Transplant-associated Thrombotic Microangiopathy Diagnosis Research Articles

Real World Application of Recently Proposed ASTCT/CIBMTR/ eBMT/ APBMT Consensus Risk Stratification for Transplant Associated Thrombotic Microangiopathy (TA-TMA) in Children

BackgroundConsensus diagnostic and risk stratification of transplant associated thrombotic microangiopathy (TA-TMA) was recently achieved from international transplantation groups (Schoettler et al, TCT, 2023). While the diagnostic criteria proposed have been applied to multiple pediatric cohorts, there are scant data applying the novel risk stratification approach in children with TA-TMA. MethodsIn this retrospective cohort study, all children undergoing an allogeneic HCT or autologous HCT for neuroblastoma were prospectively screened for TA-TMA, diagnosed and risk-stratified using Jodele criteria from August 2019- October 2023. Our institutional practice during the study period was treat all Jodele intermediate and high-risk patients (IR, HR) with eculizumab. Harmonization risk stratification criteria were retrospectively applied. All survival analyses were calculated from the day of TA-TMA diagnosis. To identify which specific harmonization high-risk feature(s) were the most important predictors for NRM, full and reduced logistic regression models were tested. The lowest BIC and optimal Mallows’ CP statistic were used to identify the best subset. SAS 9.4 (Cary, NC) was used to complete the analysis. ResultsFifty-two children were diagnosed with TA-TMA during the study period a median of 37.5 days post HCT (range 3 to 735). Using Jodele risk stratification, 11 (21%) were SR, 21 (40%) intermediate risk, and 20 (39%) high- risk (HR). Forty (77%) were treated with eculizumab. There were no statistically significant differences in NRM among Jodele risk groups, though overall survival was significantly different. Using the harmonized stratification, 49 (94%) of children were stratified as HR and 3 as SR, there were no statistically significant differences in NRM or OS between groups. Eight (15.4%) children were classified as SR using Jodele risk stratification but re-stratified as HR using the harmonization criteria. One (12.5%) died in the setting of severe GVHD and the remaining 7 patients are alive at last follow up. In a best subset model, LDH >2x ULN (OR 6.52, 95% CI 0.96-44.3, p=0.05), grade 2-4 acute GVHD at the time of TA-TMA diagnosis (OR 15.4, 95% CI 2.14- 110.68, p=0.01), and multi-organ dysfunction at the time of TA-TMA (OR 21.5, 95% CI 2.96-156.37, p=0.002) were significantly associated with NRM; elevated sC5b-9, rUPCR, and viral infections were not significantly associated with NRM. Using these best fit criteria, 14 patients were classified as SR and 38 as HR; NRM was significantly higher and OS significantly lower. DiscussionIn this cohort of children with TA-TMA retrospective application of harmonization criteria resulted in more patients stratified as HR than previously described Jodele criteria. The intention of the harmonization criteria was to identify those at highest risk of poor outcomes; while all harmonization SR patients survived, this risk stratification was very sensitive. Previous criticisms of harmonization risk stratification include limited access to sC5b-9 testing– these data suggest that concurrent MOD, acute GVHD, and LDH >2X ULN are the most important predicators of NRM in this cohort, supporting the use of harmonization risk stratification even in the absence of available sC5b-9 testing. Additional studies are needed to validate these findings.

Age, GVHD prophylaxis, and timing matter in thrombotic microangiopathy after haematopoietic cell transplantation-Asecondary CIBMTR analysis.

Most reports of risk factors (RF) for developing transplant-associated thrombotic microangiopathy (TA-TMA) and death are derived from paediatric and young adult cohorts, with minimal data on differences in RF and outcomes by age. In this secondary CIBMTR analysis, we used a previously prepared dataset that included all first allogenic haematopoietic cell transplantation (HCT) recipients with malignant or non-malignant diseases between 2008 and 2016. The incidence of TA-TMA 6 months post HCT was similar in children and adults 2.1% and 2.0% respectively. Grade 2-4 acute graft-versus-host disease (aGVHD) was a significant adjusted RF for developing TA-TMA in both children and adults. In adults, additional adjusted RFs for TA-TMA included female sex and black race, and in children an unrelated donor. Compared to a calcineurin inhibitor and sirolimus, other forms of GVHD prophylaxis had an adjusted decreased risk of developing TA-TMA in adults. Adjusted RF for death in those with TA-TMA (n = 652) included age ≥18 years old, early onset of TA-TMA diagnosis (<100 days post HCT), grade 3-4 aGVHD and a performance score of <90 prior to HCT. In this cohort, the incidence of TA-TMA was similar in children and adults, and TA-TMA timing was a newly identified RF for death.

Impact of Modification of Immunosuppressive Therapy Following Diagnosis of Transplant-Associated Thrombotic Microangiopathy in Allogeneic Hematopoietic Stem Cell Transplant Recipients: A Single Center Experience

Impact of Modification of Immunosuppressive Therapy Following Diagnosis of Transplant-Associated Thrombotic Microangiopathy in Allogeneic Hematopoietic Stem Cell Transplant Recipients: A Single Center Experience

Prospective Clinical and Biomarker Validation of the ASTCT Consensus Definition for Transplant-Associated Thrombotic Microangiopathy (TA-TMA)

