Use of eculizumab in children with allogeneic haematopoietic stem cell transplantation associated thrombotic microangiopathy - a multicentre retrospective PDWP and IEWP EBMT study

Švec, Peter; Elfeky, Reem; Galimard, Jacques‐Emmanuel; Higham, Christine S.; Dalissier, Arnaud; Quigg, Troy C.; Sánchez, D.; Lum, Su Han; Faraci, Maura; Cole, Theresa; Pichler, Herbert; Benítez‐Carabante, María Isabel; Horáková, Júlia; González-Vicent, Marta; Yanir, Asaf; Wölfl, Matthias; Weid, Nicolas von der; Protheroe, Rachel; Kriván, Gergely; Speckmann, Carsten; James, Beki; Avčin, Simona Lucija; Bertrand, Yves; Verna, Marta; Riha, Petr; Patrick, Katharine; Cesaro, Simone; Kałwak, Krzysztof; Bierings, Marc; Buechner, Jochen; Mellgren, Karin; Prohászka, Zoltán; Neven, Bénédicte; Lankester, Arjan C.; Corbacioglu, Selim

doi:10.1038/s41409-022-01852-x

Cited by 8 publications

(2 citation statements)

References 41 publications

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“…Response rates to eculizumab in this study (35%) are more in line with other reports with similar populations, 2,30 and are in contrast to another large prospective pediatric study reporting response rates of 64%. 11 Notably, the two cohorts are disparate in disease indication, race, and preparative regimen.…”

Section: Discussionsupporting

confidence: 91%

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

Schoettler,

French,

Harris

et al. 2024

American J Hematol

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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.

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Section: Discussionsupporting

confidence: 91%

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

Schoettler,

French,

Harris

et al. 2024

American J Hematol

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“… 1 , 6 Although there are no FDA-approved therapies for TA-TMA, eculizumab, a monoclonal antibody to complement C5, has resulted in improved overall survival (OS) in some studies, 7 , 8 although not all. 1 , 9 , 23 …”

Section: Introductionmentioning

confidence: 99%

Pediatric transplant–associated thrombotic microangiopathy health care utilization and implications of eculizumab therapy

Schoettler,

Lehmann,

Kao

et al. 2024

Blood Advances

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The healthcare utilization (HCU) burden of transplant associated thrombotic microangiopathy (TA-TMA) and its treatments are unknown. The objective of this study was to investigate inpatient costs associated with meeting criteria for transplant associated thrombotic microangiopathy (TA-TMA) in the first-year post-HCT. This IRB-approved retrospective multicenter study included serial children who underwent HCT from 1/1/2015 to 7/1/2019. A standardized unit cost (adjusted for geographic location, differences in cost of living, and inflation) for inpatient hospitalization was extracted from the Pediatric Health Information System data and linked to clinical data. Both total cost and cost-per-day from 15 days before stem cell infusion to 1-year post-HCT were calculated. Among children with neuroblastoma who underwent autologous HCT (n=60), 17 (28%) developed TA-TMA; there were no apparent differences in costs for TA-TMA versus no TA-TMA. Among allogeneic (allo) recipients, after adjusting for severe grade III/IV acute graft versus host disease (GVHD), infections, and HLA mismatch, costs were not different in TA-TMA (n=137) vs. no TA-TMA (n=238). Among allo HR-TMA-TMA, unadjusted costs were significantly higher in the eculizumab treated cohort (n=19, median $1,419,823, range $286,175 to $7,217,095) than supportive care (n=36, median $672,578 range $156,379 to $3,911,402, p=0.001). However, after adjusting for GI bleeding which occurred disproportionately in the eculizumab (n=6) versus supportive care (n=0) cohort, eculizumab treatment was not associated with increased total costs. More studies are needed to determine the etiology of increased HCU costs in those with HR-TA-TMA and to predict those more likely to benefit from eculizumab, reducing HCU and improving outcomes.

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Compassionate Use Narsoplimab for Severe Refractory Transplantation-Associated Thrombotic Microangiopathy in Children

Schoettler,

Patel,

Bryson

et al. 2024

Transplantation and Cellular Therapy

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Use of eculizumab in children with allogeneic haematopoietic stem cell transplantation associated thrombotic microangiopathy - a multicentre retrospective PDWP and IEWP EBMT study

Cited by 8 publications

References 41 publications

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

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

Pediatric transplant–associated thrombotic microangiopathy health care utilization and implications of eculizumab therapy

Compassionate Use Narsoplimab for Severe Refractory Transplantation-Associated Thrombotic Microangiopathy in Children

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