Transplant-Associated Thrombotic Microangiopathy in Pediatric Hematopoietic Cell Transplant Recipients: A Practical Approach to Diagnosis and Management

Transplant-associated thrombotic microangiopathy (TA-TMA) is an endothelial damage syndrome that is increasingly identified as a complication of both autologous and allogeneic hematopoietic cell transplantation (HCT) in children. If not promptly diagnosed and treated, TA-TMA can lead to significant morbidity (e.g., permanent renal injury) or mortality. However, as the recognition of the early stages of TA-TMA may be difficult, we propose a TA-TMA “triad” of hypertension, thrombocytopenia (or platelet transfusion refractoriness), and elevated lactate dehydrogenase (LDH). While not diagnostic, this triad should prompt further evaluation for TA-TMA. There is increased understanding of the risk factors for the development of TA-TMA, including those which are inherent (e.g., race, genetics), transplant approach-related (e.g., second HCT, use of HLA-mismatched donors), and related to post-transplant events (e.g., receipt of calcineurin inhibitors, development of graft-vs. -host-disease, or certain infections). This understanding should lead to enhanced screening for TA-TMA signs and symptoms in high-risk patients. The pathophysiology of TA-TMA is complex, resulting from a cycle of activation of endothelial cells to produce a pro-coagulant state, along with activation of antigen-presenting cells and lymphocytes, as well as activation of the complement cascade and microthrombi formation. This has led to the formulation of a “Three-Hit Hypothesis” in which patients with either an underlying predisposition to complement activation or pre-existing endothelial injury (Hit 1) undergo a toxic conditioning regimen causing endothelial injury (Hit 2), and then additional insults are triggered by medications, alloreactivity, infections, and/or antibodies (Hit 3). Understanding this cycle of injury permits the development of a specific TA-TMA treatment algorithm designed to treat both the triggers and the drivers of the endothelial injury. Finally, several intriguing approaches to TA-TMA prophylaxis have been identified. Future work on the development of a single diagnostic test with high specificity and sensitivity, and the development of a robust risk-scoring system, will further improve the management of this serious post-transplant complication

Physician decision making in selection of second-line treatments in immune thrombocytopenia in children.

Immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder which presents with isolated thrombocytopenia and risk of hemorrhage. While most children with ITP promptly recover with or without drug therapy, ITP is persistent or chronic in others. When needed, how to select second-line therapies is not clear. ICON1, conducted within the Pediatric ITP Consortium of North America (ICON), is a prospective, observational, longitudinal cohort study of 120 children from 21 centers starting second-line treatments for ITP which examined treatment decisions. Treating physicians reported reasons for selecting therapies, ranking the top three. In a propensity weighted model, the most important factors were patient/parental preference (53%) and treatment-related factors: side effect profile (58%), long-term toxicity (54%), ease of administration (46%), possibility of remission (45%), and perceived efficacy (30%). Physician, health system, and clinical factors rarely influenced decision-making. Patient/parent preferences were selected as reasons more often in chronic ITP (85.7%) than in newly diagnosed (0%) or persistent ITP (14.3%, P = .003). Splenectomy and rituximab were chosen for the possibility of inducing long-term remission (P < .001). Oral agents, such as eltrombopag and immunosuppressants, were chosen for ease of administration and expected adherence (P < .001). Physicians chose rituximab in patients with lower expected adherence (P = .017). Treatment choice showed some physician and treatment center bias. This study illustrates the complexity and many factors involved in decision-making in selecting second-line ITP treatments, given the absence of comparative trials. It highlights shared decision-making and the need for well-conducted, comparative effectiveness studies to allow for informed discussion between patients and clinicians

Second-line treatments in children with immune thrombocytopenia: Effect on platelet count and patient-centered outcomes

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder with isolated thrombocytopenia and hemorrhagic risk. While many children with ITP can be safely observed, treatments are often needed for various reasons, including to decrease bleeding or improve health related quality of life (HRQoL). There are a number of available second-line treatments, including rituximab, thrombopoietin-receptor agonists, oral immunosuppressive agents, and splenectomy, but data comparing treatment outcomes are lacking. ICON1 is a prospective, multi-center, observational study of 120 children starting second-line treatments for ITP designed to compare treatment outcomes including platelet count, bleeding, and HRQoL utilizing the Kids ITP Tool (KIT). While all treatments resulted in increased platelet counts, romiplostim had the most pronounced effect at 6 months (p=0.04). Only patients on romiplostim and rituximab had a significant reduction in both skin-related (84% to 48%, p=0.01 and 81% to 43%, p=0.004) and non-skin-related bleeding symptoms (58% to 14%, p=0.0001 and 54% to 17%, p=0.0006) after 1 month of treatment. HRQoL significantly improved on all treatments. However, only patients treated with eltrombopag had a median improvement in KIT scores at 1 month that met the minimal important difference (MID). Bleeding, platelet count, and HRQoL improved in each treatment group, but the extent and timing of the effect varied among treatments. These results are hypothesis generating and help to improve our understanding of the effect of each treatment on specific patient outcomes. Combined with future randomized trials, these findings will help clinicians select the optimal second-line treatment for an individual child with ITP

Transplant-Associated Thrombotic Microangiopathy in Pediatric Hematopoietic Cell Transplant Recipients: A Practical Approach to Diagnosis and Management.

