Phase 3 Trial of Concizumab in Hemophilia with Inhibitors.

BACKGROUND: Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody designed to achieve hemostasis in all hemophilia types, with subcutaneous administration. A previous trial of concizumab (explorer4) established proof of concept in patients with hemophilia A or B with inhibitors. METHODS: We conducted the explorer7 trial to assess the safety and efficacy of concizumab in patients with hemophilia A or B with inhibitors. Patients were randomly assigned in a 1:2 ratio to receive no prophylaxis for at least 24 weeks (group 1) or concizumab prophylaxis for at least 32 weeks (group 2) or were nonrandomly assigned to receive concizumab prophylaxis for at least 24 weeks (groups 3 and 4). After a treatment pause due to nonfatal thromboembolic events in three patients receiving concizumab, including one from the explorer7 trial, concizumab therapy was restarted with a loading dose of 1.0 mg per kilogram of body weight, followed by 0.2 mg per kilogram daily (potentially adjusted on the basis of concizumab plasma concentration as measured at week 4). The primary end-point analysis compared treated spontaneous and traumatic bleeding episodes in group 1 and group 2. Safety, patient-reported outcomes, and pharmacokinetics and pharmacodynamics were also assessed. RESULTS: Of 133 enrolled patients, 19 were randomly assigned to group 1 and 33 to group 2; the remaining 81 were assigned to groups 3 and 4. The estimated mean annualized bleeding rate in group 1 was 11.8 episodes (95% confidence interval [CI], 7.0 to 19.9), as compared with 1.7 episodes (95% CI, 1.0 to 2.9) in group 2 (rate ratio, 0.14 [95% CI, 0.07 to 0.29]; P<0.001). The overall median annualized bleeding rate for patients receiving concizumab (groups 2, 3, and 4) was 0 episodes. No thromboembolic events were reported after concizumab therapy was restarted. The plasma concentrations of concizumab remained stable over time. CONCLUSIONS: Among patients with hemophilia A or B with inhibitors, the annualized bleeding rate was lower with concizumab prophylaxis than with no prophylaxis. (Funded by Novo Nordisk; explorer7 ClinicalTrials.gov number, NCT04083781.).

Disease and treatment burden of patients with haemophilia entering the explorer6 non-interventional study.

OBJECTIVES: We aimed to characterise baseline disease and treatment burden in a large population with haemophilia A/B, both with (HAwI/HBwI) and without (HA/HB) inhibitors. METHODS: The prospective, non-interventional explorer6 study included patients ≥12 years old with severe HA, severe/moderate HB or HAwI/HBwI of any severity, treated according to local standard of care (excluding previous/current exposure to concizumab or emicizumab). Baseline characteristics and historical clinical data were collected and patient-reported outcomes, including treatment burden, were assessed. RESULTS: The explorer6 study enrolled 231 patients with haemophilia (84 HAwI/HBwI) from 33 countries. At baseline, patients with HA/HB treated with prophylaxis had the lowest median annualised bleeding rates (ABRs; 2.0), irrespective of haemophilia type; of these patients, 27.5% (HA) and 31.4% (HB) had target joints. Patients with HAwI/HBwI treated episodically reported the highest treatment burden. Of these patients, 28.5% (HAwI) and 25.1% (HBwI) performed sports activities in the month before screening. CONCLUSION: Despite receiving routine clinical care, historical and baseline information from patients enrolled in explorer6 showed that patients with HA/HB treated episodically and patients with HAwI/HBwI had higher ABRs, higher treatment burden and participated in sports less than those with HA/HB treated with prophylaxis. Emerging treatments could be beneficial in addressing these unmet medical needs.

Clinical Practice Patterns in Sickle Cell Disease Treatment: Disease-modifying and Potentially Curative Therapies.

