Clingen Coagulation Factor Deficiency Variant Curation Expert Panel: Meeting the Need for Recommendations to Curate Variants in the Coagulation Factor Genes

The genetics of blood coagulation has been an ongoing area of research; and with the advent of next generation sequencing panels, there is a significant increase in the number of variants identified in coagulation factor genes. Several published reports and online databases document the variants observed in patients with bleeding disorders; however, the clinical interpretation of these variants is not always straight-forward. To enable gene-specific variant interpretation in coagulation factor deficiency disorders, the National Institutes of Health (NIH)-funded effort, Clinical Genome Resource (ClinGen), has developed the Coagulation Factor Deficiency Variant Curation Expert Panel (CFD-VCEP). The CFD-VCEP is comprised of expert clinicians, genetic counselors, clinical laboratory diagnosticians and researchers working toward the goal of developing and implementing standardized protocols for sequence variant interpretation for coagulation factor genes. The CFD-VCEP adapts the 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for precise and consistent variant classification to genes involved in blood coagulation deficiencies. These guidelines recommend the use of 28 criteria codes based on the evidence category and the strength of the evidence (see Figure below). The first two genes under the purview of CFD-VCEP are F8 (OMIM: 300841) and F9 (OMIM: 300746). Pathogenic variants in the F8 and F9 genes resulting in the loss of protein function cause Hemophilia A and B, respectively. Owing to the similarity between these two genes with respect to their role in the coagulation cascade as well as the resulting phenotype, specification of variant curation guidelines for both genes has been undertaken simultaneously. With the completion of guideline specification for F8 and F9, the CFD-VCEP will subsequently continue this effort for other coagulation factor genes, while also curating F8 and F9 variants reported in ClinVar and other variant databases. Modifying the ACMG/AMP guidelines involves gene- and disease-informed specifications of the recommended criteria codes. This includes identifying which codes are applicable and which are not, defining gene- and disease-specific cut-offs such as for population frequency, and making code strength adjustments when appropriate. The specified guidelines are further refined based on their performance on a set of pilot variants (n = 30) for each gene compared to existing assertions of variant classification in ClinVar and by diagnostic laboratories represented in the CFD-VCEP. F8 and F9 variants classified by the CFD-VCEP will be submitted to ClinVar at the 3-star review status, with the tag of "FDA-recognized database", and the CFD-VCEP plans to begin this process by the second quarter of 2020. The considerations by the CFD-VCEP in the guideline-specification process and results from the pilot analysis will be discussed. This effort will lead to the standardized use of evidence criteria for the evaluation of variants in F8 and F9, which will reduce the number of variants of uncertain significance and those of conflicting interpretations, making genetic testing results more informative for providers and patients. The CFD-VCEP also encourages sharing de-identified data on variants among laboratories, which enables accurate and consistent curations. Figure Disclosures Lee: UNC Hemophilia Treatment Center: Employment. Carcao:Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kemball-Cook:European Association for Haemophilia and Allied Disorders: Other: Freelance . Leebeek:CSL Behring: Research Funding; uniQure BV: Consultancy, Research Funding; Baxalta/Shire: Research Funding. Miller:Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention: Consultancy.

Download Full-text

Off-Label Prescription of Hydroxycarbamide (Hydroxyurea, HU) for Severe Anemia: Preliminary Results from European Non-Interventional, Multicentric, Prospective Escort-HU Study

Blood ◽

10.1182/blood.v130.suppl_1.758.758 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 758-758

Author(s):

Mariane De Montalembert ◽

Gylna Loko ◽

Jerome Clouzeau ◽

Valentine Brousse ◽

Frederic Galacteros ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Expert Panel ◽

Safety Data ◽

Incidence Rates ◽

Cell Disease ◽

Advisory Committees ◽

Off Label ◽

Preliminary Results ◽

The Mean

Abstract HU is licensed in Europe in the prevention of recurrent painful vaso-occlusive crises (VOC) including acute chest syndromes in adults, adolescents and children older than 2 years with sickle-cell disease (SCD). However, based on US and European expert panel recommendations (Yawn 2014, Habibi 2015) and results from placebo-controlled clinical trials, HU could be useful in SCD patients with severe anemia without VOC since it has been demonstrated to increase total Hb level (Wang 2011) and to decrease the need for blood transfusion. We hereby present preliminary results on effectiveness and safety data related to the prescription of HU for anemia from ESCORT-HU (European Sickle Cell Disease COhoRT - HydroxyUrea), a multicentric, prospective, non-interventional European study designed to collect long-term safety data on HU in SCD population. Between January 2009 and June 2017, 1841 patients were enrolled from 63 centers in France, Germany, Greece and Italy, amongst which 126 patients (6.8%) were started on HU for anemia from 34 centers. Of these 126, 96 were HU-naive. These HU-naive patients treated for anemia ('anemic' subpopulation) were selected for analysis to evaluate effectiveness and safety of HU in this indication and compared with data in HU-naive patients treated for other SCD indications. Demographic data and Hb genotypes are displayed in Table 1. The mean age, distribution of gender, Hb genotype and the mean HU dose at initiation were comparable in the 'anemic' subpopulation and the 'non-anemic' HU-naive cohort. Not surprisingly, mean Hb level at initiation was markedly lower in the 'anemic' subpopulation (7.07 ± 0.88 g/dl) than in the 'non-anemic' HU-naive cohort (8.71 ± 1.51 g/dl), with a lower proportion of patients with history of VOC and SCD-related hospitalization prior to HU initiation. The mean HU dose after 6 months was comparable in both groups (15.6 ± 3.83 mg/kg/day and 15.4 ± 4.11 mg/kg/day, respectively). Variation of blood parameters are displayed in Table 2. Similarly to what has been observed previously, a dramatic rise in Hb concentration (> 2 g/dl) was observed. This increase was comparable in absolute value to the increase observed in non-anemic patients. An increase in HbF was observed in the "anemic" subpopulation, with a near 2-fold increase in %HbF, markedly in children. Changes in reticulocyte counts were inconclusive due to small number of patients in the dataset. Safety of HU in the population of patients treated for anemia was evaluated by comparing incidence rates of non-SCD related adverse events (AEs) in HU-naive patients treated for anemia with the 'non-anemic' HU-naive ESCORT-HU subpopulation (Table 3). With mean follow-up periods of 18.3 months in 'anemic' subpopulation and 34.2 months in 'non-anemic' HU-naive cohort, preliminary results showed no striking difference in the incidence rate of reported AEs (total and serious) between the two populations (112.5% vs 139.8%, respectively for incidence rate of total AEs), and in the distribution of AEs by System Organ Class (SOC), at least in SOC where the number of adverse events was large enough to allow for comparison between the groups. Similarly, when focusing on AE causally related to HU (as judged by the investigators), the most frequently reported toxicity in the 'anemic' population was myelosuppression (anemia, neutropenia thrombocytopenia, pancytopenia reported in 4 children, one event each), as in the 'non-anemic' HU-naive cohort, with comparable incidence rates. In conclusion, even though HU is not licensed in Europe in severe chronic anemia, European and US expert panel guidelines recommend treatment with HU in this indication. Data from ESCORT-HU observational study on a subset of SCD patients treated off label in this indication confirmed total Hb level increase while the safety profile of HU in this subpopulation did not differ significantly from the 'non-anemic' HU-naive population. Disclosures De Montalembert: Novartis: Consultancy, Honoraria, Research Funding; Addmedica: Consultancy, Honoraria, Research Funding. Brousse: Add Medica: Membership on an entity's Board of Directors or advisory committees. Galacteros: Addmedica: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Creating a Variant Database for the American Society of Hematalogy By Consensus Variant Classification of Common Genes Associated with Hematologic Malignancies