Introduction: Transplantation-associated thrombotic microangiography (TA-TMA) is a disorder that causes severe complications post-hematopoietic cell transplantation (HCT). Diagnosing TA-TMA is challenging due to non-standardized criteria. The American Society for Transplantation and Cellular Therapy (ASTCT) has proposed new consensus diagnostic criteria for standard risk (ASTCT-SR) and high risk (ASTCT-HR) but their correlation with older criteria based on microangiopathic hemolytic anemia (MAHA) or diagnostic complement biomarkers used in previous TA-TMA studies, such as levels of the terminal complement activation product sC5b-9 and the alternative complement pathway activation product Factor Ba, is unknown. Using data and samples from an ongoing prospective pediatric cohort study, we compared the two definitions and their associations with biomarkers. Methods: Patients aged 0 to 18 years who underwent first allogeneic HCT 2021-2023 at Texas Children's Hospital were included in the clinical and biomarker study. Those who did not have at least 100-day post-HCT event-free follow-up were excluded. Two different definitions for TA-TMA were applied. Clinical TMA (cTMA) was diagnosed if a patient 1) met 4/4 concurrent criteria of MAHA (schistocytosis, thrombocytopenia, anemia, and elevated lactate dehydrogenase (LDH)) at least twice in 14 days and 2) clinically adjudicated to exclude known mimics or alternative causes of TMA. In contrast, ASTCT-HR TMA was diagnosed if a patient 1) met 4/7 non-concurrent criteria (schistocytosis, thrombocytopenia, anemia, elevated LDH, elevated blood pressure, elevated urinary protein excretion, and elevated sC5b9) at least twice in 14 days and 2) had evidence of LDH &amp;gt;2x normal, proteinuria ≥1 mg/mg, elevated sC5b9, acute graft-versus-host disease, active bacterial/viral infection, or end-organ damage. Cumulative incidence of TA-TMA was assessed by the competing risk method. Overall survival was compared by the Kaplan Meier estimator and log-rank test. Biomarker levels for samples collected at day 15 (+/- 14 days) were compared using the t-test. Results: A total of 32 patients met the inclusion criteria. The median age was 5.7 years (range 1.1-18.8) and most were White (68.8%) and Hispanic (56.2%). Malignant disease was the indication for HCT in 50% of patients. While the classic MAHA-based cTMA definition had an incidence of 12.7%, the newly proposed ASTCT-HR definition doubled it to 28.5% by day-100 (Figure 1). In contrast to patients with concordant TA-TMA diagnosis (+/+) who had significantly worse post-transplant survival (p=0.0047) compared with those with concordant non-TMA (-/-), those reclassified as TA-TMA by the new definition only (-/+) had an unexpectedly good prognosis (100% survival at day 100) despite the lack of TMA-directed therapy. Longitudinal biomarker analysis was conducted on 29 patients. The highest average plasma levels of sC5b-9 and Ba during the first 100 days were observed in patients meeting both cTMA and ASTCT-HR criteria (+/+). When focused on early biomarkers measured around day 15, sC5b-9 (P=0.041) and Ba (P=0.004) were significantly elevated in the doubly positive TMA group (+/+) vs. non-TMA group (-/-) (Figure 2). We did not observe significant differences for ASTCT-HR singly positive (-/+) vs. non-TMA group (-/-). Conclusions: In the current prospective clinical and biomarker study, the recently proposed ASTCT-HR definition was more sensitive but less prognostic than the traditional cTMA definition for TA-TMA. Patients who solely met the ASTCT-HR diagnostic criteria but not the cTMA criteria had benign complement biomarker profiles and excellent survival prognosis without TMA-directed therapy. While clinicians need to be vigilant for this infrequent yet potentially severe complications, it is crucial that diagnostic criteria accurately identify affected patients given the expense and potential complications of treatment. We recommend ongoing validations of the new consensus diagnostic criteria from other prospective cohort studies with larger sample sizes and extended follow-up.

Thrombotic Microangiopathy After Hematopoietic Stem Cell and Solid Organ Transplantation: A Review for Intensive Care Physicians.

Intensive care physicians may assume the primary care of patients with transplant-associated thrombotic microangiopathy (TA-TMA), an uncommon but potentially critical complication of hematopoietic stem cell transplants (HSCTs) and solid organ transplants. TA-TMA can have a dramatic presentation with multiple organ dysfunction syndrome (MODS) associated with high morbidity and mortality. The typical presenting clinical features are hemolytic anemia, thrombocytopenia, refractory hypertension, proteinuria and worsening renal failure. Intestinal involvement, with abdominal pain, nausea and vomiting, gastrointestinal bleeding, and ascites are also common. Cardiopulmonary involvement may develop from various causes including pulmonary arteriolar hypertension, pleural and pericardial effusions, and diffuse alveolar hemorrhage. Due to other often concurrent complications after HSCT, early diagnosis and effective management of TA-TMA may be challenging. Close collaboration between ICU and transplant physicians, along with other relevant specialists, is needed to best manage these patients. There are currently no approved therapies for the treatment of TA-TMA. Plasma exchange and rituximab are not recommended unless circulating factor H (CFH) antibodies or thrombotic thrombocytopenic purpura (TTP; ADAMTS activity < 10%) are diagnosed or highly suspected. The role of the complement pathway activation in the pathophysiology of TA-TMA has led to the successful use of targeted complement inhibitors, such as eculizumab. However, the relatively larger studies using eculizumab have been mostly conducted in the pediatric population with limited data on the adult population. This review is focused on the role of intensive care physicians to emphasize the clinical approach to patients with suspected TA-TMA and to discuss diagnosis and treatment strategies.

Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) and Growth Differentiation Factor-15 (GDF-15) Leves Are Significantly Associated with Edothelial Injury Indices in Adult Allogenic Hematopoietic Cell Transplantation Recipients

