Cost-Effectiveness of a Quality Improvement Initiative for the Clinical Management of Children with Newly Diagnosed Immune Thrombocytopenia.

OBJECTIVE: To assess the cost-effectiveness of an evidence-informed institutional protocol for physicians that encouraged management of children with newly diagnosed immune thrombocytopenia (ITP) with observation over active therapy, where appropriate. STUDY DESIGN: We conducted a probabilistic cost-effectiveness analysis from an institutional perspective using a decision tree with a 1 year time horizon. Patient-level data were retrospectively ascertained for children diagnosed in pre-protocol (2007-2009) and post-protocol (2013-2018) time periods. ITP resolution was defined as achieving a sustained platelet count of >100 × 103/µL at 9-12 months after diagnosis. Outpatient care and inpatient costs were obtained from the institution and provincial sources. Intervention costs accounted for quality improvement initiative preparation and staff physician training. Incremental costs, incremental effects, and CIs were calculated from 10 000 model iterations. RESULTS: Forty-eight patients were followed for 1 year in the pre-protocol period and 84 in the post-protocol period. After protocol implementation, an average cost savings per child managed of $2055 (95% CI: $656, $3890) Canadian Dollars was observed, as was a higher proportion of resolved ITP cases. The implementation strategy remained less costly and more effective in 99.7% of model iterations. CONCLUSIONS: Implementation of an evidence-informed institutional protocol to guide physicians toward increased uptake of observation over active therapy when managing children with newly diagnosed ITP resulted in significant cost savings on a per case basis, even after accounting for training-related costs. Though the long-term cost implications regarding the sustainability of the intervention are not yet known, it is anticipated that continued institutional savings could occur.

Palliative Care Training for Pediatric Hematology/Oncology Fellows: a Canadian Perspective.

Children with cancer experience suffering, particularly at the end of life. Pediatric hematology/oncology (PHO) fellows need dedicated palliative care (PC) training in order to adequately manage this suffering. Our objectives were to understand (1) the PC training needs of Canadian PHO fellows and (2) experiences in providing PC, from the perspectives of fellows and their training program directors (PDs) and to describe (1) our experience in enhancing our institutional PC curriculum and (2) the preliminary evaluation of this curriculum. Electronic surveys were sent to all Canadian PHO fellows and PDs. Fellows participating in our curriculum were also sent post-course surveys. All 9/9 of the PDs and 63% (29/46) of the fellows completed our pre-course surveys. The majority of survey participants agreed that PHO fellows require dedicated PC training. All programs provided some PC education, but 45% of programs offered 3 or fewer hours of training per year. Only 55% (5/9) of the PDs believed that their trainees had adequate PC skills on completion of training. Fellows perceived a range of PC skills to be important but expressed low levels of comfort across these skills. Many fellows had experienced distress as a result of managing PC clinical situations, and many cited a lack of training as contributing to their distress. Despite increasing awareness of the importance of PC education for PHO fellows, this subject does not receive adequate attention in training curricula. The introduction of a Canadian national curriculum may improve the provision of PC training in education programs.

Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts.

Poor outcome after hematopoietic stem cell transplantation of patients with unclassified inherited bone marrow failure syndromes.

Classification of inherited bone marrow failure syndromes (IBMFSs) according to clinical and genetic diagnoses enables proper adjustment of treatment. Unfortunately, 30% of patients enrolled in the Canadian Inherited Marrow Failure Registry (CIMFR) with features suggesting hereditability could not be classified with a specific syndromic diagnosis. We analyzed the outcome of hematopoietic stem cell transplantation (HSCT) in unclassified IBMFSs (uIBMFSs) and the factors associated with outcome. Twenty-two patients with uIBMFSs and 70 patients with classified IBMFSs underwent HSCT. Five-year overall survival of uIBMFS patients after HSCT was inferior to that of patients with classified IBMFSs (56% vs 76.5%). The outcome of patients with uIBMFS who received cord blood was significantly lower than that of patients who received other stem cell sources (14.8% vs 90.9%). Engraftment failure was higher among patients with uIBMFS who received cord blood than those who received bone marrow. None of the following factors were significantly associated with poor survival: transfusion load, transplant indication, the intensity of conditioning regimen, human leukocyte antigen-identical sibling/alternative donor. We suggest that identifying the genetic diagnosis is essential to modulate the transplant procedure including conditioning agents and stem cell sources for better outcome and the standard cord blood transplantation (CBT) should be avoided in uIBMFS.

Androgen therapy in inherited bone marrow failure syndromes: analysis from the Canadian Inherited Marrow Failure Registry.

