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Guidelines for the diagnosis and management of adult aplastic anaemia: A British Society for Haematology Guideline
Kulasekararaj, A., Cavenagh, J., Dokal, I., Foukaneli, T., Gandhi, S., Garg, M., Griffin, M., Hillmen, P., Ireland, R., Killick, S., et al
British journal of haematology. 2024
Abstract
Pancytopenia with hypocellular bone marrow is the hallmark of aplastic anaemia (AA) and the diagnosis is confirmed after careful evaluation, following exclusion of alternate diagnosis including hypoplastic myelodysplastic syndromes. Emerging use of molecular cyto-genomics is helpful in delineating immune mediated AA from inherited bone marrow failures (IBMF). Camitta criteria is used to assess disease severity, which along with age and availability of human leucocyte antigen compatible donor are determinants for therapeutic decisions. Supportive care with blood and platelet transfusion support, along with anti-microbial prophylaxis and prompt management of opportunistic infections remain key throughout the disease course. The standard first-line treatment for newly diagnosed acquired severe/very severe AA patients is horse anti-thymocyte globulin and ciclosporin-based immunosuppressive therapy (IST) with eltrombopag or allogeneic haemopoietic stem cell transplant (HSCT) from a matched sibling donor. Unrelated donor HSCT in adults should be considered after lack of response to IST, and up front for young adults with severe infections and a readily available matched unrelated donor. Management of IBMF, AA in pregnancy and in elderly require special attention. In view of the rarity of AA and complexity of management, appropriate discussion in multidisciplinary meetings and involvement of expert centres is strongly recommended to improve patient outcomes.
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Gaining Consensus Around Patient Risk Groups and Prognostic Profiles to Guide CMV Management Among Patients With Allogeneic Hematopoietic Stem Cell Transplant: Insights From a Delphi Panel With Hematopoietic Stem Cell Transplant Experts
Graf, M., Tuly, R., Pednekar, P., Wang, C., Batt, K.
Transplantation proceedings. 2024
Abstract
INTRODUCTION This study aimed to characterize patient risk groups and prognostic profiles to optimize clinical decision-making and guide appropriate medical cytomegalovirus (CMV) management among patients with allogeneic hematopoietic stem cell transplant (HSCT). METHODS Between 8/2021 and 2/2022, a 3-round modified Delphi study was conducted to generate consensus among 10 international experts in HSCT and infectious diseases. Experts were asked about treatment and prognoses for patients in 7 distinct clinical scenarios. Furthermore, experts were asked to risk-stratify patients by pre-/post-transplant characteristics. Consensus around opting for/against a treatment was observed if ≥75% or <25% of experts reported ≥50% likelihood to recommend or if treatments were ranked inside/outside the top 2 options and ≥75% of experts were within 1 SD of mean ranks. RESULTS Experts agreed on several unmet needs in CMV disease management post-HSCT, particularly avoidance of treatment-limiting toxicities with conventional CMV therapy and the emergence of both refractory and drug-resistant treatment failures. Experts considered CMV viral load, resistance profile, and route of administration as critical to treatment selection. For newer CMV therapeutic options, experts listed a lack of long-term use data, concerns over potential resistance, high cost, and limited availability as challenges restricting adoption and successful patient management. CONCLUSIONS Experts achieved consensus around patient risk stratifications and factors influencing therapeutic options. Recommendations emerging from this Delphi study may support practicing physicians when confronted with challenging CMV scenarios in patients with HSCT.
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[Second allogeneic (update). Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]
Yafour, N., Couturier, M. A., Borel, C., Charbonnier, A., Coman, T., Fayard, A., Masouridi-Levrat, S., Yakoub-Agha, I., Roy, J.
