D‐dimer and sinusoidal obstructive syndrome‐novel poor prognostic features of thrombotic microangiopathy in children after hematopoietic cellular therapy in a single institution prospective cohort study

Abstract Transplant‐associated thrombotic microangiopathy (TA‐TMA) is a common, severe complication of allogeneic hematopoietic cellular therapy (HCT). Even when treated in many studies, morbidity and mortality rates are high. This prospective single‐institution cohort study serially enrolled all allogeneic HCT recipients from August 2019–August 2022. Patients were universally screened for TA‐TMA and intermediate and high‐risk patients were immediately treated with eculizumab. Sub‐distribution cox‐proportional hazards models were used to identify sub‐distribution hazard ratios (sHR) for multi‐organ dysfunction (MOD) and non‐relapse‐related mortality (NRM). Of 136 patients, 36 (26%) were diagnosed with TA‐TMA and 21/36 (58%) developed MOD, significantly more than those without TA‐TMA, ( p < .0001). Of those with TA‐TMA, 18 (50%) had high‐risk TA‐TMA (HR‐TA‐TMA), 11 (31%) had intermediate‐risk TA‐TMA (IR‐TA‐TMA), and 8 (22%) had standard risk (SR‐TA‐TMA). Twenty‐six were treated with eculizumab (1/8 SR, 7/11 IR, and 18/18 HR). Elevated D‐dimer predicted the development of MOD (sHR 7.6, 95% confidence interval [CI] 1.8–32.3). Children with concurrent sinusoidal obstructive syndrome (SOS) and TA‐TMA had an excess risk of MOD of 34% and data supported a biologic interaction. The adjusted NRM risk was significantly higher in the TA‐TMA patients (sHR 10.54, 95% CI 3.8–29.2, p < .0001), despite prompt treatment with eculizumab. Significant RF for NRM in TA‐TMA patients included SOS (HR 2.89, 95% 1.07–7.80) and elevated D‐dimer (HR 3.82, 95% CI 1.14–12.84). An unrelated donor source and random urine protein to creatine ratio ≥2 mg/mg were significantly associated with no response to eculizumab (odds ratio 15, 95% CI 2.0–113.6 and OR 6.5, 95% CI 1.1–38.6 respectively). TA‐TMA was independently associated with NRM despite early diagnosis and treatment with eculizumab in this large pediatric transplant cohort. Prognostic implications of D‐dimer in TA‐TMA merit further investigation as this is a readily accessible biomarker. Concurrent SOS is an exclusion criterion of many ongoing clinical trials, but these data highlight these patients could benefit from novel therapeutic approaches. Multi‐institutional clinical trials are needed to understand the impact of TA‐TMA‐targeted therapies.