Blood ◽

10.1182/blood-2020-141204 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 4-5

Author(s):

Niroshan Nadarajah ◽

Alex Wagner ◽

Rafael Bejar ◽

Mark Ewalt ◽

Annette S. Kim ◽

...

Keyword(s):

Patient Care ◽

Board Of Directors ◽

Working Group ◽

Research Funding ◽

Hematologic Malignancies ◽

Cancer Center ◽

Variant Classification ◽

Publicly Traded ◽

High Confidence ◽

Advisory Committees

Background: With the rapid decline of sequencing costs and the introduction of next-generation sequencing (NGS) instruments with higher processing capacity, the rate-limiting step in reporting genetic test results is moving away from sequencing production towards data interpretation. Powerful bioinformatics tools have been created to address this bottleneck. Though substantial advances have been made in clinical variant classification, much work remains. This is particularly true in the evaluation of somatic variants, where there is currently a high degree of variability in how members of the global molecular genetics and pathology community establish and validate bioinformatics pipelines and apply classification guidelines, and in how results are reported to clinicians. Aim: Create a reliable and widely available resource for variants relevant for hematologic malignancies and make their classification readily accessible to the wider hematology community, facilitating NGS diagnostics and improve the consistency and robustness of testing results to improve patient care . Methods: The ASH Somatic Working Group (SWG) is comprised of hematologists, hematopathologists, molecular biologists and bioinformaticians. The group was formed under the auspices of ASH two years ago to improve clarity around the various gene panels being used in our community and in the reporting of genetic variants associated with hematologic malignancies. The group collected 1) the list of genes (i.e. entity-specific panels) that are typically used in research or clinical laboratory applications at 8 different and specialized laboratories; 2) the variants within those genes and their respective internally developed tiering and interpretations among 6 laboratories; and 3) the institutional bioinformatics pipelines used for those interpretations. The working group identified 70 genes most commonly used in assays for myeloid and lymphoid diseases. A three-class system for defining somatic pathogenicity was used, to unify the submissions from 6 institutions. Pathogenic variants are those that have been clearly determined to be associated with tumorigenesis . Variants of unknown significance (VUS) may have evidence supporting or refuting their effect on somatic pathogenicity, but this evidence is not yet strong enough to classify the variants as pathogenic or benign. Benign variants have been determined not to drive tumorigenesis and are typically polymorphisms that are present throughout the (healthy) population at variable frequency. Individual variant assessment was performed by the contributing institutions using a variety of resources, including ClinVar, COSMIC, cBioPortal/OnkoKB, St. Jude PCGP, ARUP, LOVD, dbSNP and IARC databases, as well as population frequency information from gnomAD/ExAC and in-silico mutation impact prediction tools included SIFT, PolyPhen2, Mutation assessor, LRT, FATHMM, CADD, REVEL and dbNSFP. Additionally, evidence was uncovered through manual literature review. Results: Through an iterative process, the SWG has initially identified 202 variants of high confidence (with highly concordant interpretation amongst contributing laboratories) in 42 of 70 genes. These results will be publicly available as both as a multi-institutional collaborative manuscript on best practices in this field as well as a searchable web application on the ASH web site (www.hematology.org/research) to aid other clinicians and investigators. On this website variants can be queried using genomic coordinates based on hg19, GRCh38 or Gene and HGVSc nomenclature. With the ongoing process of resolving remaining discrepancies, the high-confidence data will be updated regularly, with evidence provided to support classification. Conclusions: ASH has created an application to serve as a resource for NGS diagnostics based on a systematic review process, which we anticipate will lead to more consistency in molecular testing reports for patients undergoing evaluation of myeloid and lymphoid malignancies. Regular updates will help hematology professionals to use NGS in routine patient care on an ongoing basis. Disclosures Wagner: Nationwide Children´s Hospital: Current Employment. Bejar:Genoptix/NeoGenomics: Honoraria; Forty-Seven/Gilead: Honoraria; Daiichi-Sankyo: Honoraria; Celgene/BMS: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Astex/Otsuka: Honoraria; AbbVie/Genentech: Honoraria; Aptose Biosciences: Current Employment. Ewalt:University of Colorado: Current Employment; Memorial Sloan Kettering Cancer Center: Current Employment. Kim:Brigham and Women´s Hospital: Current Employment. Le Beau:Varian Medical Systems: Membership on an entity's Board of Directors or advisory committees; American Cancer Society: Membership on an entity's Board of Directors or advisory committees. Shammo:Onconova: Research Funding; Abbive: Current equity holder in publicly-traded company; Sanofi: Speakers Bureau; Takeda: Current equity holder in publicly-traded company; Agios: Consultancy; Novartis: Consultancy; Regeneron: Consultancy; BMS: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Apellis: Consultancy; Incyte: Consultancy, Research Funding, Speakers Bureau; Baxter: Current equity holder in publicly-traded company; Alexion: Consultancy, Research Funding, Speakers Bureau. Ryan:American Society of Hematology: Current Employment. Steensma:Aprea Therapeutics: Research Funding; Arrowhead Pharmaceuticals: Current equity holder in publicly-traded company; Astex Pharmaceuticals, Otsuka: Consultancy; H3 Biosciences: Research Funding; Takeda: Consultancy; BMS/Celgene: Consultancy; Onconova: Consultancy; Arena: Current equity holder in publicly-traded company; CRISPR: Current equity holder in publicly-traded company. Zehir:Memorial Sloan Kettering Cancer Center: Current Employment; Illumina: Honoraria.