Progressive cytopenia is a serious complication among paediatric patients with inherited bone marrow failure syndromes (IBMFS). Androgens have been used to improve blood counts in different bone marrow failure conditions. Little is known about efficacy and toxicity with new androgens (i.e., danazol) in different types of IBMFS. We identified 29 patients from the Canadian Inherited Marrow Failure Registry, who received oxymetholone or danazol. Sixteen (55%) had haematological response including patients with unclassified IBMFS (45%). Danazol showed a better toxicity profile and similar efficacy compared to oxymetholone. Androgens are an effective and safe option to ameliorate bone marrow failure in IBMFS.

Diagnosis and treatment of pediatric myelodysplastic syndromes: A survey of the North American Pediatric Aplastic Anemia Consortium.

BACKGROUND: Myelodysplastic syndromes (MDS) represent a group of clonal hematopoietic stem cell disorders that commonly progress to acute myeloid leukemia (AML). The diagnostics, prognostics, and treatment of adult MDS are established but do not directly translate to children and adolescents. Pediatric MDS is a rare disease, characterized by unique cytogenetics and histology compared with adult MDS, and often arises secondary to germline predisposition or cytotoxic exposures. Our objective was to highlight aspects of diagnosis/management that would benefit from further systematic review toward the development of clinical practice guidelines for pediatric MDS. PROCEDURE: The North American Pediatric Aplastic Anemia Consortium (NAPAAC) is composed of collaborative institutions with a strong interest in pediatric bone marrow failure syndromes and hematologic malignancies. The NAPAAC MDS working group developed a national survey distributed to 35 NAPAAC institutions to assess data on (1) clinical presentation of pediatric MDS, (2) diagnostic evaluation, (3) criteria for diagnosis, (4) supportive care and treatment decisions, and (5) role of hematopoietic stem cell transplantation (HSCT). RESULTS: Twenty-eight of 35 institutions returned the survey. Most centers agreed on a common diagnostic workup, though there was considerable variation regarding the criteria for diagnosis. Although there was consensus on supportive care, treatment strategies, including the role of cytoreduction and HSCT, varied across centers surveyed. CONCLUSIONS: There is lack of national consensus on diagnosis and treatment of pediatric MDS. This survey identified key aspects of MDS management that will warrant systematic review toward the goal of developing national clinical practice guidelines for pediatric MDS.

Sirolimus Treatment of an Infant With Intrathoracic Kaposiform Hemangioendothelioma Complicated by Life-threatening Pleural and Pericardial Effusions.

Kaposiform hemangioendothelioma (KHE) is a rare infiltrative vascular tumor that may be associated with Kasabach-Merritt Phenomenon (KMP), which is a consumptive coagulopathy with potentially life-threatening thrombocytopenia. Management of KHE and KMP is challenging, and currently, there are no standardized validated treatment protocols. Mammalian target of rapamycin inhibitors have been shown to be effective in the treatment of KHE. We describe a term male who presented as a diagnostic dilemma with life-threatening pleural and pericardial effusions and severe thrombocytopenia. After extensive work-up the etiology for his condition was determined to be KHE with KMP. The patient was commenced on sirolimus and responded well to therapy with resolution of KMP.

Reduction of Extramedullary Complications in Patients With Acute Myeloid Leukemia/Myelodysplastic Syndrome Treated With Azacitidine.

The distinction between myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) often relies on an arbitrary marrow blast cutoff of 30% in pediatrics and 20% in adults. There is little data about the treatment of children with extramedullary myeloid malignancy that has features of both, MDS and AML. Herein, we report for the first time 2 patients MDS/AML (1 with Shwachman-Diamond syndrome and 1 with idiopathic MDS and monosomy 7) who presented with extramedullary complications, received treatment with azacitidine, achieved complete remission and subsequently underwent hematopoietic stem cell transplantation.

Primary immunodeficiencies and their associated risk of malignancies in children: an overview.

Primary immunodeficiency disorders represent a heterogeneous spectrum of diseases, predisposing to recurrent infections, allergy, and autoimmunity. While an association between primary immunodeficiency disorders and increased risk of cancer has been suggested since the 1970s, renewed attention has been given to this topic in the last decade, largely in light of the availability of large registries as well as advances in next generation sequencing. In this narrative review, we will give an insight of the primary immunodeficiencies that are commonly responsible for the greater number of cancers in the primary immunodeficiency disorders population. We will describe clinical presentations, underlying genetic lesions (if known), molecular mechanisms for carcinogenesis, as well as some management considerations. We will also comment on the future directions and challenges related to this topic.Conclusion: The awareness of the association between several primary immunodeficiencies and cancer is crucial to provide the best care for these patients.What is Known: • Patients with primary immunodeficiency have an increased risk of malignancy. The type of malignancy is highly dependent on the specific primary immunodeficiency disorder.What is New: • Survival in patients with primary immunodeficiency disorders has been improving, and conversely also their lifetime risk of malignancy. • International collaboration and multinational registries are needed to improve our knowledge and therapeutic strategies.

