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In: Blood, American Society of Hematology, Vol. 140, No. 11 ( 2022-09-15), p. 1200-1228

Abstract: The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic, and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2022015850

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 140, No. 21 ( 2022-11-24), p. 2228-2247

Abstract: Myeloid neoplasms and acute leukemias derive from the clonal expansion of hematopoietic cells driven by somatic gene mutations. Although assessment of morphology plays a crucial role in the diagnostic evaluation of patients with these malignancies, genomic characterization has become increasingly important for accurate diagnosis, risk assessment, and therapeutic decision making. Conventional cytogenetics, a comprehensive and unbiased method for assessing chromosomal abnormalities, has been the mainstay of genomic testing over the past several decades and remains relevant today. However, more recent advances in sequencing technology have increased our ability to detect somatic mutations through the use of targeted gene panels, whole-exome sequencing, whole-genome sequencing, and whole-transcriptome sequencing or RNA sequencing. In patients with myeloid neoplasms, whole-genome sequencing represents a potential replacement for both conventional cytogenetic and sequencing approaches, providing rapid and accurate comprehensive genomic profiling. DNA sequencing methods are used not only for detecting somatically acquired gene mutations but also for identifying germline gene mutations associated with inherited predisposition to hematologic neoplasms. The 2022 International Consensus Classification of myeloid neoplasms and acute leukemias makes extensive use of genomic data. The aim of this report is to help physicians and laboratorians implement genomic testing for diagnosis, risk stratification, and clinical decision making and illustrates the potential of genomic profiling for enabling personalized medicine in patients with hematologic neoplasms.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2022015853

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood Advances, American Society of Hematology, Vol. 6, No. 21 ( 2022-11-08), p. 5750-5762

Abstract: Advanced systemic mastocytosis (AdvSM) is a rare myeloid neoplasm, driven by the KIT D816V mutation in & gt;90% of patients. Avapritinib, a potent, highly selective D816V-mutant KIT inhibitor, is approved for treatment of adults with AdvSM by the US Food and Drug Administration, regardless of prior therapy, and the European Medicines Agency for patients with prior systemic therapy, based on EXPLORER (#NCT02561988; clinicaltrials.gov) and PATHFINDER (#NCT03580655; clinicaltrials.gov) clinical studies. We present latest pooled efficacy and safety analyses from patients who received ≥1 systemic therapy prior to avapritinib in EXPLORER/PATHFINDER. Overall response rate in response-evaluable patients (n = 31) was 71% (95% confidence interval: 52% to 86%; 22/31), including 19% (6/31) with complete remission (CR)/CR with partial recovery of peripheral blood counts (CRh). Median time to response was 2.3 months, median time to CR/CRh was 7.4 months, and median duration of response (DOR) was not reached. Reductions ≥50% in bone marrow mast cell infiltration (89%), KIT D816V variant allele fraction (66%), serum tryptase (89%), and reductions ≥35% in spleen size (70%) occurred in most patients. Median OS was not reached (median follow-up 17.7 months). Avapritinib was effective in all AdvSM subtypes, regardless of number/type of prior therapies or poor prognostic somatic mutations. Treatment-related adverse events (TRAEs) were observed in 94% of patients, most commonly grade 1/2; 57% had TRAEs of at least grade 3; 81% remained on treatment at 6 months. Avapritinib in adults with AdvSM who received prior systemic therapy was generally well tolerated, with high response rates regardless of prior systemic therapy.

