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pubmed: Curr Op Hem[Jour]



NCBI: db=pubmed; Term="Current Opinion in Hematology"[Jour]



 



Characterization, regulation, and targeting of erythroid progenitors in normal and disordered human erythropoiesis.

Characterization, regulation, and targeting of erythroid progenitors in normal and disordered human erythropoiesis.

Curr Opin Hematol. 2017 Jan 17;:

Authors: Dulmovits BM, Hom J, Narla A, Mohandas N, Blanc L

Abstract
PURPOSE OF REVIEW: The erythroid progenitors burst-forming unit-erythroid and colony-forming unit-erythroid have a critical role in erythropoiesis. These cells represent a heterogeneous and poorly characterized population with modifiable self-renewal, proliferation and differentiation capabilities. This review focuses on the current state of erythroid progenitor biology with regard to immunophenotypic identification and regulatory programs. In addition, we will discuss the therapeutic implications of using these erythroid progenitors as pharmacologic targets.
RECENT FINDINGS: Erythroid progenitors are classically characterized by the appearance of morphologically defined colonies in semisolid cultures. However, these prior systems preclude a more thorough understanding of the composite nature of progenitor populations. Recent studies employing novel flow cytometric and cell-based assays have helped to redefine hematopoiesis, and suggest that erythroid progenitors may arise from different levels of the hematopoietic tree. Moreover, the identification of cell surface marker patterns in human burst-forming unit-erythroid and colony-forming unit-erythroid enhance our ability to perform downstream functional and molecular analyses at the population and single cell level. Advances in these techniques have already revealed novel subpopulations with increased self-renewing capacity, roles for erythroid progenitors in globin gene expression, and insights into pharmacologic mechanisms of glucocorticoids and pomalidomide.
SUMMARY: Immunophenotypic and molecular characterization resolves the diversity of erythroid progenitors, and may ultimately lead to the ability to target these progenitors to ameliorate diseases of dyserythropoiesis.

PMID: 28099275 [PubMed - as supplied by publisher]




Can any patients with chronic myeloid leukemia outside of a clinical trial have their tyrosine kinase inhibitor discontinued?

Can any patients with chronic myeloid leukemia outside of a clinical trial have their tyrosine kinase inhibitor discontinued?

Curr Opin Hematol. 2017 Jan 17;:

Authors: Mauro MJ

Abstract
PURPOSE OF REVIEW: This article critically appraises the state of treatment-free remission as a strategy for patients with chronic myeloid leukemia (CML) in deep remission after therapy with tyrosine kinase inhibitors (TKIs).
RECENT FINDINGS: Approximately half of patients with CML defined fairly narrowly by trial criteria - TKI sensitive, in deep molecular remission for a defined period - can successfully maintain protective levels of response after TKI cessation. Those who cannot appear at very low risk of disease control loss and can promptly regain remission with TKI resumption. Increasing numbers of patients followed longer term in trials have proven as well as a lack of additional late relapse in either group and that 'functional cure' of CML is feasible. Both the definition of remission sufficient to attempt treatment-free remission and the trigger to resume treatment have been relaxed somewhat while outcomes have remained the same. Based on repeated confirmatory data, economic pressures, and pragmatism, the question of feasibility and safety of TKI cessation outside of clinical trials is at hand.
SUMMARY: TKI cessation outside of clinical trials, if performed under strict guidelines, utilizing optimal monitoring techniques, with counsel available from experts in the field, and after full disclosure of the risks and benefits with the patient, may be safe (see video, supplemental digital content 1, which summarizes the abstract and offers the author's perspective,http://links.lww.com/COH/A15).

PMID: 28099274 [PubMed - as supplied by publisher]




Making the most of hypomethylating agents in myelodysplastic syndrome.

Making the most of hypomethylating agents in myelodysplastic syndrome.

Curr Opin Hematol. 2017 Jan 17;:

Authors: Bhatt G, Blum W

Abstract
PURPOSE OF REVIEW: Hypomethylating agents (HMA) are the preferred therapy for patients with higher risk myelodysplastic syndromes (MDS) and an alternative therapeutic strategy for older patients with acute myeloid leukemia. These agents have improved both survival and quality of life, but results overall remain poor. The purpose of this review is to highlight recent developments in clinical research with HMA in MDS/acute myeloid leukemia over the last year.
RECENT FINDINGS: Combination of HMA with B-cell lymphoma-2 inhibitors, hedgehog inhibitors, and a variety of other agents are underway, as are further studies with reformulated HMA that have more favorable pharmacokinetics (including oral bioavailability). HMA may also be promising in maintenance therapy after allogeneic transplantation. Generally speaking, testing new agents in randomized studies after 'HMA failure,' however, may be suboptimal for assessing efficacy.
SUMMARY: No clear 'winner' as a combination partner with HMA or novel formulation of HMA has yet emerged. We concur with growing trends to test novel agents early in the drug development timeline, including the frontline treatment setting in combination with HMA, to bring new agents to Food and Drug Administration approval more quickly. HMA are standard in name only, clinical research should be the standard of care.

