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Abstract: B-cell maturation antigen (BCMA)-targeting therapeutics have dramatically improved outcomes in relapsed/refractory multiple myeloma (RRMM). However, whether the mechanisms of resistance between these therapies are shared and how the identification of such mechanisms before therapy initiation could refine clinical decision-making remains undefined. We analyzed outcomes for 72 RRMM patients treated with teclistamab, a CD3 × BCMA bispecific antibody, 42% (30/72) of whom had prior BCMA-directed therapy exposure. Malignant plasma cell BCMA expression was present in all BCMA therapy-naïve patients. Prior therapy-mediated loss of plasma cell BCMA expression before teclistamab treatment, measured by immunohistochemistry, was observed in 3 patients, none of whom responded to teclistamab, and 1 of whom also did not respond to ciltacabtagene autoleucel. Whole exome sequencing of tumor DNA from 1 patient revealed biallelic loss of TNFRSF17 following treatment with belantamab mafodotin. Low-to-undetectable peripheral blood soluble BCMA levels correlated with the absence of BCMA expression by bone marrow plasma cells. Thus, although rare, loss of BCMA expression following TNFRSF17 gene deletions can occur following any BCMA-directed therapy and prevents response to subsequent anti-BCMA-directed treatments, underscoring the importance of verifying the presence of a target antigen., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Previous research indicates disparities in the care of bereaved parents and siblings following a stillbirth in the family. The aim of this systematic review was to assess the effects of interventions aimed at reducing psychological distress among parents or siblings in high-income countries after experiencing a stillbirth., Methods: The databases CINAHL, Medline, PsycInfo, Cochrane Library, and EMBASE were searched in August 2022., Results: Four intervention studies from the United States (US), the United Kingdom (UK), Finland, and Australia, met the inclusion criteria. The interventions comprised a perinatal grief support team; a perinatal counselling service; a grief support program; and a support package including contacts with peer supporters and health care staff. No studies of interventions for siblings were found. The results could not be synthesised due to disparities in interventions and outcome measures. The risk of bias was assessed as high in all four studies and the certainty for all outcomes was rated as very low., Conclusion: More controlled trials with rigorous methods are needed to evaluate the effect of bereavement support interventions in parents and siblings after stillbirth. Future studies should include a core outcome set to make them more comparable. Most of the studies in this review were assessed to have an overall high risk of bias, mainly due to problems with missing outcome data; thus, future studies could specifically target this problem., Competing Interests: Conflict of interest None declared, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To provide guidance on rating imprecision in a body of evidence assessing the accuracy of a single test. This guide will clarify when Grading of Recommendations Assessment, Development and Evaluation (GRADE) users should consider rating down the certainty of evidence by one or more levels for imprecision in test accuracy., Study Design and Setting: A project group within the GRADE working group conducted iterative discussions and presentations at GRADE working group meetings to produce this guidance., Results: Before rating the certainty of evidence, GRADE users should define the target of their certainty rating. GRADE recommends setting judgment thresholds defining what they consider a very accurate, accurate, inaccurate, and very inaccurate test. These thresholds should be set after considering consequences of testing and effects on people-important outcomes. GRADE's primary criterion for judging imprecision in test accuracy evidence is considering confidence intervals (i.e., CI approach) of absolute test accuracy results (true and false, positive, and negative results in a cohort of people). Based on the CI approach, when a CI appreciably crosses the predefined judgment threshold(s), one should consider rating down certainty of evidence by one or more levels, depending on the number of thresholds crossed. When the CI does not cross judgment threshold(s), GRADE suggests considering the sample size for an adequately powered test accuracy review (optimal or review information size [optimal information size (OIS)/review information size (RIS)]) in rating imprecision. If the combined sample size of the included studies in the review is smaller than the required OIS/RIS, one should consider rating down by one or more levels for imprecision., Conclusion: This paper extends previous GRADE guidance for rating imprecision in single test accuracy systematic reviews and guidelines, with a focus on the circumstances in which one should consider rating down one or more levels for imprecision., Competing Interests: Declaration of competing interest The authors declare no direct financial conflict of interest. They are members or contributors to the GRADE working group. Multiple coauthors have served as methodologists on a number of systematic reviews or guidelines that provided examples for this manuscript., (Copyright © 2023. Published by Elsevier Inc.)