Therapeutic options for sickle cell disease (SCD) have increased recently as well as the development of updated national guidelines. It is not known how these options are being offered or to what degree guidelines are incorporated into clinical practice. This study aimed to describe practice patterns for pediatric hematologists regarding the use of disease-modifying and potentially curative therapies for SCD. A 9-section, cross-sectional electronic survey was disseminated during a 3-month period via SurveyMonkey, to members of the American Society of Pediatric Hematology/Oncology Hemoglobinopathy Special Interest Group (ASPHO HSIG). A total of 88 physician members of the ASPHO HSIG were surveyed. Ninety percent of respondents (72/80) start hydroxyurea routinely in patients with HbSS and HbSß 0 thalassemia, regardless of disease severity. Laboratory monitoring was recommended every 3 months for stable dosing in 63.8% (51/80). New therapies were recommended for patients on hydroxyurea who were still experiencing SCD complications: L-glutamine 68.5% (37/54) or crizanlizumab 93.1% (54/58). Voxelotor was recommended for patients on hydroxyurea with low hemoglobin in 65.1% (43/66) of cases. Matched sibling transplant was considered for any disease severity by 55.1% (38/69). Gene therapy trials are offered on-site by 29% (20/69). Our study demonstrated the enhanced utilization of hydroxyurea while revealing the unexplored potential of other disease-modifying therapies in SCD. These findings underscore the importance of continued knowledge acquisition about the long-term efficacy of new medical therapies and addressing barriers to the use of proven therapies and guide the development of future studies of optimal SCD management.

Consensus definition of essential, optimal, and suggested components of a pediatric sickle cell disease center.

Sickle cell disease (SCD) requires coordinated, specialized medical care for optimal outcomes. There are no United States (US) guidelines that define a pediatric comprehensive SCD program. We report a modified Delphi consensus-seeking process to determine essential, optimal, and suggested elements of a comprehensive pediatric SCD center. Nineteen pediatric SCD specialists participated from the US. Consensus was predefined as 2/3 agreement on each element's categorization. Twenty-six elements were considered essential (required for guideline-based SCD care), 10 were optimal (recommended but not required), and five were suggested. This work lays the foundation for a formal recognition process of pediatric comprehensive SCD centers.

The Complete Blood Count: A Practical Tool for the Pediatrician.

Every child should have a baseline hematology evaluation with hemoglobin and hematocrit levels starting at age 12 months, or younger if clinically indicated. Although history and physical examination provide key information needed to diagnose blood disorders, the addition of a complete blood count (CBC) with differential count and reticulocyte count allows the clinician to narrow the differential diagnosis and tailor the subsequent evaluation. The interpretation of CBC results is a skill that requires practice. Every clinician can learn to identify possible diagnoses before consulting a specialist. This review provides a step-by-step approach for CBC interpretation with tools to help the clinician diagnose and interpret the most common blood disorders seen in the general pediatric clinic or inpatient setting.

Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.

BACKGROUND: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR-ABL1-positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults. METHODS: We performed genomic profiling of 1725 patients with precursor B-cell ALL and detailed genomic analysis of 154 patients with Ph-like ALL. We examined the functional effects of fusion proteins and the efficacy of tyrosine kinase inhibitors in mouse pre-B cells and xenografts of human Ph-like ALL. RESULTS: Ph-like ALL increased in frequency from 10% among children with standard-risk ALL to 27% among young adults with ALL and was associated with a poor outcome. Kinase-activating alterations were identified in 91% of patients with Ph-like ALL; rearrangements involving ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B, TSLP, or TYK2 and sequence mutations involving FLT3, IL7R, or SH2B3 were most common. Expression of ABL1, ABL2, CSF1R, JAK2, and PDGFRB fusions resulted in cytokine-independent proliferation and activation of phosphorylated STAT5. Cell lines and human leukemic cells expressing ABL1, ABL2, CSF1R, and PDGFRB fusions were sensitive in vitro to dasatinib, EPOR and JAK2 rearrangements were sensitive to ruxolitinib, and the ETV6-NTRK3 fusion was sensitive to crizotinib. CONCLUSIONS: Ph-like ALL was found to be characterized by a range of genomic alterations that activate a limited number of signaling pathways, all of which may be amenable to inhibition with approved tyrosine kinase inhibitors. Trials identifying Ph-like ALL are needed to assess whether adding tyrosine kinase inhibitors to current therapy will improve the survival of patients with this type of leukemia. (Funded by the American Lebanese Syrian Associated Charities and others.).

Thromboelastography--does it impact blood component transfusion in pediatric heart surgery?

