Age, GVHD prophylaxis, and timing matter in thrombotic microangiopathy after haematopoietic cell transplantation-A secondary 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.

D-dimer and sinusoidal obstructive syndrome-novel poor prognostic features of thrombotic microangiopathy in children after hematopoietic cellular therapy in a single institution prospective cohort study.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a common, severe complication of allogeneic hematopoietic cellular therapy (HCT). Even when treated in many studies, morbidity and mortality rates are high. This prospective single-institution cohort study serially enrolled all allogeneic HCT recipients from August 2019-August 2022. Patients were universally screened for TA-TMA and intermediate and high-risk patients were immediately treated with eculizumab. Sub-distribution cox-proportional hazards models were used to identify sub-distribution hazard ratios (sHR)  for multi-organ dysfunction (MOD) and non-relapse-related mortality (NRM). Of 136 patients, 36 (26%) were diagnosed with TA-TMA and 21/36 (58%) developed MOD, significantly more than those without TA-TMA, (p < .0001). Of those with TA-TMA, 18 (50%) had high-risk TA-TMA (HR-TA-TMA), 11 (31%) had intermediate-risk TA-TMA (IR-TA-TMA), and 8 (22%) had standard risk (SR-TA-TMA). Twenty-six were treated with eculizumab (1/8 SR, 7/11 IR, and 18/18 HR). Elevated D-dimer predicted the development of MOD (sHR 7.6, 95% confidence interval [CI] 1.8-32.3). Children with concurrent sinusoidal obstructive syndrome (SOS) and TA-TMA had an excess risk of MOD of 34% and data supported a biologic interaction. The adjusted NRM risk was significantly higher in the TA-TMA patients (sHR 10.54, 95% CI 3.8-29.2, p < .0001), despite prompt treatment with eculizumab. Significant RF for NRM in TA-TMA patients included SOS (HR 2.89, 95% 1.07-7.80) and elevated D-dimer (HR 3.82, 95% CI 1.14-12.84). An unrelated donor source and random urine protein to creatine ratio ≥2 mg/mg were significantly associated with no response to eculizumab (odds ratio 15, 95% CI 2.0-113.6 and OR 6.5, 95% CI 1.1-38.6 respectively). TA-TMA was independently associated with NRM despite early diagnosis and treatment with eculizumab in this large pediatric transplant cohort. Prognostic implications of D-dimer in TA-TMA merit further investigation as this is a readily accessible biomarker. Concurrent SOS is an exclusion criterion of many ongoing clinical trials, but these data highlight these patients could benefit from novel therapeutic approaches. Multi-institutional clinical trials are needed to understand the impact of TA-TMA-targeted therapies.

Emerging therapeutic and preventive approaches to transplant-associated thrombotic microangiopathy.

PURPOSE OF REVIEW: Transplant-associated thrombotic microangiopathy (TA-TMA) is a complication that can occur in both allogeneic and autologous haematopoietic cellular therapy (HCT) recipients and is associated with significant morbidity and mortality. Although TA-TMA is a complex disease, there is emerging evidence that complement activation and endothelial dysfunction play a key role in the pathophysiology of the disease. The use of eculizumab has improved survival in patients with high risk and severe disease, but mortality rates in treated patients still exceed 30%, highlighting the need for novel approaches. RECENT FINDINGS: There are multiple ongoing and planned clinical trials investigating novel complement agents in TA-TMA and other TMAs. Drugs vary by targets of the complement system, mechanism, and form of administration. Clinical trial designs include single arm studies that span across multiple age groups including children, and double-blind, randomized, placebo-controlled studies. These studies will provide robust data to inform the care of patients with TA-TMA in the future. In addition to multiple promising therapeutic agents, preventing TA-TMA is an emerging strategy. Agents known to protect the endothelium from damage and augment endothelial function by promoting anti-inflammatory and antithrombotic effects may have a role in preventing TA-TMA or ameliorating the severity, though additional studies are needed. SUMMARY: Novel therapeutic agents for TA-TMA inhibition of the complement system are under investigation and prophylactic strategies of endothelial protection are emerging. Further understanding of the pathophysiology of the disease may identify additional therapeutic targets. Multiinstitutional, collaborative clinical trials are needed to determine the safety and efficacy of these agents going forward.

DICER1-associated central nervous system sarcoma in children: comprehensive clinicopathologic and genetic analysis of a newly described rare tumor.