Bulletin du cancer. 2024;111(2s):S29-s39
Abstract
Relapse after allogeneic hematopoietic cell transplantation (allo-HCT) remains a major concern because it is associated with poor survival. A second allo-HCT is a valid option in this situation. During the 13th annual harmonization workshops of the francophone Society of bone marrow transplantation and cellular therapy (SFGM-TC), a designated working group reviewed the literature in order to update the second allo-HCT recommendations elaborated during the previous workshop (2016). The main indication for a second allo-HCT remains relapse of initial hematologic malignancy. Disease status; complete remission (CR), and relapse time after the first allo-HCT>6 months impact positively the overall survival of patients after the second allo-HCT. Donor change is a valid option, particularly if there is HLA loss on leukemic cells after a first haploidentical or following a mismatched allo-HCT is documented. Reduced intensity conditioning is recommended, while a sequential protocol is a reasonable option in patients with proliferative disease. A post-transplant maintenance strategy after hematological recovery is recommended as soon as day 60, even if the immunosuppressive treatment has not yet been stopped. Hypomethylating agents, and targeted therapies such as anti FLT3, anti BCL2, anti-IDH1/2, TKI, anti-TP53, anti-CD33, anti-CD19, anti-CD22, anti-CD30, check point inhibitors, and CAR-T cells can be used as a bridge to transplant or as an alternative treatment to the second allo-HCT.
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4.
[Allogeneic hematopoietic stem cell transplantation and treatment with CAR-T cells - identification of psycho-social vulnerability factors: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]
Polomeni, A., Ainaoui, M., Berr, A., de Bentzman, N., Denis, M., Friser, V., Magro, L., Yakoub-Agha, I.
Bulletin du cancer. 2023
Abstract
Allogeneic hematopoietic stem cell transplantation (HCT) and CAR-T cells therapy are treatments with curative aim for certain hematological malignancies, refractory or relapse. Nevertheless, they carry the risk of morbidity and mortality and may have a significant psychosocial impact, particularly for HCT. It is therefore necessary to identify psychological difficulties and social problems, as well as the patient's resources, and those of his entourage, in order to improve his overall management. The objective of this evaluation is not to pose contraindications to treatments, but to adapt the personalized care project. This identification must be carried out early on in the pre-HCT assessment journey to enable the implementation of appropriate actions by the various care providers. Based on a review of the literature, we designed a psychosocial data collection grid that can be initiated in pre-transplant and updated by accompanying the patient at each stage of follow-up (discharge from hospital, day-hospital follow-up, D100 evaluation). This grid is divided into 3 axes: socio-family context, psychological and somatic aspects. This tool allows the traceability of the interventions of different professionals and is a support for multidisciplinary exchanges.
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5.
Genetic Findings of Potential Donor Origin following Hematopoietic Cell Transplantation: Recommendations on Donor Disclosure and Genetic Testing from the World Marrow Donor Association (WMDA): WMDA Guidelines on Genetic Findings of Donor Origin
Pryce, A., Van, E. E., Cody, M., Oakes, J., DeSalvo, A., Bannon, S., Burlton, C., Pawson, R., Fingrut, W., Barriga, F., et al
Transplantation and cellular therapy. 2023
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Editor's Choice
Abstract
Following hematopoietic cell transplantation, recipients are subjected to extensive genetic testing to monitor the efficacy of the transplant and identify relapsing malignant disease. This testing increasingly includes the use of large gene panels which may lead to incidental identification of genetic and molecular information of potential donor origin. Deciphering whether variants are of donor origin, and if so, whether there are clinical implications for the donor, can prove challenging. In response to queries from donor registries and transplant centers regarding best practice in managing donors when genetic mutations of potential donor origin are identified, the Medical Working Group of the World Marrow Donor Association established an expert group to review available evidence and to develop a framework to aid decision-making. These guidelines aim to provide recommendations on pre-donation consenting, post-donation testing of recipients and informing and managing donors when findings of potential donor origin are identified in recipients post-transplantation. It is recognised that registries will have different access to resources and financing structures. Therefore, where possible, we have made suggestions on how recommendations can be adapted.
PICO Summary
Population
An expert group convened by the Medical Working Group of the World Marrow Donor Association
Intervention
Provide recommendations on pre-donation consenting, post-donation testing of recipients
Comparison
None
Outcome
These guidelines aim to provide recommendations on pre-donation consenting, post-donation testing of recipients and informing and managing donors when findings of potential donor origin are identified in recipients post-transplantation.
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Management of patients with germline predisposition to haematological malignancies considered for allogeneic blood and marrow transplantation: Best practice consensus guidelines from the UK Clinical Genetics Group (UKCGG), CanGene-CanVar, NHS England Genomic Laboratory Hub (GLH) Haematological Malignancies Working Group and the British Society of Blood and Marrow Transplantation and cellular therapy (BSBMTCT)
Clark, A., Thomas, S., Hamblin, A., Talley, P., Kulasekararaj, A., Grinfeld, J., Speight, B., Snape, K., McVeigh, T. P., Snowden, J. A.
