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 to 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 = .04). Only patients on romiplostim and rituximab had a significant reduction in both skin‐related (84% to 48%, P = .01 and 81% to 43%, P = .004) and non‐skin‐related bleeding symptoms (58% to 14%, P = .0001 and 54% to 17%, P = .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.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
The decision to initiate second‐line treatment in children with immune thrombocytopenia (ITP) is complex and involves many different factors.
Methods
In this prospective, observational, ...longitudinal cohort study of 120 children from 21 centers, the factors contributing to the decision to start second‐line treatments for ITP were captured. At study entry, clinicians were given a curated list of 12 potential reasons the patient required a second‐line treatment. Clinicians selected all that applied and ranked the top three reasons.
Results
Quality of life (QOL) was the most frequently cited reason for starting a second‐line therapy. Clinicians chose it as a reason to treat in 88/120 (73%) patients, as among the top three reasons in 68/120 (57%), and as the top reason in 32/120 (27%). Additional factors ranked as the top reason to start second‐line treatment included severity of bleeding (22/120, 18%), frequency of bleeding (19/120, 16%), and severity of thrombocytopenia (18/120, 15%). Patients for whom QOL (p = .006) or sports participation (p = .02) were ranked reasons were more likely to have chronic ITP, whereas those for whom severity (p = .003) or frequency (p = .005) of bleeding were ranked reasons were more likely to have newly diagnosed or persistent ITP. Parental anxiety, though rarely the primary impetus for treatment, was frequently cited (70/120, 58%) as a contributing factor.
Conclusion
Perceived QOL is the most frequently selected reason pediatric patients start second‐line therapies for ITP. It is critical that studies of treatments for childhood ITP include assessments of their effects on QOL.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary
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.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Essential thrombocythemia (ET) and polycythemia vera (PV) are clonal myeloproliferative disorders that are often difficult to distinguish from other causes of elevated blood cell counts. Assays that ...could reliably detect clonal hematopoiesis would therefore be extremely valuable for diagnosis. We previously reported 3 X-chromosome transcription-based clonality assays (TCAs) involving theG6PD, IDS, andMPP1genes, which together were informative in about 65% of female subjects. To increase our ability to detect clonality, we developed simple TCA for detecting the transcripts of 2 additional X-chromosome genes: Bruton tyrosine kinase (BTK) and 4-and-a-half LIM domain 1 (FHL1). The combination of TCA established the presence or absence of clonal hematopoiesis in about 90% of female subjects. We show that both genes are subject to X-chromosome inactivation and are polymorphic in all major US ethnic groups. The 5 TCAs were used to examine clonality in 46 female patients along with assays for erythropoietin-independent erythroid colonies (EECs) and granulocyte PRV-1 mRNA levels to discriminate polycythemias and thrombocytoses. Of these, all 19 patients with familial polycythemia or thrombocytosis had polyclonal hematopoiesis, whereas 22 of 26 patients with clinical evidence of myeloproliferative disorder and 1 patient with clinically obscure polycythemia were clonal. Interestingly, interferon α therapy in 2 patients with PV was associated with reversion of clonal to polyclonal hematopoiesis. EECs were observed in 14 of 14 patients with PV and 4 of 12 with ET, and increased granulocyte PRV-1 mRNA levels were found in 9 of 13 patients with PV and 2 of 12 with ET. Thus, these novel clonality assays are useful in the diagnosis and follow-up of polycythemic conditions and disorders with increased platelet levels.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The congenital polycythemic disorders with elevated erythropoietin (Epo) have been until recently an enigma, and abnormality in the hypoxia-sensing pathway has been hypothesized as a possible ...mechanism. The tumor suppressor von Hippel-Lindau (VHL) participates in the hypoxia-sensing pathway, as it binds to the proline-hydroxylated form of the hypoxia-inducible factor 1α (HIF-1α) and mediates its ubiquitination and proteosomal degradation. The loss of VHL function may result in the accumulation of HIF-1α and overproduction of HIF-1 downstream target genes including Epo. VHL syndrome is an autosomal dominant disorder predisposing to the development of tumors, due to inherited mutations in the VHL gene. Some rare patients with VHL syndrome have polycythemia, which has been attributed to Epo production by a tumor. It was recently found that homozygosity for theVHL Arg200Trp mutation is the cause of Chuvash polycythemia, an autosomal recessive polycythemic disorder characterized by elevated serum Epo and hypersensitivity of erythroid cells to Epo. We evaluated the role of VHL in 8 children with a history of polycythemia and an elevated serum Epo level and found 3 different germline VHL mutations in 4 of them. One child was homozygous for the Arg200Trp VHL mutation, and another compound heterozygous for the Arg200Trp and the Val130Leu mutations. Two children (siblings) were heterozygous for an Asp126Tyr mutation, one of them fulfilling some criteria of VHL syndrome. We propose that mutations of the VHL gene represent an important cause of pediatric sporadic polycythemias with an inappropriately high serum Epo concentration.