Background: Osteonecrosis (ON) is a prevalent (30-50% by age 30) yet underdiagnosed complication in patients with sickle cell disease (SCD), commonly affecting the femoral and humeral head. SCD ON is ...progressive resulting in chronic intractable pain and disability. Various imaging modalities are available for the diagnosis of ON and a number of staging methods have been proposed to classify its severity. Numerous surgical and non-surgical treatments exist for different stages of ON. There is a lack of consensus on how to best investigate, classify and treat patients with SCD ON. A previous systematic review included only 1 randomized controlled trial (RCT) but the majority of the literature are non-randomized studies.
Objectives: To systematically review and summarize the available evidence from randomized and non-randomized studies with regard to the classification, diagnosis, treatment options and outcome of ON of the hips in SCD adults.
Methods: Searches were conducted using the following search concepts: (sickle cell disease OR sickle cell anemia OR hemoglobin SC disease) AND (osteonecrosis OR avascular necrosis OR bone and joint complications) NOT Bisphosphonate-Associated Osteonecrosis of the Jaw. Related terms were also searched in order to maximize sensitivity. MEDLINE, Embase, CINAHL, Current Controlled Trials, and Cochrane Central Register of Controlled Trials were queried. Two independent reviewers (DM-A and AP) excluded abstracts based on pre-defined criteria. A third reviewer (KK) resolved all conflicts. Full-text of included abstracts were translated to English as needed, extracted by DM-A, AP, KK and YP and screened based on the inclusion/exclusion criteria. Two assessors (DM-A and KK) independently assessed trial quality of extracted data. Study limitations (risk of bias) and confidence in effect estimates (quality of evidence) were assessed using the Newcastle-Ottawa Quality Assessment Scale for cohort studies.
Results and Discussion: 25 studies (1 RCT, 1 case-control, 10 prospective and 13 retrospective studies) were included from 544 unique citations (kappa=0.82). A total of 2,640 participants (median number of patients/study 34, range 10-1,031) with mean age of participants in each study between 19 and 40 years. Majority were HbSS (n=1,888), followed by 302 HbSC, 98 HbS/thalassemia, 27 sickle cell trait, 22 unspecified SCD genotype and 1 HbS/hereditary persistence of fetal hemoglobin. The male to female distribution was equal. Mean duration of follow-up was between 3 and 19 years. Majority (n=12) of the studies included symptomatic patients only. Nine studies used x-rays only to identify ON and 9 used x-ray with CT and/or MRI. Classification of ON between studies was heterogeneous (Ficat and Arlet: 3, Steinberg: 4, Ficat: 4, Mitchell 1987: 1, Arlet: 1, no classification scheme: 12). Treatment modalities used were extremely diverse. Of the 22 studies that described an intervention: 11 used hip arthroplasty only, 1 with cement injection only, 1 with core decompression only, and 9 used a combination of surgical and non-surgical interventions. There was also tremendous heterogeneity with the outcomes reported which precluded the conduct of any meta-analysis. The revision rate after hip arthroplasty, cement injection, and core decompression were 21% (range 3-40%), 13%, and 12% respectively. Median difference in Harris Hip Score post-hip arthroplasty was 52 (range 44-58), and 25 post-cement injection. The median rate of prosthesis infection post-hip arthroplasty was 5.5% (range 2-34%). Summary statistics were not possible on other outcome measurements since they were used in single study. Risk of bias in all the studies was moderate to high.
Conclusion: The heterogeneity in diagnosing, classifying and treating ON makes the development of a consensus guideline difficult. Ficat and Arlet, Steinberg, and Ficat were the most common method in ON staging. Hip arthroplasty alone or in combination with non-surgical interventions were the most commonly used treatment options. Although hip arthroplasty offers post-surgical pain relief, it is associated with high rates of revision. The paucity of RCT and the high risk of bias with the existing non-randomized studies highlight the importance of developing prospective controlled studies examining existing and novel therapies using a unified approach in determining the severity of ON and outcome measures.