Introduction: Endothelial dysfunction is a common denominator of graft-versus-host disease (GVHD) and transplant-associated thrombotic microangiopathy (TA-TMA). Among endothelial injury indices, the Endothelial Activation and Stress Index (EASIX) has been studied in allogeneic hematopoietic cell transplantation recipients (allo-HCT) recipients, while others including suPAR and GDF-15 have been determined only in other patient populations with hematologic diseases, such as in patients with Multiple Myeloma, AL- amyloidosis and Sickle Cell Disease. We hypothesized that suPAR and GDF-15 would reflect endothelial injury in allo-HCT recipients. Methods: We enrolled consecutive adult TA-TMA (classified according to current standardized criteria), acute and/or chronic graft-versus-host-disease (GVHD), control allogeneic hematopoietic cell transplantation (alloHCT) recipients and apparently healthy individuals of similar age and gender in a 1:1:1:1 ratio. Plasma was collected and stored immediately at -80 oC at the first day of confirmed TA-TMA or GVHD diagnosis and at a similar post-transplant period in control recipients. EASIX [lactate dehydrogenase (U/L) × creatinine (mg/dL)/thrombocytes (10⁹ cells per L)] was calculated at day 0, 30, 100 and at last follow-up. Soluble C5b-9/membrane attack complex, suPAR and GDF-15 levels were measured using immunoenzymatic techniques. Results: We studied 20 TA-TMA, 20 GVHD, 20 control alloHCT patients, and 20 healthy controls. We found significantly higher suPAR and GDF-15 levels in TA-TMA and GVHD patients compared to alloHCT and healthy controls (p&amp;lt;0.001, Bonferroni's correction). Then, we further analyzed characteristics of the alloHCT population. TA-TMA developed at a median of 125 post-transplant day (range 9-2931); whereas the first day of confirmed GVHD diagnosis was at a median of 78 post-transplant day (range 16-145). Both GDF-15 and suPAR concentrations were associated with EASIX at day 100 (r=0.351, p=0.012 and r=0.338, p=0.015, respectively) and last follow-up (r=0.473, p&amp;lt;0.001 and r=0.410, p=0.020, respectively). Among the laboratory values used to calculate EASIX (LDH, creatinine, platelets), suPAR was associated with creatinine and platelets at day 100 and last follow-up; while GDF-15 only with platelets at both time points, suggesting that the association with EASIX is not driven by laboratory values per se. Interestingly, only suPAR and not GDF-15 levels was associated with soluble C5b-9 levels (p=0.013), a marker reflecting high risk in TA-TMA. Conclusion: Our study shows for the first time that suPAR and GDF-15 reflect endothelial injury in allo-HCT recipients. In accordance with other patient populations, suPAR emerges as a marker of renal dysfunction, characterizing high-risk in endothelial injury syndromes and in particular, TA-TMA. However, prior to their clinical usefulness, these biomarkers must undergo through rigorous validation in multiple cohorts.

Survival analysis of transplant-associated thrombotic microangiopathy under different diagnostic criteria and the efficacy of plasma exchange.

BACKGROUND Transplant-associated thrombotic microangiopathy (TA-TMA) is a serious complication of hematopoietic stem cell transplantation (HSCT). The efficacy and survival of plasma exchange (PE) for TA-TM have not been fully clarified. In addition, there is a lack of consensus on diagnostic criteria for TA-TMA. MATERIAL AND METHODS We retrospectively analyzed32 patients diagnosed with TA-TMA by different diagnostic criteria from January 2018 to February 2022 at the First Medical Center of the PLA General Hospital. RESULTS (1) The patients with TA-TMA treated with PE in this study had a remission rate of 42.8%, a 100-day OS of 47.6%, and a 6-month OS of 38.1%. The only factor affecting the response to PE treatment was the number of PE sessions (P = 0.047). (2) III-IV aGVHD prior to TA-TMA diagnosis (P = 0.002), renal or neurological dysfunction (P = 0.021), and the time to onset of TA-TMA (P = 0.002) were independent risk factors for overall survival with TA- TMA. (3) Probable TA-TMA had the highest survival rate, but the Jodele criteria are expected to diagnose earlier and provide the greatest benefit to patients. CONCLUSIONS PE is an effective treatment for TA-TMA especially in cases where complement blockers are not available. In addition, probable TA-TMA improved prognostic survival through early detection of patients with TA-TMA. There is a need for further large prospective trials to identify the population more suitable for PE treatment of TA-TMA and more valid diagnostic criteria.

Endothelial Injury Syndromes after Allogeneic Hematopoietic Stem Cell Transplantation: Angiopetin-2 as a Novel Predictor of the Outcome and the Role of Functional Autoantibodies against Angiotensin II Type 1 and Endothelin A Receptor.

Transplant-associated thrombotic microangiopathy (TMA) occurs in a significant percentage of patients after allogeneic stem cell transplantation (allo-SCT) and is associated with significant morbidity and mortality. The aim of the present study was to examine the association of serum angiopoetin-2 (Ang2) levels and the presence of antibodies against angiotensin II type 1 (AT1R) and ndothelin A Recreptor (ETAR) with the outcome of patients with TMA and/or graft-versus-host disease (GVHD) after allo-SCT. Analysis of our data showed that elevated serum Ang2 levels at the time of TMA diagnosis are significantly associated with increased non-relapse mortality and decreased overall survival. To our knowledge, this is the first study demonstrating an association between raised Ang2 levels and poor outcomes in patients with TMA. Antibodies against AT1R (AT1R-Abs) and ETAR (ETAR-Abs) were detected in 27% and 23% of the patients, respectively, but there was no association between the presence of autoantibodies and the outcome of patients with TMA. However, a significant finding was the strong positive correlation between the presence of AT1R-Abs with the occurrence of chronic fibrotic GVHD, such as scleroderma and cryptogenic organizing pneumonia, raising the possibility of the contribution of autoantibodies in the pathogenesis of fibrotic GVHD manifestations.

Advances in Diagnosis and Treatment of Transplant-Associated Thrombotic Microangiopathy --Review

Transplantation-associated thrombotic microangiopathy (TA-TMA) is one of the serious complications mostly occurring within 100 days after hematopoietic stem cell transplantation (HSCT). Risk factors of TA-TMA include genetic predispositions, GVHD, and infections. The pathophysiological mechanisms of TA-TMA start with endothelial injury caused by complement activation, which leads to microvascular thrombosis, and microvascular hemolysis, ultimately resulting in multi-organ dysfunction. In recent years, the development of complement inhibitors has markedly improved the prognosis of TA-TMA patients. This review will give an update on risk factors, clinical manifestations, diagnosis, and treatment of TA-TMA, so as to provide references for clinical practice.

Risk Factors for Symptomatic Pericardial Effusions Posthematopoietic Stem Cell Transplant.

