Eculizumab and Other Therapies for the Treatment of High-Risk Transplant-Associated Thrombotic Microangiopathy

Introduction

Man in a hospital bed | Image credit: Gorodenkoff | stock.adobe.com

Hematopoietic stem cell transplantation (HSCT)-associated thrombotic microangiopathy (TA-TMA) is a well-known complication of HSCT that is associated with high rates of mortality and morbidity.¹ The pathophysiology of TA-TMA is complex but can best be characterized by several factors including endothelial cell activation, complement dysregulation, thrombocytopenia, and microvascular hemolytic anemia.^2-4

Most cases of TA-TMA are clinically characterized by the TA-TMA triad: hypertension (>99% for age, sex, and height) generally requiring more than 2 antihypertensive agents, de novo thrombocytopenia refractory to platelet transfusions, and elevated lactate dehydrogenase (LDH). Some other findings include proteinuria, elevated D-dimers, and falling haptoglobin. Once TMA is suspected, individual patients can be further stratified based on their risk for poor prognosis, which can help guide treatment decisions.^5,6 The diagnostic and risk stratification criteria can be found in Table 1.⁷

Eculizumab

Eculizumab (Soliris; Alexion), a C5 inhibitor preventing cleavage into C5a and C5b, is widely considered the first-line therapy for high-risk TA-TMA. In one prospective study evaluating the use of eculizumab therapy for high-risk TA-TMA, it significantly improved survival and recovery of organ function at 6 months post-treatment as compared with untreated historical controls.⁸ A primary prognostic marker is the evidence of circulating soluble terminal complement activation (elevated sC5b-9) at the time of TMA diagnosis. A large cohort study of pediatric patients with diagnosed TA-TMA shows that those with a higher sC5b-9 (defined as elevated sC5b-9 ≥244 ng/mL) at the initiation of therapy of eculizumab are less likely to respond and will subsequently require more doses.⁹ Individualized dosing may also be required for patients with significant bleeding to optimize outcomes.¹⁰

Another important point to note with eculizumab therapy is that all participants should be started on antimicrobial prophylaxis to cover N. meningitidis, because vaccination is known to be infective during the early transplantation phase. This should be continued until eculizumab clearance (serum drug concentration <11 µg/mL) and CH50 recovery to normal levels have been documented.⁸ For the same reason, patients and providers must be registered with the Soliris Risk Evaluation and Mitigation Strategies program before the patient can receive infusions of eculizumab.

Other Therapies

Therapeutic plasma exchange (TPE) has been used for TA-TMA, although it has since fallen out of favor due to low response rates of less than 50%, mortality rates remaining above 80%, and risks for significant complications.^1,11,12 If TPE is used concurrently with eculizumab, supplemental doses of eculizumab should be administered per package labeling.¹³

Another agent that has shown promise as prophylaxis is defibrotide (Defitelio; Jazz Pharmaceuticals). Defibrotide is an antiplatelet agent that reduces endothelial cell activation and increases endothelial cell-mediated fibrinolysis. One small study of 25 individuals shows that, when used for pediatric patients undergoing HSCT who are at high risk for TA-TMA, defibrotide reduces the incidence of TA-TMA from 18% to 40% without prophylaxis to 4% with prophylaxis. Further research to validate this small study is warranted.¹⁴

Conclusions

Eculizumab is the recommended first-line treatment for high-risk TA-TMA as a complication of HSCT. This is supported by a recent prospective study in which eculizumab drastically improved survival over a historical cohort not receiving it.⁸

References

1. Jodele S, Dandoy CE, Myers KC, et al. New approaches in the diagnosis, pathophysiology, and treatment of pediatric hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Transfus Apher Sci. 2016;54(2):181-190. doi:10.1016/j.transci.2016.04.007

2. Elemary M, Sabry W, Seghatchian J, Goubran H. Transplant-associated thrombotic microangiopathy: Diagnostic challenges and management strategies. Transfus Apher Sci. 2019;58(3):347-350. doi:10.1016/j.transci.2019.04.022

3. Lazana I. Transplant-associated thrombotic microangiopathy in the context of allogenic hematopoietic stem cell transplantation: where we stand. Int J Mol Sci. 2023;24(2):1159. doi:10.3390/ijms24021159

4. Young JA, Pallas CR, Knovich MA. Transplant-associated thrombotic microangiopathy: theoretical considerations and a practical approach to an unrefined diagnosis. Bone Marrow Transplant. 2021;56(8):1805-1817. doi:10.1038/s41409-021-01283-0

5. Dvorak CC, Higham C, Shimano KA. Transplant-Associated Thrombotic Microangiopathy in Pediatric Hematopoietic Cell Transplant Recipients: A Practical Approach to Diagnosis and Management. Front Pediatr. 2019;7:133. doi:10.3389/fped.2019.00133

6. Jodele S, Davies SM, Lane A, et al. Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults. Blood. 2014;124(4):645-653. doi:10.1182/blood-2014-03-564997

7. Schoettler ML, Carreras E, Cho B, et al. Harmonizing Definitions for Diagnostic Criteria and Prognostic Assessment of Transplantation-Associated Thrombotic Microangiopathy: A Report on Behalf of the European Society for Blood and Marrow Transplantation, American Society for Transplantation and Cellular Therapy, Asia-Pacific Blood and Marrow Transplantation Group, and Center for International Blood and Marrow Transplant Research. Transplant Cell Ther. 2023;29(3):151-163. doi:10.1016/j.jtct.2022.11.015

8. Jodele S, Dandoy CE, Aguayo-Hiraldo P, et al. A prospective multi-institutional study of eculizumab to treat high-risk stem cell transplantation-associated TMA. Blood. 2024;143(12):1112-1123. doi:10.1182/blood.2023022526

9. Jodele S, Dandoy CE, Lane A, et al. Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab. Blood. 2020;135(13):1049-1057. doi:10.1182/blood.2019004218

10. Mizuno K, Dandoy CE, Teusink-Cross A, Davies SM, Vinks AA, Jodele S. Eculizumab precision-dosing algorithm for thrombotic microangiopathy in children and young adults undergoing HSCT. Blood Adv. 2022;6(5):1454-1463. doi:10.1182/bloodadvances.2021006523

11. Ho VT, Cutler C, Carter S, et al. Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2005;11(8):571-575. doi:10.1016/j.bbmt.2005.06.001

12. Rizvi MA, Vesely SK, George JN, et al. Complications of plasma exchange in 71 consecutive patients treated for clinically suspected thrombotic thrombocytopenic purpura-hemolytic-uremic syndrome. Transfusion. 2000;40(8):896-901. doi:10.1046/j.1537-2995.2000.40080896.x

13. Alexion Pharmaceuticals, Inc. Soliris (eculizumab) [package insert]. FDA. Updated June 2019. Accessed July 3, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125166s431lbl.pdf

14. Higham CS, Shimano KA, Melton A, et al. A pilot trial of prophylactic defibrotide to prevent serious thrombotic microangiopathy in high-risk pediatric patients. Pediatr Blood Cancer. 2022;69(5):e29641. doi:10.1002/pbc.29641