Kuo:Novartis Canada: Honoraria, Other: Advisory Board; Alexion Pharmaceuticals: Honoraria, Other: Advisory Board.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Introduction:Sickle cell disease (SCD) patients can suffer from devastating complications of their disease as a result of chronic hemolysis and vasculopathy. Chronic blood transfusion can effectively ...prevent some of the most severe organ damage such as cerebral vasculopathy. However, alloimmunization remains a major concern for chronically transfused patients, even if prophylactic antigen matching is performed for C, E and Kell antigens. Variants in the Rh blood group have been well described in people of African descent and must be considered when transfusing patients with SCD. The main objectives of this study were to determine the frequency of variants in the Rh and Duffy blood groups and to identify compatible blood donors presenting similar Rh variants
Methods: Extended erythrocyte phenotypes were routinely done at diagnosis for every SCD patient followed at the SCD clinic of CHU Sainte-Justine. Serologic testing was performed by standard methods. Upon informed consent, genotyping for Rh and Fy blood groups was also proposed to all SCD patients. DNA analyses were used to predict D phenotype (including RHD pseudogene), C, c, E, e antigen profile, FY phenotype with GATA-1 status, and to confirm critical position in the RHD (DAU cluster, zygosity) and RHCEgenes (position 48, 254, 733, 1006). The study was approved by the local Research Ethics Board (REB).
Results: 203 SCD patients were evaluated: HbSS 64.3%, HbSC 29.6%, HbSb0 3.1%, HbSb+ 2.5% and HbSDIran 0.5%. ABO blood groups followed published prevalence: Group O 48.7%, A 26.2%, B 20.4%and AB 4.7%. 90.2% of patients had either a normal RHD*01 or RHD*10.00 gene which would predict a normal D+ phenotype. Twenty patients would require D− units (9.8%) to reduce their alloimmunization risk (D−, weak partial D and partial D). The RHCE genotyping results were as followed: normal c allele 61.2%, normal e allele 39.3%, partial e allele 34.1% and weak e allele 17.6%. Most RHCE alleles present in the cohort reflected variants previously reported in individuals of African descent. Most patients were compound heterozygotes. 45.8% of RHCE alleles were considered normal: RHCE*ce, RHCE*Ce and RHCE*cE. Fy(a-b-) phenotype was found in 91.6% of patients (186/203).
The list of RHCE variant alleles observed in the cohort was compared to Héma-Québec’s (blood supplier for the province of Quebec) African descent blood donor database. For partial e, weak partial e and rare hrB− phenotypes, only D+ donors are available whereas some of the patients are D−. The same is true for one Sec− (RH46, high-prevalence antigen) patient for which no donor is available. As for CEAG− recipients (partial ce-phenotype), two compatible blood donors were identified by screening O− units from donors of African descent. Overall, five patients (2.4%) may not have suitable donors in our blood bank based upon genotype compatibility. Twenty other patients could be added to this calculation because of a variant e allele in trans to a normal E allele.
Conclusions: The RH and FY results indicate that very few patients require rare blood units. More than 90% present a normal D antigen and are Fy(a−b−), similar to most blood donors of African ancestry. However, RHCE variants could be more problematic in terms of finding compatible units. This study showed a large array of RH variants, although most are present in heterozygous form accompanied by a normal allele. This could explain the low alloimmunization rate of 3% for Rh antigens observed in this cohort (overall alloimmunization rate of 18.9%). However, as all patients were younger than 18 years old, they will probably be exposed to more blood transfusion during their adult life. Having their RH and FY genotype readily available should make the blood donors’ selection easier. Further prospective studies are needed to evaluate if such an approach will lower the alloimmunization rate.
