Organ dysfunction in pediatric patients with HSCT-TMA treated with ravulizumab

Abstract Background: Hematopoietic stem cell transplantation–associated thrombotic microangiopathy (HSCT-TMA) is a life-threating complication of HSCT. Severe HSCT-TMA results in organ dysfunction and death in >50% of children. Currently, there are no approved treatments for HSCT-TMA. Ravulizumab (rav) is a long-acting C5 inhibitor currently under investigation for treatment of adult and pediatric patients with HSCT-TMA. In a phase 3, open-label, single-arm trial (NCT04557735) evaluating rav in children with HSCT-TMA, rav resulted in clinically meaningful overall survival of 87.2% (95% CI, 71.8-94.5) at 6 months post-HSCT-TMA diagnosis. Objective:To describe protocol-defined organ dysfunction, including the renal, cardiopulmonary, central nervous, and gastrointestinal (GI) systems, at baseline and 6 months in children with HSCT-TMA treated with rav during the phase 3 trial. Methods: Eligible participants were ≥28 days to <18 years of age, weighed ≥5 kg, received an HSCT 12 months before screening, and had HSCT-TMA that persisted for ≥72 hours despite initial management. TMA was diagnosed with 4 inclusion criteria: 1) de novo thrombocytopenia or transfusion refractoriness; 2) lactate dehydrogenase above the upper limit of normal for age or presence of schistocytes; 3) proteinuria ≥1 mg/mg; and 4) de novo anemia or hypertension. Participants received weight-based rav loading doses on day (D) 1, D5, and D10 followed by maintenance doses starting on D15 every 4 weeks (weight <20 kg) or every 8 weeks (weight ≥20 kg) up to 6 months (26 weeks). Protocol-specified clinical change in 4 categories (cardiopulmonary, central nervous, GI, and renal) was recorded at baseline and 26 weeks after enrollment. Cardiopulmonary involvement included hypertension, pulmonary hypertension, pulmonary edema, serositis conditions related to the heart and lung (pericardial and pleural effusion), or ventilatory or respiratory support. GI dysfunction included GI bleeding and GI pain. Central nervous system (CNS) dysfunction included posterior reversible encephalopathy syndrome, headache, confusion, visual loss, and seizures. Renal dysfunction included change in urine protein-creatinine ratio (UPCR) and estimated glomerular filtration rate (eGFR) based on creatinine.Results: 41 participants were enrolled in the study. Participants had a median (range) age of 6.0 (<1 to 17) years and were predominantly White (53.7%) and female (51.2%). Median (range) time of TMA occurrence after HSCT was 57 (3-240) days, and time to start treatment after TMA diagnosis was 6.0 (0-27) days. Cardiopulmonary involvement at TMA diagnosis was reported in 70.7% (29/41) of participants at baseline (including hypertension [n=22], pericardial effusion [n=9], and pleural effusion [n=7]). At week 26, 36.7% (11/30) had cardiopulmonary involvement (including hypertension [n=6], pericardial effusion [n=2], and pleural effusion [n=2]). GI pain was observed in 19.5% (8/41) of participants at baseline and 6.7% (2/30) at week 26. GI bleeding was observed in 4.9% (2/41) at baseline and 3.3% (1/30) at week 26. CNS dysfunction was reported in 7.3% (3/41) of participants at baseline and 10.0% (3/30; headache: n=2, visual loss: n=1) at week 26. Participants presented with significantly elevated median (range) UPCR at 2.50 (0.24-29.87) mg/mg at baseline (n=41) that decreased to 0.43 (0.09-5.26) mg/mg by week 26 (n=21); median (range) change from baseline (∆BL) was −2.54 (−24.61 to 0.04) mg/mg (n=21). Median (range) eGFR was 114 (17-304) mL/min/1.73 m2 at baseline (n=36) and 102 (10-197) mL/min/1.73 m2 at week 26 (n=26); median (range) ∆BL was 3.4 (−126 to 100) mL/min/1.73 m2 (n=23). Of 41 participants, 13 discontinued study treatment (adverse event, n=7 [3 events in 2 participants were related to study treatment]; physician decision, n=4; death, n=1; other, n=1).