The spectrum of neoplasms associated with DICER1 variants continues to expand, with the recent addition of primary "DICER1-associated central nervous system sarcoma" (DCS). DCS is a high-grade malignancy predominantly affecting pediatric patients. Six pediatric DCS were identified through a combination of clinical diagnostic studies, archival inquiry, and interinstitutional collaboration. Clinical, histologic, immunohistologic, and molecular features were examined. Genomic findings in the 6 DCS were compared with those in 14 additional DICER1-associated tumors sequenced with the same assay. The six patients presented at ages 3-15 years with CNS tumors located in the temporal (n = 2), parietal (n = 1), fronto-parietal (n = 1), and frontal (n = 2) lobes. All underwent surgical resection. Histologic examination demonstrated high-grade malignant spindle cell tumors with pleuropulmonary blastoma-like embryonic "organoid" features and focal rhabdomyoblastic differentiation; immature cartilage was seen in one case. Immunohistochemically, there was patchy desmin and myogenin staining, and patchy loss of H3K27me3, and within eosinophilic cytoplasmic globules, alfa-fetoprotein staining. Biallelic DICER1 variants were identified in all cases, with germline variants in two of five patients tested. DCS demonstrated genomic alterations enriched for Ras pathway activation and TP53 inactivation. Tumor mutational burden was significantly higher in the 6 DCS tumors than in 14 other DICER1-associated tumors examined (mean 12.9 vs. 6.8 mutations/Mb, p = 0.035). Postoperative care included radiation (n = 5) and chemotherapy (n = 3); at the last follow-up, three patients were alive without DCS, and three had died of disease. Our analysis expands the clinical, histologic, immunohistological, and molecular spectrum of DCS, identifying distinctive features that can aid in the diagnosis, multidisciplinary evaluation, and treatment of DCS.

Thrombotic Microangiopathy Following Pediatric Autologous Hematopoietic Cell Transplantation: A Report of Significant End-Organ Dysfunction in Eculizumab-Treated Survivors.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a known complication of autologous hematopoietic cell transplantation (aHCT), particularly in children with neuroblastoma. We describe a pediatric single-institution experience of TA-TMA after aHCT. Data were abstracted from the medical record of patients who underwent aHCT between January 1, 2008, and July 1, 2018, at Boston Children's Hospital. TA-TMA was diagnosed using either the International Working Group criteria or the "probable TA-TMA criteria" of Cho et al. Overall, 318 aHCTs were performed in 243 patients. Nine patients (3.7%) were diagnosed with TA-TMA. TA-TMA occurred most frequently in children with neuroblastoma (n = 7; 78%), all of whom were conditioned with carboplatin, etoposide, and melphalan. The median age at aHCT in children who developed TA-TMA was 3 years, 5 months (range, 18 months to 25 years). TMA was diagnosed at a median of 35 days (range, 8 to 106 days) after stem cell infusion. On a retrospective chart review using the same criteria used by the provider, patients met criteria a median of 5 days before the clinical diagnosis (range, 0 to 58 days). Eight patients had renal involvement at presentation, including nephrotic range proteinuria and severe hypertension, requiring from 2 to 6 antihypertensive medications. Two patients presented with multiorgan failure. Six patients were treated with eculizumab a median of 0 days after TA-TMA diagnosis (range, 0 to 11 days). On retrospective review, patients were treated a median of 18 days (range, 0 to 58 days) after meeting criteria for TA-TMA. Before initiation of therapy, 4 of 6 patients checked for serum complement levels had normal values, 1 had elevated CH50 and 1 had elevated sC59-b and CH50. All patients had CH50 levels within the target range (≤3 CAE) after induction therapy. Two patients (33%) had no response to eculizumab and died of multiorgan failure. The other 4 had both a hematologic response with transfusion independence (median, 6.5 weeks; range, 4 to 9 weeks) and renal response, defined as resolution of nephrotic range proteinuria (median, 21 weeks; range, 13 to 25 weeks). Among the eculizumab-treated survivors, 2 patients remained on prolonged eculizumab therapy, and one had recurrence of TA-TMA after discontinuation of eculizumab. All 4 eculizumab treated survivors have persistent organ dysfunction. Three children were treated with supportive care only; 2 died of relapsed cancer, and the third is alive with stage 2 chronic kidney disease. The median duration of follow-up after TA-TMA diagnosis was 2.5 years (range, 9 months to 4 years). The 1-year overall survival was 78% (SE = 14%). However, regardless of treatment, no survivors had complete normalization of function in all organs. Three children with normal serum CH50 and sc5b-9 levels responded to eculizumab. This report highlights the importance of maintaining a high suspicion for TA-TMA after aHCT. Further study is warranted to identify individual risk factors for TMA after aHCT, predict the response to eculizumab, and capture long-term sequelae in survivors.

Severe, persistent neurotoxicity after transplant-associated thrombotic microangiopathy in a pediatric patient despite treatment with eculizumab.