No relevant conflicts of interest to declare.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pyruvate kinase (PK) catalyzes the second ATP-forming step in glycolysis. Erythrocytes lack mitochondria and are dependent on glycolysis for energy. Recessively inherited mutations in the pyruvate ...kinase (PKLR) gene are the most common defect in the glycolytic pathway associated with chronic nonspherocytic hemolytic (CNSHA) anemia. Symptomatology is variable, ranging from well compensated anemia to severe disease with lifelong transfusion dependence. Genetic analyses of PK-deficient patients have shown most carry missense, frameshift, and nonsense mutations that lead to qualitative or quantitative defects in pyruvate kinase. We studied CNSHA PK-deficient patients from 13 kindreds with one (n=8) or no (n=5) amino acid altering mutations identified in the PKLR gene. To search for potential splicing or regulatory mutations on the other allele, or an alternate red blood cell diagnosis, whole exome sequencing (WES) or whole genome sequencing (WGS) of genomic DNA from affected patients was performed. Five patients with no PKLR coding region mutations had other rare genetic variants predicted to be damaging or previously associated with hematologic disease, including a GATA1 mutation previously associated with PK deficiency, a KIF23 mutation, and 3 with pathogenic PIEZO1 mutations. DNA of patients from 5 other kindreds with single coding region mutations; 1) R486W; 2) G319D; 3) R510Q; 4) A392T; and 5) R510Q, had WGS performed. Genomic analyses did not identify deletional or structural variants in or around the PKLR locus. Haplotyping did not reveal any common shared alleles between the 5 kindreds. Detailed sequence analysis identified unique deep intronic mutations in the PKLR gene in affected members from all 5 kindreds: 1) intron 7 G>A, 2) intron 7 T>G, 3) intron 9 T>A, 4) intron 9 G>A, and 5) exon 7/intron 7 boundary G>A. Four of the 5 mutations were not found in the 1000 Genomes database, while the fifth was found at a frequency of 0.0006. The Scroogle algorithm predicted all 5 mutations would perturb normal mRNA processing; kindred 1) create a novel 3' acceptor splice site; 2) disrupt an intron splicing enhancer or create a 3' splice acceptor site, 3) and 4) create novel 5' donor splice sites, and 5) disrupt a wild type 5' donor splice site. Minigene assays were performed to examine whether these PKLR intron mutations influenced splicing in vitro. Each minigene contained the ANK1 erythroid promoter, a patient-specific PKLR fragment with a mutant intronic allele inserted into intron 2 of the HBG1 gene, and the HBG1 3'untranslated region and polyA signal. After transformation in K562 cells, minigene-specific RNA was harvested, RT-PCR performed, followed by shotgun subcloning of PKLR cDNA. Sequence analysis of plasmid DNA identified aberrant PKLR mRNA isoforms from all 5 minigenes including partial exon skipping, single or multiple exon skipping, and/or partial intron retention. Specifically, kindred 1) skip exon 8 or skip exons 7-9; 2) skip exons 7-8 or skip exons 7-9; 3) insert 38bp 5' of exon 10 or skip exon 10, 4) delete first 67bp of exon 10 or skip exon 10; 5) skip exon 7-8 or skip exon 7-9. In aggregate, these isoforms all to lead to frameshift, with premature chain termination predicted to trigger nonsense mediated decay. Splicing studies from primary patient reticulocyte RNA are ongoing. Three patients with heterozygous PKLR mutations, S8A, V134D, and V460M, had no obvious disease-associated variants detected on WGS. These variants, particularly V134D and V460M, could lead to a dominant negative phenotype. These results indicate that detailed investigation, including whole genome sequencing, lead to a specific hematologic diagnosis in most pyruvate-kinase deficient patients. They also show that in a subset of patients, intron mutations leading to aberrant splicing may be a genetic mechanism associated with pyruvate kinase deficiency. This may be an under recognized mechanism of genetic disease.
Glader:Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Grace:Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy; Agios Pharmaceuticals: Research Funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Introduction
Inherited bone marrow failure syndromes (IBMFSs) are rare genetic disorders characterized by abnormal hematopoiesis resulting in cytopenias and increased risk of myelodysplastic syndrome ...(MDS) and acute myeloid leukemia (AML). Once patients develop MDS the only curative therapy is hematopoietic stem cell transplant (HSCT). The rate of progression from early MDS to advanced MDS and AML is variable and risk factors for progression in IBMFS patients are poorly defined. We hypothesized that certain variables could predict the likelihood of progression from early stages of IBMFS-associated MDS/clonal hematopoiesis to advanced MDS or AML, and that the type of disease progression may impact overall survival (OS).
Methods
Data were collected from patients prospectively enrolled in the Canadian Inherited Marrow Failure Registry (CIMFR), a collaboration of 1 adult and 16 pediatric hospitals in Canada that care for >95% of pediatric IBMFS patients. IBMFS patients were diagnosed as having a specific syndrome or unclassified IBMFS (UCIBMFS) based on published criteria from our lab and others'. Diagnostic criteria for pediatric MDS defined by Hasle et al. were used. Progression of MDS was defined as 1 or more of: (1) a new cytogenetic abnormality, (2) progression in cytopathology from refractory cytopenia (RC) or refractory cytopenia with ringed sideroblasts (RCRS) to refractory cytopenia with dysplasia (RCD), refractory cytopenia with excess blasts (RCEB) or AML, or (3) increased degree of cytopenia severity. Time to progression was described by Kaplan-Meier analysis and risk factors were evaluated using the Cox proportional hazards model.