Kidney and inferior vena cava abnormalities with leg thromboses (KILT) syndrome: A case report and literature review.

Venous thromboembolism (VTE) is now increasingly recognized within paediatrics. A Canadian VTE registry has estimated the incidence as 0.7 to 1.0 per 100,000 population, with a peak in infancy and adolescence. Congenital inferior vena cava agenesis (IVCA) is an important risk factor that may be unfamiliar to paediatricians. Several case reports have since described an association between IVCA, VTE, and renal hypoplasia, which has been referred to as KILT syndrome (Kidney and IVC abnormalities with Leg Thromboses). We describe the first reported paediatric case of KILT syndrome in Canada. In any young patient presenting with a spontaneous DVT, particularly, if it is bilateral in nature with no co-existing risk factors for thrombus formation, we recommend investigating for the possibility of an underlying congenital vena cava anomaly. The use of prolonged anticoagulant therapy is supported by the inherent life-long risk of recurrent thrombosis associated with IVC anomalies.

Immunosuppressive therapy for pediatric aplastic anemia: a North American Pediatric Aplastic Anemia Consortium study.

Quality of response to immunosuppressive therapy and long-term outcomes for pediatric severe aplastic anemia remain incompletely characterized. Contemporary evidence to inform treatment of relapsed or refractory severe aplastic anemia for pediatric patients is also limited. The clinical features and outcomes for 314 children treated from 2002 to 2014 with immunosuppressive therapy for acquired severe aplastic anemia were analyzed retrospectively from 25 institutions in the North American Pediatric Aplastic Anemia Consortium. The majority of subjects (n=264) received horse anti-thymocyte globulin (hATG) plus cyclosporine (CyA) with a median 61 months follow up. Following hATG/CyA, 71.2% (95%CI: 65.3,76.6) achieved an objective response. In contrast to adult studies, the quality of response achieved in pediatric patients was high, with 59.8% (95%CI: 53.7,65.8) complete response and 68.2% (95%CI: 62.2,73.8) achieving at least a very good partial response with a platelet count ≥50×109L. At five years post-hATG/CyA, overall survival was 93% (95%CI: 89,96), but event-free survival without subsequent treatment was only 64% (95%CI: 57,69) without a plateau. Twelve of 171 evaluable patients (7%) acquired clonal abnormalities after diagnosis after a median 25.2 months (range: 4.3-71 months) post treatment. Myelodysplastic syndrome or leukemia developed in 6 of 314 (1.9%). For relapsed/refractory disease, treatment with a hematopoietic stem cell transplant had a superior event-free survival compared to second immunosuppressive therapy treatment in a multivariate analysis (HR=0.19, 95%CI: 0.08,0.47; P=0.0003). This study highlights the need for improved therapies to achieve sustained high-quality remission for children with severe aplastic anemia.

A Quality Improvement Bundle to Improve Informed Choice for Children With Typical, Newly Diagnosed Immune Thrombocytopenia.

IVIG has been the predominant therapy for the initial management of children with newly diagnosed immune thrombocytopenia at our hospital. With current guidelines supporting more conservative management, we undertook a quality improvement initiative to lead practice change. Over a 2-year time period (2013 to 2015), we strove to decrease use of hospital resources (use of IVIG, length of stay) while optimizing family satisfaction. An interdisciplinary working group was struck and a quality improvement bundle was implemented. The bundle comprised a patient information sheet; an evidence-informed, consensus-based protocol; and promotion of shared decision-making via stakeholder engagement and education. Data were collected prospectively; baseline data from a 2007 to 2009 audit were used for comparison. In total, 27 patients were included. Mean initial platelet count was 4×10/L. Bleeding was classified as none or mild in 56% of patients. IVIG use decreased from 88% to 55% of patients, corticosteroid prescription increased from 6% to 15%, and observation increased from 6% to 30% of patients. Hospital length of stay decreased from 47 to 36 hours. Family satisfaction was stable across treatment groups. Through introduction of a quality improvement initiative, we were able to improve family-centered care and decrease use of hospital resources.

Response to treatment with azacitidine in children with advanced myelodysplastic syndrome prior to hematopoietic stem cell transplantation.

