Venous Thromboembolism in Pediatric Inflammatory Bowel Disease: A Scoping Review.

OBJECTIVES: In addition to gastrointestinal symptoms, pediatric inflammatory bowel disease (pIBD) may present with extra-intestinal manifestations including venous thromboembolism (VTE). Prevention and treatment guidelines for VTE in pediatric patients are needed. In this scoping review, we sought to detail the available data on the prevention and management of VTE in pIBD. METHODS: Using PRISMA extension for Scoping Reviews (PRISMA-ScR), we identified, screened, graded quality of, and analyzed, literature on VTE in pediatric IBD, published between 1967 and 2023. RESULTS: Data were extracted from 107 studies (including 216 patients). IBD patients with VTE had a median age of 14 years. Children with VTE more frequently had ulcerative colitis (70%, n = 216), developed their VTE within the first year of IBD diagnosis (52%, n = 97), had recent steroid use (62%, n = 50), and had central venous catheters (38%, n = 42). Cerebral venous sinus thrombus was the most common VTE type (34% of all VTE). Testing for thrombophilia conditions was rarely available but 65% (n = 23) of subjects tested had elevated Factor VIII activity. While most patients made a full recovery, 5% (n = 11) died secondary to their VTE. CONCLUSIONS: While randomized clinical trials assessing interventions to prevent and treat VTE in pIBD would be ideal, the feasibility of doing such studies is low. However, there has been an increase in interest in this topic and an increase in literature over the past decade. As such, a consensus statement from a multidisciplinary group of experts based on available literature and clinical experience would be valuable for practicing clinicians.

Perspective: Pivotal translational hematology and therapeutic insights in chronic myeloid hematopoietic stem cell malignancies.

Despite much of the past 2 years being engulfed by the devastating consequences of the SAR-CoV-2 pandemic, significant progress, even breathtaking, occurred in the field of chronic myeloid malignancies. Some of this was show-cased at the 15th Post-American Society of Hematology (ASH) and the 25th John Goldman workshops on myeloproliferative neoplasms (MPN) held on 9th-10th December 2020 and 7th-10th October 2021, respectively. The inaugural Post-ASH MPN workshop was set out in 2006 by John Goldman (deceased) and Tariq Mughal to answer emerging translational hematology and therapeutics of patients with these malignancies. Rather than present a resume of the discussions, this perspective focuses on some of the pivotal translational hematology and therapeutic insights in these diseases.

Clinical features associated with thrombotic events in children with myeloproliferative neoplasms.

In children with MPNs, clots are most common in those with JAK2 mutations and those with polycythemia vera.

Use of pegylated interferon in young patients with polycythemia vera and essential thrombocythemia.

Myeloproliferative neoplasms (MPN) are rare disorders in young patients, and because of this, standardized treatment recommendations are not available. Pediatric patients are more frequently treated with hydroxyurea than interferon, yet there are no data suggesting this is the best practice. Current treatment guidelines for adults suggest using interferon as upfront therapy in young patients. We reviewed the cases of 13 young patients with polycythemia vera or essential thrombocythemia, who were treated with interferon. Extreme thrombocytosis was well controlled and the medication was tolerated by many. Our work shows the need for prospective studies evaluating interferon in our youngest patients with MPN.

Health and Financial Burdens Associated With Venous Thrombosis in Hospitalized Children With Inflammatory Bowel Disease.

ABSTRACT: Venous thromboembolism (VTE) is a known complication in children with inflammatory bowel disease (IBD). Despite awareness of the increased thrombosis risk in this population, prophylaxis is not standardly used and there is limited published guidance for thrombosis prevention. To better appreciate the impact of thrombosis in this population, we compared children with IBD who did or did not have a VTE, using the Pediatric Health Information System inpatient database from 2009 to 2017. In hospitalized children with IBD, VTE was associated with longer median hospital stays (11 vs 5 days), need for intensive care unit admission (30.2% vs 4.8%), higher median adjusted costs ($32.8k vs $12.3k) and hospital charges ($96.6k vs $36k), and in-hospital death (1.5% vs 0.2%) (P  < 0.001 in all comparisons). These findings highlight the need to determine and implement appropriate strategies to reduce VTE rates in children with IBD, given its association with high morbidity, mortality, and cost.