Results
Of 601 patients enrolled in CIMFR, 59 (9.8%) developed cytogenetic clones/MDS. Thirteen (22%) had Fanconi Anemia (FA), 13 (22%) had Shwachman-Diamond Syndrome (SDS), 10 (16.9%) had UCIBMFS, and 23 (39%) had other marrow failure syndromes (i.e. Dyskeratosis Congenita, Severe Congenital Neutropenia, Diamond Blackfan Anemia, GATA2-related disorders). The majority presented with cytogenetic clones/RC (n=45, 76%), 9 (15%) had RCEB, 3 (5%) RCD and 1 (1.7%) RCRS. The most common cytogenetic abnormalities at presentation were -7/-7q (n=18, 30%) and isochromosome 7q10 (n=7, 12%). Four patients had complex cytogenetics (6.8%). Of the patients who developed MDS, 32 (54%) went to HSCT.
Patients who developed MDS had significantly worse OS (HR 3, 95% CI 2 to 6, p<0.0001), which varied by IBMFS category. MDS patients with UCIBMFS had a statistically significant lower OS compared to those without MDS (HR 5.7, 95% CI 1.7 to 18.6, p=0.004). In contrast, patients with FA had poor OS regardless of whether or not they developed MDS.
Twenty four MDS patients (40%) had disease progression, with a median time to progression of 4.7 months (1.14-131). Nine patients (38%) with disease progression had FA, 5 (21%) had SDS, 4 (17%) had UC, and 6 (25%) had other marrow failure syndromes. Ten patients (42%) developed more advanced cytopathology, 10 (42%) a new cytogenetic abnormality, and 5 (20%) worsening cytopenias. Eight patients progressed from RC to RCEB, with a median time to progression of 5.7 months (1.14 to 113). Progression to more advanced cytopathology was associated with lower OS (HR 2.7, 95% CI 1.0 to 7.4, p=0.046). Median time to progression of cytogenetics was 4.13 months (1.14 to 131), which was not predictive of worse OS (p=0.22). Notably, there was no difference in OS or risk of progression between the -7/-7q and isochromosome 7q groups (p=0.644). Finally, patients who progressed due to worsening cytopenias had significantly lower OS compared to those who did not (p=0.011), but numbers were small. Seventeen (71%) of the MDS patients who progressed underwent HSCT.
Conclusion
Development of MDS has a significant adverse impact on the OS of IBMFS patients, with disease progression occurring 4.7 months from MDS diagnosis. Progression to advanced cytopathology is associated with decreased survival, while worsening cytogenetic clones and cytopenias may not carry the same risk. Importantly, isochromosome 7q10 is also associated with a risk of progression to more severe hematological disease, and may have an impact on survival. Further analysis of additional variables (i.e. HSCT) will provide insight into the important predictors of survival and disease progression, and help to guide treatment decisions for this high-risk patient population.
No relevant conflicts of interest to declare.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: Over the last decade major progress has been made in developing new diagnostic methods and in phenotypic and molecular classification of inherited bone marrow failure syndromes (IBMFSs). ...Nevertheless, data from the Canadian Inherited Marrow Failure Registry (CIMFR) indicates that 28% of patients with inherited bone marrow failure syndromes (IBMFS) cannot be assigned a specific syndromic diagnosis. These unclassified IBMFS (UIBMFS) cases may represent either novel syndromes or atypical presentations of previously described disorders. Hematopoietic stem cell transplantation (HSCT) is the only curative option for bone marrow failure and malignant myeloid transformation in IBMFSs. However, it is unknown whether the application of this treatment to UIBMFS patients without an ability to modify the procedure according to the underlying genetic and syndromic diagnosis affects outcome. To our knowledge, there are no published transplant data on cohorts of patients with UIBMFSs. The aims of this study were to evaluate the outcome and prognostic factors of HSCT in a cohort of patients with UIBMFSs and to determine whether the knowledge of the syndromic/genetic diagnosis before HSCT has an impact on transplant outcome.
Methods: Patients were enrolled on the CIMFR if they were diagnosed with a specific IBMFSs (e.g. Fanconi anemia), and/or they had bone marrow failure and either a family history of bone marrow, or physical malformations or a diagnosis before the age of one year. Patients were considered as having an UIBMFS if they fulfilled the above criteria, but could not be assigned a specific syndromic diagnosis since they did not meet the diagnostic criteria for any known IBMFS. HSCT data were extracted from the CIMFR database and analyzed. Descriptive statistics were used to compare between groups. Cox proportional hazards model was used for univariate analysis to identify risk factors for worse overall survival post HSCT in patients with UIBMFSs.