Type of Medium: Online Resource

ISSN: 2473-9529 , 2473-9537

URL: Article

DOI: 10.1182/bloodadvances.2022007539

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 2876449-3

In: Blood Advances, American Society of Hematology, Vol. 7, No. 9 ( 2023-05-09), p. 1713-1724

Abstract: Mast cell leukemia (MCL) is a rare subtype of systemic mastocytosis defined by ≥20% mast cells (MC) on a bone marrow aspirate. We evaluated 92 patients with MCL from the European Competence Network on Mastocytosis registry. Thirty-one (34%) patients had a diagnosis of MCL with an associated hematologic neoplasm (MCL-AHN). Chronic MCL (lack of C-findings) comprised 14% of patients, and only 4.5% had “leukemic MCL” (≥10% circulating MCs). KIT D816V was found in 62/85 (73%) evaluable patients; 9 (11%) individuals exhibited alternative KIT mutations, and no KIT variants were detected in 14 (17%) subjects. Ten evaluable patients (17%) had an abnormal karyotype and the poor-risk SRSF2, ASXL1, and RUNX1 (S/A/R) mutations were identified in 16/36 (44%) patients who underwent next-generation sequencing. Midostaurin was the most common therapy administered to 65% of patients and 45% as first-line therapy. The median overall survival (OS) was 1.6 years. In multivariate analysis (S/A/R mutations excluded owing to low event rates), a diagnosis of MCL-AHN (hazard ratio [HR] , 4.7; 95% confidence interval [CI], 1.7-13.0; P = .001) and abnormal karyotype (HR, 5.6; 95% CI, 1.4-13.3; P = .02) were associated with inferior OS; KIT D816V positivity (HR, 0.33; 95% CI, 0.11-0.98; P = .04) and midostaurin treatment (HR, 0.32; 95% CI, 0.08-0.72; P = .008) were associated with superior OS. These data provide the most comprehensive snapshot of the clinicopathologic, molecular, and treatment landscape of MCL to date, and should help further inform subtyping and prognostication of MCL.

Type of Medium: Online Resource

ISSN: 2473-9529 , 2473-9537

URL: Article

DOI: 10.1182/bloodadvances.2022008292

Language: English

Publisher: American Society of Hematology

Publication Date: 2023

detail.hit.zdb_id: 2876449-3

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 218-218

Abstract: Background: In general, patients with hematological diseases are predisposed to develop infections. Severe COVID-19 infection associated with high mortality is more likely in these patient cohorts compared to the general population. Due to immune defects related to the primary disease and/or to immunosuppressive treatment regimes, vaccination efficacy may be reduced in patients with hematological diseases. So far, data on this area are limited. Aim: To evaluate vaccination-related antibody response to BNT162b2, mRNA-1273, and ChADOx1 in patients with hematological disorders. Patients and methods: In this interim analysis of a prospective, observational single-center study, we report antibody levels at least 2 weeks after COVID-19 vaccination. A FDA/CE approved electrochemiluminescent assay (ECLIA) (Elecsys®, Roche, Mannheim, Germany) was used to quantify antibodies, pan Ig (including IgG) against the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. The assay has a measurement range of 0.4 to 250 U/mL, with a concentration ≥0.8 U/ml considered as positive. Data were analyzed for patients without detection of anti-N (nucleocapsid) SARS-CoV-2 antibody (i.e., without having passed SARS-CoV-2 infection). All tests were performed according to the manufacturer's