Assessment of provider practices regarding venous thromboembolism management and prevention in pediatric acute leukemia patients.

Despite the known occurrence of venous thromboembolism (VTE) in the pediatric oncology population, there are no leukemia-specific VTE treatment guidelines. The primary objective of this study was to assess current practices regarding the management and prevention of VTE in the pediatric acute lymphoblastic leukemia (ALL) population. We performed a cross sectional, anonymous, electronic survey of members of the American Society of Hematology and the pediatric subcommittee of VENUS (VTE Network US of the Hemostasis and Thrombosis Research Society). Survey items included questions on demographics and clinical practice. Of 870 surveys distributed, 154 were submitted, giving a 17.7% response rate. Treatment duration, re-imaging timeline, and class of anticoagulants used were reported for catheter-associated deep vein thrombus, pulmonary embolism, and cerebral venous sinus thrombosis. While there are some common themes regarding VTE management, there is notable variation in the overall practice as well as with the decision to continue anticoagulation in the presence of thrombocytopenia. Given the variation seen, a multi-center, prospective clinical trial is urgently needed for developing consensus guidelines for the management of VTE in children with ALL.

Emerging translational science discoveries, clonal approaches, and treatment trends in chronic myeloproliferative neoplasms.

The 60th American Society of Hematology (ASH) held in San Diego in December 2018 was followed by the 13th Post-ASH chronic myeloproliferative neoplasms (MPNs) workshop on December 4 and 5, 2018. This closed annual workshop, first introduced in 2006 by Goldman and Mughal, was organized in collaboration with Alpine Oncology Foundation and allowed experts in preclinical and clinical research in the chronic MPNs to discuss the current scenario, including relevant presentations at ASH, and address pivotal open questions that impact translational research and clinical management. This review is based on the presentations and deliberations at this workshop, and rather than provide a resume of the proceedings, we have selected some of the important translational science and treatment issues that require clarity. We discuss the experimental and observational evidence to support the intimate interaction between aging, inflammation, and clonal evolution of MPNs, the clinical impact of the unfolding mutational landscape on the emerging targets and treatment of MPNs, new methods to detect clonal heterogeneity, the challenges in managing childhood and adolescent MPN, and reflect on the treatment of systemic mastocytosis (SM) following the licensing of midostaurin.

Pediatric Gastroenterologists' Approach to Venous Thromboembolism Prophylaxis in Pediatric Inflammatory Bowel Disease.

The risk of venous thromboembolism (VTE) is significantly increased in patients with inflammatory bowel disease (IBD). For the adult population, prophylaxis guidelines exist to help guide physicians in their management of high-risk IBD patients. Although it is known that children with IBD also experience increased rates of VTE, there is no clear consensus on how best to prevent these unwanted complications. We sought to better understand practicing pediatric gastroenterologists' awareness of this issue and practices surrounding prevention of VTE in their pediatric patients. We found that pediatric gastroenterologists are well aware of the increased risk for VTE in children with IBD, that anticoagulant prophylaxis is infrequently used for pediatric patients, and that the most commonly cited reason for not providing prophylaxis is the lack of available guidelines in the literature.

Tumor-specific HSP90 inhibition as a therapeutic approach in JAK-mutant acute lymphoblastic leukemias.