BACKGROUND: The administration of blood products during pediatric cardiac surgery is common. We sought to determine if thromboelastography (TEG) is a cost-effective tool to reduce blood product transfusion in open pediatric cardiac surgery. MATERIALS AND METHODS: A retrospective case-control study was undertaken for 150 pediatric cardiac patients requiring cardiopulmonary bypass from January 2010-May 2012, in a University-affiliated pediatric hospital. Fifty sequential patients operated on when TEG was used were compared with 100 control patients before TEG availability. Groups were matched 2:1 for age and risk adjustment for congenital heart surgery score. Blood product utilization was compared between groups, as were outcomes metrics such as postoperative complications, length of stay, and hospital costs of transfusions. RESULTS: Demographic variables, risk adjustment for congenital heart surgery score classifications, and cardiopulmonary bypass times were similar between groups. Red cell and plasma transfusion were comparable between groups. TEG patients saw a substantial reduction in the administration of platelet (1 versus 2.2 U; P < 0.0001) and cryoprecipitate (0.7 versus 1.7 U; P < 0.0001) transfusions. A greater than 50% reductions in hospital costs of platelet ($595 versus $1309) and cryoprecipitate ($39 versus $94) transfusions were observed in the TEG group. Mortality, length of stay, ventilator requirements, postoperative bleeding, and thrombotic events were equivalent. CONCLUSIONS: Intraoperative TEG use reduced platelet and cryoprecipitate transfusions without an increase in postoperative complications. TEG is a cost-effective method to direct blood product replacement.

Pharmacokinetics and analgesic effects of methadone in children and adults with sickle cell disease.

BACKGROUND: Vaso-occlusive episodes (VOEs) are a significant source of morbidity among children and adults with sickle cell disease (SCD). There is little information on methadone use for SCD pain. This investigation evaluated methadone pharmacokinetics in children and adults with SCD, with a secondary aim to assess pain relief and opioid consumption. PROCEDURE: Participants included children (<18 years) and adults with a VOE requiring hospitalization. Patients were randomly assigned to receive standard care (opioid patient-controlled analgesia; control group) or one dose of intravenous methadone (0.1-0.125 mg/kg) in addition to standard care (methadone group). Venous methadone and metabolite concentrations were measured. Pain scores, pain relief scores, and opioid consumption were recorded. RESULTS: Twenty-four children (12 methadone, 12 controls) and 23 adults (11 methadone, 12 controls) were studied. In children, the half-life of R- and S-methadone enantiomers was 34 ± 16 and 24 ± 9 hr, respectively. In adults, R- and S-methadone half-lives were 52 ± 17 and 38 ± 12 hr, respectively. Pain scores were lower (P = 0.002) and pain relief scores were higher (P = 0.0396) in children receiving methadone versus controls. There was no difference in pain scores and pain relief in adults receiving methadone versus controls. There was no difference in opioid consumption between methadone and control groups, in both adults and children. CONCLUSIONS: Intravenous methadone disposition in children and adults with SCD was comparable to that in subjects without SCD from prior studies. Methadone produced more pain relief than standard care in children with SCD. Higher methadone doses may be more effective and should be evaluated in both children and adults with SCD.

The risk of hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type 2.

Genetic disorders of lymphocyte cytotoxicity predispose patients to hemophagocytic lymphohistiocytosis (HLH). Reduced lymphocyte cytotoxicity has been demonstrated in Hermansky-Pudlak syndrome type 2 (HPS2), but only a single patient was reported who developed HLH. Because that patient also carried a potentially contributing heterozygous RAB27A mutation, the risk for HLH in HPS2 remains unclear. We analyzed susceptibility to HLH in the pearl mouse model of HPS2. After infection with lymphocytic choriomeningitis virus, pearl mice developed all key features of HLH, linked to impaired virus control caused by a moderate defect in CTL cytotoxicity in vivo. However, in contrast to perforin-deficient mice, the disease was transient, and all mice fully recovered and controlled the infection. An additional heterozygous Rab27a mutation did not aggravate the cytotoxicity defect or disease parameters. In the largest survey of 22 HPS2 patients covering 234 patient years, we identified only 1 additional patient with HLH and 2 with incomplete transient HLH-like episodes, although cytotoxicity or degranulation was impaired in all 16 patients tested. HPS2 confers a risk for HLH that is lower than in Griscelli or Chediak-Higashi syndrome, probably because of a milder defect in cytotoxicity. Preemptive hematopoietic stem cell transplantation does not appear justified in HPS2.