instructions in an accredited laboratory at the University Hospital Mannheim. Results: Between February 2021 and July 2021, a total of 175 patients with hematological diseases were included in this study. The median age was 66 years (range 21-90 years), and 81 (46.3%) were female. The antibody levels were measured at least 14 days (median, 58 days) after the 2 nd vaccination. The patients were vaccinated with BNT162b2 (BioNTech, n=134), mRNA-1273 (Moderna, n=19), ChADOx1 (AstraZeneca, n=12), or got the first vaccination with BNT162b2 and the second with ChADOx1 (n=10). Overall, 145/175 (82.9%) were diagnosed with a malignant hematological disease (myeloid neoplasms, n=108; lymphoid neoplasms, n=37) and 30/175 with a non-malignant hematological disease (autoimmune disease, n=24; benign, n=6). 124 patients (70.1%) were on active therapy, and 51 patients (29.1%) were previously treated or treatment naïve. Correlation to specific therapies is ongoing and will be presented. In general, vaccination-related antibody response was positive (≥0.8 U/mL) in 148/175 (84.6%) patients with a median level of 208.6 U/mL (range 0.8-250.00) and negative ( & lt;0.8 U/mL) in 27/175 (15.4%) patients. The distribution of the negative cohort regarding the disease subgroups were as followed: myeloid neoplasms 7/27 (25.9%), lymphoid neoplasms 16/27 (59.3%), non-malignant hematological disease 4/27 (14.8%). Within the negative cohort, 21/27 (77.8%) were treated on active therapy, 6/27 (22.2%) were previously treated or treatment naïve. In myeloid neoplasms, patients with classical myeloproliferative neoplasm (MPN) had the highest negative result for antibodies with 4/7 (57.1%) followed by myelodysplastic syndrome (MDS) 2/7 (28.6%). Interestingly, all patients with chronic myeloid leukemia (CML) had a measurable immune response. In lymphoid neoplasms, patients with low-grade non-hodgkin lymphoma (NHL) (predominately chronic lymphocytic leukemia, CLL) had the highest negative antibody result 13/16 (81.3%) followed by high-grade NHL 4/8 (50%; predominately diffuse large b-cell lymphoma, DLBCL). In non-malignant hematological diseases, only patients with autoimmune diseases had a negative result. Conclusion: A remarkable group of patients with hematological disease were measured with no or low immune response after 2 nd COVID-vaccination, especially those with low-grade NHL, MDS and autoimmune disease. It seems that the percentage of patients with MPN and low response is less critical. No problems appeared in CML patients. Further explorations are needed with focus on potential risk of COVID infections despite full vaccination: The potential of 3 rd booster vaccination should be explored within clinical trials. Disclosures Reiter: AOP Orphan Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Blueprint Medicines: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Abbvie: Membership on an entity's Board of Directors or advisory committees; Deciphera: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses. Kreil: Novartis: Research Funding. Hofmann: Amgen: Honoraria; BMS: Honoraria; Novartis: Honoraria. Jawhar: Takeda: Honoraria, Other: Travel support; Blueprint Medicines: Honoraria; Stemline: Consultancy, Honoraria; Celgene: Other: Travel support; Novartis: Consultancy, Honoraria, Other: Travel support, Speakers Bureau. Saussele: Roche: Honoraria; Pfizer: Honoraria; Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-146832