Results: Among the patients enrolled in the CIMFR, 22 with UIBMFSs and 68 with classified IBMFSs (CIBMFSs) underwent HSCT between January 2001 and December 31, 2017. Transplanted patients with UIBMFSs were hematologically characterized by multilineage cytopenia (n=13), single-lineage cytopenia (n=1), myelodysplastic syndrome (MDS) (n=5) or acute myeloid leukemia (AML) (n=3). Patients with CIBMFSs had Fanconi anemia (n=30), dyskeratosis congenita (n=7), Shwachman-Diamond syndrome (n=9), Kostmann syndrome (n=6), Diamond-Blackfan anemia (n=4) or others (n= 11). Median age at diagnosis of patients with UIBMFSs was 4.18 years (range; 0 to 32.0 years) and median age at HSCT for UIBMFSs was 5.74 years (range; 0.17-66.67 years). Median time between diagnosis of UIBMFS and HSCT was 0.48 years (range; 0.12 - 34.67), this was significantly shorter than that of CIBMFS (1.77 years, range; 0.17 - 15 years, P=0.014). Six patients (27.3%) of UIBMFS and 9 patients (19.7%) with CIBMFS underwent HSCT for MDS-RCEB or AML (P=0.15).
The overall 5-year survival of UIBMFS patients was significantly inferior to that of CIBMFS patients: 56±11.4% vs. 76±5.5%, respectively (P=0.047). 5-year overall survival of patients with UIBMFSs was significantly worse among those whose stem cell source was cord blood (15±13.3%) vs. those who received other stem cell sources (91±8.7%, P=0.04), while stem cell source did not affect prognosis of patients with CIBMFSs. Engraftment failure among UIBMFS patients who received cord blood was significantly higher than engraftment failure among those who received bone marrow (55.6% vs. 9.1%, P=0.024). No other factors reached statistical significance when the impact of stem cell source on overall survival was analyzed, including transfusion load, transplant indications, intensity of conditioning regimens, related/non-related donor, degree of human leukocyte antigen (HLA) matching or identifying a diagnosis after HSCT.
Conclusion: Identifying the syndromic diagnosis of IBMFSs is critically important when considering HSCT. The worse HSCT outcome of UIBMFSs in this study might be related to an inability to tailor the transplant approach to the patient specific phenotype and genotype. Our data suggest that cord blood should be avoided as a stem cell source in patients with UIBMFSs.
No relevant conflicts of interest to declare.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: Pyruvate kinase deficiency (PKD) is the most common cause of chronic hereditary non-spherocytic hemolytic anemia. The spectrum of disease in PKD is broad, ranging from an incidentally ...discovered mild anemia to a severe transfusion-dependent anemia. Splenectomy partially ameliorates the anemia and reduces the transfusion burden in the majority of patients. Because hemoglobin poorly correlates with symptoms in PKD, transfusion requirements are typically used clinically to classify disease severity with those who are regularly transfused despite splenectomy recognized as the most severely affected subgroup.
Aim: To compare demographics, complications, and laboratory results between the most severely-affected PKD patients (those that are splenectomized and regularly transfused) with non-regularly transfused splenectomized PKD patients.
Methods: After ethics committee approval, patients were enrolled on the PKD Natural History Study, a prospective 30 site international study. All patients had molecularly confirmed PKD. Only splenectomized patients were included in the analysis. Transfusion frequency was observed over a 3-year period. Patients were divided into two groups based on transfusion frequency: the severe phenotype group was defined as those who receive regular transfusions (≥6 discrete red cell transfusion episodes per year) and the control group did not receive regular transfusions. Phenotype stability over the 3-year period was also assessed.