Interstitial lung disease and pulmonary fibrosis in Hermansky-Pudlak syndrome type 2, an adaptor protein-3 complex disease.

Pulmonary fibrosis develops in Hermansky-Pudlak syndrome (HPS) types 1 and 4. Limited information is available about lung disease in HPS type 2 (HPS-2), which is characterized by abnormal function of the adaptor protein-3 (AP-3) complex. To define lung disease in HPS-2, one child and two adults with HPS-2 were evaluated at the National Institutes of Health on at least two visits, and another child was evaluated at the University of Texas Health Science Center San Antonio. All four subjects with HPS-2 had findings of interstitial lung disease (ILD) on a high-resolution computed tomography scan of the chest. The predominant feature was ground glass opacification. Subject 1, a 14-year-old male, and subject 4, a 4-year-old male, had severe ILD, pulmonary fibrosis, secondary pulmonary hypertension and recurrent lung infections. Lung biopsy performed at 20 months of age in subject 1 revealed interstitial fibrosis and prominent type II pneumocyte hyperplasia without lamellar body enlargement. Subject 2, a 27-year-old male smoker, had mild ILD. Subject 3, a 22-year-old male nonsmoker and brother of subject 2, had minimal ILD. Severe impairment of gas exchange was found in subjects 1 and 4 and not in subjects 2 or 3. Plasma concentrations of transforming growth factor-ß1 and interleukin-17A correlated with severity of HPS-2 ILD. These data show that children and young adults with HPS-2 and functional defects of the AP-3 complex are at risk for ILD and pulmonary fibrosis.

Multi-modal intervention for the inpatient management of sickle cell pain significantly decreases the rate of acute chest syndrome.

INTRODUCTION: Pain in children with sickle cell disease (SCD) is the leading cause of acute care visits and hospitalizations. Pain episodes are a risk factor for the development of acute chest syndrome (ACS), contributing to morbidity and mortality in SCD. Few strategies exist to prevent this complication. METHODS: We performed a before-and-after prospective multi-modal intervention. All children with SCD admitted for pain during the 2-year study period were eligible. The multi-modal intervention included standardized admission orders, monthly house staff education, and one-on-one patient and caregiver education. RESULTS: A total of 332 admissions for pain occurred during the study period; 159 before the intervention and 173 during the intervention. The ACS rate declined by 50% during the intervention period 25% (39 of 159) to 12% (21 of 173); P = 0.003. Time to ACS development increased from 0.8 days (0.03-5.2) to 1.7 days (0.03-5.8); P = 0.047. No significant difference was found in patient demographics, intravenous fluid amount administered, frequency of normal saline bolus administration, or cumulative opioid amount delivered in the first 24 hr. Patient controlled analgesia-use was more common after the intervention 52% (82 of 159) versus 73% (126 of 173; P = 0.0001) and fewer patients required changes in analgesic dosing within the first 24 hr after admission (26%, 42 of 159 vs. 16%, 28 of 173; P = 0.015). CONCLUSIONS: A multi-modal intervention to educate and subsequently change physician's behavior likely decreased the rate of ACS in the setting of a single teaching hospital.

Multi-modal intervention and prospective implementation of standardized sickle cell pain admission orders reduces 30-day readmission rate.

INTRODUCTION: The National Association of Children's Hospitals (NACHRI) and the Centers for Medicare and Medicaid Services (CMS) recently introduced 30-day hospital readmission rate as a quality care indicator in children with sickle cell disease (SCD). Based on previous research identifying risk factors for 30-day readmission in our patient population, we designed and implemented a multi-modal intervention to reduce 30-day readmission rate in children with SCD and pain. METHODS: A before-and-after study design was performed to evaluate an intervention containing three components: (1) standardized SCD-pain admission orders; (2) monthly SCD-pain in-service for house physicians for the first 6-months; and (3) continuous patient/caregiver education. Following order implementation, we prospectively collected data on all children admitted for SCD-pain over a 6-month period. We compared the 30-day readmission rate after the intervention to the rate during the same 6-month interval in the previous calendar year prior to the availability of pre-specified SCD-pain orders. RESULTS: A total of 89 admissions, in 68 individuals, were eligible for the standardized orders during the prospective time period and were compared to 85 admissions in 56 individuals during the control period. Pre-specified SCD-pain orders were used in 93% of eligible admissions during the intervention. Readmission rate within 30 days was lower for the intervention cohort than the control cohort, 11% (10/89) versus 28% (24/85), P = 0.007, 95% CI 0.1-0.7. CONCLUSIONS: A multi-modal intervention was successful in decreasing 30-day hospital readmission rate for children with SCD and pain. Provider education was the most important component of the multi-modal intervention.