The development of the dual Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib for the treatment of myeloproliferative neoplasms (MPNs) has led to studies of ruxolitinib in other clinical contexts, including JAK-mutated acute lymphoblastic leukemia (ALL). However, the limited ability of JAK inhibition to induce molecular or clinicopathological responses in MPNs suggests a need for development of better therapies for JAK kinase-dependent malignancies. Here, we demonstrate that heat shock protein 90 (HSP90) inhibition using a purine-scaffold HSP90 inhibitor in early clinical development is an effective therapeutic approach in JAK-dependent ALL and can overcome persistence to JAK-inhibitor therapy in ALL cells.

Primary thrombocytosis in children.

Myeloproliferative neoplasms are uncommon disorders in children, for which we have limited understanding of the pathogenesis and optimal management. JAK2 and MPL mutations, while common drivers of myeloproliferative neoplasms in adult patients, are not clearly linked to pediatric disease. Management and clinical outcomes in adults have been well delineated with defined recommendations for risk stratification and treatment. This is not the case for pediatric patients, for whom there is neither a standard approach to workup nor any consensus regarding management. This review will discuss thrombocytosis in children, including causes of thrombocytosis in children, the limited knowledge we have regarding pediatric primary thrombocytosis, and our thoughts on potential risk stratification and management, and future questions to be answered by laboratory research and collaborative clinical study.

Increased Frequency of Clonal Hematopoiesis of Indeterminate Potential in Bloom Syndrome Probands and Carriers.

Background: Bloom Syndrome (BSyn) is an autosomal recessive disorder caused by biallelic germline variants in BLM, which functions to maintain genomic stability. BSyn patients have poor growth, immune defects, insulin resistance, and a significantly increased risk of malignancies, most commonly hematologic. The malignancy risk in carriers of pathogenic variants in BLM (BLM variant carriers) remains understudied. Clonal hematopoiesis of indeterminate potential (CHIP) is defined by presence of somatic mutations in leukemia-related genes in blood of individuals without leukemia and is associated with increased risk of leukemia. We hypothesize that somatic mutations driving clonal expansion may be an underlying mechanism leading to increased cancer risk in BSyn patients and BLM variant carriers. Methods: To determine whether de novo or somatic variation is increased in BSyn patients or carriers, we performed and analyzed exome sequencing on BSyn and control trios. Results: We discovered that both BSyn patients and carriers had increased numbers of low-frequency, putative somatic variants in CHIP genes compared to controls. Furthermore, BLM variant carriers had increased numbers of somatic variants in DNA methylation genes compared to controls. There was no statistical difference in the numbers of de novo variants in BSyn probands compared to control probands. Conclusion: Our findings of increased CHIP in BSyn probands and carriers suggest that one or two germline pathogenic variants in BLM could be sufficient to increase the risk of clonal hematopoiesis. These findings warrant further studies in larger cohorts to determine the significance of CHIP as a potential biomarker of aging, cancer, cardiovascular disease, morbidity and mortality.

Cytoreductive therapy in younger adults with polycythemia vera: a meta-analysis of safety and outcomes.

ABSTRACT: Cytoreductive therapy is not routinely recommended for younger patients with polycythemia vera (PV) due to concern that treatment toxicity may outweigh therapeutic benefits. However, no systematic data support this approach. To support objective risk/benefit assessment of cytoreductive drugs in patients with PV aged <60 years (PV<60), this systematic review and meta-analysis was conducted to evaluate toxicity and disease-related complications in PV<60 treated with interferon alfa (rIFN-α) or hydroxyurea (HU). A search of PubMed, Scopus, Web of Science and Embase identified 693 unique studies with relevant keywords, of which 14 met inclusion criteria and were selected for analysis. The weighted average age of patients treated with rIFN-α was 48 years (n = 744 patients; 12 studies) and for HU was 56 years (n = 1397; 8 studies). The weighted average duration of treatment for either drug was 4.5 years. Using a Bayesian hierarchical model, the pooled annual rate of discontinuation due to toxicity was 5.2% for patients receiving rIFN-α (n = 587; 95% confidence interval [CI], 2.2-8.2) and 3.6% for HU (n = 1097; CI, 1-6.2). The average complete hematologic response for rIFN-α and HU was 62% and 52%, respectively. Patients experienced thrombotic events at a pooled annual rate of 0.79% and 1.26%; secondary myelofibrosis at 1.06% and 1.62%; acute myeloid leukemia at 0.14% and 0.26%; and death at 0.87% and 2.65%, respectively. No treatment-related deaths were reported. With acceptable rates of nonfatal toxicity, cytoreductive treatment, particularly with disease-modifying rIFN-α, may benefit PV<60. Future randomized trials prioritizing inclusion of PV<60 are needed to establish a long-term benefit of early cytoreductive treatment in these patients.