Competing Interests: Declaration of Competing Interest All authors are member of the GRADE Guidance Group. HJS and GG are cochairs of GRADE.

Objectives: To update previous Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidance by addressing inconsistencies and interpreting subgroup analyses., Study Design and Setting: Using an iterative process, we consulted with members of the GRADE working group through multiple rounds of written feedback and discussions at GRADE working group meetings., Results: The guidance complements previous guidance with clarification in two areas: (1) assessing inconsistency and (2) assessing the credibility of possible effect modifiers that might explain inconsistency. Specifically, the guidance clarifies that inconsistency refers to variability in results, not in study characteristics; that inconsistency assessment for binary outcomes requires consideration of both relative and absolute effects; how to decide between narrower and broader questions in systematic reviews and guidelines; that, with the same evidence, ratings of inconsistency may differ depending on the target of certainty rating; and how GRADE inconsistency ratings relate to a statistical measure of inconsistency I 2 depending on the context in which one views results. The second part of the guidance illustrates, based on a worked example, the use of the instrument to assess the credibility of effect modification analyses. The guidance explains the stepwise process of moving from a subgroup analysis to assessing the credibility of effect modification and, if found credible, to subgroup-specific effect estimates and GRADE certainty ratings., Conclusion: This updated guidance addresses specific conceptual and practical issues that systematic review authors frequently face when considering the degree of inconsistency in estimates of treatment effects across studies., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study is to provide updated guidance on when The Grading of Recommendations Assessment, Development and Evaluation (GRADE) users should consider rating down more than one level for imprecision using a minimally contextualized approach., Study Design and Setting: Based on the first GRADE guidance addressing imprecision rating in 2011, a project group within the GRADE Working Group conducted iterative discussions and presentations at GRADE Working Group meetings to produce this guidance., Results: GRADE suggests aligning imprecision criterion for systematic reviews and guidelines using the approach that relies on thresholds and confidence intervals (CI) of absolute effects as a primary criterion for imprecision rating (i.e., CI approach). Based on the CI approach, when a CI appreciably crosses the threshold(s) of interest, one should consider rating down two or three levels. When the CI does not cross the threshold(s) and the relative effect is large, one should implement the optimal information size (OIS) approach. If the sample size of the meta-analysis is far less than the OIS, one should consider rating down more than one level for imprecision., Conclusion: GRADE provides updated guidance for imprecision rating in a minimally contextualized approach, with a focus on the circumstances in which one should seriously consider rating down two or three levels for imprecision., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidance to rate the certainty domain of imprecision is presently not fully operationalized for rating down by two levels and when different baseline risk or uncertainty in these risks are considered. In addition, there are scenarios in which lowering the certainty of evidence by three levels for imprecision is more appropriate than lowering it by two levels. In this article, we conceptualize and operationalize rating down for imprecision by one, two and three levels for imprecision using the contextualized GRADE approaches and making decisions., Methods: Through iterative discussions and refinement in online meetings and through email communication, we developed draft guidance to rating the certainty of evidence down by up to three levels based on examples. The lead authors revised the approach according to the feedback and the comments received during these meetings and developed GRADE guidance for how to apply it. We presented a summary of the results to all attendees of the GRADE Working Group meeting for feedback in October 2021 (approximately 80 people) where the approach was formally approved., Results: This guidance provides GRADE's novel approach for the considerations about rating down for imprecision by one, two and three levels based on serious, very serious and extremely serious concerns. The approach includes identifying or defining thresholds for health outcomes that correspond to trivial or none, small, moderate or large effects and using them to rate imprecision. It facilitates the use of evidence to decision frameworks and also provides guidance for how to address imprecision about implausible large effects and trivial or no effects using the concept of the 'review information size' and for varying baseline risks. The approach is illustrated using practical examples, an online calculator and graphical displays and can be applied to dichotomous and continuous outcomes., Conclusion: In this GRADE guidance article, we provide updated guidance for how to rate imprecision using the partially and fully contextualized GRADE approaches for making recommendations or decisions, considering alternate baseline risks and for both dichotomous and continuous outcomes., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: This article describes GRADE guidance for assessing imprecision when rating the certainty of the evidence from network meta-analysis., Study Design and Setting: A project group within the GRADE working group conducted iterative discussions, computer simulations, and presentations at GRADE working group meetings to produce and obtain approval for this guidance., Results: When addressing imprecision of a network estimate, reviewers should consider the 95% confidence or credible interval, and the optimal information size. If the 95% confidence or credible interval crosses a pre-specified threshold, reviewers should rate down the certainty of the evidence. If the 95% confidence interval does not cross any pre-specfied threshold, reviewers should consider the optimal information size. Because addressing the optimal information size may be challenging, reviewers can use the effect size to decide if any calculations are necessary. When the size of the effect is modest or the optimal information size is met, reviewers should not rate down for imprecision., Conclusion: Reviewers should use this guidance when to appropriately address imprecision in the context of the assessment of certainty of evidence from network meta-analysis., (Copyright © 2021. Published by Elsevier Inc.)