BACKGROUND: TA-TMA is a described complication of aHCT in children with neuroblastoma. Outcomes are poor with mortality rates approaching 60%. Described late effects in survivors include chronic kidney disease and persistent pulmonary hypertension. CASE: We report a case of a 2-year-old with neuroblastoma who developed severe TA-TMA 35 days after high dose chemotherapy and autologous stem cell rescue. He presented with respiratory failure, pericardial and pleural effusions, hemolysis, hypertension, and mild altered mental status. He was mechanically ventilated for 3 weeks and after sedation was lifted, he was minimally responsive. He was treated with eculizumab with resolution of hemolysis, kidney injury and polyserositis. Initially he was more responsive; however, after almost a year of intensive therapy he remained nonverbal and had persistent irritability and behavioral changes. He had an extensive negative evaluation. On day +345, he presented with severe, refractory epilepsy. Three years after TA-TMA, he continues to have severe neurologic disabilities. CONCLUSIONS: To our knowledge, persistent neurologic toxicity has not been reported in TA-TMA. However, deficits and seizures are reported in other TMAs, particularly in children with atypical HUS who present with significant neurologic changes at diagnosis. Our patient's persistent neurologic disability despite eculizumab response in all other involved organs may reflect irreversible damage. This case describes a new long-term sequela of TA-TMA and highlights the need for further studies to understand both acute and long-term neurologic complications of this disease.

Increasing observation rates in low-risk pediatric immune thrombocytopenia using a standardized clinical assessment and management plan (SCAMP® ).

An observational approach is recommended in newly diagnosed children with immune thrombocytopenia (ITP) at low risk of bleeding; however, there is no standard definition of risk. A standardized clinical assessment and management plan (SCAMP® ), a modifiable practice guideline, was implemented and revised (SCAMP-1 and SCAMP-2) and applied to 71 newly diagnosed patients with ITP. The Buchanan and Adix bleeding score guided treatment and was modified by stratifying by low- and high-risk grade 3 bleeding in SCAMP-2. Observation rates increased from 40% to 74% from SCAMP-1 to SCAMP-2 (P < 0.05) with no bleeding complications. We propose a modified bleeding score that increased observation rates in low-risk patients with ITP.

Treatment and outcomes of immune cytopenias following solid organ transplant in children.

BACKGROUND: Immune cytopenias are a recognized life-threatening complication following pediatric solid organ transplants (SOT), but treatment responses and overall outcome are not well described. The aim of this study was to evaluate the demographic characteristics, response to treatments, and outcomes of a cohort of patients who developed immune cytopenias following SOT. PROCEDURE: In this single center retrospective review, patients with immune cytopenias after SOT were identified by electronic medical record (EMR) search and transplant databases from 1995-2012. RESULTS: Of 764 SOT patients, 19 (2.4%) developed immune cytopenias. Incidence varied widely by transplant type from 1.2% (renal) to 23.5% (multivisceral). Autoimmune hemolytic anemia (AIHA) was the most common immune cytopenia. Overall median time from transplant to immune cytopenia was 8 m and varied by transplant type from 3 m (liver) to 74 m (heart). Standard therapies for immune cytopenias were often used and ineffective. The most effective therapy for the immune cytopenia was changing immunosuppression from tacrolimus to another agent. Three of 19 patients died; none directly attributed to the immune cytopenia. CONCLUSIONS: Immune cytopenias are not rare after SOT, and patients usually do not respond well to traditional first line therapies. Provided that the risk of organ rejection is otherwise manageable, temporary cessation of tacrolimus could be more widely explored in this challenging clinical context. Pediatr Blood Cancer 2015;62:214-218. © 2014 Wiley Periodicals, Inc.

Pediatric transplant-associated thrombotic microangiopathy health care utilization and implications of eculizumab therapy.

ABSTRACT: The health care use (HCU) burden of transplant-associated thrombotic microangiopathy (TA-TMA) and its treatments are unknown. The objective of this study was to investigate inpatient costs associated with meeting criteria for TA-TMA in the first year after hematopoietic cell transplant (HCT). This institutional review board-approved retrospective multicenter study included serial children who underwent HCT from 1 January 2015 to 1 July 2019. A standardized unit cost (adjusted for geographic location, differences in cost of living, and inflation) for inpatient hospitalization was extracted from the Pediatric Health Information System data and linked to clinical data. Both total cost and cost per day from 15 days before stem cell infusion to 1-year after HCT were calculated. Among allogeneic (allo) transplant recipients, after adjusting for severe grade 3/4 acute graft-versus-host disease (GVHD), infections, and HLA mismatch, costs were not different in TA-TMA (n = 137) vs no TA-TMA (n = 238). Severe GVHD was significantly associated with increased costs. Among allo high-risk (HR) TMA-TMA, unadjusted costs were significantly higher in the eculizumab-treated cohort (n = 19) than in the supportive care group (n = 36). However, after adjusting for gastrointestinal bleeding that occurred disproportionately in the eculizumab (n = 6) vs supportive care (n = 0) cohort, eculizumab treatment was not associated with increased total costs. More studies are needed to determine the etiology of increased HCU costs in those with HR-TA-TMA and predict those more likely to benefit from eculizumab, reducing HCU and improving outcomes.

