Search

Hematological toxicity represents the most common grade ≥3 toxicity after chimeric antigen receptor (CAR) T-cell therapy. However, its underlying pathophysiology is incompletely understood and its grading and management remains ill-defined. To inform the forthcoming European Hematology Association/European Society for Blood and Marrow Transplantation (EHA/EBMT) guidelines on the management of "immune effector cell-associated hematotoxicity" (ICAHT), we undertook a survey of experienced clinicians using an online survey focusing on (1) grading, (2) risk-stratification and diagnostic work-up, (3) short-term, and (4) long-term management of ICAHT. There were 81 survey respondents across 18 countries. A high degree of variability was noted for cytopenia grading in regards to depth, duration, and time from CAR-T infusion. The majority of experts favored pre-CAR-T bone marrow studies, especially in case of a high-risk profile. Most respondents felt that the work-up for patients with severe hematotoxicity should rule-out viral infections (96%), substrate deficiency (80%), or coincident sHLH/MAS (serum ferritin, 92%), and should include bone marrow aspiration (86%) and/or biopsy (61%). Clinicians were divided as to whether the occurrence of coincident immunotoxicity should influence the decision to apply G-CSF, and when to initiate G-CSF support. In case of prolonged thrombocytopenia, most survey participants favored thrombopoietin agonists (86%). Conversely, autologous hematopoietic cell boosts represented the preferred choice for neutropenia (63%), although they were frequently not available and no consensus was reached regarding the optimal trigger point. These findings underline the current heterogeneity of practice patterns regarding ICAHT and invite the development of consensus guidelines, which may harmonize grading, establish standard operating procedures for diagnosis, and set management guidelines., Competing Interests: KR: Kite/Gilead: Research Funding and travel support; Novartis: Honoraria; BMS/Celgene: Consultancy, Honoraria; School of Oncology of the German Cancer Consortium (DKTK): fellowship; Else Kröner Forschungskolleg (EKFK) within the Munich Clinician Scientist Program (MCSP): funding. FO: Travel, Accommodations, Expenses: Takeda, Kyowa Kirin International, Medac. CB: inventor of different patents on cancer immunotherapy and genetic engineering; member of Advisory Boards and Consultant for, Intellia, Kite/Gilead, Miltenyi, Kiadis, QuellTx, Janssen, Chroma, Genyo, Pancancer-T, Alia, and received research support from Intellia Therapeutics. AS: Honoraria: Takeda, Bristol Myers Squibb, Merck Sharp and Dohme, Celgene, Janssen, Sanofi, Roche, Novartis, Gilead Sciences, Janssen-Cilag; Consulting or Advisory Role: Takeda, Bristol Myers Squibb, Gilead Sciences, Celgene, Janssen, Novartis; Speakers’ Bureau: Takeda; Travel, Accommodations, Expenses: Kite/Gilead. JGG: Received honoraria from Amgen, BMS Gilead/Kite, Janssen, Novartis, and received research funding from AZ, BMS and Janssen. IY-A: Received honoraria from Novartis, Gilead/Kite, BMS and Janssen. MS: Morphosys: Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Seattle Genetics: Research Funding; AMGEN: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria, Research Funding; Roche AG: Consultancy, Research Funding. None of the mentioned conflicts of interest were related to financing of the content of this article. All the other authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a hematological malignancy characterized by recurrent skin nodules, an aggressive clinical course with rapid involvement of hematological organs, and a poor prognosis with overall survival. The rarity of the disease results in a few large-scale studies, a lack of controlled clinical trials for its management, and a lack of evidence-based guidelines. Here, we present a review of unmet clinical needs on the management of BPDCN by a panel of eleven experts involved in the research and clinical practice of BPDCN. Recommendations and proposals were achieved by multiple-step formalized procedures to reach a consensus after a comprehensive analysis of the scientific literature. The panel analyzed the critical issues of diagnostic pathway, prognostic stratification, therapy for young and fit patients and elderly and unfit patients, indication for allotransplant and for autotransplant, indication for central nervous system prophylaxis, and management of pediatric BPDCN patients. For each of these issues, consensus opinions were provided and, when appropriate, proposals for advancement in clinical practice were addressed. The hope is that this comprehensive overview will serve to improve the practice of BPDCN and inform the design and implementation of new studies in the field., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Atypical chronic myeloid leukemia (aCML) is a BCR-ABL1 -negative clonal disorder, which belongs to the myelodysplastic/myeloproliferative group. This disease is characterized by recurrent somatic mutations in SETBP1 , ASXL1 and ETNK1 genes, as well as high genetic heterogeneity, thus posing a great therapeutic challenge. To provide a comprehensive genomic characterization of aCML we applied a high-throughput sequencing strategy to 43 aCML samples, including both whole-exome and RNA-sequencing data. Our dataset identifies ASXL1 , SETBP1 , and ETNK1 as the most frequently mutated genes with a total of 43.2%, 29.7 and 16.2%, respectively. We characterized the clonal architecture of 7 aCML patients by means of colony assays and targeted resequencing. The results indicate that ETNK1 variants occur early in the clonal evolution history of aCML, while SETBP1 mutations often represent a late event. The presence of actionable mutations conferred both ex vivo and in vivo sensitivity to specific inhibitors with evidence of strong in vitro synergism in case of multiple targeting. In one patient, a clinical response was obtained. Stratification based on RNA-sequencing identified two different populations in terms of overall survival, and differential gene expression analysis identified 38 significantly overexpressed genes in the worse outcome group. Three genes correctly classified patients for overall survival., Competing Interests: The authors declare no competing interests., (Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)