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background Sickle cell disease (SCD) is the most common monogenic disease worldwide. Benefits of preventive measures such as early penicillin prophylaxis and ease of neonatal diagnosis led to the ...inclusion of SCD in newborn screening programs (NSP) in the US and later in several Canadian provinces. Universal NSP was implemented in the province of Québec (QcNSP) in November 2013, close in time to the recommendation of early hydroxyurea (HU) therapy. Our study objective was to evaluate how the QcNSP impacted the clinical outcomes of SCD infants and children followed at CHU Ste-Justine between the age of 0-5 years of age. We hypothesized that the introduction of QcNSP has shortened the time to referral to SCD comprehensive centres and the time to HU initiation, while also reducing the number of acute SCD complications. Methodology This is a retrospective cohort study of patients referred to the pediatric comprehensive SCD centre at CHU Sainte-Justine (Montreal), a leading tertiary pediatric center in Canada from Jan 1-2000, to Dec 31-2019. To be included, patients had to be followed for at least two years. Two cohorts were defined: Cohort Pre-QcNSP included patients who had their first visit between January 1 st 2000 and October 31 st2013, whereas cohort post-QcNSP included patients who had their first visit between November 1st 2013 and December 31 st 2019. SCD genotypes were stratified into two groups: HbSS/Sß 0 and SC/Sß +. Reasons for referral were extracted. A Kaplan-Meier curve for hospitalization-free survival (HFS), a poisson regression for the number of VOC emergency (ED) visits and a logistic regression for clinical outcomes, adjusting for age at first visit, gender, place of birth, follow-up period and QcNSP were computed. The software R version 4.2.1 was used for all statistical analyses. The study was approved by the local IRB. Results Of 600 files examined, 410 met the inclusion criteria. 253 were referred pre-QcNSP, 157 post-QcNSP. There were equal gender representations in both groups, and no statistical differences between genotype representation between cohorts. Median age at 1st visit decreased from 1.2 IQR: 0.2-6.0 pre-QcNSP to 0.2 years IQR:0.1-4.8 post-QcNSP (p<0.001). The percentage of children born in the province of Qc diagnosed through NS increased from 48.1% (79) pre-QcNSP to 100% (102) post-QcNSP (p<0.004). The percentage of undiagnosed children born in Qc and referred after a first SCD-related complication (DRC) dropped from 42% to 0% (p<0.0001). The median age of HU-introduction for SS patients decreased from 4.5 IQR:2.6-5.5 pre-QcNSP to 0.75 years IQR:0.8-1.08 post-QcNSP (p<0.001). Similarly, the percentage of SS patients receiving HU by the age of 2 years old significantly increased from 28.6% preQcNSP to 59.3% post-DN patients (p=0.003). The overall percentage of SS patients eventually receiving HU was nevertheless statistically not different between cohorts (89.7% (61/68) post-QcNSP vs 82.5% (80/97) pre-QcNSP). The number of hospitalizations in HbSS/Sß 0 decreased from 2 hospitalizations/pt-year pre-QcNSP IQR 1.0-3.0 to 1.0 IQR: 0.6-1.4 (p<0.001). Hospitalization-free survival (HFS) also improved (257 days post-QcNSP vs. 140 days pre-QcNSP, p<0.001) for HbSS/Sß 0 patients. Similarly, HFS for VOC was significantly longer post-QcNSP (1320 days vs. 573 days, p<0.002). Evaluating ED visits for VOC, HbSS/Sß 0 children referred pre-QcNSP had much greater risk of ED-VOC visits than post-QcNSP (1.44, CI 1.22-1.67); similarly, SS/Sb 0 children referred for DRC vs NS had a higher risk of ED-visit for VOC (0.25, CI 0.02-0.48). There was however no statistical difference in SC/Sß + patients. Conclusion. In Quebec, the universalization of the NSP has enabled early detection and referral of children with SCD to comprehensive care centre. Earlier access to this expertise ensures that children benefit from the essential preventive interventions that are vaccination, prophylactic penicillin, early HU-use as well as caregiver education. These combined interventions may explain in part the improvement in acute events. This cohort study highlights that universal NSP of SCD is an essential public health measure.
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NUK, OILJ, SAZU, SBCE, UL, UM, UPCLJ, UPUK
Inherited bone marrow failure syndromes (IBMFSs) comprise a genetically heterogeneous group of diseases with hematopoietic failure and a wide array of physical malformations. Copy number variants ...(CNVs) were reported in some IBMFSs. It is unclear what impact CNVs play in patients evaluated for a suspected diagnosis of IBMFS. Clinical and genetic data of 323 patients from the Canadian Inherited Marrow Failure Registry from 2001 to 2014, who had a documented genetic work-up, were analyzed. Cases with pathogenic CNVs (at least 1 kilobasepairs) were compared to cases with other mutations. Genotype-phenotype correlations were performed to assess the impact of CNVs. Pathogenic nucleotide-level mutations were found in 157 of 303 tested patients (51.8%). Genome-wide CNV analysis by single nucleotide polymorphism arrays or comparative genomic hybridization arrays revealed pathogenic CNVs in 11 of 67 patients tested (16.4%). In four of these patients, identification of CNV was crucial for establishing the correct diagnosis as their clinical presentation was ambiguous. Eight additional patients were identified to harbor pathogenic CNVs by other methods. Of the 19 patients with pathogenic CNVs, four had compound-heterozygosity of a CNV with a nucleotide-level mutation. Pathogenic CNVs were associated with more extensive non-hematological organ system involvement (
=0.0006), developmental delay (
=0.006) and short stature (
=0.04) compared to nucleotide-level mutations. In conclusion, a significant proportion of patients with IBMFSs harbor pathogenic CNVs which were associated with a more extensive non-hematological phenotype in this cohort. Patients with a phenotype suggestive of IBMFSs but without identification of pathogenic nucleotide-level mutations should undergo specific testing for CNVs.
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