Objective: To provide practical principles and examples to help GRADE users make optimal choices regarding their ratings of certainty of evidence using a minimally or partially contextualized approach., Study Design and Setting: Based on the GRADE clarification of certainty of evidence in 2017, a project group within the GRADE Working Group conducted iterative discussions and presentations at GRADE Working Group meetings to refine this construct and produce practical guidance., Results: Systematic review and health technology assessment authors need to clarify what it is in which they are rating their certainty of evidence (i.e., the target of their certainty rating). The decision depends on the degree of contextualization (partially or minimally contextualized), thresholds (null, small, moderate or large effect threshold), and where the point estimate lies in relation to the chosen threshold(s). When the 95% confidence interval crosses multiple possible thresholds (i.e., including both large benefit and large harm), it is not worthwhile for authors to determine the target of certainty rating., Conclusion: GRADE provides practical principles to help systematic review and health technology assessment authors specify the target of their certainty of evidence rating., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: This article provides GRADE guidance on how authors of evidence syntheses and health decision makers, including guideline developers, can rate the certainty across a body of evidence for comparative test accuracy questions., Study Design and Setting: This guidance extends the previously published GRADE guidance for assessing certainty of evidence for test accuracy to scenarios in which two or more index tests are compared. Through an iterative brainstorm-discussion-feedback process within the GRADE working group, we developed a guidance accompanied by practical examples., Results: Rating the certainty of evidence for comparative test accuracy shares many concepts and ideas with the existing GRADE guidance for test accuracy. The rating in comparisons of test accuracy requires additional considerations, such as the selection of appropriate comparative study designs, additional criteria for judging risk of bias, and the consequences of using comparative measures of test accuracy. Distinct approaches to rating certainty are required for comparative test accuracy studies and between-study (indirect) comparisons., Conclusion: This GRADE guidance will support transparent assessment of the certainty for a body of comparative test accuracy evidence., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Daratumumab-based combination therapies have shown high rates of complete response (CR) and minimal residual disease negativity in patients with multiple myeloma. However, daratumumab, an IgGκ monoclonal antibody, interferes with electrophoretic techniques making it difficult to reliably define residual disease versus CR, especially in patients with IgGκ multiple myeloma., Methods: Enrichment with polyclonal sheep antibody-coated magnetic microparticles combined with MALDI-TOF mass spectrometry (MALDI-TOF MS) analysis was used to detect M-proteins in serial samples from newly diagnosed multiple myeloma patients treated with daratumumab-based therapy. The performance of the MALDI-TOF MS assay was compared to that of a routine test panel (serum protein electrophoresis (SPEP), immunofixation (IFE) and serum free light chain (FLC))., Results: Comparison of MALDI-TOF MS to SPEP/IFE/FLC showed a concordance of 84.9% (p < 0.001). When MALDI-TOF MS and FLC results were combined, the M-protein detection rate was the same or better than the routine test panel. For the 9 patients who obtained CR during follow-up, MALDI-TOF MS detected an M-protein in 46% of subsequent samples. Daratumumab could be distinguished from the M-protein in 215/222 samples., Conclusion: MALDI-TOF MS is useful in assessing CR in patients treated with monoclonal antibody-based therapies., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The 2016 International Myeloma Working Group consensus recommendations emphasize high-sensitivity methods for minimal residual disease (MRD) detection, treatment response assessment, and prognostication. Next-generation sequencing (NGS) of IGH gene rearrangements is highly specific and sensitive, but its description in routine clinical practice and performance comparison with high-sensitivity flow cytometry (hsFC) remain limited. In this large, single-institution study including 438 samples from 251 patients, the use of NGS targeting the IGH and IGK genes for clonal characterization and monitoring, with comparison to hsFC, is described. The index clone characterization success rate was 93.6% (235/251), which depended on plasma cell (PC) cellularity, reaching 98% when PC ≥10% and below 80% when PC <5%. A total of 85% of cases were successfully characterized using leader and FR1 primer sets, and most clones showed high somatic hypermutation rates (median, 8.1%). Among monitoring samples from 124 patients, 78.6% (147/187) had detectable disease by NGS. Concordance with hsFC was 92.9% (170/183). Discordant cases