British journal of haematology. 2023
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Abstract
Germline predisposition to haematological cancers is increasingly being recognised. Widespread adoption of high-throughput and whole genome sequencing is identifying large numbers of causative germline mutations. Constitutional pathogenic variants in six genes (DEAD-box helicase 41 [DDX41], ETS variant transcription factor 6 [ETV6], CCAAT enhancer binding protein alpha [CEBPA], RUNX family transcription factor 1 [RUNX1], ankyrin repeat domain containing 26 [ANKRD26] and GATA binding protein 2 [GATA2]) are particularly significant in increasing the risk of haematological cancers, with variants in some of these genes also associated with non-malignant syndromic features. Allogeneic blood and marrow transplantation (BMT) is central to management in many haematological cancers. Identification of germline variants may have implications for the patient and potential family donors. Beyond selection of an appropriate haematopoietic stem cell donor there may be sensitive issues surrounding identification and counselling of hitherto asymptomatic relatives. If BMT is needed, there is frequently a clinical urgency that demands a rapid integrated multidisciplinary approach to testing and decision making involving haematologists in collaboration with Clinical and Laboratory Geneticists. Here, we present best practice consensus guidelines arrived at following a meeting convened by the UK Cancer Genetics Group (UKCGG), the Cancer Research UK (CRUK) funded CanGene-CanVar research programme (CGCV), NHS England Genomic Laboratory Hub (GLH) Haematological Oncology Malignancies Working Group and the British Society of Blood and Marrow Transplantation and Cellular Therapy (BSBMTCT).
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Indication and management of allogeneic haematopoietic stem-cell transplantation in myelofibrosis: updated recommendations by the EBMT/ELN International Working Group
Kröger, N., Bacigalupo, A., Barbui, T., Ditschkowski, M., Gagelmann, N., Griesshammer, M., Gupta, V., Hamad, N., Harrison, C., Hernandez-Boluda, J. C., et al
The Lancet. Haematology. 2023
Abstract
New options for medical therapy and risk scoring systems containing molecular data are leading to increased complexity in the management of patients with myelofibrosis. To inform patients' optimal care, we updated the 2015 guidelines on indications for and management of allogeneic haematopoietic stem-cell transplantation (HSCT) with the support of the European Society for Blood and Marrow Transplantation (EBMT) and European LeukemiaNet (ELN). New recommendations were produced using a consensus-building methodology after a comprehensive review of articles released from January, 2015 to December, 2022. Seven domains and 18 key questions were selected through a series of questionnaires using a Delphi process. Key recommendations in this update include: patients with primary myelofibrosis and an intermediate-2 or high-risk Dynamic International Prognostic Scoring System score, or a high-risk Mutation-Enhanced International Prognostic Score Systems (MIPSS70 or MIPSS70-plus) score, or a low-risk or intermediate-risk Myelofibrosis Transplant Scoring System score should be considered candidates for allogeneic HSCT. All patients who are candidates for allogeneic HSCT with splenomegaly greater than 5 cm below the left costal margin or splenomegaly-related symptoms should receive a spleen-directed treatment, ideally with a JAK-inhibitor; HLA-matched sibling donors remain the preferred donor source to date. Reduced intensity conditioning and myeloablative conditioning are both valid options for patients with myelofibrosis. Regular post-transplantation driver mutation monitoring is recommended to detect and treat early relapse with donor lymphocyte infusion. In a disease where evidence-based guidance is scarce, these recommendations might help clinicians and patients in shared decision making.
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Hematopoietic Cell Transplantation in the Management of Myelodysplastic Syndrome: An Evidence-Based Review from the American Society for Transplantation and Cellular Therapy Committee on Practice Guidelines
DeFilipp, Z., Ciurea, S. O., Cutler, C., Robin, M., Warlick, E. D., Nakamura, R., Brunner, A. M., Dholaria, B., Walker, A. R., Kröger, N., et al
Transplantation and Cellular Therapy. 2023;29(2):71-81
Abstract
The sole curative therapy for myelodysplastic syndrome (MDS) is allogeneic hematopoietic cell transplantation (HCT). Here this therapeutic modality is reviewed and critically evaluated in the context of the evidence. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the recommendations. A panel of MDS experts comprising transplantation and nontransplantation physicians developed consensus treatment recommendations. This review summarizes the standard MDS indications for HCT and addresses areas of controversy. Recent prospective trials have confirmed that allogeneic HCT confers survival benefits in patients with advanced or high-risk MDS compared with nontransplantation approaches, and the use of HCT is increasing in older patients with good performance status. However, patients with high-risk cytogenetic or molecular mutations remain at high risk for relapse. It is unknown whether administration of novel therapies before or after transplantation may decrease the risk of disease relapse in selected populations. Ongoing and future studies will investigate revised approaches to disease risk stratification, patient selection, and post-transplantation approaches to optimize allogeneic HCT outcomes for patients with MDS.