Download Full-text

Characterization of Germline Variants in Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-118673 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4499-4499

Author(s):

Fernanda Martins Rodrigues ◽

Qingsong Gao ◽

Kuan-lin Huang ◽

Adam David Scott ◽

Steven M. Foltz ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Rare Variants ◽

Variant Classification ◽

Advisory Committees ◽

Germline Variants ◽

Pathogenic Variants ◽

Gene And Protein Expression

Abstract Multiple myeloma (MM) is an incurable hematological malignancy characterized by the clonal proliferation of malignant plasma cells in the bone marrow. Like other cancers, MM is a genetically complex and heterogeneous disease. One of its distinctive characteristics is that it is preceded by a pre-malignant condition known as monoclonal gammopathy of undetermined significance (MGUS), which then progresses to asymptomatic (smoldering) multiple myeloma (SMM) and, ultimately, to late-stage MM. Its progression through these stages is determined by a sequence of genomic aberrations, starting with germline events that predispose to the disease, followed by early initiating events and the later acquisition of mutations that contribute to disease progression. Although considerable progress has been made in the past 6 years in cataloguing somatic events underlying MM development and progression, little is known about its genetic predisposition. Therefore, large-scale germline genomic variant studies are urgently needed. Recently, our group has published the largest-scale pan-cancer study of >10K adult and >1K pediatric cases that revealed new insights on germline predisposition variants across 33 cancer types (853 pathogenic or likely pathogenic variants) (Huang et al., 2018). Here, we aim to apply a similar strategy to MM cases. The CoMMpass study, promoted by MMRF (Multiple Myeloma Research Foundation) is a longitudinal, prospective observational study involving the collection and analysis of sequencing and clinical data from >1K MM patients at diagnosis and relapse. We performed germline variant calling on 808 normal samples from this dataset using GenomeVIP (https://github.com/ding-lab/GenomeVIP), which integrates multiple tools: VarScan2 and Genome Analysis ToolKit (GATK) for the identification of single nucleotide variants (SNVs) and indels; and Pindel for indel prediction. Variants were limited to coding regions of full length transcripts obtained from Ensembl release 70 plus the additional two base pairs flanking each exon that cover splice donor/acceptor sites. SNVs were based on the union of raw GATK and VarScan calls. Indels were required to be called by at least two out of the three callers (GATK, Pindel, VarScan). Variant calls from all tools were merged, filtered (allelic depth ≥ 5 for the alternative allele; rare variants with allele frequency ≤ 0.01 in 1000 Genomes and ExAC), and annotated using Variant Effect Predictor (VEP), resulting in an average of 1,653 variants per sample. Further, we applied CharGer (Characterization of Germline Variants, https://github.com/ding-lab/CharGer) to classify the identified germline variants as pathogenic, likely pathogenic, and prioritized variants of unknown significance (VUS). CharGer is an automatic variant classification pipeline developed by our group which adopts ACMG-AMP guidelines specifically for rare variants in cancer. Here, we were able to classify a total of 635 germline variants as pathogenic and 150 as likely pathogenic, affecting 90% of samples. Among pathogenic variants, 28 were found in known cancer predisposition genes including BRCA1 and BRCA2 - which have been previously associated with MM risk - BRIP1, CHEK2, TP53, TERT, and PMS2. Ongoing analyses include: functional characterization of these variants, identifying genes with enriched pathogenic or likely pathogenic variants in our dataset; investigation of LOH and two-hit (biallelic) events; gene and protein expression analyses in carriers of pathogenic germline variants of the respective gene; scanning for rare, germline copy number variations (CNVs); and identification of variants in post-translational modification sites that may affect protein signaling. Additionally, we are currently working on improving our CharGer tool by integrating new tumor associated data, such as DNA-Seq, RNA-Seq, Methyl-Seq and MS proteomics data, to improve variant classification. The preliminary results and analysis strategies described here will allow for efficient and cost-effective discovery of genetic changes relevant to MM etiology. Ultimately, we hope this work will impact our overall understanding of the genetics underlying MM predisposition, allowing for the development of better prevention and early detection strategies. Disclosures Vij: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

A Phase IV, Multicenter, Open-Label Study of Emicizumab Prophylaxis in Persons with Hemophilia a with or without FVIII Inhibitors Undergoing Minor Surgical Procedures

Blood ◽

10.1182/blood-2020-134906 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 30-31

Author(s):

Miguel A. Escobar ◽

Amy Dunn ◽

Doris Quon ◽

Ben Trzaskoma ◽

Lucy Lee ◽

...