PMID: 28099273 [PubMed - as supplied by publisher]




Mixed-phenotype acute leukemia: current challenges in diagnosis and therapy.

Mixed-phenotype acute leukemia: current challenges in diagnosis and therapy.

Curr Opin Hematol. 2017 Jan 17;:

Authors: Wolach O, Stone RM

Abstract
PURPOSE OF REVIEW: Mixed-phenotype acute leukemia (MPAL) is a rare disease that poses many diagnostic and therapeutic challenges. Patients with MPAL are considered to have poor outcomes. The difficulties in classifying this leukemia, the lack of prospectively collected data concerning therapeutic outcomes, and rare incidence result in much uncertainty as to the best approach for patients with MPAL.
RECENT FINDINGS: Recent studies demonstrated that most MPALs are associated with cytogenetic abnormalities; genetic sequencing studies disclose a high frequency of somatic mutations in genes encoding epigenetic regulators, tumor suppressors, and transcription factors. The limited available data suggest that higher remission rates are achieved with acute lymphoblastic leukemia-like induction regimens compared with acute myeloid leukemia-type approaches. Allogeneic transplantation in first remission may be associated with improved survival compared with consolidation chemotherapy.
SUMMARY: Advances in understanding the genetic landscape of MPAL may allow a more biologically driven classification of this heterogeneous group of leukemias in the future that will lead to optimized therapies for individual patients. Most data that inform therapy are based on retrospective, uncontrolled studies; prospective trials that incorporate targeted approaches based on genetics and immunophenotype are needed.

PMID: 28099272 [PubMed - as supplied by publisher]




Innovative strategies for adverse karyotype acute myeloid leukemia.

Innovative strategies for adverse karyotype acute myeloid leukemia.

Curr Opin Hematol. 2017 Jan 17;:

Authors: Blum S, Greve G, Lübbert M

Abstract
PURPOSE OF REVIEW: Adverse karyotype acute myeloid leukemia is a disease particularly of older patients, but also observed in younger patients. Despite all efforts, standard chemotherapy is still generally applied in fit patients, as already for decades, and for nearly all different subtypes of acute myeloid leukemia. Lack of more specifically targeted therapy and the often older age of the patients are complicating treatment, and in the subgroup of patients achieving a complete remission, the strikingly high frequency of relapse is a characteristic of this disease. This review aims to give an overview of current treatment approaches as well as emerging therapies.
RECENT FINDINGS: Currently, the approach of a targeted therapy specific to the genetic and/or epigenetic aberrations detected in the individual patient is still not possible, and a 'one treatment fits all' course of action is still used, with allografting as curative consolidation. However, first immunotherapeutic approaches are emerging as treatment options and first phase 1 and 2 studies are described.
SUMMARY: Treatment of acute myeloid leukemia with adverse karyotype is still not individualized, most treatment options currently not being curative. This can change in the near future, but recent findings will have to be implemented into larger phase 3 studies before being standard of care.

PMID: 28099271 [PubMed - as supplied by publisher]




Dyserythropoiesis of myelodysplastic syndromes.
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Dyserythropoiesis of myelodysplastic syndromes.

Curr Opin Hematol. 2017 Jan 07;:

Authors: Lefèvre C, Bondu S, Le Goff S, Kosmider O, Fontenay M

Abstract
PURPOSE OF REVIEW: Myelodysplastic syndromes (MDS) are heterogeneous diseases of the hematopoietic stem cell in the elderly. Anemia is the main symptom that mostly correlates with dysplastic erythropoiesis in the bone marrow. We will review the recent advances in understanding the diverse mechanisms of dyserythropoiesis.
RECENT FINDINGS: Dyserythropoiesis defined as 10% dysplastic erythroid cells in the bone marrow is found in more than 80% of early MDS. Immature erythroblasts accumulate at the expense of mature erythroblasts due to differentiation arrest and apoptosis. In early MDS with dyserythropoiesis, caspase-dependent cleavage of the erythroid transcription factor GATA-1 occurring in basophilic erythroblasts accounts for impairment of final maturation. Depending on initiating genetic alteration, specific mechanisms contribute to erythroid defect. In MDS with 5q deletion, the haploinsufficiency of ribosomal protein gene, RPS14, opposes the transition of immature to mature erythroblasts by inducing a p53-dependent ribosome stress, cell cycle arrest and apoptosis. Recent work identifies the activation of a p53-S100A8/9 innate immune pathway that both intrinsically and extrinsically contributes to defective erythropoiesis. In MDS with ring sideroblasts, a paradigm of dyserythropoiesis, a unique mutation in SF3B1 splicing factor gene induces a multiplicity of alterations at RNA level that deeply modifies the patterns of gene expression.
SUMMARY: Insights in the pathophysiology of MDS with dyserythropoiesis may guide the choice of the appropriate therapy, for instance lenalidomide in MDS with del(5q). A better understanding of the mechanisms of dyserthropoiesis is required to treat anemia in non-del(5q) MDS, especially in case of resistance to first-line therapy by erythropoiesis-stimulating agents.

PMID: 28072603 [PubMed - as supplied by publisher]




'Janus kinase-ing' up the treatment of primary myelofibrosis: building better combination strategies.
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'Janus kinase-ing' up the treatment of primary myelofibrosis: building better combination strategies.

Curr Opin Hematol. 2017 Jan 07;:

Authors: Assi R, Verstovsek S, Daver N

Abstract
PURPOSE OF REVIEW: The article discusses the promising agents that are approved or currently under investigation for the treatment of myelofibrosis and reviews the ongoing Janus kinase (JAK) inhibitors-based combinatorial strategies in this setting.
RECENT FINDINGS: Myelofibrosis is a Philadelphia-negative myeloproliferative neoplasm with constitutive JAK/STAT activation. The JAK-inhibitor ruxolitinib is the only approved drug for this disease in the United States and Europe based on two randomized phase III studies that demonstrated clinically meaningful reduction in spleen size, improvement in symptoms, quality of life, and an overall survival advantage with prolonged follow-up. Emerging data have revealed the complex molecular architecture of myelofibrosis with clonal evolution playing a central role in disease progression or transformation. These molecular pathways may explain the heterogeneous benefits obtained by JAK-inhibitors in patients with myelofibrosis. In addition, the genetic and epigenetic mutations appear to work in concert with overactive JAK/STAT signaling and contribute to myelofibrosis pathogenesis and prognosis, suggesting a potential to exploit them as potential therapeutic targets.
SUMMARY: Combining JAK-inhibitors with agents that target parallel prosurvival pathways or agents that enhance hematopoiesis may enhance efficacy and/or mitigate on-target myelosuppression, thereby extending the therapeutic benefits observed with JAK-inhibitors alone.

PMID: 28072602 [PubMed - as supplied by publisher]




What are the most promising new agents in acute myeloid leukemia?
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What are the most promising new agents in acute myeloid leukemia?

Curr Opin Hematol. 2016 Dec 26;:

Authors: Sallman DA, Lancet JE

Abstract
PURPOSE OF REVIEW: Although the treatment paradigm for acute myeloid leukemia (AML) had been largely unchanged for many years, in-depth molecular characterization has revolutionized our understanding of mutations that drive the disease, subsequently serving to guide current clinical investigation. Furthermore, recent advances in the field have highlighted the importance of optimizing known efficacious agents by improving drug delivery or bypassing resistance mechanisms. The current status of novel agents which are shaping the clinical management of AML patients are summarized in this review.
RECENT FINDINGS: Practice changing findings over the past year include improved overall survival (OS) in a molecularly defined AML subgroup as well as in elderly patients with secondary AML (sAML). Specifically, synergistic combination of daunorubicin and cytarabine (i.e., CPX-351) was found to improve OS in sAML patients. Furthermore, although multiple mutation specific inhibitors have been developed, optimal combination with additional agents appears critical, as monotherapies have not resulted in durable remissions or improved outcomes. Improved OS via the addition of midostaurin to intensive chemotherapy in FLT3 mutant AML supports this concept.
SUMMARY: For the first time in AML, personalized therapy has become possible through improved understanding of the molecular architecture and survival pathways of an individual's disease. The landscape of AML treatment is encouraging, with multiple novel agents likely to gain approval over the next 5 years.

PMID: 28030373 [PubMed - as supplied by publisher]