Risk factors for hospital readmission within 30 days: a new quality measure for children with sickle cell disease.

BACKGROUND: The National Association of Children's Hospitals and Related Institutions (NACHRI) established hospital readmission within 30 days as a benchmark for quality care in children with Sickle Cell Disease (SCD). Among children with SCD, limited data exists to identify risk factors for readmission and whether they are modifiable. PROCEDURE: We performed a retrospective cohort study to identify risk factors for readmission. All admissions for children with SCD in a 1-year period were reviewed; cases were defined as children with SCD readmitted within 30 days after their first admission during the study period and controls, children with SCD who were not readmitted. RESULTS: We identified 30 cases and 70 controls. No difference in demographic data was found between groups. The most common admission and readmission diagnosis was pain, 78 and 70%, respectively. The greatest risk factor for readmission was no outpatient hematology follow-up within 30 days of discharge (OR 7.7, 95% CI 2.4-24.4). A diagnosis of asthma was also a risk factor for readmission (OR 2.9, 95% CI 1.2-7.3). Patients who required supplemental oxygen to maintain saturations in the normal range and were on room air for < or =24 hr at discharge were also more likely to be readmitted (OR 3.3, 95% CI 1.1-9.7). Multivariate analysis identified lack of outpatient follow-up and disease severity, defined as > or =3 admissions in the previous 12 months as predictors for readmission (R(2) = 0.41). CONCLUSIONS: Potentially modifiable risk factors exist to decrease the rate of readmission of children with SCD admitted to the hospital for pain.

Vaso-occlusive episodes in older children with sickle cell disease: emergency department management and pain assessment.

OBJECTIVE: To describe emergency department (ED) management of older children with sickle cell disease (SCD) experiencing a vaso-occlusive episode (VOE) and factors associated with disposition and ED return. STUDY DESIGN: We retrospectively reviewed ED visits of children age >/=8 years with SCD over the course of 1 year. Data were collected from the electronic medical record and the SCD database. RESULTS: VOE was diagnosed 279 times in 105 patients; 45 of the patients had 1 ED visit, 25 had 2 ED visits, and 16 had >/=5 ED visits. The overall admission rate was 178/279 (64%), 166 on the first ED visit and 12 on a return visit within 72 hours. Use of home opioids, duration of VOE, and hemoglobin concentration were not associated with disposition. Discharge after 2 doses of intravenous (IV) morphine occurred in 33 patients. Pain relief after 1 dose, using a FACES scale of 1 to 5, differed significantly between the admitted patients and the discharged patients (1.1 vs 2.5; P < .0001). CONCLUSION: Suboptimal pain relief after 1 dose of IV morphine was associated with admission from the ED. Further investigation of pain relief, using validated pain assessment scales, as an outcome in VOE management is warranted.

Use of thalidomide to diminish growth velocity in a life-threatening congenital intracranial hemangioma.

Infantile or capillary hemangioma is the most common vascular tumor of childhood. The tumors most frequently affect the head and neck area, but rare cases of intracranial lesions have been reported. Their natural history is marked by initial rapid growth velocity followed by a plateau and, in most cases, subsequent involution. Although the lesions are considered benign, 10% of affected children develop life-threatening complications (mortality rate 20-80% in this subgroup). When surgical intervention or other methods of local control are not possible, therapeutic options are limited. Corticosteroids have been the mainstay of therapy but therapeutic response is not predictable and the infectious risk is not negligible. Interferon alpha-2a may also be effective but has significant toxicities. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have been implicated in the pathogenesis of hemangiomas, and antiangiogenesis agents are being evaluated in the treatment of these tumors. Thalidomide may be an ideal therapy for life-threatening hemangiomas because it inhibits new blood vessel formation by antagonizing both the bFGF and VEGF pathways and has a more acceptable toxicity profile than other agents. The authors present the case of an infant born with a life-threatening, unresectable intracranial hemangioma in which treatment with thalidomide resulted in a good clinical outcome.