Real-World Application of Recently Proposed ASTCT/CIBMTR/EBMT/APBMT Consensus Risk Stratification for Transplantation-Associated Thrombotic Microangiopathy in Children.

Consensus diagnostic and risk stratification of transplantation-associated thrombotic microangiopathy (TA-TMA) was recently achieved from international transplantation groups. Although the proposed diagnostic criteria have been applied to multiple pediatric cohorts, there are scant data applying the novel risk stratification approach in children with TA-TMA. In 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 the Jodele criteria from August 2019 to October 2023. Our institutional practice during the study period was treat all Jodele intermediate-risk (IR) and high-risk (HR) patients with eculizumab. Harmonization risk stratification criteria were applied retrospectively. All survival analyses were calculated from the day of TA-TMA diagnosis. To identify which specific harmonization high-risk features were the most important predictors for nonrelapse mortality (NRM), full and reduced logistical regression models were tested. The lowest Bayes information criterion and optimal Mallows CP statistic were used to identify the best subset. The analysis was performed with SAS 9.4 (SAS Institute, Cary, NC). Fifty-two children were diagnosed with TA-TMA during the study period, at a median of 37.5 days post-HCT (range, 3 to 735 days). Using Jodele risk stratification, 11 (21%) were SR, 21 (40%) were IR, and 20 (39%) were HR. Forty (77%) were treated with eculizumab. There were no statistically significant differences in NRM among Jodele risk groups, although overall survival (OS) differed significantly. Using the harmonized stratification, 49 children (94%) were stratified as HR and 3 as standard risk (SR), there were no statistically significant differences in NRM or OS between groups. Eight children (15.4%) were classified as SR using Jodele risk stratification but restratified as HR using the harmonization criteria. One child (12.5%) died in the setting of severe GVHD, and the remaining 7 were alive at the last follow-up. In a best subset model, lactate dehydrogenase (LDH) level >2 times the upper limit of normal (ULN) (odds ratio [OR], 6.52, 95% confidence interval [CI], .96 to 44.3; P = .05), grade II-IV acute graft-versus-host disease (GVHD) at the time of TA-TMA diagnosis (OR, 15.4; 95% CI, 2.14 to 110.68; P = .01), and organ dysfunction at the time of TA-TMA (OR, 21.5; 95% CI, 2.96 to 156.37; P = .002) were significantly associated with NRM; elevated sC5b-9, urine protein/creatinine ratio, and viral infections were not significantly associated with NRM. Using these best-fit criteria, 14 patients were classified as SR and 38 were classified as HR, NRM was significantly higher, and OS was significantly lower. In this cohort of children with TA-TMA, retrospective application of the harmonization criteria resulted in more patients stratified as HR compared to use of the previously described Jodele criteria. The intention of the harmonization criteria was to identify those at greatest 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 organ dysfuncion, acute GVHD, and LDH >2 times ULN are the most important predictors of NRM in this cohort, allowing risk stratification even in the absence of available sC5b-9 testing. Additional studies are needed to validate these findings.

Epidemiology of Diffuse Alveolar Hemorrhage in Pediatric Allogeneic Hematopoietic Cell Transplant Recipients.