Keyword(s):

Board Of Directors ◽

Surgical Procedures ◽

Research Funding ◽

Coagulation Factor ◽

Publicly Traded ◽

Open Label ◽

Advisory Committees ◽

Excessive Bleeding ◽

Open Label Study ◽

Minor Surgical Procedures

Introduction: Emicizumab is a subcutaneously administered, bispecific, humanized monoclonal antibody that bridges factor (F)IXa and FX to restore the function of missing activated FVIII in persons with hemophilia A (PwHA). This study (NCT03361137) was designed to evaluate the safety and efficacy of emicizumab prophylaxis in PwHA with or without FVIII inhibitors undergoing minor surgical procedures without additional prophylaxis with bypassing agents (BPAs; for patients with FVIII inhibitors) or FVIII (for patients without FVIII inhibitors). Methods: This Phase IV, multicenter, single-arm, open-label study enrolled PwHA of any age, with or without FVIII inhibitors, who were scheduled to undergo minor surgical procedures. Patients were required to have received a minimum of four loading doses of emicizumab (3mg/kg once weekly for 4 weeks) prior to surgical procedure; subsequent maintenance doses of emicizumab were 1.5mg/kg once weekly, 3mg/kg every 2 weeks, or 6mg/kg every 4 weeks. Patients were required to be adherent to emicizumab prophylaxis. Treatment with emicizumab was scheduled to continue for at least 1 month after surgery. No other prophylactic treatment with coagulation factor was permitted. Outcome measures included incidence of excessive bleeding intra-operatively and until discharge from surgery, use of BPAs or FVIII to control bleeding (intra- and post-operatively), incidence of adverse events (AEs), and the percentage of patients with complications requiring hospitalization or return to surgery. Excessive bleeding was defined as a rating of fair to poor on the hemostatic rating scale and translates to an intra- and/or post-operative blood loss of ≥25% over expectation for a patient without hemophilia prior to discharge from surgery. Patients were followed for 28 days following discharge from surgery. Results: Between June 28, 2018 and March 13, 2020, 14 PwHA undergoing minor surgeries were enrolled (with FVIII inhibitors n=11; without FVIII inhibitors n=3); one PwHA with FVIII inhibitors enrolled but did not have surgery and discontinued prematurely, therefore the surgery analysis population comprised 13 patients (with FVIII inhibitors n=10; without FVIII inhibitors n=3). The majority (78.6%) of those enrolled were <18 years of age and all surgeries were either central venous access device (CVAD) removal (n=11) or dental procedures (n=2; Table 1). Of the 10 patients with FVIII inhibitors, one CVAD removal led to excessive bleeding during surgery with a need for BPA therapy, two patients undergoing CVAD removal received BPA therapy during surgery but had no reported excessive bleeding, three (two CVAD removals, one dental extraction) had post-operative bleeding that required use of a BPA (Table 2). Seven patients with FVIII inhibitors had zero bleeds after discharge from surgery. None of the three PwHA without FVIII inhibitors had excessive bleeding necessitating FVIII treatment during surgery or until discharge; two CVAD removals resulted in zero bleeds post-operatively and one dental extraction led to a post-operative bleed that did not require treatment. No serious AEs, thromboembolic events (TEs), thrombotic microangiopathies (TMAs) or deaths were reported during the study. Overall, 10 AEs occurred in five patients with FVIII inhibitors (headache n=3, limb injury, procedural pain, pyrexia, constipation, device occlusion, adhesiolysis, and hematoma, all n=1); no AEs were reported in patients without FVIII inhibitors. There were no AEs leading to dose modification, interruption or withdrawal of treatment, and no patient in either group had surgical complications requiring hospitalization or a return to surgery. The study was terminated early due to low enrollment and the limited variety of surgery types. Conclusions: In this study of mostly pediatric PwHA with and without FVIII inhibitors receiving emicizumab prophylaxis, minor surgeries were safely performed. The majority of surgeries were performed without additional prophylactic coagulation factor, however the small sample size should be considered here. There were no serious AEs, TEs, TMAs, or deaths. These findings are consistent with results from previous studies of patients undergoing minor surgery while receiving emicizumab prophylaxis. Disclosures Escobar: National Hemophilia Foundation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dunn:Genentech, Inc.: Consultancy; Nationwide Children's Hospital: Current Employment; World Federation of Hemophilia USA: Membership on an entity's Board of Directors or advisory committees; Medscape: Honoraria; Spire: Honoraria; ATHN: Research Funding; Takeda: Research Funding; BioMarin: Research Funding; uniQure: Consultancy. Quon:Octapharma: Honoraria; Bayer: Honoraria; Biomarin: Honoraria, Speakers Bureau; Bioverativ/Sanofi: Honoraria, Speakers Bureau; Genentech, Inc./F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; Novo Nordisk: Honoraria, Speakers Bureau; Shire/Takeda: Speakers Bureau; Orthopaedic Institute for Children: Current Employment. Trzaskoma:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Lee:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Ko:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Carpenter:Novo Nordisk: Honoraria; Genentech, Inc.: Honoraria; American Thrombosis and Hemostasis Network: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Research Funding; Shire: Research Funding; Hemostasis & Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees; American Academy of Pediatrics: Other: PREP Heme/Onc editorial board; Kedrion: Honoraria.

Download Full-text

Myeloid Malignancy Variant Curation Expert Panel: An ASH-Sponsored Clingen Expert Panel to Optimize and Validate Acmg/AMP Variant Interpretation Guidelines for Genes Associated with Inherited Myeloid Neoplasms

Blood ◽

10.1182/blood-2018-99-118979 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5849-5849

Author(s):

Lucy Godley ◽

Xi Luo ◽

Justyne Ross ◽

Sarah Jackson ◽

Anupriya Agarwal ◽

...

