronic GVHD were reported. 6 patients had mild, 4 moderate and 13 severe chronic GVHD. 24/32 patients with L-aGVHD, O-cGVHD, or C-cGVHD received systemic therapy as initial treatment. Systemic therapies included steroids alone (17%, 4/24), steroids and sirolimus (8%, 2/24), steroids and cyclosporine (58%, 14/24), and CSA alone (17%, 4/24). At 6 months, CR/PR was achieved in 78% L-aGVHD patients, 44% O-cGVHD patients, and 43% C-cGVHD patients. 2 year CR/PR was achieved in 89% L-aGVHD patients, 63% O-cGVHD patients, and 71% C-cGVHD patients. The 1-year non-relapse mortality (NRM) was 11% (95%CI: 0–30) for L-aGVHD, 13% (95%CI: 0–29) for O-cGVHD, and 14% (95%CI: 1–28) for C-cGVHD as compared to 34% (95%CI: 23–47) for early onset acute GVHD. Patients with L-aGVHD, O-cGVHD and/or C-cGVHD had higher 2-year NRM than those without (Hazard Ratio: 2.8, 95%CI: 1.0–7.9, p=0.049). <h3>Conclusion</h3> Patients with L-aGVHD, O-cGVHD, and/or C-cGVHD had a higher likelihood of poor NRM. These data suggest that pediatric patients with L-aGVHD may respond better to treatment than those with O-cGVHD or C-cGVHD. Future research should further investigate the risks and nature of L-aGVHD, O-cGVHD and C-cGVHD to better understand how to prevent and treat GVHD in children.