BACKGROUND: Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary toxicity that can arise after hematopoietic cell transplantation (HCT). Risk-factors and outcomes are not well-understood due to a sparsity of cases spread across multiple centers. OBJECTIVES: The objectives of this epidemiologic study were to characterize the incidence, outcomes, transplant-related risk factors and co-morbid critical care diagnoses associated with post-HCT DAH. STUDY DESIGN: Retrospective analysis was performed on a multi-center cohort of 6,995 patients ≤21 years old who underwent allogeneic HCT between 2008-2014 identified through the Center for International Blood and Marrow Transplant Research registry and cross-matched with the Virtual Pediatric Systems database to obtain critical care characteristics. A multivariable Cox-proportional hazard model was used to determine risk factors for DAH. Logistic regression models were used to determine critical care diagnoses associated with DAH. Survival outcomes were analyzed using both a landmark approach and Cox-regression with DAH as a time-varying covariate. RESULTS: DAH occurred in 81 patients at a median 54 days post-HCT (IQR 23-160 days), with a 1-year post-transplant cumulative incidence probability of 1.0% (95% CI 0.81-1.3%) and was noted in 7.6% of all PICU patients. Risk factors included transplant for non-malignant hematologic disease (Referent: malignant hematologic disease, HR=1.98, 95% CI 1.22-3.22, p=0.006), use of calcineurin inhibitor plus mycophenolate mofetil (CNI + MMF) as GvHD prophylaxis, (Referent: calcineurin inhibitor plus methotrexate, HR=1.89, 95% CI 1.07-3.34, p=0.029), and grade III-IV acute GvHD (HR=2.67, 95% CI 1.53-4.66, p<0.001). Critical care admitted patients with DAH had significantly higher rates of systemic hypertension, pulmonary hypertension, pericardial disease, renal failure, and bacterial/viral/fungal infections (p<0.05) than those without DAH. From the time of DAH, median survival was 2.2 months and one-year overall survival was 26% (95% CI 17-36%). Among all HCT patients, the development of DAH when considered was associated with a seven-fold increase in unadjusted all-cause post-HCT mortality (HR 6.96, 95% CI 5.42-8.94, p<0.001). In a landmark analysis of patients alive 2 months post-HCT, patients who developed DAH had a one-year overall survival of 33% (95% CI 18-49%) versus 82% (95% CI 81-83%) for patients without DAH (p<0.001). CONCLUSION: Although DAH is rare, it is associated with high mortality in the post-HCT setting. Our data suggest that clinicians should have a heightened index of suspicion of DAH in patients with pulmonary symptoms in the context of non-malignant hematologic transplant indication, use of CNI + MMF as GvHD prophylaxis and severe acute GvHD. Further investigations and validation of modifiable risk factors are warranted given poor outcomes.

Compassionate Use Narsoplimab for Severe Refractory Transplantation-Associated Thrombotic Microangiopathy in Children.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a common and potentially severe complication of hematopoietic cell transplantation. TA-TMA-directed therapy with eculizumab, a complement C5 inhibitor, has resulted in a survival benefit in some studies. However, children with TA-TMA refractory to C5 inhibition with eculizumab (rTA-TMA) have mortality rates exceeding 80%, and there are no other known therapies. Narsoplimab, an inhibitor of the MASP-2 effector enzyme of the lectin pathway, has been studied in adults with TA-TMA as first-line therapy with a response rate of 61%. Although there are limited data on narsoplimab use as a second-line agent in children, we hypothesized, that complement pathways proximal to C5 are activated in rTA-TMA, and that narsoplimab may ameliorate rTA-TMA in children. In this single-center study, children were enrolled on single-patient, Institutional Review Board-approved compassionate use protocols for narsoplimab treatment. Clinical complement lab tests were obtained at the discretion of the treating physician, although all patients were also offered participation in a companion biomarker study. Research blood samples were obtained at the time of TA-TMA diagnosis, prior to eculizumab treatment, at the time of refractory TA-TMA diagnosis prior to the first narsoplimab dose, and 2 weeks after the first narsoplimab dose. Single ELISA kits were used to measure markers of complement activation according to the manufacture's instructions. Five children with rTA-TMA received narsoplimab; 3 were in multiorgan failure and 2 had worsening multiorgan dysfunction at the time of treatment. Additional comorbidities at the time of treatment included sinusoidal obstructive syndrome (SOS; n = 3), viral infection (n = 3), and steroid-refractory stage 4 lower gut grade IV acute graft-versus-host disease (aGVHD, n = 3). Two infants with concurrent SOS and no aGVHD had resolution of organ dysfunction; 1 also developed transfusion-independence (complete response), and the other's hematologic response was not assessable in the setting of leukemia and chemotherapy (partial response). One additional patient achieved transfusion independence but had no improvement in organ manifestations (partial response), and 2 patients treated late in the course of disease had no response. Narsoplimab was well tolerated without any attributed adverse effects. Three patients consented to provide additional research blood samples. One patient with resolution of organ failure demonstrated evidence of proximal pathway activation prior to narsoplimab treatment with subsequent declines in Ba, Bb, C3a, and C5a and increases in C3 in both clinical and research lab tests. Otherwise, there was no clear pattern of other complement markers, including MASP-2 levels, after therapy. In this cohort of ill children with rTA-TMA and multiple comorbidities, 3 patients benefited from narsoplimab. Notably, the 2 patients with resolution of organ involvement did not have steroid-refractory aGVHD, which is thought to be a critical driver of TA-TMA. Additional studies are needed to determine which patients are most likely to benefit from narsoplimab and which markers may be most helpful for monitoring lectin pathway activation and inhibition.

Pulmonary hypertension in the intensive care unit after pediatric allogeneic hematopoietic stem cell transplant: incidence, risk factors, and outcomes.

