A new paradigm: Diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury

Abstract

Hematopoietic stem cell transplantation (HSCT)-associated thrombotic microangiopathy (TA-TMA) is now a well-recognized and potentially severe complication of HSCT that carries a high risk of death. In those who survive, TA-TMA may be associated with long-term morbidity and chronic organ injury. Recently, there have been new insights into the incidence, pathophysiology, and management of TA-TMA. Specifically, TA-TMA can manifest as a multi-system disease occurring after various triggers of small vessel endothelial injury, leading to subsequent tissue damage in different organs. While the kidney is most commonly affected, TA-TMA involving organs such as the lung, bowel, heart, and brain is now known to have specific clinical presentations. We now review the most up-to-date research on TA-TMA, focusing on the pathogenesis of endothelial injury, the diagnosis of TA-TMA affecting the kidney and other organs, and new clinical approaches to the management of this complication after HSCT.

Phase 1 study of the anti-CD22 immunotoxin moxetumomab pasudotox for childhood acute lymphoblastic leukemia

“…Additionally, HUS seemed to occur with higher frequency in patients who had previously undergone stem-cell transplantation (8 of 26 vs 2 of 29; P 5 .0346 by Fisher's exact test), and TMA is a well-described posttransplantation complication. 29 Importantly, HUS/TMA resolved after study drug discontinuation in all but 1 patient. HUS/TMA did not seem to prohibit subsequent treatment with stem-cell transplantation or T-cell therapy, because 2 patients with grade 2 HUS/TMA received second allogeneic stem-cell transplants as next therapy after achieving CRc in this trial, and 1 with grade 4 HUS subsequently received CAR-transduced T-cell therapy.…”

None of the above: thrombotic microangiopathy beyond TTP and HUS

“…Prognostic guidelines for use of eculizumab and pharmacodynamics monitoring derived from single-center prospective studies in pediatric patients have been published. 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).…”

“…55 TA-TMA commonly affects the kidneys and results in transfusion-dependent anemia and thrombocytopenia; however, it can also present with multisystem organ injury that includes: pulmonary hypertension, intestinal TMA, posterior reversible encephalopathy syndrome (secondary to uncontrolled hypertension), and polyserositis. 56 …”

“…Although not universally accepted, 53,54,56 TA-TMA should be viewed as a unique form of TMA, distinct from TTP and aHUS. The multisystem injury seen in TA-TMA has several triggers that are unique to this population (immune dysregulation caused by infections, chemotherapy, and graft-versus-host disease [GVHD]), leading to endothelial injury and complement activation.…”

Eculizumab therapy in adults with allogeneic hematopoietic cell transplant-associated thrombotic microangiopathy

“…7,8,13,14 In the first prospective study of TMA in pediatric patients, incidence was reported to be as high as 35% and presence of TMA associated with higher non-relapse mortality than in patients without TMA. 1 Jodele et al 15 proposed that TMA is characterized by multi-organ endothelial injury affecting kidneys, gut, serosal surfaces, heart, skin and lungs, all in the setting of hemolytic anemia and thrombocytopenia. Martinez et al 16 studied 221 consecutive patients and noted a 31% incidence of TMA at 100 days post HCT.…”