Advanced myelodysplastic syndrome harbors a high risk of progression to acute myeloid leukemia and poor prognosis. In children, there is no established treatment to prevent or delay progression to leukemia prior to hematopoietic stem cell transplantation. Azacitidine is a hypomethylating agent, which was shown to slow progression to leukemia in adults with myelodysplastic syndrome. There is little data on the efficacy of azacitidine in children. We reviewed 22 pediatric patients with advanced myelodysplastic syndrome from a single center, diagnosed between January 2000 and December 2015. Of those, eight patients received off-label azacitidine before hematopoietic stem cell transplantation. A total of 31 cycles were administered and modification or delay occurred in four of them due to cytopenias, infection, nausea/vomiting, and transient renal impairment. Bone marrow blast percentages in azacitidine-treated patients decreased significantly from a median of 15% (range 9-31%) at the start of treatment to 5.5% (0-12%, P=0.02) before hematopoietic stem cell transplantation. Following azacitidine treatment, four patients (50%) achieved marrow remission, and none progressed. In contrast, three untreated patients (21.4%) had progressive disease characterized by >50% increase in blast counts or progression to leukemia. Azacitidine-treated patients had significantly increased 4-year event-free survival (P=0.04); predicted 4-year overall survival was 100% versus 69.3% in untreated patients (P=0.1). In summary, azacitidine treatment prior to hematopoietic stem cell transplantation was well tolerated in pediatric patients with advanced myelodysplastic syndrome, led to partial or complete bone marrow response in seven of eight patients (87.5%), and correlated with superior event-free survival in this cohort.

Improving diagnostic precision, care and syndrome definitions using comprehensive next-generation sequencing for the inherited bone marrow failure syndromes.

BACKGROUND: Phenotypic overlap among the inherited bone marrow failure syndromes (IBMFSs) frequently limits the ability to establish a diagnosis based solely on clinical features. >70 IBMFS genes have been identified, which often renders genetic testing prolonged and costly. Since correct diagnosis, treatment and cancer surveillance often depend on identifying the mutated gene, strategies that enable timely genotyping are essential. METHODS: To overcome these challenges, we developed a next-generation sequencing assay to analyse a panel of 72 known IBMFS genes. Cases fulfilling the clinical diagnostic criteria of an IBMFS but without identified causal genotypes were included. RESULTS: The assay was validated by detecting 52 variants previously found by Sanger sequencing. A total of 158 patients with unknown mutations were studied. Of 75 patients with known IBMFS categories (eg, Fanconi anaemia), 59% had causal mutations. Among 83 patients with unclassified IBMFSs, we found causal mutations and established the diagnosis in 18% of the patients. The assay detected mutant genes that had not previously been reported to be associated with the patient phenotypes. In other cases, the assay led to amendments of diagnoses. In 20% of genotype cases, the results indicated a cancer surveillance programme. CONCLUSIONS: The novel assay is efficient, accurate and has a major impact on patient care.

The impact of category, cytopathology and cytogenetics on development and progression of clonal and malignant myeloid transformation in inherited bone marrow failure syndromes.

Inherited bone marrow failure syndromes are a group of rare, heterogeneous genetic disorders with a risk of clonal and malignant myeloid transformation including clonal marrow cytogenetic abnormalities, myelodysplastic syndrome and acute myeloid leukemia. The clinical characteristics, risk classification, prognostic factors and outcome of clonal and malignant myeloid transformation associated with inherited bone marrow failure syndromes are largely unknown. The aims of this study were to determine the impact of category, cytopathology and cytogenetics, the three components of the "Category Cytology Cytogenetics" classification of pediatric myelodysplastic syndrome, on the outcome of clonal and malignant myeloid transformation associated with inherited bone marrow failure. We used data from the Canadian Inherited Marrow Failure Registry. Among 327 patients with inherited bone marrow failure syndrome enrolled in the registry, the estimated risk of clonal and malignant myeloid transformation by the age of 18 years was 37%. The risk of clonal and malignant myeloid transformation varied according to the type of inherited bone marrow failure syndrome but was highest in Fanconi anemia. The development of clonal and malignant myeloid transformation significantly affected overall survival. Mortality varied based on cytopathological group. The largest group of patients had refractory cytopenia. Clonal marrow cytogenetic abnormalities were identified in 87% of patients with clonal and malignant myeloid transformation, and different cytogenetic groups had different impacts on disease progression. We conclude that category, cytopathology and cytogenetics in cases of clonal and malignant myeloid transformation associated with inherited bone marrow failure syndromes have an important impact on outcome and that the classification of such cases should incorporate these factors.

Clinical outcomes of splenectomy in children: report of the splenectomy in congenital hemolytic anemia registry.