encompassed 8 of 124 hsFC MRD+/NGS MRD- patients (6.5%) and 4 of 124 hsFC MRD-/NGS MRD+ patients (3.2%), all with low-level disease near detection limits for both assays. Among concordant hsFC MRD-/NGS MRD- cases, only 5 of 24 patients (20.8%) showed subsequent overt relapse at 3-year follow-up. HsFC and NGS showed similar operational sensitivity, and the choice of test may depend on practical, rather than test performance, considerations., (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objectives: This article provides updated GRADE guidance about how authors of systematic reviews and health technology assessments and guideline developers can rate the certainty of evidence (also known as quality of the evidence or confidence in the estimates) of a body of evidence addressing test accuracy (TA) on the domains imprecision, inconsistency, publication bias, and other domains. It also provides guidance for how to present synthesized information in evidence profiles and summary of findings tables., Study Design and Setting: We present guidance for rating certainty in TA in clinical and public health and review the presentation of results of a body of evidence regarding tests., Results: Supplemented by practical examples, we describe how raters of the evidence can apply the GRADE domains inconsistency, imprecision, and publication bias to a body of evidence of TA studies., Conclusion: Using GRADE in Cochrane and other reviews as well as World Health Organization and other guidelines helped refining the GRADE approach for rating the certainty of a body of evidence from TA studies. Although several of the GRADE domains (e.g., imprecision and magnitude of the association) require further methodological research to help operationalize them, judgments need to be made on the basis of what is known so far., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: This article provides updated GRADE guidance about how authors of systematic reviews and health technology assessments and guideline developers can assess the results and the certainty of evidence (also known as quality of the evidence or confidence in the estimates) of a body of evidence addressing test accuracy (TA)., Study Design and Setting: We present an overview of the GRADE approach and guidance for rating certainty in TA in clinical and public health and review the presentation of results of a body of evidence regarding tests. Part 1 of the two parts in this 21st guidance article about how to apply GRADE focuses on understanding study design issues in test accuracy, provide an overview of the domains, and describe risk of bias and indirectness specifically., Results: Supplemented by practical examples, we describe how raters of the evidence using GRADE can evaluate study designs focusing on tests and how they apply the GRADE domains risk of bias and indirectness to a body of evidence of TA studies., Conclusion: Rating the certainty of a body of evidence using GRADE in Cochrane and other reviews and World Health Organization and other guidelines dealing with in TA studies helped refining our approach. The resulting guidance will help applying GRADE successfully for questions and recommendations focusing on tests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Advances in technologies for genomic profiling, primarily with next generation sequencing, have lead to a better understanding of the complex genomic landscape in multiple myeloma. Integrated analysis of whole genome, exome and transcriptome sequencing has lead to new insights on disease drivers including translocations, copy number alterations, somatic mutations, and altered gene expression. Disease progression in multiple myeloma is largely driven by structural variations including the traditional immunoglobulin heavy chain (IGH) translocations and hyperdiploidy which are early events in myelomagenesis as well as more complex events spanning over multiple chromosomes and involving amplifications and deletions. In this review, we will discuss recent insights on the genomic landscape of multiple myeloma and their implications for disease progression and personalized treatment. We will review how sequencing assays compare to current clinical methods and give an overview of modern technologies for interrogating genomic aberrations., Competing Interests: Declaration of competing interest MH has received funding from the Multiple Myeloma Research Foundation, the Swedish Research Council, and the Swedish Blood Cancer Foundation. MH has received honoraria from Intellisphere, LLC. The authors report no relevant conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: Clear communication of systematic review findings will help readers and decision makers. We built on previous work to develop an approach that improves the clarity of statements to convey findings and that draws on Grading of Recommendations Assessment, Development and Evaluation (GRADE)., Study Design and Setting: We conducted workshops including 80 attendants and a survey of 110 producers and users of systematic reviews. We calculated acceptability of statements and revised the wording of those that were unacceptable to ≥40% of