Pericardial effusions are a known complication posthematopoietic stem cell transplant (HSCT), causing significant morbidity. We aimed to evaluate the risk factors associated with the development of high-grade effusions requiring interventions. Procedure. A retrospective chart review of all HSCT patients over a period of 7 years (2013-2019) in a single institution in the Northeastern United States is conducted. All patients who developed an effusion requiring intervention were included. Patient's clinical characteristics were compared with all others transplanted during the same time period. Echocardiogram findings of the affected patients were compared to a case-control cohort of unaffected patients with similar age and diagnosis. Chi-square and paired t-tests were utilized to ascertain statistical differences between the groups. A total of 15 patients out of 201 (7.5%) transplanted at our institution developed a moderate or large pericardial effusion requiring pericardiocentesis or a pericardial window. Of this cohort, 13 (87%) underwent a myeloablative preparative regimen, 13 (87%) had cyclophosphamide as part of their regimen, 13 (87%) had recent treatment for viral reactivation, 6 (40%) had an underlying hemoglobinopathy diagnosis, and only 4 (27%) had an active diagnosis of GVHD. A myeloablative preparative regimen had a higher rate of effusion requiring intervention, although it was not statistically significant, and concurrent GVHD was not predictive of effusion development. However, exposure to cyclophosphamide, recent treatment for viral reactivation, and a diagnosis of transplant-associated thrombotic microangiopathy (Ta-TMA) were highly associated with effusions. The latter was associated with increased mortality. The duration of pericardial effusion correlated with the pretransplant echocardiogram left ventricle end diastolic diameter z-score and apical 4-chamber left ventricular peak average strain measurement. Potential risk factors for pericardial effusions post-HSCT include a diagnosis of Ta-TMA, active viral infection, exposure to cyclophosphamide, and a higher left ventricle end diastolic diameter z-score. This information may help guide management for these patients, including identifying high-risk subjects, determining the frequency of echocardiograms, and determining specific echocardiogram measures to follow over time.

Efficacy and Prognosis of Transplant-Associated Thrombotic Microangiopathy Based on Different Prognostic Risk Models

To investigate the clinical features of transplant-associated thrombotic microangiopathy (TA-TMA) and the prognostic value of different prognostic risk models for TA-TMA. The clinical characteristics of 32 TA-TMA patients diagnosed at the First Medical Center of the PLA General Hospital from January 2018 to February 2022 in terms of short-term prognosis and influencing factors were retrospectively analyzed. In addition, the risk population composition ratio, treatment response, and overall survival between the BATAP risk model and the TMA index model were compared, as well as the efficacy of two prognostic risk models for predicting death in patients with TA-TMA. Independent risk factors affecting the short-term prognosis of TA-TMA include III-IV aGVHD prior to TA-TMA diagnosis (P=0.001), renal or neurological dysfunction (P=0.006), and Hb<70 g/L (P=0.043). In the TMA index model, treatment response was worst in the high-risk group (P=0.008), while there was no significant difference in treatment response between different risk groups in the BATAP model (P=0.105). In the BATAP model, there was a statistically significant difference in the OS between the three groups of low risk, intermediate risk, and high risk (87.5% vs 61.1% vs 16.7%, χ2＝6.7, P=0.014). In the TMA index model, there was a statistically significant difference in the OS between the three groups of low risk, intermediate risk, and high risk (77.8% vs 45.5% vs 0.0%, χ2＝7.3, P=0.017). The area under the ROC curve (AUC) of the TMA index model was 0.745 (95%CI: 0.56-0.88, P<0.05), and the AUC of the BATAP model was 0.743 (95%CI: 0.56-0.88, P<0.05), indicating that both prognostic risk models have good predictive value. The short-term prognosis of TA-TMA patients might be accurately determined using both the BATAP model and the TMA index model. When predicting the efficacy of TA-TMA in different risk groups, the TMA index model may perform better than the BATAP model.

Transplant-Associated Thrombotic Microangiopathy in the Context of Allogenic Hematopoietic Stem Cell Transplantation: Where We Stand.

Transplant-associated thrombotic microangiopathy (TA-TMA) constitutes a significant contributor to the increased morbidity and mortality after allogenic hematopoietic stem cell transplantation (allo-HSCT). TA-TMA is a heterogenous disease, characterized by the triad of endothelial cell activation, complement dysregulation and microvascular hemolytic anemia, which may affect all organs. The lack of consensus diagnostic criteria, along with the common clinical features mimicking other diseases that complicate allo-HSCT, make the diagnosis of TA-TMA particularly challenging. Significant effort has been made to recognize specific risk factors predisposing to the development of TA-TMA and to identify serum biomarkers predicting the development of the disease. With regard to treatment, therapeutic plasma exchange (TPE) has been traditionally used, although with doubtful efficacy. On the other hand, the pivotal role of complement activation in the pathophysiology of TA-TMA has led to the exploration of the therapeutic potential of complement inhibitors in this setting. Eculizumab has been proposed as a first-line therapeutic agent in TA-TMA, owing to the very promising results in both pediatric and adult clinical trials. Pharmacokinetic and pharmacodynamic studies and CH50 levels are of paramount importance in the allo-HSCT setting, as a different dosing schedule (more intensive-in dose and frequency-at the beginning) seems to be required for successful outcomes. Furthermore, Narsoplimab, a MASP-2 inhibitor, recently received a Breakthrough Therapy Designation from the FDA for the treatment of TA-TMA after allo-HSCT. Finally, the decision to withdraw the CNIs, although initially advised by the Bone and Marrow Transplant Clinical Trials Network Committee, remains debatable owing to the controversial results of recent clinical trials. This review summarizes the current updates on pathophysiology, diagnosis and therapeutic approaches and emphasizes future goals and perspectives.

Recipient-Specific Antibodies (RSA) in Mismatched Related Transplants May Induce Transplant-Associated Thrombotic Microangiopathy (TA-TMA)