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Germline predisposition traits in allogeneic hematopoietic stem-cell transplantation for myelodysplastic syndromes: a survey-based study and position paper on behalf of the Chronic Malignancies Working Party of the EBMT
Gurnari, C., Robin, M., Godley, L. A., Drozd-Sokołowska, J., Włodarski, M. W., Raj, K., Onida, F., Worel, N., Ciceri, F., Carbacioglu, S., et al
The Lancet. Haematology. 2023
Abstract
The recent application of whole exome or whole genome sequencing unveiled a plethora of germline variants predisposing to myeloid disorders, particularly myelodysplastic neoplasms. The presence of such variants in patients with myelodysplastic syndromes has important clinical repercussions for haematopoietic stem-cell transplantation, from donor selection and conditioning regimen to graft-versus-host disease prophylaxis and genetic counselling for relatives. No international guidelines exist to harmonise management approaches to this particular clinical scenario. Moreover, the application of germline testing, and how this informs clinical decisions, differs according to the expertise of individual clinical practices and according to different countries, health-care systems, and legislations. Leveraging the global span of the European Society for Blood and Marrow Transplantation (EBMT) network, we took a snapshot of the current European situation on these matters by disseminating an electronic survey to EBMT centres experienced in myelodysplastic syndromes transplantation. An international group of haematologists, transplantation physicians, paediatricians, nurses, and experts in molecular biology and constitutional genetics with experience in myelodysplastic syndromes contributed to this Position Paper. The panel met during multiple online meetings to discuss the results of the EBMT survey and to establish suggested harmonised guidelines for such clinical situations, which are presented here.
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Prospective clinical and biomarker validation of the ASTCT consensus definition for transplant-associated thrombotic microangiopathy (TA-TMA)
Ma, S., Bhar, S., Guffey, D., Kim, R. B., Jamil, M., Amos, C. I., Lee, S. J., Hingorani, S. R., Sartain, S. E., Li, A.
Transplantation and cellular therapy. 2023
Abstract
INTRODUCTION Transplantation-associated thrombotic microangiography (TA-TMA) is a disorder that causes severe complications post-allogeneic hematopoietic cell transplantation (allo-HCT). Diagnosing TA-TMA is challenging due to non-standardized criteria. In this study, we aimed to evaluate the new TA-TMA consensus definition from the American Society for Transplantation and Cellular Therapy (ASTCT) panel as part of an ongoing prospective pediatric cohort study and to compare the impact and outcomes of employing the current clinical TMA definition (cTMA) versus the new consensus definition. METHODS We included patients aged 0 to 18 years who underwent their first allo-HCT from May 2021 to January 2023 at Texas Children's Hospital. We compared the incidence, biomarkers, and outcomes of TA-TMA applying the previous and recently proposed screening algorithms and definitions. RESULTS While the classic microangiopathic hemolytic anemia (MAHA)-based cTMA definition led to an incidence of 12.7%, the ASTCT-HR definition doubled the incidence to 28.5% by day 100. In contrast to patients with concordant diagnosis (+/+) who had significantly worse post-transplant survival, those reclassified as TA-TMA by the new definition only (-/+) had significantly different prognosis (100% survival at day 100) despite the lack of TMA-directed therapy. Furthermore, biomarkers of the terminal and alternative complement pathways (sC5b9 and Ba, respectively) were significantly elevated around day 15 in the concordant group (+/+) but not in the discordant group (-/+) when compared to the non-TMA patients. CONCLUSIONS The recently proposed ASTCT consensus TA-TMA diagnosis is more sensitive and allows earlier recognition of manifestation that requires closer clinical monitoring but risks over-diagnosis and over-treatment. We recommend additional prospective validation.