Results: 154 splenectomized patients with PKD were included: 30 patients in the severe PKD phenotype group and 124 patients in the comparison PKD group. Results of the analysis comparing the two groups are described in the Table. Severely affected patients were more likely to be female (77% versus 51%, p=0.013), older at the time of splenectomy (median age: 5 versus 3.6, p=0.011), have iron overload (93% vs. 51%, p<0.0001), have received chelation therapy (90% vs. 42%, p<0.0001), and had more lifetime transfusions (median: 77 versus 15, p<0.0001). Rates of other PKD complications including pulmonary hypertension, extramedullary hematopoiesis, liver cirrhosis, endocrinopathy, and bone fracture appear similar between the two groups. Laboratory values, including hemoglobin, total bilirubin, normalized PK enzyme activity, and median absolute reticulocyte count appear similar between the two groups. The underlying genetic mutation patterns (missense mutations versus non-missense mutations) were also similar between the groups. Phenotype stability over time was highly variable: of the patients with a severe phenotype at enrollment, 62% had a severe phenotype during the first follow-up year and 39% had a severe phenotype at the second follow-up year.
Conclusions: Patients with PKD who are regularly transfused despite splenectomy appeared to have similar rates of PKD-associated complications (except for iron overload) and similar relevant laboratory values and genotypes when compared to those who are not regularly transfused after splenectomy. The similarity observed between severe phenotype patients and comparison patients with PKD may result from a protective effect of transfusion (e.g. reduction of bone fractures and extramedullary hematopoiesis) or could suggest transfusion-dependence is an artificial signifier of disease severity, reflective of provider practices and patient symptoms rather than an actual distinct phenotype. Transfusion requirements in severe PKD appear to fluctuate significantly over time.
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Al-Samkari:Dova: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Moderna: Consultancy. van Beers:RR Mechatronics: Research Funding; Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding. Barcellini:Agios: Consultancy, Other: Advisory board; Apellis: Consultancy; Incyte: Consultancy, Other: Advisory board; Bioverativ: Consultancy, Other: Advisory board; Novartis: Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau. Eber:Agios Pharmaceuticals, Inc.: Consultancy. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chonat:Alexion: Other: advisory board; Agios Pharmaceuticals, Inc.: Other: advisory board. Kuo:Pfizer: Consultancy; Novartis: Consultancy, Honoraria; Celgene: Consultancy; Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy. Despotovic:Dova: Honoraria; Novartis: Research Funding; Amgen: Research Funding. Kwiatkowski:Celgene: Consultancy; Terumo: Research Funding; Apopharma: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy; Imara: Consultancy; Novartis: Research Funding. Thompson:Baxalta: Research Funding; Novartis: Consultancy, Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Rothman:Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Agios: Honoraria, Research Funding. Verhovsek:Sickle Cell Awareness Group of Ontario: Membership on an entity's Board of Directors or advisory committees; Sickle Cell Disease Association of Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding; Canadian Haemoglobinopathy Association: Membership on an entity's Board of Directors or advisory committees; Vertex: Consultancy. Kunz:Novartis: Membership on an entity's Board of Directors or advisory committees. Sheth:CRSPR/Vertex: Other: Clinical Trial Steering committee; Apopharma: Other: Clinical trial DSMB; Celgene: Consultancy. London:United Therapeutics: Consultancy; ArQule, Inc: Consultancy. Grace:Novartis: Research Funding; Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Introduction: Pyruvate kinase (PK) deficiency causes a defect in the glycolytic pathway, leading to a hereditary hemolytic anemia. Management is supportive and consists of splenectomy, transfusions, ...and chelation therapy.
Aim: To better understand the comorbidity and complication profile of adults with PK deficiency, and the extent to which transfusion frequency contributes, the objectives of this study were to (1) quantify the prevalence of comorbidities and complications according to transfusion history and (2) compare the types and rates of select comorbidities and complications with the general population.
Methods: Data were obtained from the enrollment survey of the PK Deficiency Natural History Study (NHS), a longitudinal, retrospective and prospective cohort study in which clinical, laboratory, transfusion, and radiologic data were collected; all participants were confirmed to have 2 mutations in the PKLR gene. Patients (n=122) were eligible for this analysis if they were ≥18 years of age and had sufficient data on transfusion history to enable classification into 1 of 3 cohorts: “Ever Regularly Transfused” (ERT, defined as ≥6 transfusions in any 12-month period), “Never Regularly Transfused” (NRT, defined as having ≥1 lifetime transfusion but never having >4 transfusions in any 12-month period), or “Never Transfused” (NT). To contextualize the findings, the frequencies of select conditions were compared with an age- and gender-matched cohort of individuals from the insured, general US population who did not have any hemolytic anemia diagnoses and had ≥5 years of continuous enrollment in the Truven MarketScan administrative claims database. The NHS reported lifetime prevalence rates, whereas rates obtained from the MarketScan data were based on diagnosis and procedure codes over varying look-back periods; therefore, to minimize bias, we limited PK deficiency vs. general population comparisons to (1) chronic conditions that require lifetime management and would thus still be recorded in claims data years after initial diagnosis, and/or (2) conditions for which a diagnosis/procedure date was available in the NHS and could be matched in time to the average 8-year look-back period for the general population. Frequencies were compared across mutually exclusive cohorts using Fisher's exact 2-tailed tests of significance.