The outcomes of children with congenital hemolytic anemia (CHA) undergoing total splenectomy (TS) or partial splenectomy (PS) remain unclear. In this study, we collected data from 100 children with CHA who underwent TS or PS from 2005 to 2013 at 16 sites in the Splenectomy in Congenital Hemolytic Anemia (SICHA) consortium using a patient registry. We analyzed demographics and baseline clinical status, operative details, and outcomes at 4, 24, and 52 weeks after surgery. Results were summarized as hematologic outcomes, short-term adverse events (AEs) (≤30 days after surgery), and long-term AEs (31-365 days after surgery). For children with hereditary spherocytosis, after surgery there was an increase in hemoglobin (baseline 10.1 ± 1.8 g/dl, 52 week 12.8 ± 1.6 g/dl; mean ± SD), decrease in reticulocyte and bilirubin as well as control of symptoms. Children with sickle cell disease had control of clinical symptoms after surgery, but had no change in hematologic parameters. There was an 11% rate of short-term AEs and 11% rate of long-term AEs. As we accumulate more subjects and longer follow-up, use of a patient registry should enhance our capacity for clinical trials and engage all stakeholders in the decision-making process.

The role of Tc-99m-DTPA nuclear medicine GFR studies in pediatric solid tumor patients.

BACKGROUND: Technetium-99m-diethylene-triamine-pentaacetate (Tc-99m-DTPA) nuclear medicine studies allow for accurate monitoring of glomerular filtration rate (GFR) in cancer patients receiving chemotherapy. However, these scans may be logistically challenging and are associated with some radiation exposure. OBJECTIVES: The purpose of this study was to retrospectively review the use of Tc-99m-DTPA studies to evaluate the subgroup of children with low GFR by Tc-99m-DTPA who may most benefit from this procedure-namely, the patients with a normal serum creatinine (SCr) and GFR estimated by Schwartz (Sch) calculation who may otherwise not have their renal dysfunction recognized. We further determined how the GFR result modified the treatment plan for these patients. METHODS: Patients aged 2 to 18 years with solid tumors diagnosed from 2000 to 2007 were identified. Tc-99m-DTPA results, corresponding height and SCr, were recorded and GFR Sch calculated. The clinical course of patients with Tc-99m-DTPA <80 mL/min/1.73 m and a normal SCr and GFR Sch were reviewed in detail. RESULTS: Of 714 Tc-99m-DTPA studies in 231 patients, 41 (5.7%) in 24 patients (10.4%) reported a GFR result of <80 mL/min/1.73 m. Of those 41 studies, 16 (39%, 13 patients) were associated with normal SCr and normal GFR Sch. Of these 13 patients, 11 (85%) had 1 or more clinical risk factors suggestive of preexisting renal disease. Three patients had modifications to their chemotherapy. CONCLUSIONS: There were few abnormal Tc-99m-DTPA results reported in this population. The majority of patients with abnormal Tc-99m-DTPA studies and normal SCr had clinical risk factors for renal dysfunction. A future prospective study may better help to define oncology patients for whom Tc-99m are essential for estimating renal function.

Value-Based Care for Healthy Children With First Episode of Febrile Neutropenia.

OBJECTIVES: There is a lack of guidance on the management of febrile neutropenia in otherwise healthy children, including the need for hospitalization and antibiotic administration, leading to significant practice variation in management. The aim of this initiative was to decrease the number of unnecessary hospitalizations and empirical antibiotics prescribed by 50% over a 24-month period for well-appearing, previously healthy patients older than 6 months presenting to the emergency department with a first episode of febrile neutropenia. METHODS: A multidisciplinary team of stakeholders was assembled to develop a multipronged intervention strategy using the Model for Improvement. A guideline for the management of healthy children with febrile neutropenia was created, coupled with education, targeted audit and feedback, and reminders. Statistical control process methods were used to analyze the primary outcome of the percentage of low-risk patients receiving empirical antibiotics and/or hospitalization. Balancing measures included missed serious bacterial infection, emergency department (ED) return visit, and a new hematologic diagnosis. RESULTS: Over the 44-month study period, the mean percentage of low-risk patients hospitalized and/or who received antibiotics decreased from 73.3% to 12.9%. Importantly, there were no missed serious bacterial infections, no new hematologic diagnoses after ED discharge, and only 2 ED return visits within 72 hours without adverse outcomes. CONCLUSIONS: A guideline for the standardized management of febrile neutropenia in low-risk patients increases value-based care through reduced hospitalizations and antibiotics. Education, targeted audit and feedback, and reminders supported sustainability of these improvements.