Keyword(s):

Research Funding ◽

Expert Panel ◽

Clinical Laboratory ◽

Sequence Variant ◽

Variant Interpretation ◽

Advisory Committees ◽

Myeloid Malignancy ◽

Myeloid Malignancies ◽

Germline Variation ◽

American Society

Abstract Clinical Genome Resource (ClinGen) is an NIH/NHGRI-funded effort dedicated to building an authoritative central resource that defines the clinical relevance of genes and variants for use in precision medicine and research. ClinGen has developed both gene and variant expert panels to adapt the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for consistent and accurate variant classification of specific genes and diseases. Here, we describe a new effort initiated in 2018 and supported by the American Society of Hematology (ASH) in collaboration with ClinGen to develop expert panels. This effort was motivated by the increasing use of genomics in clinical hematology and the lack of resources containing expert interpretation of germline variation. This panel, named the ClinGen Myeloid Malignancy Variant Curation Expert Panel is focused on the curation and annotation of variants in genes associated with familial/inherited risk for myeloid malignancies. Our team consists of expert clinicians, clinical laboratory diagnosticians, and researchers interested in developing and implementing standardized protocols for sequence variant specific annotations of genes in inherited myeloid malignancies. The optimization of the ACMG/AMP guidelines encompasses disease-/gene-informed specifications or strength adjustments of existing rules, including defining gene-specific population frequency cutoffs, and specifying recommendations for the use of computational/predictive data, as supported by published functional and clinical data in addition to guidance on ACMG/AMP variant interpretation provided by the ClinGen effort. Our initial focus has been to organize sub-groups of teams to develop approaches for evaluating ACMG/AMP codes to interpret germline variants of the RUNX1 gene. Once the curation of RUNX1 variants is underway, we will extend our focus to include CEBPA, DDX41, ETV6, and GATA2. These efforts will be bolstered by encouraging submission of existing variant interpretations to ClinVar or other public variant databases by the Hematology community. In summary, the ClinGen Myeloid Malignancy Variant Curation Expert Panel aims to develop recommendations to optimize ACMG/AMP criteria for standardization of variant interpretation in myeloid leukemia genes and make expert-reviewed and interpreted variants available to the hematology community through ClinVar and the ClinGen website (www.clinicalgenome.org) to support patient care and research. Disclosures DiNardo: Karyopharm: Honoraria; Agios: Consultancy; Medimmune: Honoraria; Celgene: Honoraria; Bayer: Honoraria; Abbvie: Honoraria. Nichols:Incyte: Research Funding; Alpine Immune Sciences: Research Funding. Plon:Baylor Genetics: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

ROTATION THROMBOELASTOMETRY FOR THE DIAGNOSIS OF FACTOR DEFICIENCY AND MANAGEMENT OF THE HEMOSTATIC THERAPY IN PATIENTS WITH INHERITED COAGULATION DISORDERS

Hematology and Transfusiology ◽

10.35754/0234-5730-2019-64-3-297-316 ◽

2019 ◽

Vol 64 (3) ◽

pp. 297-316

Author(s):

G. M. Galstyan ◽

O. A. Polevodova ◽

E. V. Yakovleva ◽

A. E. Shchekina

Keyword(s):

Blood Coagulation ◽

Plasma Sample ◽

Coagulation Factor ◽

Coagulation Factors ◽

Blood Coagulation Factors ◽

Congenital Deficiency ◽

Factor Deficiency ◽

Coagulation Factor Deficiency ◽

Hemostatic Therapy ◽

Fvii Deficiency

Introduction. Rotation thromboelastometry (ROTEM) is a method for studying haemostasis at the place of providing care, which allows identification of disorders on the basis of extrinsic and / or intrinsic coagulation pathways.Aim. To study the possibility of using ROTEM for diagnosing the deficiency of individual blood coagulation factors, as well as for monitoring the efficacy and safety of haemostatic therapy in such coagulopathies.Materials and methods. The study included 9 patients with a congenital deficiency in various coagulation factors. The authors performed ROTEM, as well as coagulological tests to determine activated partial thromboplastin time, Quick’s value, fibrinogen and the plasma activity of coagulation factors FV, FVII, FVIII, FIX, FXI and FXII. In order to exclude the effects of heparin or hyperfibrinogenaemia, HEPTEM and / or FIBTEM were conducted. In order to identify the deficiency of individual coagulation factors, the authors used standard plasma samples and plasma deficient in one of the coagulation factors. The citrated blood under study was mixed with standard plasma and that deficient in one of the studied factors in a 2:1 ratio for subsequent repetition of the EXTEM and / or INTEM tests. Coagulation factor deficiency was confirmed by a change in the CT parameter.Results. Isolated prolongation of EXTEM CT was detected in the setting of FVII deficiency; while INTEM CT prolongation occurred under the deficiency of FVIII, FIX, FXI, FXII, with simultaneous EXTEM and INTEM CT prolongation being observed in the context of FVII deficiency. The test of a mixture of citrated blood and standard plasma revealed shortened EXTEM CT in the setting of FVII deficiency and shortened INTEM CT under the deficiency of FVIII, FIX, FXI, FXII, with the shortening of both EXTEM and INTEM CT being detected in the setting of FV deficiency. In a sample containing a mixture of whole blood and plasma deficient in the studied factor, CT remained prolonged or increased. Clinical examples of using ROTEM for diagnosing coagulation factor deficiency are presented.Conclusion. The normalisation of ROTEM parameters in a standard plasma sample along with the preservation of hypocoagulation in a factor-deficient plasma sample confirms the coagulation factor deficiency. ROTEM provides the possibility of monitoring the efficacy of haemostatic therapy for congenital deficiencies in individual blood coagulation factors.

Download Full-text

Strategies for Securing and Maintaining Predictable Efficacy with Recombinant Activated Factor VII in On-Demand Treatment of Haemophilia Patients with Inhibitors.