HLA incompatibility increases the risk of transplant-related complications. Specifically, donor-specific antibodies (DSA) in mismatched related transplants (mm-HCT) increase the risk of graft failure. Less is known about the role of recipient-specific antibodies (RSA) detected in donors, as the immune status of the donor is not routinely examined before transplant with regard to anti-HLA antibodies. These antibodies may be transferred together with transplanted cells or produced by memory donor cells. We hypothesize that donor-derived RSA may induce immune-mediated complement activation in the classical pathway (CH50), leading to overproduction of membrane attack complex (MAC) and exacerbation of endothelial damage. Here we present preliminary epidemiological data regarding the presence of DSA and RSA, and the impact of RSA antibodies on transplant-related complications, especially transplant-associated thrombotic microangiopathy (TA-TMA) and acute graft-versus-host disease (aGvHD). Methods We prospectively analyzed the presence of anti-HLA antibodies in 20 pairs of donors and recipients qualified for mm-HCT. All recipients suffered from hematological malignancies and received a myeloablative conditioning regimen and immunosuppression consisting of post-transplant cyclophosphamide, tacrolimus, and mycophenolate mofetil. Patients’ and donors’ immunization status were tested with the solid phase method. Tests were carried out using a flow fluorometer across the screening range (Luminex Screen, One Lambda, USA). In the group of positive samples for anti-HLA class I and/or II antibodies, identification of the specificity of the HLA antibodies was performed (Luminex Single Antigen Beads, One Lambda, USA). Reagents enabling the determination of anti-HLA antibodies in the IgG class were used. All results were presented as mean fluorescence intensity (MFI) values. Monitoring of complement activation on days 30, 60, and 100 post-transplant was started after completing epidemiological data in the first 10 pairs. All patients were checked for TA-TMA and GvHD development during routine post-transplant visits. TA-TMA screening included TA-TMA triad: hypertension or kidney injury, LDH increase and decrease in number of platelets or refractoriness to transfusions, and additionally decrease in hemoglobin concentration, proteinuria, and clinical presentation with TA-TMA involved organ damage. Schistocytes as non-objective and nonrepeatable markers were excluded from diagnostic criteria. Results Anti-HLA antibodies were detected in 9/20 (45%) of recipients, and in 9/20 (45%) of the donors despite the lack of any transfusion history in donor group. Neither the presence of DSA nor RSA was affected by gender. RSAs were present more often in donors (7/9; 77%) than DSAs in recipients (2/9; 22%); p=0.052. Data summarizing MFI values and type of antibodies are presented in table 1. Laboratory diagnosis of TA-TMA met 12/20 (60%) patients, with a significant clinical presentation including severe hypertension (3) pericarditis (1), gastrointestinal (5), or neurological (6) impairment in 8/12 (66%). All patients with RSA (7/7; 100%) developed TA-TMA compared to no-RSA group (5/13; 38%) (p<0.01). TA-TMA-mediated organ damage was noticed more often in the RSA population (5/7; 71%) compared to the no-RSA group (3/13, 23%) (p<0.01); (Table 2). A trend for higher activation of CH50 and MAC in RSA compared to a no-RSA group was noted with a mean CH50 93 vs. 82 (p=0,16), and MAC 1428 vs. 1007 (p=0,24) respectively. A trend for higher maximum concentrations of tacrolimus 14 vs 10.7 (p=0.07) was observed in patients with TA-TMA. There was no impact of ABO incompatibility on TA-TMA development. During the time of observation 6 patients (30%) developed aGvHD - grades I, II, and III were diagnosed in 3, 1, and 2 patients respectively. Only 1 patient with RSA developed aGvHD. There was no correlation between RSA and GvHD occurrence (RSA 1/7, no-RSA 5/13, p=0.26) and between aGvHD and TA-TMA. CMV reactivation was documented in 13/20 (65%) patients, with no differences between the RSA and no-RSA groups (p=0.65). Conclusions RSAs occur surprisingly often in the donor population, irrespectively to the donor`s gender and the lack of transfusions history. The exact role of these antibodies is not fully understood; however, our data may suggest their impact on complement activation and TA-TMA induction. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Epidemiology and outcomes of pediatric transplant-associated thrombotic microangiopathy in Hong Kong.

Transplant-associated thrombotic microangiopathy (TA-TMA) is an under-recognized yet potentially devastating complication of hematopoietic stem cell transplantation (HSCT) which had increased awareness in recent years. This report summarizes the demographics and outcomes of pediatric TA-TMA in Hong Kong. All patients aged below 18 years who underwent HSCT in the Hong Kong Children's Hospital and were diagnosed to have TA-TMA during the 2-year period from April 1, 2019 to March 31, 2021 were included. A total of 73 transplants (51 allogeneic and 22 autologous) in 63 patients had been performed. Six patients (four males and two females) developed TA-TMA at a median duration of 2.5 months post-HSCT. The incidence rate was 9.52%. Of the six TA-TMA patients, five underwent allogenic one underwent autologous HSCT, respectively. Three of them were histologically proven. All four patients with cyclosporine had stopped the drug once TA-TMA was suspected. Median six doses of eculizumab were administered to five out of six patients. Three patients died (two due to fungal infection and one due to acute-on-chronic renal failure) within 3 months upon diagnosis of TA-TMA. Among three survivors, two stabilized with mild stage 2 chronic kidney disease (CKD) while the other suffered from stage 5 end-stage CKD requiring lifelong dialysis. In conclusion, recognition and diagnosis of TA-TMA are challenging. Early recognition and prompt administration of complement blockage with eculizumab may be beneficial in selected cases. Further prospective research studies are recommended to improve the management and outcomes of TA-TMA.

P1344: METHODOLOGY OF AN INTERNATIONAL MULTI-CENTER RETROSPECTIVE REVIEW OF TRANSPLANT-ASSOCIATED THROMBOTIC MICROANGIOPATHY (TA-TMA) BY THE TA-TMA WORKING GROUP

Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is a serious and potentially life-threatening complication after allogeneic hematopoietic cell transplantation (alloHCT). Multiple sets of clinical diagnostic criteria for TA-TMA have been developed in adult and pediatric settings based on single-institution chart review or expert panels, but none have been rigorously evaluated across multiple centers to assess validity or reproducibility. The TA-TMA Working Group is conducting a multi-national, multi-center, retrospective study to identify and confirm potential adult and pediatric cases of TA-TMA. The aim of creating a large cohort of adjudicated TA-TMA cases is to better understand the incidence, risk factors, clinical outcomes, and healthcare resource utilization (HRU) associated with this condition. Aims: To describe the multiple-adjudication methodology employed to confirm diagnosis of TA-TMA across adult and pediatric transplant centers. Methods: Twelve US and EU centers retrospectively screened medical records of patients who received alloHCT between 2015 and 2017 using 5 criteria: schistocytosis (>2 per high-power field); LDH level above ULN; doubling of baseline creatinine; platelet refractoriness (50% decrease in platelet count and/or platelet count less than individual center’s transfusion threshold x 4 days despite transfusions); and decreased haptoglobin. Cases meeting ≥3 criteria within a 10-day period during the first 12 months after alloHCT were considered potential TA-TMA and were further evaluated by 2 clinicians from each transplant center. Patients who had a positive biopsy, were diagnosed with TA-TMA or aHUS, or had received eculizumab following alloHCT were considered to have definite TA-TMA. Of all positive cases determined by local adjudications, 30% will be randomly selected for central adjudication by independent adult and pediatric adjudication committees. Central adjudicators have access to relevant laboratory and radiologic data. In cases with 2 discordant decisions, a third central adjudicator will be assigned to break the tie. In cases of 3 discordant decisions regarding the diagnosis of TA-TMA, the case will be forwarded for discussion led by the central adjudication chair. All cases determined as positive TA-TMA after local and central adjudication will be aggregated and analyzed to evaluate clinical outcomes, risk factors for TA-TMA, disease course, survival and non-relapse mortality, and HRU. Results: As of March 1, 2022, 3,732 cases have been screened at 11 transplant centers and 836 were considered potential TA-TMA that met ≥3 criteria. To date, local adjudication at 8 centers determined 179 cases were positive TA-TMA. Due to variations in laboratory standards at different centers, a challenge encountered in this study was harmonization of screening criteria. For example, labs at several centers did not quantify number of schistocytes as part of their CBC, which restricted screening of potential TA-TMA cases to 4 criteria, leading to some cases being categorized as “unknown.” These outcomes highlight the differences in assessing TA-TMA at multiple centers. Summary/Conclusion: This is the first multi-center comprehensive retrospective study to evaluate TA-TMA with a formalized process for independent local and central adjudication to verify TA-TMA diagnosis. The large cohort of TA-TMA cases identified in this study should enable validation of current and future diagnostic criteria, improve our understanding of prognostic/risk factors, and enhance awareness of this disease.

Transplantation-Associated Thrombotic Microangiopathy Risk Stratification: Is There a Window of Opportunity to Improve Outcomes?

Transplantation-associated thrombotic microangiopathy (TA-TMA) can range from a self-limiting condition to a lethal transplantation complication. It is important to identify TA-TMA patients at risk for severe multiorgan endothelial injury to implement targeted therapies in a timely manner. Current therapeutic approaches with complement blockade have improved survival markedly in high-risk TA-TMA patients, yet one-third of these patients respond inadequately to eculizumab therapy. Poor response may indicate that substantial endothelial injury has already occurred and raises the possibility that earlier intervention may improve outcomes. The goal of this study was to identify additional TA-TMA patients who would benefit from early targeted intervention and update TA-TMA risk stratification methods to reflect these findings. We studied 130 HSCT recipients with a diagnosis of TA-TMA who were screened prospectively and stratified into 3 TA-TMA risk groups (high-risk, n=64; moderate-risk, n=48; 18 low-risk, n=18). We specifically examined TA-TMA biomarkers and clinical outcomes in subjects who were not offered complement blocking therapy (moderate-risk and low-risk TA-TMA subjects) and compared them with those who received TA-TMA-targeted therapy (high-risk TA-TMA subjects). One-year post-HSCT survival for subjects with untreated moderate-risk TA-TMA was similar to those with high-risk TA-TMA receiving eculizumab therapy (71% versus 66%; P=.40), indicating that a subset of moderate-risk patients may benefit from therapy. A detailed analysis of moderate-risk subjects highlighted the importance of relative as well as absolute complement pathway activation in determining organ injury. We demonstrated that activated terminal complement (measured by elevated blood sC5b-9) alone is a valuable indicator of reduced survival. Moderate-risk TA-TMA subjects with elevated sC5b-9 levels had a nearly 3-fold higher risk of mortality that was statistically significant in multivariant analyses (P=.01). A "dose effect" also was observed, and higher sC5b-9 levels were associated with worse outcomes. Furthermore, all moderate-risk patients with sustained sC5b-9 elevation for >2 weeks ultimately developed multiorgan dysfunction syndrome (MODS). This indicates that scheduled sC5b-9 measurements could promptly identify patients at risk for poor outcomes and would facilitate early TA-TMA-directed therapy to prevent organ injury. Untreated low-risk TA-TMA patients had a 1-year post-HSCT survival of 94% and should be observed without targeted interventions. Routine TA-TMA screening and complement-blocking therapies have markedly improved the outcomes for high-risk TA-TMA patients, and our study suggests that additional patients may benefit from TA-TMA treatment. This study provides further support for prospective TA-TMA screening as an integral tool for identifying patients at greatest risk for organ injury and death from TA-TMA. An updated TA-TMA risk algorithm that incorporates relevant laboratory biomarkers, clinical findings, and comorbid conditions was generated using this study's findings, and we propose clinical implementation of this algorithm for the management of TA-TMA.

Response Rates, Non-Relapse Mortality, and Financial Implications of Transplant-Associated Thrombotic Microangiopathy Treated with Eculizumab