Too many white cells-TAM, JMML, or something else?

Leukocytosis is a common finding in pediatric patients, and the differential diagnosis can be broad, including benign reactive leukocytosis and malignant myeloproliferative disorders. Transient abnormal myelopoiesis is a myeloproliferative disorder that occurs in young infants with constitutional trisomy 21 and somatic GATA1 mutations. Most patients are observed, but outcomes span the spectrum from spontaneous resolution to life-threatening complications. Juvenile myelomonocytic leukemia is a highly aggressive myeloproliferative disorder associated with altered RAS-pathway signaling that occurs in infants and young children. Treatment typically involves hematopoietic stem cell transplantation, but certain patients can be observed. Early recognition of these and other myeloproliferative disorders is important and requires a clinician to be aware of these diagnoses and have a clear understanding of their presentations. This paper discusses the presentation and evaluation of leukocytosis when myeloproliferative disorders are part of the differential and reviews different concepts regarding treatment strategies.

Bloom syndrome patients and mice display accelerated epigenetic aging.

Bloom syndrome (BSyn) is an autosomal recessive disorder caused by variants in the BLM gene, which is involved in genome stability. Patients with BSyn present with poor growth, sun sensitivity, mild immunodeficiency, diabetes, and increased risk of cancer, most commonly leukemias. Interestingly, patients with BSyn do not have other signs of premature aging such as early, progressive hair loss and cataracts. We set out to determine epigenetic age in BSyn, which can be a better predictor of health and disease over chronological age. Our results show for the first time that patients with BSyn have evidence of accelerated epigenetic aging across several measures in blood lymphocytes, as compared to carriers. Additionally, homozygous Blm mice exhibit accelerated methylation age in multiple tissues, including brain, blood, kidney, heart, and skin, according to the brain methylation clock. Overall, we find that Bloom syndrome is associated with accelerated epigenetic aging effects in multiple tissues and more generally a strong effect on CpG methylation levels.

Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis.

The discovery of JAK2 and MPL mutations in patients with myeloproliferative neoplasms (MPNs) provided important insight into the genetic basis of these disorders and led to the development of JAK2 kinase inhibitors for MPN therapy. Although recent studies have shown that JAK2 kinase inhibitors demonstrate efficacy in a JAK2V617F murine bone marrow transplantation model, the effects of JAK2 inhibitors on MPLW515L-mediated myeloproliferation have not been investigated. In this report, we describe the in vitro and in vivo effects of INCB16562, a small-molecule JAK2 inhibitor. INCB16562 inhibited proliferation and signaling in cell lines transformed by JAK2 and MPL mutations. Compared with vehicle treatment, INCB16562 treatment improved survival, normalized white blood cell counts and platelet counts, and markedly reduced extramedullary hematopoeisis and bone marrow fibrosis. We observed inhibition of STAT3 and STAT5 phosphorylation in vivo consistent with potent inhibition of JAK-STAT signaling. These data suggest JAK2 inhibitor therapy may be of value in the treatment of JAK2V617F-negative MPNs. However, we did not observe a decrease in the size of the malignant clone in the bone marrow of treated mice at the end of therapy, which suggests that JAK2 inhibitor therapy, by itself, was not curative in this MPN model.