Blood ◽

10.1182/blood.v114.22.4443.4443 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4443-4443

Author(s):

Benny Sørensen ◽

Yesim Dargaud ◽

Gili Kenet ◽

Jeanne M. Lusher ◽

Andrew Mumford ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Expert Panel ◽

Real Life ◽

Treatment Strategies ◽

Factor Vii ◽

Advisory Committees ◽

Recombinant Activated Factor Vii ◽

On Demand ◽

Activated Factor Vii

Abstract Abstract 4443 Introduction Practical strategies for securing and maintaining predictable efficacy with recombinant activated factor VII (rFVIIa) remain to be fully described. We intend to document such strategies as applicable to on-demand treatment of haemophilia patients with inhibitors. In a minority of patients who appear refractory to bypassing-agent therapy, effective strategies may help to optimise treatment — inappropriate therapy can delay bleed cessation and waste valuable resources. Methods At a recent Novo Nordisk-sponsored meeting held in San Francisco in December 2008, an expert panel of physicians discussed strategies for securing and maintaining predictable efficacy with rFVIIa for on-demand treatment of spontaneous bleeds in haemophilia patients with inhibitors. Some of the strategies discussed (choice of rFVIIa dose according to patient age, site of bleed, and bleed severity, as well as timing of therapy, use of home treatment, treatment monitoring and dealing with severe or difficult-to-treat bleeds) were included in a questionnaire, which was sent to a selected international group of physicians who are involved in the treatment of inhibitor patients. An honorarium (of ≤50, Euro 50 or $50 for physicians in the UK, Europe and the United States respectively) was offered by Novo Nordisk in recognition of the time taken to complete the survey. Questionnaires varied slightly according to variations in licensed use of rFVIIa in these countries. The aim of the survey was to obtain insight into the ways in which on-demand treatment of spontaneous bleeds in haemophilia patients with inhibitors is managed in real-life clinical practice and to find strategies to ensure predictable efficacy with rFVIIa. Results Data were analysed from 28 completed questionnaires. Most respondents (59%) recommend 1×270μg/kg as the initial dose of rFVIIa in both children (aged <15 years) and adults (aged >15 years) and repeated doses (2-3) of 90μg/kg were also widely used (33-41%). In case further haemostatic support is needed, 55% suggest 1×90μg/kg every 2-3 hours whereas another 40% suggest 1×270μg/kg until haemostasis is achieved. Treatment strategies for target joints, muscle and mucocutaneous bleeds were recommended to be adjusted by increasing the initial dosage of rFVIIa or shortening the dosage interval. In the case of mucocutaneous bleeds, respondents also recommend adjuvant antifibrinolytic therapy. All respondents recommended administration of rFVIIa within 1 hour following the first sign of bleeding; in 70% of cases, the first dose of rFVIIa was stated to be given within 2 hours. In total, 76% of respondents advocated home therapy. Most (93%) encouraged patients to keep a diary of bleeds. The haemostatic effect was predominantly monitored by observing: decreased pain, decreased swelling, and improved mobility. In cases of abnormal bleeds, all severe bleeds, as well as bleeds that do not respond to 2-3 doses of rFVIIa, clinicians recommended that patients contact the haemophilia centre. The interval of rFVIIa dosing was reported to be shortened in 21.8-48.4% of such cases. In cases of unexpected efficacy, 57-60% of respondents reported that they perform detailed laboratory investigation of coagulation factors and platelet function (including a detailed history of drugs/agents that may affect primary haemostasis). From 55 to 76% of respondents reported the use of physiotherapy, in particular in target joints and post surgery. Conclusions Although variations exist in how on-demand rFVIIa is used in different bleeding scenarios in inhibitor patients, many clinicians follow similar strategies. Treatment strategies, which focus on securing and maintaining predictable efficacy, will be developed both from expert panel recommendations and from clinicians' real-life experiences. Such strategies will benefit inhibitor patients, expediting bleed cessation and providing effective use of resources. Disclosures: Sørensen: Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxter: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Wyeth: Research Funding; Bayer: Speakers Bureau; Grifols: Research Funding. Kenet:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi- Aventis- Daichii: Membership on an entity's Board of Directors or advisory committees. Lusher:Novo Nordisk: Consultancy. Mumford:Novo Nordisk: Consultancy. Pipe:Baxter: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Wyeth: Speakers Bureau; Inspiration Biopharmaceuticals: Research Funding; CSL Behring: Honoraria. Tiede:Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Download Full-text

Distinct Gene Expression Signatures in Patients with Richter's Syndrome and Chronic Lymphocytic Leukemia with Prior Exposure to Ibrutinib

Blood ◽

10.1182/blood-2020-136172 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 30-31

Author(s):

Hanyin Wang ◽

Shulan Tian ◽

Qing Zhao ◽

Wendy Blumenschein ◽

Jennifer H. Yearley ◽

...

Keyword(s):

Gene Expression ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Activation ◽

