A pragmatic multi-institutional approach to understanding transplant-associated thrombotic microangiopathy after stem cell transplant

Abstract

Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe complication of hematopoietic stem cell transplantation (HSCT). A single-center prospective screening study has shown that the incidence of TA-TMA is much higher than prior retrospective studies that did not systematically screen. These data have not been replicated in a multicenter study. Our objective was to determine the incidence and risk factors for TA-TMA and compare outcomes of pediatric HSCT patients with and without TA-TMA. Patients were prospectively screened for TA-TMA at participating centers using a simple to implement and inexpensive strategy from the start of the preparative regimen through day +100. TA-TMA was diagnosed if ≥4 of 7 laboratory/clinical markers diagnostic for TA-TMA were present concurrently or if tissue histology showed TA-TMA. A total of 614 patients (359 males; 58%) received prospective TA-TMA screening at 13 pediatric centers. TA-TMA was diagnosed in 98 patients (16%) at a median of 22 days (interquartile range, 14-44) posttransplant. Patients with TA-TMA had significantly increased bloodstream infections (38% [37/98] vs 21% [107/51], P ≤ .001), mean total hospitalization days (68; 95% confidence interval [CI], 63-74 vs 43; 95% CI, 41-45; P ≤ .001), and number of days spent in the intensive care unit (10.1; 95% CI, 6.4-14; vs 1.6; 95% CI, 1.1-2.2; P ≤ .001) in the first 100 days after HSCT compared with patients without TA-TMA. Overall survival was significantly higher in patients without TA-TMA (93%; 490/516) compared with patients with TA-TMA (78%; 76/98) (P ≤ .001). These data support the need for systematic screening for TA-TMA and demonstrate the feasibility and efficacy of an easy to implement strategy to do so.

Practical review of current approaches to diagnosis and treatment of transplant-associated thrombotic microangiopathy

“…proportion of patients had mutations in complement-related genes and clear laboratory signs of complement activation [11,12]. In this cohort, evaluation of eculizumab concentrations demonstrated higher drug clearance than in paroxysmal nocturnal hemoglobinuria as one of the mechanisms behind the lack of efficacy.…”

“…This difference might represent identification and inclusion of mild TA-TMA cases in the prospective studies. In these recent studies TA-TMA was associated with additional 15% mortality when compared to patients without TA-TMA, also reflecting the spectrum of TA-TMA severity [9,11].…”

“…There are ethnic differences in the incidence of complement-associated TA-TMA. Hence, the exact percentage of this clinical entity may vary across countries [11]. However, in the adult population there is only limited data on complement activation after unmanipulated haploidentical transplantation [30], and In the general population of adult patients several relatively different entities can be distinguished: GVHD-related, drug-induced (primarily, calcineurin and mTOR inhibitors), infection-related (cytomegalovirus and herpes type 6 are most frequently reported viruses), and those associated with other HSCT toxicities.…”

“…Mortality in the majority of case series exceeded 50% [5][6][7][8][9]. In the modern era, the incidence varies from 3% in the registry studies in predominantly adult population [10] to 16% in the pediatric prospective studies [11]. This difference might represent identification and inclusion of mild TA-TMA cases in the prospective studies.…”

Pulmonary Complications After Pediatric Stem Cell Transplant

“…Pulmonary complications occur in approximately 25% and 27% of pediatric and adult HSCT recipients, respectively, and are a leading cause of transplant-related mortality (5). Overall, about 9% of HSCT recipients require invasive ventilation and 10% require non-invasive ventilation (4)(5)(6)(7)(8)(9)(10)(11). However, it is likely that pulmonary complications are underreported in both adult and pediatric patients.…”