Transplant-associated thrombotic microangiopathy (TA-TMA) is an endothelial damage syndrome that is increasingly identified as a complication of both autologous and allogeneic hematopoietic cell transplantation (HCT) in children. If not promptly diagnosed and treated, TA-TMA can lead to significant morbidity (e.g., permanent renal injury) or mortality. However, as the recognition of the early stages of TA-TMA may be difficult, we propose a TA-TMA "triad" of hypertension, thrombocytopenia (or platelet transfusion refractoriness), and elevated lactate dehydrogenase (LDH). While not diagnostic, this triad should prompt further evaluation for TA-TMA. There is increased understanding of the risk factors for the development of TA-TMA, including those which are inherent (e.g., race, genetics), transplant approach-related (e.g., second HCT, use of HLA-mismatched donors), and related to post-transplant events (e.g., receipt of calcineurin inhibitors, development of graft-vs. -host-disease, or certain infections). This understanding should lead to enhanced screening for TA-TMA signs and symptoms in high-risk patients. The pathophysiology of TA-TMA is complex, resulting from a cycle of activation of endothelial cells to produce a pro-coagulant state, along with activation of antigen-presenting cells and lymphocytes, as well as activation of the complement cascade and microthrombi formation. This has led to the formulation of a "Three-Hit Hypothesis" in which patients with either an underlying predisposition to complement activation or pre-existing endothelial injury (Hit 1) undergo a toxic conditioning regimen causing endothelial injury (Hit 2), and then additional insults are triggered by medications, alloreactivity, infections, and/or antibodies (Hit 3). Understanding this cycle of injury permits the development of a specific TA-TMA treatment algorithm designed to treat both the triggers and the drivers of the endothelial injury. Finally, several intriguing approaches to TA-TMA prophylaxis have been identified. Future work on the development of a single diagnostic test with high specificity and sensitivity, and the development of a robust risk-scoring system, will further improve the management of this serious post-transplant complication

Autoimmune Cytopenias in Pediatric Hematopoietic Cell Transplant Patients

Background: Autoimmune cytopenias (AICs) are potentially life-threatening complications following hematopoietic cell transplantation (HCT), yet little is understood about the mechanism by which they develop. We hypothesized that discordant B cell and T cell recovery is associated with AICs in transplant patients, and that this might differ based on transplant indication.Methods: In this case control study of children who underwent HCT at our institution, we evaluated the clinical and transplant characteristics of subjects who developed AICs compared to a control group matched by transplant indication and donor type. In cases, we analyzed the state of immune reconstitution, including B cell recovery, T cell recovery, and chimerism, immediately prior to AIC onset. Subjects were stratified by primary indication for transplant as malignancy (n = 7), primary immune deficiency (PID, n = 9) or other non-malignant disease (n = 4). We then described the treatment and outcomes for 20 subjects who developed AICs.Results: In our cohort, cases were older than controls, were more likely to receive a myeloablative conditioning regimen and had a significantly lower prevalence of chronic GVHD. There were distinct differences in the state of immune recovery based on transplant indication. None of the patients (0/7) transplanted for primary malignancy had T cell recovery at AIC onset compared to 71% (5/7) of patients with PID and 33% (1/3) of patients with non-malignant disease. The subset of patients with PID and non-malignant disease who achieved T cell reconstitution (6/6) prior to AIC onset, all demonstrated mixed or split chimerism. Subjects with AIHA or multi-lineage cytopenias had particularly refractory courses with poor treatment response to IVIG, steroids, and rituximab.Conclusions: These results highlight the heterogeneity of AICs in this population and suggest that multiple mechanisms may contribute to the development of post-transplant AICs. Patients with full donor chimerism may have early B cell recovery without proper T cell regulation, while patients with mixed or split donor chimerism may have residual host B or plasma cells making antibodies against donor blood cells. A prospective, multi-center trial is needed to develop personalized treatment approaches that target the immune dysregulation present and improve outcomes in patients with post-transplant AICs.</p

Daratumumab in life-threatening autoimmune hemolytic anemia following hematopoietic stem cell transplantation.

New-onset autoimmune hemolytic anemia (AIHA) occurs in 2% to 6% of pediatric patients post-hematopoietic stem cell transplantation (HSCT) and is a significant complication. Incomplete immune recovery following HSCT may predispose to immune dysregulation including autoimmune cytopenias. We describe an innovative therapy for AIHA refractory to proteasome inhibition. In potentially life-threatening AIHA in the context of HSCT, daratumumab may be an effective rescue therapy

Phase 3 randomised trial of eltrombopag versus standard first-line pharmacological management for newly diagnosed immune thrombocytopaenia (ITP) in children: study protocol

IntroductionImmune thrombocytopaenia (ITP) is an acquired disorder of low platelets and risk of bleeding. Although many children can be observed until spontaneous remission, others require treatment due to bleeding or impact on health-related quality of life. Standard first-line therapies for those who need intervention include corticosteroids, intravenous immunoglobulin and anti-D globulin, though response to these agents may be only transient. Eltrombopag is an oral thrombopoietin receptor agonist approved for children with chronic ITP who have had an insufficient response to corticosteroids, intravenous immunoglobulin or splenectomy. This protocol paper describes an ongoing open-label, randomised trial comparing eltrombopag to standard first-line management in children with newly diagnosed ITP.Methods and analysisRandomised treatment assignment is 2:1 for eltrombopag versus standard first-line management and is stratified by age and by prior treatment. The primary endpoint of the study is platelet response, defined as ≥3 of 4 weeks with platelets &gt;50×109/L during weeks 6-12 of therapy. Secondary outcomes include number of rescue therapies needed during the first 12 weeks, proportion of patients who do not need ongoing treatment at 12 weeks and 6 months, proportion of patients with a treatment response at 1 year, and number of second-line therapies used in weeks 13-52, as well as changes in regulatory T cells, iron studies, bleeding, health-related quality of life and fatigue. A planned sample size of up to 162 randomised paediatric patients will be enrolled over 2 years at 20 sites.Ethics and disseminationThe study has been approved by the centralised Baylor University Institutional Review Board. The results are expected to be published in 2023.Trial registration numberNCT03939637