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Best Practice & Research. Clinical Haematology

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https://www.readbyqxmd.com/read/27890263/innate-immunity-and-the-new-forward-genetics
#1
REVIEW
Bruce Beutler
As it is a hard-wired system for responses to microbes, innate immunity is particularly susceptible to classical genetic analysis. Mutations led the way to the discovery of many of the molecular elements of innate immune sensing and signaling pathways. In turn, the need for a faster way to find the molecular causes of mutation-induced phenotypes triggered a huge transformation in forward genetics. During the 1980s and 1990s, many heritable phenotypes were ascribed to mutations through positional cloning. In mice, this required three steps...
December 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27890262/what-is-the-role-of-novel-thrombopoietic-agents-in-the-management-of-acute-leukemia
#2
REVIEW
David J Kuter
The role of novel thrombopoietic agents in the management of acute leukemia is a tale of two molecules, romiplostim and eltrombopag. Both are thrombopoietin (TPO) receptor agonists with somewhat different mechanisms of action. Romiplostim is a peptide TPO receptor agonist that activates the TPO receptor by binding to it just like TPO. Eltrombopag is a nonpeptide TPO receptor agonist that activates the TPO receptor by binding to the transmembrane domain. Both TPO receptor agonists increase platelet counts in healthy humans and in those with immune thrombocytopenia...
December 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27890261/consolidation-chemotherapy-prior-to-hematopoietic-cell-transplantation-for-adults-with-acute-myeloid-leukemia-in-first-remission
#3
REVIEW
Frederick R Appelbaum
Whether patients with acute myeloid leukemia (AML) should receive routine consolidation chemotherapy prior to transplant remains a significant question. Consolidation therapy may be advisable in the face of transplant delays, such as donor identification, insurance clearance, or transplant center scheduling, to prevent relapse prior to transplant. However, in cases where physicians have a choice, the question of the value of consolidation chemotherapy continues to be debated. This paper reviews the value of consolidation therapy in 4 different transplant settings...
December 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27890260/the-role-of-second-transplants-for-leukemia
#4
REVIEW
Daniel Weisdorf
Management of relapsed leukemia following allogeneic transplantation is challenging. Intensive chemotherapy, donor lymphocyte infusions (DLI), or second transplantation have some value, but most reported series describe only a limited number of patients surviving beyond 2 or 3 years following relapse. Additionally, understandable selection-bias of reports describing the outcomes of intensive management approaches for relapsed leukemia confound generalizability to a broader population. However numerous reports suggest that second allogeneic transplantation for relapsed leukemia following an initial transplant may produce extended disease control and survival for patients with favorable performance status, remission at the time of second transplant, and most importantly a long interval between initial transplant and relapse...
December 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27890259/how-important-is-nk-alloreactivity-and-kir-in-allogeneic-transplantation
#5
REVIEW
Brian C Shaffer, Katharine C Hsu
Relapse of acute myelogenous leukemia (AML) after allogeneic hematopoietic cell transplantation (allo HCT) is a major cause of death in transplant recipients. Efforts to control relapse by promoting donor T-cell alloreactivity, such as withdrawal of immune suppression or donor lymphocyte infusions, are limited by the propensity to induce graft versus host disease (GVHD) and by inadequate efficacy. Therefore, options for AML patients who have relapsed AML after allo HCT are few and outcomes are poor. Similar to T-cells, natural killer (NK) cells have potent anti-leukemia effector capacity, and yet unlike T-cells, NK cells do not mediate GVHD...
December 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27890258/should-anyone-with-philadelphia-chromosome-positive-all-who-is-negative-for%C3%A2-minimal-residual-disease-receive-a-hematopoietic-stem-cell-transplant-in-first-remission
#6
REVIEW
Mark R Litzow
Outcomes for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in the pre-imatinib era were poor, particularly if patients did not receive an allogeneic hematopoietic stem cell transplant. This led to the recommendation that all patients with Ph+ ALL, if they were transplant candidates, should be transplanted. With the introduction of imatinib and subsequently other tyrosine kinase inhibitors, patient outcomes improved dramatically, raising the question of whether transplant in first complete molecular remission for these patients is really necessary...