Background: Hematopoietic cell transplantation associated thrombotic microangiopathy (TA-TMA) shares common features with atypical hemolytic uremic syndrome (aHUS) and thrombotic thrombocytopenic purpura. TA-TMA affects multiple organ systems resulting in multi-organ failure and non-relapse mortality (NRM). Recently, complement activation has been associated with TA-TMA leading to utilization of complement blockade in TMA. Eculizumab is a humanized monoclonal antibody that binds to C5 and prevents the formation of the membrane attack complex (C5b-9) or the terminal complement pathway. Eculizumab may be an effective treatment for pediatric TA-TMA patients; however, there are limited data regarding its use in adult TA-TMA patients. Furthermore, eculizumab is an expensive medication and there are no published data regarding the financial implications of TA-TMA treated with eculizumab. The purpose of this study was to examine the response rates, NRM, and financial implications of TA-TMA treated with eculizumab.Methods: We performed a retrospective cohort study of patients with TA-TMA who received eculizumab at our institution between January 1, 2012, and April 9, 2017. TA-TMA was defined according to the BMT-CTN criteria with evidence of hemolysis, elevated LDH, renal dysfunction and negative Coombs' test. Serum complement biomarkers (C5b-9) were used to support the diagnosis when platelet or red blood cell transfusion dependence occurred with organ dysfunction or tissue evidence of microangiopathy. Patients were vaccinated against Neisseria meningitides and received appropriate antibiotic prophylaxis. Eculizumab therapy was initiated at the Food and Drug Administration-approved dosing schedule for aHUS: 900 mg intravenously weekly for the first 4 weeks followed by 1200 mg intravenously every other week beginning on week 5 for a total of 8 weeks, with some patients requiring longer than an 8 week course. The primary outcome was complete response to eculizumab therapy and responders were defined by achievement of transfusion independence and improvement in creatinine. Secondary outcomes included non-relapse mortality (NRM), inpatient cost, number of comorbidities, number of infections, number of hospitalizations, and hospital length of stay (LOS). Comorbidities were defined as any documented medical problem other than the reason for transplant and TA-TMA.Results: Twenty patients were included in the study (Table 1). The median (range) time from transplant to diagnosis of TA-TMA was 139 (14-388) days. The median (range) time from diagnosis of TA-TMA to first dose of eculizumab was 2 (0-272) days. The complete response rate was 55%. The median (range) number of doses of eculizumab was 6.5 (2-17) for responders compared to 3 (1-7) for non-responders including both inpatient and outpatient doses (p= 0.01). There were no significant differences between the number of hospitalizations for responders and non-responders. However, responders had shorter LOS and lower inpatient costs than non-responders. The median (range) LOS was 9 days (0-92) for responders compared to 61 days (26-94) for non-responders (p= 0.03). The median (range) total inpatient cost was $259,734 (0-1,670,070) for responders compared to $1,525,758 (385,092-1,948,190) for non-responders (p= 0.003). The itemized inpatient costs are shown in Figure 1. Patients who responded to eculizumab tended to be younger with less comorbidities. In fact, patients were 33% less likely to respond to eculizumab for every additional documented comorbidity at the time of TA-TMA diagnosis (HR=0.67 [95% CI 0.49-0.92]). The NRM was 1/11 (9%) for responders and 9/9 (100%) for non-responders (HR=0.07 [95% CI: 0.007-0.66]).Conclusions: TA-TMA is an important complication of HCT that is associated with high NRM and financial toxicity. Our data suggests that patients who respond to eculizumab have lower NRM, LOS, and financial costs than non-responders. There was a statistically non-significant trend in incidence of steroid-refractory GVHD in the non-responder group; additionally non-responders received significantly fewer doses than responders, which may explain partly the lower response rates compared to the 80% response rates in aHUS. Patient age and the number of comorbidities at the time of diagnosis of TA-TMA may be important predictive factors for response to eculizumab. [Display omitted] DisclosuresMims:Novartis: Honoraria. Hofmeister:Janssen: Research Funding; Karyopharm: Research Funding; Celgene: Research Funding; Thrassos: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Takeda: Research Funding. Walker:Gilead: Research Funding. Vasu:Stemline Therapeutics: Research Funding; Boehringer-Ingelheim: Research Funding.

Transplant Associated Thrombotic Microangiopathy (TA-TMA) Commonly Occurs after Steroid-Refractory or Dependent Gastrointestinal (GI) Graft Versus Host Disease (GVHD) and Contributes to Post-Transplant Morbidity

Background: Hematopoietic cell transplantation associated thrombotic microangiopathy (TA-TMA) shares common features with atypical hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. TA-TMA affects multiple organ systems resulting in multi-organ failure and non-relapse mortality. Recently, complement activation has been shown to be associated with TA-TMA leading to utilization of complement blockade as a therapeutic intervention in TA-TMA. We sought to evaluate the incidence of TA-TMA in patients with GVHD. We hypothesized that patients with gastrointestinal (GI) GVHD with transfusion dependence and renal dysfunction have a concomitant diagnosis of TA-TMA and that this contributes to worse outcomes.Methods: We performed a retrospective review of 124 patients with grade 3/4 GI GVHD admitted October 2008-October 2016. Patients who did not achieve a response by 7 days of 2mg/kg steroids were defined as steroid-refractory and patients who had flare of GVHD symptoms requiring a second course of 2mg/kg steroids were defined as steroid-dependent GVHD. We collected transplant-related data, number of hospitalizations, infections, length of stay and number of platelet/ pRBC transfusions. We assigned patients to groups by likelihood of TA-TMA based on presence of two out of three criteria: (1) > 2 transfusions after first GI biopsy, (2) evidence of hemolysis (schistocytes or nucleated RBCs) with negative Coombs' test and (3) evidence of renal dysfunction. 29/124 patients had paired samples for measurement of complement activation at time of GVHD diagnosis and 2-6 weeks later. Markers of complement activation included C5a and C5b-9 (terminal complement pathway), C4d (Classical pathway), and BBPlus (Alternative pathway).Results: The median age at transplant was 54 years (19-72) and 40.3% were female. Reduced intensity or non-myeloablative conditioning was used in 66.1% of patients and all but 10 patients received tacrolimus. The median time to GVHD onset was 38 days (range: 12-273).TA-TMA and GVHD. A total of 84 (67.7%) subjects met at least 2 criteria for TA-TMA. TA-TMA typically occurred after GVHD at a median of 142 days post-transplant and 78 days post-GVHD. The median time to GVHD was 38 days (12-273). Patients with steroid-refractory GVHD received more platelet and pRBC transfusions than those with steroid-responsive GVHD (p = 0.0018 and 0.0068, respectively) at 2 and 4 weeks post GVHD diagnosis (Figure 1). Patients with steroid-refractory or dependent GVHD were more likely to develop TA-TMA than those with steroid-responsive GVHD. Regardless of responsiveness of GVHD to steroids and accounting for differences in follow-up, patients with TA-TMA had longer length of hospital stay (median: 53 v. 25.5 days, p < 0.001) than patients without TA-TMA.Post-transplant infections in all patients included CMV reactivation (46.8%), other viral infection (60.5%), fungal infection (12.1%), and bacterial infection (65.3%). Renovascular complications included new or worsening hypertension (18.6%), acute kidney injury (45.2%), need for hemodialysis (16.9%), and proteinuria >30mg/dL (75.8%). In multivariable analysis, the risk factors for developing TA-TMA from time of transplant included acute GVHD, viral infection other than CMV, and fungal infection (Table 1).At 2-4 weeks after GVHD diagnosis, differential upregulation of alternative pathway (BBPlus) was seen in patients who went on to develop TA-TMA. It is notable that no differences in complement activation were seen at initial GVHD diagnosis, suggesting that TA-TMA appears to be a secondary event that follows GVHD.Discussion: We show that GVHD is a risk factor for development of TA-TMA and that patients with steroid-refractory/dependent GVHD are more likely to have TA-TMA than steroid-responsive patients. Patients with both GVHD and TA-TMA receive more transfusions and have longer hospitalizations than those with GVHD alone. Our work suggests that the alternative complement pathway (BBPlus) is upregulated in patients with GVHD and TA-TMA, suggesting that complement blockade may be evaluated as a therapeutic strategy in these patients. Prospective study is warranted to understand the triggers of TA-TMA in patients with GVHD, particularly the role of viral and fungal infections and whether complement biomarkers could differentiate between steroid-responsive and steroid refractory/dependent GVHD. [Display omitted] DisclosuresWilliam:Miragen: Consultancy, Honoraria. Blum:Pfizer: Consultancy; Boerhinger Ingelheim: Research Funding; Astellas: Consultancy. Jaglowski:Pharmacyclics: Consultancy, Research Funding. Mims:Novartis: Honoraria. Brammer:Celgene: Research Funding. Hofmeister:Karyopharm: Research Funding; Roche: Research Funding; Janssen: Research Funding; Thrassos: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Celgene: Research Funding. Walker:Gilead: Research Funding. Vasu:Stemline Therapeutics: Research Funding; Boehringer-Ingelheim: Research Funding.