Expression Profiles ◽

Lymphocytic Leukemia ◽

B Cell Activation ◽

Advisory Committees ◽

Upregulated Genes

Introduction: Richter's syndrome (RS) represents transformation of chronic lymphocytic leukemia (CLL) into a highly aggressive lymphoma with dismal prognosis. Transcriptomic alterations have been described in CLL but most studies focused on peripheral blood samples with minimal data on RS-involved tissue. Moreover, transcriptomic features of RS have not been well defined in the era of CLL novel therapies. In this study we investigated transcriptomic profiles of CLL/RS-involved nodal tissue using samples from a clinical trial cohort of refractory CLL and RS patients treated with Pembrolizumab (NCT02332980). Methods: Nodal samples from 9 RS and 4 CLL patients in MC1485 trial cohort were reviewed and classified as previously published (Ding et al, Blood 2017). All samples were collected prior to Pembrolizumab treatment. Targeted gene expression profiling of 789 immune-related genes were performed on FFPE nodal samples using Nanostring nCounter® Analysis System (NanoString Technologies, Seattle, WA). Differential expression analysis was performed using NanoStringDiff. Genes with 2 fold-change in expression with a false-discovery rate less than 5% were considered differentially expressed. Results: The details for the therapy history of this cohort were illustrated in Figure 1a. All patients exposed to prior ibrutinib before the tissue biopsy had developed clinical progression while receiving ibrutinib. Unsupervised hierarchical clustering using the 300 most variable genes in expression revealed two clusters: C1 and C2 (Figure 1b). C1 included 4 RS and 3 CLL treated with prior chemotherapy without prior ibrutinib, and 1 RS treated with prior ibrutinib. C2 included 1 CLL and 3 RS received prior ibrutinib, and 1 RS treated with chemotherapy. The segregation of gene expression profiles in samples was largely driven by recent exposure to ibrutinib. In C1 cluster (majority had no prior ibrutinb), RS and CLL samples were clearly separated into two subgroups (Figure 1b). In C2 cluster, CLL 8 treated with ibrutinib showed more similarity in gene expression to RS, than to other CLL samples treated with chemotherapy. In comparison of C2 to C1, we identified 71 differentially expressed genes, of which 34 genes were downregulated and 37 were upregulated in C2. Among the upregulated genes in C2 (majority had prior ibrutinib) are known immune modulating genes including LILRA6, FCGR3A, IL-10, CD163, CD14, IL-2RB (figure 1c). Downregulated genes in C2 are involved in B cell activation including CD40LG, CD22, CD79A, MS4A1 (CD20), and LTB, reflecting the expected biological effect of ibrutinib in reducing B cell activation. Among the 9 RS samples, we compared gene profiles between the two groups of RS with or without prior ibrutinib therapy. 38 downregulated genes and 10 upregulated genes were found in the 4 RS treated with ibrutinib in comparison with 5 RS treated with chemotherapy. The top upregulated genes in the ibrutinib-exposed group included PTHLH, S100A8, IGSF3, TERT, and PRKCB, while the downregulated genes in these samples included MS4A1, LTB and CD38 (figure 1d). In order to delineate the differences of RS vs CLL, we compared gene expression profiles between 5 RS samples and 3 CLL samples that were treated with only chemotherapy. RS samples showed significant upregulation of 129 genes and downregulation of 7 genes. Among the most significantly upregulated genes are multiple genes involved in monocyte and myeloid lineage regulation including TNFSF13, S100A9, FCN1, LGALS2, CD14, FCGR2A, SERPINA1, and LILRB3. Conclusion: Our study indicates that ibrutinib-resistant, RS-involved tissues are characterized by downregulation of genes in B cell activation, but with PRKCB and TERT upregulation. Furthermore, RS-involved nodal tissues display the increased expression of genes involved in myeloid/monocytic regulation in comparison with CLL-involved nodal tissues. These findings implicate that differential therapies for RS and CLL patients need to be adopted based on their prior therapy and gene expression signatures. Studies using large sample size will be needed to verify this hypothesis. Figure Disclosures Zhao: Merck: Current Employment. Blumenschein:Merck: Current Employment. Yearley:Merck: Current Employment. Wang:Novartis: Research Funding; Incyte: Research Funding; Innocare: Research Funding. Parikh:Verastem Oncology: Honoraria; GlaxoSmithKline: Honoraria; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; AbbVie: Honoraria, Research Funding; Merck: Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Kenderian:Sunesis: Research Funding; MorphoSys: Research Funding; Humanigen: Consultancy, Patents & Royalties, Research Funding; Gilead: Research Funding; BMS: Research Funding; Tolero: Research Funding; Lentigen: Research Funding; Juno: Research Funding; Mettaforge: Patents & Royalties; Torque: Consultancy; Kite: Research Funding; Novartis: Patents & Royalties, Research Funding. Kay:Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Research Funding; Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; MEI Pharma: Research Funding; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees. Braggio:DASA: Consultancy; Bayer: Other: Stock Owner; Acerta Pharma: Research Funding. Ding:DTRM: Research Funding; Astra Zeneca: Research Funding; Abbvie: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; alexion: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Identifying Factors That Predict for Unplanned Readmissions for Acute Myeloid Leukemia Patients Receiving Consolidation Cytarabine Based Therapies

Blood ◽

10.1182/blood-2019-128807 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3433-3433

Author(s):

Caitlin Siebenaller ◽

Madeline Waldron ◽

Kelly Gaffney ◽

Brian P. Hobbs ◽

Ran Zhao ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Smoking Status ◽

Consolidation Therapy ◽

Peripheral Vascular ◽

Consolidation Chemotherapy ◽

Advisory Committees ◽

History Of ◽

Acute Myeloid

Background: Younger patients (pts) with acute myeloid leukemia (AML) who enter a remission after intensive induction chemotherapy routinely receive at least one cycle of consolidation therapy with high dose cytarabine (HiDAC). This is commonly administered over a five-day inpatient stay, after which pts are discharged home as their blood counts nadir. It is thus a natural consequence of therapy that readmission for febrile neutropenia (FN) occurs, which can impact measures of quality and value in this population. Precise descriptions of incidence, type, and severity of infection, if identified, are lacking, and thus it is unknown to what standard cancer centers should be held for anticipated readmission. We measured these rates, and attempted to identify predictive factors for readmission. Methods: Adult AML pts ≥ 18 years of age who received at least one cycle of HiDAC consolidation (1000-3000 mg/m2 for six doses) in 2009-2019 were included. Our primary aim was to identify predictive factors for readmission after the first cycle of consolidation chemotherapy. The following pt characteristics and co-morbid conditions were analyzed: age, gender, body mass index (BMI), smoking status, AML cytogenetic risk status, history of diabetes, peripheral vascular disease, cardiovascular disease, chronic pulmonary disease, hepatic impairment, and other cancers. Secondary aims included: estimating rates of all-cause readmissions among all HiDAC cycles, defining the rate of FN readmissions, estimating rates of intensive care unit (ICU) admissions, clinical (e.g., probable pneumonia per imaging) and microbiologically-documented infections, prophylactic (ppx) medications used, and mortality. Statistical analyses interrogated potential risk factors for evidence of association with hospital readmission after the first cycle of consolidation chemotherapy. Results: We identified 182 AML pts who fit inclusion criteria. The median age was 50 years (range 19-73); 55% were female and 45% were male. Statistical analyses revealed no association with readmission after cycle 1 for cytogenetic risk (p=0.85), history of heart failure (p= 0.67), chronic pulmonary disease (p=1), connective tissue disease (p=0.53), cerebrovascular accident (p=0.63), diabetes (p=0.63), gender (p=0.07), history of lymphoma (p=0.53), other solid tumors (p=0.53), liver disease (p=1), myocardial infarction (p=0.71), peripheral vascular disease (p=1), or smoking status (p= 0.52). For 480 HiDAC cycles analyzed (88% at 3000 mg/m2), the overall readmission rate was 50% (242/480), of which 85% (205/242) were for FN. Those readmissions which were not FN were for cardiac complications (chest pain, EKG changes), non-neutropenic fevers or infections, neurotoxicity, bleeding or clotting events, or other symptoms associated with chemotherapy (nausea/vomiting, pain, etc.). Median time to FN hospital admission was 18 days (range 6-27) from the start of HiDAC. Of the 205 FN readmissions, 57% had documented infections. Of these infections, 41% were bacteremia, 23% fungal, 16% sepsis, 12% other bacterial, and 8% viral. Of 480 HiDAC cycles, ppx medications prescribed included: 92% fluoroquinolone (442/480), 81% anti-viral (389/480), 30 % anti-fungal (142/480), and 3% colony stimulating factor (14/480). Only 7% (14/205) of FN readmissions resulted in an ICU admission, and 1% (3/205) resulted in death. Conclusions: Approximately half of patients treated with consolidation therapy following intensive induction therapy can be expected to be readmitted to the hospital. The majority of FN readmissions were associated with clinical or microbiologically documented infections and are not avoidable, however ICU admission and death associated with these complications are rare. Readmission of AML pts following HiDAC is expected, and therefore, should be excluded from measures of value and quality. Disclosures Waldron: Amgen: Consultancy. Hobbs:Amgen: Research Funding; SimulStat Inc.: Consultancy. Advani:Macrogenics: Research Funding; Abbvie: Research Funding; Kite Pharmaceuticals: Consultancy; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Glycomimetics: Consultancy, Research Funding. Nazha:Incyte: Speakers Bureau; Abbvie: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmacutical: Research Funding; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee; Tolero, Karyopharma: Honoraria. Gerds:Imago Biosciences: Research Funding; Roche: Research Funding; Celgene Corporation: Consultancy, Research Funding; Pfizer: Consultancy; CTI Biopharma: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Sierra Oncology: Research Funding. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Mukherjee:Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Comparable Outcomes between Unrelated Donor (8/8 or 7/8 matched) and Haploidentical Donor for Allogeneic Stem Cell Transplantation in Adult Patients with Severe Aplastic Anemia