participants., Results: Most participants agreed statements should be based on size of effect and certainty of evidence. Statements for low, moderate and high certainty evidence were acceptable to >60%. Key guidance, for example, includes statements for high, moderate and low certainty for a large effect on intervention x as: x results in a large reduction…; x likely results in a large reduction…; x may result in a large reduction…, respectively., Conclusions: Producers and users of systematic reviews found statements to communicate findings combining size and certainty of an effect acceptable. This article provides GRADE guidance and a wording template to formulate statements in systematic reviews and other decision tools., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The objective of the study was to clarify how the Grading of Recommendations Assessment, Development and Evaluation (GRADE) concept of certainty of evidence applies to certainty ratings of test accuracy., Study Design and Setting: After initial brainstorming with GRADE Working Group members, we iteratively refined and clarified the approaches for defining ranges when assessing the certainty of evidence for test accuracy within a systematic review, health technology assessment, or guideline., Results: Ranges can be defined both for single test accuracy and for comparative accuracy of multiple tests. For systematic reviews and health technology assessments, approaches for defining ranges include some that do not require value judgments regarding downstream health outcomes. Key challenges arise in the context of a guideline that requires ranges for sensitivity and specificity that are set considering possible effects on all critical outcomes. We illustrate possible approaches and provide an example from a systematic review of a direct comparison between two test strategies., Conclusions: This GRADE concept paper provides a framework for assessing, presenting, and making decisions based on the certainty of evidence for test accuracy. More empirical research is needed to support future GRADE guidance on how to best operationalize the candidate approaches., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this paper is to describe a conceptual framework for how to consider health equity in the Grading Recommendations Assessment and Development Evidence (GRADE) guideline development process., Study Design and Setting: Consensus-based guidance developed by the GRADE working group members and other methodologists., Results: We developed consensus-based guidance to help address health equity when rating the certainty of synthesized evidence (i.e., quality of evidence). When health inequity is determined to be a concern by stakeholders, we propose five methods for explicitly assessing health equity: (1) include health equity as an outcome; (2) consider patient-important outcomes relevant to health equity; (3) assess differences in the relative effect size of the treatment; (4) assess differences in baseline risk and the differing impacts on absolute effects; and (5) assess indirectness of evidence to disadvantaged populations and/or settings., Conclusion: The most important priority for research on health inequity and guidelines is to identify and document examples where health equity has been considered explicitly in guidelines. Although there is a weak scientific evidence base for assessing health equity, this should not discourage the explicit consideration of how guidelines and recommendations affect the most vulnerable members of society., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: This article introduces the rationale and methods for explicitly considering health equity in the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology for development of clinical, public health, and health system guidelines., Study Design and Setting: We searched for guideline methodology articles, conceptual articles about health equity, and examples of guidelines that considered health equity explicitly. We held three meetings with GRADE Working Group members and invited comments from the GRADE Working Group listserve., Results: We developed three articles on incorporating equity considerations into the overall approach to guideline development, rating certainty, and assembling the evidence base and evidence to decision and/or recommendation., Conclusion: Clinical and public health guidelines have a role to play in promoting health equity by explicitly considering equity in the process of guideline development., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To clarify the grading of recommendations assessment, development and evaluation (GRADE) definition of certainty of evidence and suggest possible approaches to rating certainty of the evidence for systematic reviews, health technology assessments, and guidelines., Study Design and Setting: This work was carried out by a project group within the GRADE Working Group, through brainstorming and iterative refinement of ideas, using input from workshops, presentations, and discussions at GRADE Working Group meetings to produce this document, which constitutes official GRADE guidance., Results: