Pegcetacoplan for patients with transplant-associated thrombotic microangiopathy treatment: A real-world report of six cases

Abstract Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe, life-threatening complication of hematopoietic stem cell transplantation (HSCT) driven by complement-mediated endothelial injury. While complement (C)5 inhibitors like eculizumab are used, responses are variable, and mortality remains high. Pegcetacoplan, a C3 inhibitor, offers a novel approach by targeting a more proximal and central step in the complement cascade. We present the first real-world case series on the off-label use of pegcetacoplan for pediatric TA-TMA. Methods: This retrospective case series describes six pediatric patients (median age 11 years; range 4–13) diagnosed with TA-TMA following allogeneic HSCT at NBK Children's Hospital, Kuwait. Data on patient demographics, transplant characteristics, clinical and laboratory features at TA-TMA diagnosis, prior therapies, pegcetacoplan treatment regimens, and clinical outcomes were extracted from electronic health records. Diagnosis was established using modified Jodele criteria, and clinical response was defined by the normalization or improvement of hematologic parameters (platelet count, LDH, schistocytes) and renal function (serum creatinine, proteinuria). Results: The cohort included patients transplanted for acute lymphoblastic leukemia (n=2), β-thalassemia (n=2), sickle cell disease (n=1), and severe combined immunodeficiency (n=1). The median time to neutrophil engraftment was 19.5 days (range: 14-24), and the median time to platelet engraftment was 26 days (range: 18-90). TA-TMA was diagnosed at a median of 103 days post-HSCT (range: 21–881), with presentations including renal impairment (n=5), new-onset hypertension (n=4), and neurological symptoms (n=3). Significant complicating factors included concurrent graft versus host disease (GVHD), veno-occlusive disease (VOD), and viral infections. This cohort included one patient refractory to plasma exchange and another who had failed both eculizumab and ravulizumab. Pegcetacoplan was administered subcutaneously twice weekly. Five of six patients (83%) achieved a rapid and complete resolution of TA-TMA features, with normalization of laboratory markers within two weeks of initiation. One patient with severe, established multi-organ dysfunction at the time of treatment initiation had a partial response but remained dialysis-dependent due to chronic kidney injury. Pegcetacoplan was well-tolerated in all patients, with no treatment-emergent adverse events reported, even when co-administered with complex immunosuppressive and antimicrobial regimens. Conclusion: This case series provides the first real-world evidence suggesting that proximal C3 inhibition with pegcetacoplan may be an effective and safe therapeutic option for pediatric TA-TMA. Treatment was associated with rapid and complete remissions, including in patients refractory to C5 inhibitors and other conventional therapies. These encouraging findings support the investigation of pegcetacoplan in prospective clinical trials to formally establish its role in the management of this severe HSCT complication.