December 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27890257/is-there-justification-for-4-cycles-of-consolidation-therapy-in-aml
#7
REVIEW
Richard F Schlenk
The concept of postremission therapy in acute myeloid leukemia is quite old, dating back to a trial conducted in 1988 by the Cancer and Leukemia Group B. Yet even with more than 20 years of investigation into the optimal number of cycles for consolidation therapy, the answer is still not entirely clear. Dose intensity also has an impact on the number of courses of consolidation therapy administered, as do the cytogenetics of the patients. This review examines how to direct the future of consolidation therapy outside of allogeneic transplantation and discusses the issues to consider in choosing the number of courses of consolidation, including the effect minimal residual disease may have in guiding decisions regarding consolidation treatment...
December 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27890256/why-the-stagnation-in-effective-therapy-for-mds
#8
REVIEW
William Blum
The question posed above assumes that we are going nowhere in therapies for myelodysplastic syndromes (MDS) and asks, why? Yet, in recent years novel and effective therapies for MDS indeed have begun to emerge, particularly in patients with lower-risk disease. Beyond this, however, most of the progress has been limited to advances in allogeneic transplantation for higher-risk patients. This discussion will focus first on areas where we have moved beyond "stagnation," including these advances in supportive care for lower-risk patients and in emerging transplant gains...
December 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27890255/chimeric-antigen-receptor-t-cell-therapy-in-aml-how-close-are-we
#9
REVIEW
Saar Gill
The majority of patients presenting with acute myeloid leukemia (AML) initially respond to chemotherapy but post-remission therapy is required to consolidate this response and achieve long-term disease-free survival. The most effective form of post-remission therapy relies on T cell immunotherapy in the form of allogeneic hematopoietic cell transplantation (HCT). However, patients with active disease cannot usually expect to be cured with HCT. This inherent dichotomy implies that traditional T cell-based immunotherapy in the form of allogeneic HCT stops being efficacious somewhere between the measurable residual disease (MRD) and the morphologically obvious range...
December 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27890254/why-are-there-so-few-randomized-trials-for-patients-with-primary-refractory-acute-myeloid-leukemia
#10
REVIEW
Elihu Estey
Fewer patients with primary refractory AML ("PREF") are entered into phase 3 trials than are patients with relapsed AML. This is particularly noteworthy because data from phase 3 trials for newly diagnosed AML indicated PREF and relapse are equally common. Here I discuss three possible reasons for this discrepancy. First, there is disagreement whether the criterion for PREF AML should be failure of one or two courses of initial induction therapy. Second, there may be an impression that PREF AML is qualitatively worse than relapsed AML...
December 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27890253/a-cryptic-translocation-leading-to-nup98-phf23-fusion-in-aml
#11
REVIEW
Yi Ning
Chromosome translocations leading to gene fusions have emerged as important oncogenic drivers of various types of malignancies. Detection and characterization of these fusion genes not only help diagnosis and management of specific malignancies, but also contribute to our understanding of the genetic basis and pathogenesis of these diseases. NUP98 gene encodes a 98 kDa nucleoporin, which is a component of the nuclear pore complex that mediates transport of mRNA and proteins between the nucleus and the cytoplasm...
December 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27890252/aml-in-2016-where-we-are-now
#12
REVIEW
Jacob M Rowe
A high relapse rate for patients with acute myeloid leukemia (AML) is still a major barrier to the long-term survival of these patients. Nevertheless, considerable progress has been made both in the biology and therapy of the disease. Specifically, progress has been made in the areas of integrated genomic analysis for prognosis, the widening application of minimal residual disease (MRD) monitoring in clinical practice, the development of new agents, and the increasing use of drugs, such as IDH and FLT3 inhibitors, as a bridge to transplant...
December 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27839571/discontinuation-of-tki-therapy-and-functional-cure-for-cml
#13
REVIEW
François-Xavier Mahon
Stopping tyrosine kinase inhibitor (TKI) therapy after achieving a sustained deep molecular response is an emerging treatment goal for patients with chronic myeloid leukaemia in chronic phase (CML-CP). Indeed, the feasibility of stopping TKI therapy has been confirmed in various studies. The Stop Imatinib 1 (STIM1) study has shown a consistent follow-up which allowed defining a new criterion of clinical outcome evaluation, the treatment free remission (TFR). However, announcing a definitive cure remains a challenge owing to the discovery that TKIs spare quiescent leukaemic stem cells (LSC)...