Results: ERT (n=65), NRT (n=30), and NT patients (n=27) had a mean age of 34.2, 39.5, and 37.2 years at enrollment, respectively (not significant ns), with 46.2%, 56.7%, and 59.3%, respectively, being male (ns). ERT patients trended toward being more likely than NT patients to be Amish and have the homozygous R479H splice variant (30.8% vs 11.1% p=0.064) but were significantly less likely to have a missense/missense PKLR genotype (32.3% vs 70.4% p=0.001). Compared with the general population, patients with PK deficiency had significantly higher rates of splenectomy, cholecystectomy, osteoporosis, liver cirrhosis, pulmonary hypertension, and current prophylactic antibiotic and anticoagulant use (Table). Rates of splenectomy, cholecystectomy, and osteoporosis were significantly higher in patients with PK deficiency, regardless of transfusion cohort, and both ERT and NRT patients had significantly higher rates of liver cirrhosis than individuals from the general population. A gradient was seen across transfusion cohorts for other conditions. Notably, 83.1% of ERT patients, 50.0% of NRT patients, and 25.9% of NT patients had a history of liver iron overload. ERT patients were also significantly more likely than NRT and NT patients to have had a splenectomy, cholecystectomy, and/or thrombosis, and to currently use prophylactic antibiotics. Findings were consistent when the analysis was restricted to non-Amish patients with PK deficiency.
Conclusions: Patients with PK deficiency have higher rates of select comorbidities and complications than age- and gender-matched individuals who do not have PK deficiency. Even patients with PK deficiency who have never been transfused are at increased risk of complications of the disease and its treatment.
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Boscoe:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yan:Agios Pharmaceuticals, Inc.: Consultancy. Hedgeman:IBM Watson Health: Employment. van Beers:Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding. Al-Samkari:Agios: Consultancy, Research Funding; Dova: Consultancy, Research Funding; Moderna: Consultancy. Barcellini:Incyte: Consultancy; Alexion: Consultancy, Speakers Bureau; Agios Pharmaceuticals, Inc.: Consultancy; Novartis: Speakers Bureau; Apellis: Consultancy; bioverativ: Consultancy. Eber:Agios Pharmaceuticals, Inc.: Consultancy. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chonat:Alexion: Other: advisory board; Agios Pharmaceuticals, Inc.: Other: advisory board. Rothman:Agios: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Kuo:Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Kwiatkowski:Agios: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Imara: Consultancy; Apopharma: Research Funding; Novartis: Research Funding; Celgene: Consultancy; Terumo: Research Funding. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Neufeld:Octapharma, Shire Pharmaceuticals (Baxalta), Novo Nordisk, Celgene, NHLBI/NIH: Research Funding; Octapharma, Agios, Acceleron, Grifols, Pfizer, CSL Behring, Shire Pharmaceuticals (Baxalta), Novo Nordisk, ApoPharma, Genentech, Novartis, Bayer Healthcare: Consultancy; Octapharma: Other: study investigator, NuProtect study (Octapharma-sponsored). Holzhauer:Agios Pharmaceuticals, Inc.: Consultancy. Verhovsek:Sickle Cell Disease Association of Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding; Canadian Haemoglobinopathy Association: Membership on an entity's Board of Directors or advisory committees; Vertex: Consultancy; Sickle Cell Awareness Group of Ontario: Membership on an entity's Board of Directors or advisory committees. Kunz:Novartis: Membership on an entity's Board of Directors or advisory committees. Sheth:Apopharma: Other: Clinical trial DSMB; Celgene: Consultancy; CRSPR/Vertex: Other: Clinical Trial Steering committee. Despotovic:Novartis: Research Funding; Dova: Honoraria. Grace:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: Inherited bone marrow failure syndromes (IBMFSs) comprise a group of genetic disorders affecting blood cell production in bone marrow, resulting in single or multilineage cytopenias. ...Patients with IBMFSs often have physical malformations and are at risk of developing leukemia and solid tumors. With advances in sequencing technologies, causal nucleotide-level mutations can readily be identified in many IBMFSs. In about half of IBMFS cases, however, a molecular mutation is not detected. Copy number variation (CNVs) have been reported to cause IBMFSs. Unfortunately, genome-wide methods to identify CNVs have major limitations as they may miss small lesions (e.g. by oligonucleotide or CGH arrays) or may have low sensitivity due to low read depths (e.g. by whole genome sequencing).