Von Willebrand Factor as a Predictor for Transplant-Associated Thrombotic Microangiopathy.

Transplant-associated thrombotic microangiopathy (TA-TMA) after hematopoietic stem cell transplantation (HSCT) is a severe complication associated with underlying endothelial damage. Secreted and released von Willebrand factor (vWF) correlates with endothelial cell injury, but its role in predicting prognosis for TA-TMA is unclear. In this prospective study, we evaluated the relationship between vWF and the incidence of TA-TMA after HSCT. A total of 79 consecutive patients undergoing HSCT from August 2016 to June 2018 were enrolled. Twenty-three (29%) patients met the established diagnostic criteria. Patients with TA-TMA had significantly higher nonrelapse mortality compared with those without TA-TMA (78.3% vs 8.9%; P < .001). Multivariable analysis demonstrated that vWF was a predictive biomarker for TA-TMA. The vWF value was higher for the TA-TMA group (mean ± standard deviation, 380.7% ± 78.8% vs 284.9% ± 104.5%; P < .001), and the area under the curve for vWF in the diagnosis of TA-TMA was 0.756. Furthermore, patients with ≥325% vWF had a higher 2-year cumulative hazard of TA-TMA (53.1% ± 8.2% vs 7.5% ± 4.2%; P < .001) and a lower 2-year survival (32.1% ± 9.1% vs 83.7% ± 6.2%; P < .001) compared with those with <325% vWF.Conclusion:von Willebrand factor is a useful predictor and prognostic measure for TA-TMA, which may help clinicians identify and manage this life-threatening disease earlier.

Easix Is Strongly Associated with Complement Activation and Overall Survival in Adult Allogeneic Hematopoietic Cell Transplantation Recipients

Introduction: Endothelial dysfunction is a common denominator of graft-versus-host disease (GVHD) and transplant-associated thrombotic microangiopathy (TA-TMA). The latter is also characterized by excessive complement activation. Recent studies have introduced the Endothelial Activation and Stress Index (EASIX) as a potential predictor of survival in patients with GVHD. We hypothesized that EASIX would predict complement activation and survival in patients with GVHD and TA-TMA. Methods: We enrolled consecutive adult TA-TMA (International Working Group/IWG criteria), acute and/or chronic GVHD and control allogeneic hematopoietic cell transplantation (HCT) recipients in a 1:1:1 ratio (January 2015-December 2018). Plasma was collected and stored immediately at -80oC at the first day of confirmed TA-TMA or GVHD diagnosis and at a similar post-transplant period in control recipients. EASIX [lactate dehydrogenase (U/L) × creatinine (mg/dL)/thrombocytes (10⁹ cells per L)] was calculated at day 0, 30, 100 and last follow-up. Complement activation was detected measuring soluble C5b-9/membrane attack complex (ELISA, Quidel). Results: We studied 20 TA-TMA, 20 GVHD and 20 control patients (Table 1). TA-TMA developed at a median of 125 post-transplant day (range 9-2931); whereas the first day of confirmed GVHD diagnosis was at a median of 78 post-transplant day (range 16-145). EASIX at day 100 and last follow-up differed significantly among groups (p=0.014 and p=0.001, Table 1), although there was no significant difference between TA-TMA and GVHD patients. In contrast, soluble C5b-9 was significantly higher in TA-TMA compared to GVHD (p=0.008) and control patients (p&lt;0.001, Bonferroni's correction). Soluble C5b-9 levels were strongly associated with EASIX at day 100 and last follow-up (r=0.318, p=0.018 and r=0.321, p=0.020). Among laboratory values used to calculate EASIX (LDH, creatinine, platelets), C5b-9 was associated only with creatinine levels at day 100 (r=0.316, p=0.023), suggesting that the association between EASIX and C5b-9 is not driven by laboratory values per se. Furthermore, EASIX at day 0 and last follow-up was significantly associated with overall survival (p=0.013 and p=0.046). Among other pre-transplant factors studied (age, disease type and phase at transplant, donor), EASIX at day 0 was an independent predictor of overall survival (beta=2.627, p=0.029). Conclusion: Our study shows for the first time that EASIX predicts complement activation and overall survival in patients with endothelial dysfunction syndromes and control HCT recipients. Our findings suggest that EASIX may be a useful dynamic marker reflecting the course of endothelial dysfunction in these patients. Disclosures No relevant conflicts of interest to declare.