Blood ◽

10.1182/blood-2019-130419 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4619-4619

Author(s):

Jee Yon Shin ◽

Sung-Soo Park ◽

Gi June Min ◽

Silvia Park ◽

Sung-Eun Lee ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Advisory Committees ◽

Sibling Donor ◽

Alternative Donor ◽

Matched Sibling ◽

Grade Ii

Background Either allogeneic hematopoietic stem cell transplantation (SCT) from HLA-matched sibling donor or immunosuppressive therapy (IST) has been recommended as one of the standard treatments for severe aplastic anemia (SAA). Regarding only 30% of chance finding HLA‐matched sibling donor, SCT from an alternative donor including unrelated (URD) or haplo-identical related donor (HAPLO) is considered to be a treatment option after failure to IST in patients who lack of a HLA-matched sibling donor. The aim of this study was to compare the outcomes of URD SCT and HAPLO SCT for SAA patients. Method Consecutive 152 adult patients with SAA who received first SCT between March 2002 and May 2018 were included: 73 of HLA-well-matched (8/8) URD (WM-URD), 34 of HLA-mismatched URD (MM-URD), and 45 of HAPLO. With the intention to have a follow-up period at least 1 year, data were analyzed at May 2019. A conditioning regimen with total body irradiation (TBI) and cyclophosphamide was used for URD-SCT, whereas that with TBI and fludarabine was administered for HAPLO-SCT (Lee et al, BBMT 2011;17:101, Park et al, BBMT 2017;23:1498, Lee et al, Am J Hematol 2018;93:1368). The combination of tacrolimus and methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. Results The median follow-up was 53.4 (range, 0.2-174.1) months. The median age of URD and HAPLO cohort was 30 (range 18-59) and 34 (range 18-59) years, respectively. Except for one and three patients who failed respective a neutrophil and platelet engraftment, other patients achieved neutrophil and platelet engraftments with median 11 and 15 days for WM-URD, 13 and 16.5 days for MM-URD, and 12 and 14 days for HAPLO, respectively. The five-years overall survival (OS), failure-free survival (FFS), and cumulative incidences (CIs) of graft-failure and transplant-related mortality were similar among three groups: 88.3%, 85.5%, 2.7%, and 11.7% for WM-URD; 81.7%, 81.7%, 0%, and 18.3% for MM-URD, and 86.3%, 84.1%, 6.7%, and 9.2% for HAPLO. The 180-days CI of grade II-IV acute GVHD in WM-URD, MM-URD and HAPLO were 35.6%, 52.9%, and 28.9%, respectively; and moderate to severe chronic GVHD were 28.7%, 38.7% and 11.8% in respective cohort. The CI of grade II-IV acute GVHD and moderate to severe chronic GVHD were significantly higher in MM-URD than those in HAPLO (both, p=0.026). ATG is the only factor affecting both grade II-IV acute GVHD (Hazard ratio 0.511, p=0.01) and moderate to severe chronic GVHD (Hazard ratio 0.378, p=0.003) in multivariate analysis. Other complications including CMV DNAemia, hemorrhagic cystitis, invasive fungal disease, secondary malignancy, and sinusoidal obstruction syndrome were similar among three groups. Survival outcomes of a subgroup of ≥ 2 allele MM-URD (n=16) extracted form MM-URD were inferior that of other donor types (n=136): 75.0% vs. 86.9% (p=0.163) for 5-year OS and 75.0% vs. 84.7% (p=0.272) for 5-year FFS. Conclusion This study shows that there were no significant differences between alternative donor sources in the absence of suitable matched sibling donor. Host/donor features and urgency of transplant should drive physician towards the best choice among alternative donor sources for SAA patients treated with SCT. However, selection of ≥ 2 allele MM-URD should not be recommended due to high incidence of GVHD and inferior outcomes. Figure Disclosures Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; Otsuka: Honoraria. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

Download Full-text