Purpose: This study's purpose was to determine, after standard analysis of a next generation sequencing gene panel for causal mutations, whether re-analysis by normalized coverage value could identified CNVs and to characterize the genetic lesions.
Methods & Materials: Patients with IBMFSs were enrolled in The Canadian Inherited Marrow Failure Registry (CIMFR). Genomic DNA was analyzed by next-generation panel gene panel of over 72 IBMFS-associated genes. After analysis for nucleotide level mutations, the NextGene software was used to detect copy number variation using nucleotide read depth in test samples versus normalized control coverage values. Monoalleic copy number deletions were indicated by ratio of <0.33;biallelic deletion was considered when the value was close to zero. PCR or Affymetrix SNP6.0 array were used to validate deletions.
Results: Of the 258 patients who tested by the IBMFS next-generation gene panel, 93 (36%) were found to have causal nucleotide level mutations. 168 patients without identified mutations underwent analysis for copy number variation, of which 10 (6%) were found to have deletions. Genes most commonly exhibiting monoallelic deletions included RPS19, RPL11 and RPL5 (5 Diamond-Blackfan anemia patients). One patients with MDS was found to have monoalleic deletion of GATA2 . Moreover, a bialleic deletion of exon 1-5 in FANCA gene was detected in one Fanconi anemia patient. Lastly, we also identified monoalleic deletions of RBM8A in two thrombocytopenia with absent radii patients and of PARN in one unclassified pancytopenia patient. The last three patients were found to also have a nucleotide level mutation on the other allele by the NGS panel (compound heterozygousity). All the above deletions were validated by another method (PCR or Affymetrix SNP6.0 array).
Conclusions: CNVs can be detected in some IBMFSs by next-generation sequencing (NGS) panels by careful analysis of normalized coverage values. Such analysis should become standard practice before usage of other mutation detection strategies such as CNV microarray or whole exome/genome sequencing, since the later techniques may not detect certain CNVs that can be detected by gene panels.
Klaassen:Amgen: Consultancy; Baxalta: Honoraria; Biogen Canada LTD: Consultancy; Hoffman-La Roche LTD: Consultancy; Agios Pharmaceuticals: Consultancy; Octapharma: Honoraria. Dror:Alexion Canada: Research Funding.
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Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Purpose
To evaluate bone morbidity and the response to intravenous (IV) bisphosphonate therapy in children with Sickle Cell Disease (SCD).
Methods
We conducted a retrospective review of ...patient records from 2003 to 2019 at three Canadian pediatric tertiary care centers. Radiographs, magnetic resonance images, and computed tomography scans were reviewed for the presence of avascular necrosis (AVN), bone infarcts, and myositis. IV bisphosphonates were offered for bone pain management. Bone mineral density was assessed by dual-energy X-ray absorptiometry (DXA).
Results
Forty-six children (20 girls, 43%) had bone morbidity at a mean age of 11.8 years (SD 3.9) including AVN of the femoral (17/46, 37%) and humeral (8/46, 17%) heads, H-shaped vertebral body deformities due to endplate infarcts (35/46, 76%), and non-vertebral body skeletal infarcts (15/46, 32%). Five children (5/26, 19%) had myositis overlying areas of AVN or bone infarcts visualized on magnetic resonance imaging. Twenty-three children (8/23 girls) received IV bisphosphonate therapy. They all reported significant or complete resolution of bone pain. There were no reports of sickle cell hemolytic crises, pain crises or stroke attributed to IV bisphosphonate therapy. Bone mineral apparent density Z-score increased at the lumbar spine (N=14, mean change +0.6, SD 0.4) and total body less head (N=14, mean change +0.5, SD 0.4) after IV bisphosphonate therapy (mean 1.5 years, SD 0.8).
Conclusion
Children with SCD have the potential for extensive and early-onset bone morbidity. In this series, IV bisphosphonates were effective for bone pain analgesia and did not trigger sickle cell complications.
Presentation: No date and time listed
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