Objective: To determine the incidence, risk factors, and outcomes of pulmonary hypertension (PH) in the pediatric intensive care unit (PICU) after pediatric hematopoietic stem cell transplant (HCT). Methods: This was a retrospective study of pediatric patients who underwent allogeneic HCT between January 2008-December 2014 at a center contributing to the Center for International Blood and Marrow Transplant Research data registry. Incidence of PH was assessed from PICU diagnostic codes from records merged from the Virtual Pediatric Systems database. Regression and survival analyses identified factors associated with post-HCT PH. Additional post-HCT morbidities and survival after PH were also assessed. Results: Among 6,995 HCT recipients, there were 29 cases of PH, a cumulative incidence of 0.42% (95% CI 0.27%-0.57%) at 60 months post-HCT. In the sub-cohort of 1,067 patients requiring intensive care after HCT, this accounted for a PH prevalence of 2.72% (95% CI 1.74-3.69%). There was an increased risk of developing PH associated with Black/African American race, metabolic disorders, partially HLA-matched or cord blood allografts, graft-versus-host prophylaxis regimen, and lower pre-HCT functional status. Patients who developed PH had significant PICU comorbidities including heart failure, pulmonary hemorrhage, respiratory failure, renal failure, and infections. Survival at 6 months after diagnosis of post-HCT PH was 51.7% (95% CI 32.5%-67.9%). Conclusions: PH is a rare but serious complication in the pediatric post-HCT population. A significant burden of additional comorbidities, procedural interventions, and risk of mortality is associated with its development. Close monitoring and prompt intervention for this severe complication are necessary in this vulnerable population.

Sickle cell disease is a risk factor for transplant-associated thrombotic microangiopathy in children.

Transplant-associated thrombotic microangiopathy (TA-TMA) and sickle cell disease (SCD) share features of endothelial and complement activation. Thus, we hypothesized that SCD is a risk factor for TA-TMA and that prehematopoietic cellular transplantation (HCT) markers of endothelial dysfunction and complement activation would be higher in patients with SCD. Children who underwent initial haploidentical or matched sibling donor HCT between January 2015 and June 2020 were included in this institutional review board-approved, single institution, retrospective study. Of the 115 children, 52 had SCD, and 63 underwent HCT for non-SCD indications. There was no significant difference in severe grade 3 to 4 acute graft-versus-host disease (GVHD) between recipients of HCT with or without SCD. The non-SCD cohort had significantly more cytomegalovirus-positive recipients, radiation-containing preparative regimens, and peripheral blood stem cell graft sources (P ≤ .05), all described risk factors for developing TA-TMA. Despite this, 7 of 52 patients (13%) with SCD developed TA-TMA compared with 1 of 63 patients (2%) without SCD (P = .015). Risk was highest in those who underwent haploidentical HCT (odds ratio [OR], 33; 95% confidence interval [CI], 1.4-793.2). Adjusting for HLA match, GVHD, post-HCT viral infection, stem cell source, and myeloablation, SCD remained a risk for developing TA-TMA (OR, 12.22; 95% CI, 1.15-129.6). In available pre-HCT samples, there was no difference in complement biomarkers between those with SCD and those without, though patients with SCD did have significantly higher levels of markers of endothelial activation, soluble vascular cell adhesion molecule 1, and P-selectin. In conclusion, children with SCD merit careful screening for TA-TMA after HCT, particularly those receiving a haploidentical HCT.

Pulmonary Manifestations and Vascular Changes in Pediatric Transplantation-Associated Thrombotic Microangiopathy.