September 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27839570/management-of-cml-blast-crisis
#14
REVIEW
Rüdiger Hehlmann, Susanne Saußele, Astghik Voskanyan, Richard T Silver
Tyrosine kinase inhibitors (TKI) have moderately improved survival in BC, but a median survival of less than 1 year is still unsatisfactory. This article reviews the various tests required for diagnosis of BC, features at diagnosis, treatment modalities (intensive chemotherapy, TKI, allo-SCT and a selection of investigational agents), options of prevention and predictors of progression. The best prognosis is observed in patients that achieve a 2nd CP. Allo-SCT probably further improves prognosis of patients in 2nd CP...
September 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27839569/monitoring-and-defining-early-response-where-to-draw-the-line
#15
REVIEW
Susan Branford
Over recent years the early response to therapy has been established as a robust and critical determinant of long term outcome to tyrosine kinase inhibitor therapy. Molecular monitoring has taken centre stage with the incorporation of molecular milestone values into treatment recommendations and guidelines. However, establishing a reliable molecular method that is standardized to the international reporting scale is not a trivial undertaking and more recent data suggest that a single timepoint molecular assessment may not be optimal for identifying the patients at highest risk of treatment failure...
September 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27839568/beyond-tyrosine-kinase-inhibitors-combinations-and-other-agents
#16
REVIEW
Emilie Cayssials, Francois Guilhot
The modern therapeutic strategy for patients with chronic myeloid leukemia (CML) has been successfully altered by first and subsequently second generation tyrosine kinase inhibitors. However, despite high rate of molecular response, minimal residual disease persists in the majority of patients. Thus other approaches are warranted in order to eliminate the leukemia stem cells. Targeting CML stem cells could be of clinical benefit and a number of new agents are currently tested in phase I/II trials. Also immunological approaches with vaccination strategies and combination of tyrosine kinase inhibitors with various form of interferons are actively ongoing...
September 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27839567/nccn-and-eln-what-do-the-guidelines-tell-us
#17
REVIEW
Kendra Sweet, Javier Pinilla-Ibarz
The prognosis for patients with Chronic Myeloid Leukemia is vastly different in 2016 compared to 20 years ago, and this is due to the development of BCR-ABL tyrosine kinase inhibitors (TKIs). As newer, more potent, TKIs have been developed and approved over the past 15 years, the decision about which drug to use as first line therapy, and when to switch treatment in particular patients has become more complicated. The National Comprehensive Cancer Network (NCCN) and the European LeukemiaNet (ELN) have developed treatment and monitoring guidelines to aide in the management of these patients...
September 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27839566/making-the-diagnosis-the-tools-and-risk-stratification-more-than-just-bcr-abl
#18
REVIEW
Daniel Egan, Jerald Radich
The implementation of cytogenetic and molecular techniques into standard clinical practice has improved our ability to more accurately diagnose and monitor CML. Routine peripheral blood BCR-ABL transcript testing can help monitor response, predict outcome, and detect early resistance or poor adherence to TKI therapy. The widely-used Sokal, Hasford and EUTOS clinical risk stratification scores were developed in patients receiving chemotherapy, interferon and imatinib, respectively; their predictive ability in patients receiving next-generation tyrosine kinase inhibitors (TKIs) remains to be established...
September 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27839565/chronic-myeloid-leukemia-is-it-dusk-or-dawn
#19
EDITORIAL
Michael J Mauro
No abstract text is available yet for this article.
September 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27825470/monoclonal-igm-related-al-amyloidosis
#20
REVIEW
Paolo Milani, Giampaolo Merlini
Monoclonal immunoglobulin M (IgM)-related light chain (AL) amyloidosis, which accounts for 5%-7% of all AL amyloidosis cases, is a distinct clinical entity that poses specific challenges to clinicians. Several studies reported that although there is a substantial overlap, the pattern of organ involvement is peculiar, with higher frequencies of lung, lymph nodes, and peripheral nervous system involvement. A recent collaborative study from three European referral centers, defined that cardiac involvement, advanced Mayo disease stage, neuropathic, and liver involvement were independent factors that had impact on survival in IgM-AL amyloidosis patients...
June 2016: Best Practice & Research. Clinical Haematology
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