Is complement blockade an acceptable therapeutic strategy for hematopoietic cell transplant-associated thrombotic microangiopathy?

Abstract

Diagnosis and management of hematopoietic cell transplant-associated thrombotic microangiopathy (TA-TMA) are very complex and controversial, given multiple ongoing issues and comorbidities in sick transplant recipients. Complement activation via classic and alternative pathways is emerging as a potential pathogenetic mechanism in the development of TA-TMA. Complement-centric diagnostic strategy using functional and genetic tests may possibly support diagnosis, enhance molecular understanding and direct drug development. Complement blockade using eculizumab has shown some promising rates of hematologic responses, however, survival may still be poor. Early discontinuation of calcineurin inhibitor where feasible, use of eculizumab, aggressive infection prophylaxis, close monitoring and early treatment of potential complications including GvHD and organ failure may improve outcomes. A number of complement inhibitors are in the development and may change treatment paradigm. Future studies are important to better understand TA-TMA as a disease process and may aim to confirm the role of complement activation in TA-TMA, enhance diagnostic strategy, determine therapeutic approaches and strategies to reduce the risk of other complications particularly infection and GvHD.

None of the above: thrombotic microangiopathy beyond TTP and HUS

“…56 Although the data are preliminary and from singlecenter studies, the lack of other effective treatment options argues that it would be reasonable to consider eculizumab for patients with TA-TMA, especially in patients with proteinuria and elevated sC5b-9 at the time of diagnosis. 73 A randomized study evaluating a novel complement inhibitor in TA-TMA is currently ongoing in the United State and Europe (www.ClinicalTrials.gov, #NCT02763644).…”

Hematopoietic stem cell transplant-associated thrombotic microangiopathy: current paradigm and novel therapies

“…Recently, researchers have cast some light on the possible roles of nitric oxide (NO) 10,11 and complement system 12,13 in the pathophysiology of TA-TMA. 14 There have been reports of successful use of NO donors 10 and complement blocking drugs [15][16][17] in the management of TA-TMA. In light of these recent research findings, we will discuss the pathophysiology and potential new markers of TA-TMA, followed by a comprehensive review of treatment options.…”

Thrombotic Microangiopathy and the Kidney

“…Again, this is likely to be multifactorial, with risk factors including CNIs, graft versus host disease, HLA mismatch, chemotherapy, radiation therapy, and infections (99). Rare genetic variants in aHUS associated genes (98) and FH autoantibodies (100) have been infrequently reported in post bone marrow transplant TMA.…”