Although transplant-associated thrombotic microangiopathy (TA-TMA) commonly complicates pediatric hematopoietic cellular therapy (HCT), pulmonary manifestations and histology of TA-TMA (pTA-TMA) are rarely reported, with scant data available on timing, risk factors, pathogenesis, and outcomes. Pulmonary hypertension (PH) and diffuse alveolar hemorrhage (DAH) are recognized manifestations of pTA-TMA. The objective of this study was to characterize the pathologic findings, outcomes, and coincident diagnoses preceding biopsy-proven pTA-TMA. In Institutional Review Board- approved retrospective studies, available lung tissue was reviewed at 2 institutions between January 2016 and August 2021 to include those with pulmonary vascular pathology. Histologic features of pTA-TMA were present in 10 children with prior respiratory decline after an allogeneic HCT (allo-HCT; n = 9) or autologous HCT (n = 1). Pathologic lesions included muscular medialization, microthrombi, and red cell fragments, in addition to perivasculitis and intimal arteritis. Parenchymal findings included diffuse alveolar damage, organizing pneumonia, and plasmocytic infiltrates. Six children were clinically diagnosed with TA-TMA, and all were treated with eculizumab, at a median of 2.5 days after clinical diagnosis (range, 0 to 11 days). Four were identified postmortem. Coincident pulmonary infection was confirmed in 8 of the 10 patients. Five allo-HCT recipients (56%) experienced graft-versus-host disease (GVHD; 4 acute, 1 chronic) prior to the onset of respiratory symptoms. Two patients (20%) had clinically recognized DAH, although 9 (90%) had evidence of DAH on histology. Although all 10 patients underwent echocardiography at the time of symptom onset and 9 had serial echocardiograms, only 2 patients had PH detected. Treatments varied and included sildenafil (n = 3), steroids (n = 1), and eculizumab (n = 6). One patient was alive at the time of this report; the remaining 9 died, at a median of 52 days after onset of respiratory symptoms (range 4 to 440 days) and a median of 126 days post-HCT (range, 13 to 947 days). pTA-TMA is a heterogeneous histologic disease characterized by arteriolar inflammation, microthrombi, and often DAH. pTA-TMA presented with respiratory decline with systemic TA-TMA in all patients. Clinicians should maintain a high degree of suspicion for DAH in patients with TA-TMA and pulmonary symptoms. Coincident rates of GVHD and pulmonary infections were high, whereas the rate of PH identified by echocardiography was 20%. Outcomes were poor despite early use of eculizumab and other therapies. Our data merit consideration of pTA-TMA in patients with acute respiratory decline in the setting of systemic TA-TMA, GVHD, and infection. Investigation of additional therapies for pTA-TMA is needed as well. © 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Short-Course Empiric Antibiotics in Children Undergoing Allogeneic Hematopoietic Cell Transplantation.

Fever is common in children undergoing hematopoietic cell transplantation (HCT). Empiric antibiotic (EA) therapy is initiated and often continued until neutrophil engraftment. Prolonged antibiotic exposure reduces microbiome diversity and causes overgrowth of pathogenic organisms, leading to such complications as infections from antibiotic-resistant organisms and Clostridium difficile colitis. Shorter courses of EA therapy have been studied in adults undergoing HCT without significant safety concerns, but data in children are lacking. We instituted a single-center preintervention/ postintervention quality improvement (QI) project to assess the feasibility of short-course EA therapy for first fever in patients undergoing HCT. We aimed to reduce the median duration of broad-spectrum antibiotic use in eligible patients from 20 days in 2020 to 10 days in 2021. Patients were eligible for the intervention, limiting EAs to 7 days for first fever, if they were admitted for their first allogeneic HCT, were afebrile for >24 hours, had no infection requiring systemic treatment, and were hemodynamically stable. Outcome measures included days of EA therapy for first fever and total broad-spectrum antibiotic use during the period of hospitalization, defined as the time from the start of conditioning to 30 days after HCT or hospital discharge, whichever occurred first. Balancing measures included bloodstream infection (BSI), fever, and intensive care (ICU) admission within 3 days of stopping EA therapy. Project criteria were applied retrospectively to patients who underwent HCT in 2020 to construct a preintervention short-course-eligible cohort. During the intervention period, 41 patients underwent allogeneic HCT, of whom 17 (41%) were eligible for short-course EA therapy. Among eligible patients, the median age was 5.3 years, 47% had an underlying malignancy, and 88% received myeloablative conditioning. There were no differences in demographic or HCT characteristics between patients eligible for short-course EA during the intervention and preintervention period (n = 24). The short-course EA schedule was adhered to by 14 of the 17 eligible patients (82%). The duration of EA for first fever and total broad-spectrum antibiotic use was significantly decreased in the short-course EA-eligible patients compared to the preintervention cohort, from a median of 17 days to 8 days and from 20 days to 10 days, respectively (P < .01). Of the 14 patients adhering to short-course EA, 2 experienced a balancing measure of recurrent fever requiring resumption of EA, but no infection was identified. There were no BSIs, ICU admissions, or deaths during the hospitalization period in patients who received short-course EA. In this single-center QI project, short-course EA for initial fever was successfully applied to children undergoing allogeneic HCT using strict criteria and led to a significant decrease in broad-spectrum antibiotic use during hospitalization. These results should be validated in a prospective clinical trial to include the impact of short-course EA on antibiotic-resistant organisms, the intestinal microbiome, and HCT outcomes.

Diffuse alveolar hemorrhage after hematopoietic cell transplantation- response to treatments and risk factors for mortality.