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2565-2565

Abstract: Introduction: Systemic mastocytosis (SM) is a mast cell (MC) neoplasm driven by the KIT D816V mutation in approximately 95% of cases, resulting in MC hyperactivation and accumulation in various organs. Diagnosis of SM includes evaluation of MC aggregates in extracutaneous organs, atypical MC morphology and expression of CD25 with or without CD2, detection of the KIT D816V mutation, and a serum tryptase level of & gt;20 ng/ml. In addition to these diagnostic parameters, expression of CD30 has been observed on neoplastic MCs in patients with SM. Avapritinib, a highly potent and selective KIT D816V inhibitor, is now approved by the FDA for use in advanced SM (AdvSM) based on the phase 1 EXPLORER and phase 2 PATHFINDER studies. In EXPLORER, avapritinib markedly reduced the bone marrow (BM) MC burden in patients with AdvSM. Here, we describe a comprehensive evaluation of the effect of avapritinib on MC burden, morphology, and immunohistochemistry in BM, BM cellularity and fibrosis, as well as changes in selected hematologic parameters in patients with AdvSM from the pivotal phase 2 open-label, single-arm PATHFINDER (NCT03580655) study. Methods: Patients aged ≥18 years with centrally confirmed AdvSM were treated with avapritinib 200 mg once daily. Peripheral blood smears, bone marrow biopsies (BMBs), and aspirates (BMAs) were obtained at screening, and after 8 and 24 weeks. Evaluations of morphology were performed using standard Wright-Giemsa and H & E staining, while immunohistochemistry was performed on formalin-fixed EDTA-decalcified BM sections using standard techniques for tryptase, CD117, CD25, and CD30. Staining was also performed to detect reticulin and collagen fibrosis. Complete blood counts and differentials were performed at screening, and after 8 and 24 weeks. Results: In an interim analysis of PATHFINDER, the overall response rate (per modified International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis response) was 75% in 32 evaluable patients with AdvSM who received avapritinib. Reductions of ≥50% in BM MCs were observed in 88% (44/50) of patients and 60% of patients (30/50) had elimination of BM MC aggregates. Following treatment with avapritinib, an overall decrease in MC burden was observed in BMBs with a mean decrease of 64% at Week 8 (n=47) and 73% at Week 24 (n=24), and was associated with a decrease in the percentage of MC aggregates. Avapritinib treatment also resulted in reductions of the proportion of CD25+ and CD30+ MCs in BMBs by Week 8 and Week 24 (Table). In BMAs, avapritinib reduced the mean MC burden from 11% (out of total nucleated cells; n=47; range 0-72) at screening to 3% (range 0-47) by Week 8 (n=43) and 3% (range 0-30) at Week 24 (n=24), with decreases in immature and spindle-shaped MCs (Table). Of 5 patients with circulating MCs at screening and post-screening sample measurements (all with SM with associated hematologic neoplasm diagnoses), all had no detectable MCs by Week 8. Cellularity in BMBs decreased from a mean of 86% at screening to 68% at Week 8 and 59% by Week 24. Fibrosis was present in BMBs in 58 of 59 patients (98%) at screening, 40/44 (91%) at Week 8, and 22/25 (88%) at Week 24; reticulin fibrosis (MF score) and collagen fibrosis (Grade) was reduced during avapritinib treatment in those patients presenting with increased fibrosis. However, no significant changes in osteosclerosis scores were noted. In peripheral blood, a marked decrease in mean eosinophil counts and reductions in white blood cell, neutrophil, monocyte counts were also observed. Platelet counts decreased while hemoglobin levels remained relatively consistent through Week 24 (Table). Conclusions: Avapritinib demonstrated rapid (Week 8) and profound (Week 24) reductions in neoplastic MC burden characterized by a reduction of the total MC burden in BMBs and BMAs with return to a normal morphologic appearance and normal immunophenotype, usually over 6 cycles. This was accompanied by a normalization of BM cellularity, as well as a decrease in fibrosis and marked improvement in hematologic parameters. These improvements in disease histopathology, along with known deep molecular remission of KIT D816V, suggest the potential for modification of AdvSM disease natural history. Figure 1 Figure 1. Disclosures George: Blueprint Medicines: Consultancy; Celgene: Consultancy; Bristol Meyers Squibb: Consultancy; Incyte Corporation: Consultancy. Fredericks: Blueprint Medicines Corporation: Current Employment. Reiter: Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; AOP Orphan Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Deciphera: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Blueprint Medicines: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees. Radia: Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Study steering group member, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Education events; EXPLORER and PATHFINDER studies: Other: Member of the Response Adjudication Committee; Cogent Biosciences Incorporated: Other: Study Steering Committee. Deininger: Novartis: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Fusion Pharma, Medscape, DisperSol: Consultancy; Incyte: Consultancy, Honoraria, Research Funding; SPARC, DisperSol, Leukemia & Lymphoma Society: Research Funding; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding. Lin: Blueprint Medicines Corporation: Current Employment, Current holder of individual stocks in a privately-held company. Sen: Blueprint Medicines Corporation: Current Employment, Current holder of individual stocks in a privately-held company. Gotlib: Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Kartos: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cogent Biosciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair for the Eligibility and Central Response Review Committee, Research Funding; Allakos: Consultancy; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dimitrijević: Blueprint Medicines Corporation: Current Employment, Current holder of individual stocks in a privately-held company. DeAngelo: Takeda: Consultancy; GlycoMimetics: Research Funding; Abbvie: Research Funding; Shire: Consultancy; Novartis: Consultancy, Research Funding; Forty-Seven: Consultancy; Incyte Corporation: Consultancy; Jazz: Consultancy; Pfizer: Consultancy; Blueprint Medicines Corporation: Consultancy; Autolus: Consultancy; Amgen: Consultancy; Agios: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-146873

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 1509-1511

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-166986

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7