Certainty of evidence is best considered as the certainty that a true effect lies on one side of a specified threshold or within a chosen range. We define possible approaches for choosing threshold or range. For guidelines, what we call a fully contextualized approach requires simultaneously considering all critical outcomes and their relative value. Less-contextualized approaches, more appropriate for systematic reviews and health technology assessments, include using specified ranges of magnitude of effect, for example, ranges of what we might consider no effect, trivial, small, moderate, or large effects., Conclusion: It is desirable for systematic review authors, guideline panelists, and health technology assessors to specify the threshold or ranges they are using when rating the certainty in evidence., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To describe the grading of recommendations assessment, development and evaluation (GRADE) interactive evidence to decision (EtD) frameworks for tests and test strategies for clinical, public health, or coverage decisions., Study Design and Setting: As part of the GRADE Working Group's DECIDE project, we conducted workshops, user testing with systematic review authors, guideline developers and other decision makers, and piloted versions of the EtD framework., Results: EtD frameworks for tests share the structure, explicitness, and transparency of other EtD frameworks. They require specifying the purpose of the test, linked or related management, and the key outcomes of concern for different test results and subsequent management. The EtD criteria address test accuracy and assessments of the certainty of the additional evidence necessary for decision making. When there is no direct evidence of test effects on patient-important outcomes, formal or informal modeling is needed to estimate effects. We describe the EtD criteria based on examples developed with GRADEpro (www.gradepro.org), GRADE's software that also allows development and dissemination of interactive summary of findings tables., Conclusion: EtD frameworks for developing recommendations and making decisions about tests lay out the sequential steps in reviewing and assessing the different types of evidence that need to be linked., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Many malignancies, including multiple myeloma and its precursor, monoclonal gammopathy of unknown significant, are associated with an elevated risk of thromboembolism. There is limited information on the risk of thrombosis in patients with Waldenström macroglobulinemia (WM) and lymphoplasmacytic lymphoma (LPL)., Objectives: To assess the risk of venous and arterial thrombosis in WM/LPL patients in a large population-based cohort study in Sweden., Patients/methods: A total of 2190 patients with WM/LPL and 8086 matched controls were identified through Swedish registers between 1987 and 2005. Information on occurrence of venous and arterial thrombosis after the diagnosis of WM/LPL was obtained through the centralized Swedish Patient Register, with follow-up to 2006. Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs)., Results: Patients with WM/LPL had a significantly increased risk of venous thrombosis and the highest risk was observed during the first year following diagnosis (HR = 4.0, 95% CI 2.5-6.4). The risk was significantly elevated 5 (HR = 2.3, 95% CI 1.7-3.0) and 10 years after diagnosis (HR = 2.0, 95% CI 1.6-2.5). There was no increased risk of arterial thrombosis during any period of follow-up time (10-year HR = 1.0, 95% CI 0.9-1.1)., Conclusions: Venous thrombosis is a significant cause of morbidity in patients with WM/LPL. The potential role of thromboprophylaxis in WM/LPL, especially during the first year after diagnosis and in patients treated with thrombogenic agents, needs to be assessed to further improve outcome in WM/LPL patients., (© 2014 International Society on Thrombosis and Haemostasis.)

Polycythemia vera, essential thrombocythemia, and primary myleofibrosis are chronic myeloproliferative neoplasms (MPNs) associated with an increased morbidity and mortality. MPNs are also associated with progression to acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). The "true" rate of transformation is not known mainly due to selection bias in clinical trials and underreporting in population-based studies. The outcome after transformation is dismal. The underlying mechanisms of transformation are incompletely understood and in part remain an area of controversy. There is an intrinsic propensity in MPNs to progress to AML/MDS, the magnitude of which is not fully known, supporting a role for nontreatment-related factors. High doses of alkylating agents, P(32) and combined cytoreductive treatments undoubtedly increase the risk of transformation. The potential leukemogenic role of hydroxyurea has been a matter of debate due to difficulties in performing large prospective randomized trials addressing this issue. The main focus of this review is to elucidate therapy-related leukemic transformation in MPNs with a special focus on the role of hydroxyurea., (Copyright © 2014 Elsevier Ltd. All rights reserved.)