Outcomes in pediatric patients with HSCT-TMA treated with ravulizumab

Background: Hematopoietic stem cell transplantation–associated thrombotic microangiopathy (HSCT-TMA) is a rare, life-threatening complication that can result in multiorgan failure and death. Historically, severe HSCT-TMA has a 6-month survival rate as low as 18% in pediatric populations. Terminal complement activation is a key driver of disease. There are no approved therapies for HSCT-TMA.Ravulizumab (rav), a monoclonal antibody against C5, is being evaluated as a treatment for HSCT-TMA in adult and pediatric populations. Objective: To evaluate protocol-defined complete and partial TMA responses, hematologic response, survival, and nonrelapse mortality (NRM) after treatment with rav in children with HSCT-TMA. Methods: A phase 3, open-label, single-arm trial (NCT04557735) of rav was conducted in children aged ≥28 days to <18 years who: 1) received HSCT within 12 months; 2) had HSCT-TMA persisting ≥72 hours despite initial management; and 3) weighed ≥5 kg. The study aimed to enroll patients presenting with early HSCT-TMA, which was diagnosed with 4 inclusion criteria: 1) de novo thrombocytopenia or transfusion refractoriness; 2) lactate dehydrogenase (LDH) 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 loading doses on days 1, 5, and 10, and maintenance doses every 4 weeks (weight <20 kg) or 8 weeks (weight ≥20 kg) from day 15 through week 26. The primary endpoint was complete TMA (cTMA) response during the 26-week treatment period. Protocol-defined cTMA response criteria were platelet count >50,000/mm3(baseline platelets ≤50,000/mm3) or ≥50% increase in platelet count (baseline platelets >50,000/mm3) without platelet transfusion support in the previous 7 days, normalization of LDH with absence of schistocytes (≤1% or “none”), and ≥50% reduction in urine protein/creatinine ratio from baseline. Each response criterion must have been met at 2 separate assessments ≥24 hours apart and any measurement in between. Protocol-defined partial TMA response was meeting ≥1 but not all of the cTMA response criteria. Secondary endpoints included hematologic response (criteria included platelet count and LDH), overall survival (OS), and NRM. Results: Of 41 participants enrolled and treated, 28 (68.3%) completed the 26-week treatment period, and 13 discontinued study treatment. The median (range) age of participants was 6.0 (<1 to 17) years, and approximately half were female (51.2%) and White (53.7%). The most frequent transplant indication for HSCT was malignancy in 27 (65.9%) participants; 38 (92.7%) participants received allogeneic HSCT. By week 26, cTMA response was observed in 7 (17.1%) participants. Hematologic response occurred in 10 (24.4%) participants. As individual components of hematologic response, 24 (58.5%) and 15 (36.6%) participants met the platelet (including transfusion independence) and LDH response criteria, respectively. Hemoglobin response of ≥10 g/dL, including absence of red blood cell transfusions, was observed in 17 (41.5%) participants. The presence or absence of schistocytes varied throughout the study with no clear trends. Protocol-defined complete or partial TMA response occurred in 29 of 41 participants (70.7%) meeting ≥1 criterion. The Kaplan-Meier estimate of OS was 92.6% (95% CI, 78.8-97.6) at 100 days and 87.2% (95% CI, 71.8-94.5) at 26 weeks. All deaths during the treatment period were due to NRM (n=5); causes of death were multiorgan failure (n=2), hypoxic respiratory failure (n=1), heart failure (n=1), and septic shock (n=1). Conclusions: In this single-arm study, children diagnosed with HSCT-TMA and treated with rav for 26 weeks were observed to have complete and partial TMA responses alongside a clinically meaningful OS of 87.2%. Further posthoc analyses will be performed in subgroups of participants.