Diffuse alveolar hemorrhage (DAH) is a life-threatening complication of hematopoietic cellular therapy (HCT). This study aimed to evaluate the effect of DAH treatments on outcomes using data from consecutive HCT patients clinically diagnosed with DAH from 3 institutions between January 2018-August 2022. Endpoints included sustained complete response (sCR) defined as bleeding cessation without recurrent bleeding, and non-relapse mortality (NRM). Forty children developed DAH at a median of 56.5 days post-HCT (range 1-760). Thirty-five (88%) had at least one concurrent endothelial disorder, including transplant-associated thrombotic microangiopathy (n=30), sinusoidal obstructive syndrome (n=19), or acute graft versus host disease (n=10). Fifty percent had a concurrent pulmonary infection at the time of DAH. Common treatments included steroids (n=17, 25% sCR), inhaled tranexamic acid (INH TXA,n=26, 48% sCR), and inhaled recombinant activated factor VII (INH fVIIa, n=10, 73% sCR). NRM was 56% 100 days after first pulmonary bleed and 70% at 1 year. Steroid treatment was associated with increased risk of NRM (HR 2.25 95% CI 1.07-4.71, p=0.03), while treatment with INH TXA (HR 0.43, 95% CI 0.19- 0.96, p=0.04) and INH fVIIa (HR 0.22, 95% CI 0.07-0.62, p=0.005) were associated with decreased risk of NRM. Prospective studies are warranted to validate these findings.

BCMA CAR-T induces complete and durable remission in refractory plasmablastic lymphoma.

Plasmablastic lymphoma (PBL) is a rare subtype of aggressive large B-cell lymphoma, with a dismal prognosis despite aggressive therapies. New approaches are needed for those with refractory disease. PBL expresses antigens similar to multiple myeloma (MM), including B-cell maturation antigen (BCMA). Chimeric antigen receptor T-cell (CAR-T) therapy directed against BCMA has shown efficacy for the treatment of heavily pretreated MM with low rates of grades 3 and 4 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) in a phase Ib/II trial (A Study of JNJ-68284528, a CAR-T Directed Against BCMA in Participants With Relapsed or Refractory Multiple Myeloma (CARTITUDE-1), NCT03548207). However, data for the use of BCMA CAR-T for treating PBL are lacking.We report a challenging case of multiple refractory PBL that emerged from B-cell acute lymphoblastic leukemia in an adolescent who failed to respond to an allogeneic hematopoietic cell transplant. The patient developed rapidly advancing disease despite withdrawal of immunosuppression, treatment with etoposide, ibrutinib, and daratumumab, prompting consideration of BCMA CAR-T (under emergency investigational new drug (eIND)). The patient achieved a complete remission (CR), without recurrent acute graft versus host disease (GVHD), CRS or ICANS after BCMA CAR-T therapy. BCMA CAR-T expansion was detected in vivo, peaking on day 15. The patient remains in CR for more than a year post CAR-T therapy, supporting consideration of immunotherapy for future patients with refractory PBL, a disease with few treatment options.

A systematic review of diagnostic, prognostic, and risk blood and urine biomarkers of transplant-associated thrombotic microangiopathy.

Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of allogeneic and autologous hematopoietic cellular therapy (HCT), associated with significant morbidity and mortality. Although the central drivers of the disease are thought to be endothelial damage and complement activation, no specific diagnostic biomarkers have been identified. TA-TMA is typically diagnosed using criteria comprised of non-specific clinical and laboratory features. Some patients will have a self-remitting course, but more than half develop multi-organ dysfunction or die, making prognostic biomarkers critical. Prevention of TA-TMA, an approach central to other HCT complications such as graft-versus-host disease, is largely untested in part due to a lack of identified early high-risk biomarkers. We conducted a systematic review to summarize the diagnostic, early risk, and prognostic biomarkers of TA-TMA. We screened the titles and abstracts of 1524 citations. After screening out duplications, we read the abstracts of 979 papers and fully reviewed 132 full-text publications. Thirty-one publications fulfilled the inclusion criteria of more than five patients with TA-TMA and a reported measure of association with diagnosis, prognosis, or risk of later development of the disease. Fourteen studies (45%) were with adults, 12 (39%) were with children <18 years old, three included both children and adults, and two did not report age. There were 53 biomarker or biomarker signature entries, and a total of 27 unique biomarkers. Only four biomarkers reported sensitivity and specificity. The single biomarker with the most robust data was sC5b-9, which conferred diagnostic, prognostic, and risk implications. Studies of combinations of biomarkers were rare. No meta-analyses were performed because of significant heterogeneity between studies. The limitations of studies included small sample size, study designs with a high risk of bias (i.e., case-control), the timing of sample collection, and the selection of controls. Furthermore, only two (6%) studies included a training and validation cohort. Cut-off points are needed to stratify groups, as most biomarkers do not have normal values, or normal values cannot be assumed in the HCT setting. In the future, multi-institutional, collaborative efforts are needed to perform rigorously designed, prospective studies with serially enrolled patients, with samples collected at the time of TA-TMA diagnosis, careful selection of controls, and validation of selected biomarkers and cut-off points in a separate cohort.