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Special Issue "AML in the Molecular Age: From Biology to Clinical Management"

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383).

Deadline for manuscript submissions: closed (20 September 2014)

Special Issue Editors

Guest Editor
Dr. Celalettin Ustun (Website)

Division of Hematology, Oncology and Transplantation, University of Minnesota, 420 Delaware Street SE, MMC 480 Minneapolis, MN 55455, USA
Phone: +612 624 5109
Fax: +612 625 6919
Interests: AML; elderly AML; alloHCT; infectious complications; systemic mastocytosis
Guest Editor
Dr. Lucy A. Godley (Website)

Section of Hematology/Oncology, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, MC 2115, Chicago, IL 60637, USA
Phone: +773 702 4140
Fax: +773 702 9268
Interests: DNA methylation; hydroxymethylation; inherited susceptibility to hematopoietic malignancies

Special Issue Information

Dear Colleagues,

We appreciate your willingness to contribute an article to the upcoming Special Issue of the Journal of Clinical Medicine, which will focus on “AML in the Molecular Age: From Biology to Clinical Management”. In this Special Issue, we aim to discuss important scientific and clinical ongoing activities in AML. Scientific subjects will include articles concerning the epigenetic mechanisms of disease/therapy as well as the role of the immune system in AML. Very interesting and uncommon subjects will include discussions of extramedullary disease and evaluations of the central nervous system by various imaging techniques. Experts will describe the role of hypomethylating agents in the management of AML and currently emerging and promising investigational therapies. Clinical success relies greatly on supportive therapy, and we will discuss supportive therapy, including infection prophylaxis. Allogeneic hematopoietic stem cell transplantation remains the most effective measure for curing aggressive AML, and a variety of topics will be considered: donor selection, age of recipient, which has been increasing seemingly without limit; therefore, recipient/donor assessments are more important than ever in the aging population. Alternative donor use (e.g., cord blood and haploidentical individuals) has been increasing dramatically; when and who should be considered, what is being investigated? With significant changes occurring with respect to both donors and recipients, the pros and cons of using of anti-thymocyte globulin use in conditioning regimens will be also described.
We have included an overall outline here for your review and ask that you forward to us your final title by 20 August, 2014. We remind you that there will be NO page charges or extra charges for color figures. Articles will be due to us on September 20, 2014

Once again, we look forward to your participation.
With best regards,

Dr. Celalettin Ustun
Dr. Lucy A. Godley
Guest Editors

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 300 CHF (Swiss Francs). English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.


Keywords

  • hypomethylating agents
  • novel therapy
  • epigenetics
  • allogeneic hematopoietic cell transplantation
  • T cell depletion
  • umbilical cord blood transplantation

Published Papers (11 papers)

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Review

Open AccessReview Alternative Donor Transplantation for Acute Myeloid Leukemia
J. Clin. Med. 2015, 4(6), 1240-1268; doi:10.3390/jcm4061240
Received: 14 April 2015 / Revised: 18 May 2015 / Accepted: 21 May 2015 / Published: 9 June 2015
Cited by 1 | PDF Full-text (247 KB) | HTML Full-text | XML Full-text
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy for adult patients with acute myeloid leukemia (AML), but its use for consolidation therapy after first remission with induction chemotherapy used to be limited to younger patients and those with suitable donors. [...] Read more.
Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy for adult patients with acute myeloid leukemia (AML), but its use for consolidation therapy after first remission with induction chemotherapy used to be limited to younger patients and those with suitable donors. The median age of AML diagnosis is in the late 60s. With the introduction of reduced-intensity conditioning (RIC), many older adults are now eligible to receive allo-HCT, including those who are medically less fit to receive myeloablative conditioning. Furthermore, AML patients commonly have no human leukocyte antigen (HLA)-identical or medically suitable sibling donor available to proceed with allo-HCT. Technical advances in donor matching, suppression of alloreactivity, and supportive care have made it possible to use alternative donors, such as unrelated umbilical cord blood (UCB) and partially HLA-matched related (haploidentical) donors. Outcomes after alternative donor allo-HCT are now approaching the outcomes observed for conventional allo-HCT with matched related and unrelated donors. Thus, with both UCB and haploidentical donors available, lack of donor should rarely be a limiting factor in offering an allo-HCT to adults with AML. Full article
(This article belongs to the Special Issue AML in the Molecular Age: From Biology to Clinical Management)
Open AccessReview Intracranial CNS Manifestations of Myeloid Sarcoma in Patients with Acute Myeloid Leukemia: Review of the Literature and Three Case Reports from the Author’s Institution
J. Clin. Med. 2015, 4(5), 1102-1112; doi:10.3390/jcm4051102
Received: 18 December 2014 / Revised: 4 May 2015 / Accepted: 5 May 2015 / Published: 21 May 2015
Cited by 4 | PDF Full-text (298 KB) | HTML Full-text | XML Full-text
Abstract
Myeloid sarcoma (MS) of the central nervous system (CNS) is a rare presentation of leukemic mass infiltration outside of the bone marrow. It may involve the subperiosteum and dura mater and, on rare occasions, can also invade the brain parenchyma. The disease [...] Read more.
Myeloid sarcoma (MS) of the central nervous system (CNS) is a rare presentation of leukemic mass infiltration outside of the bone marrow. It may involve the subperiosteum and dura mater and, on rare occasions, can also invade the brain parenchyma. The disease is most commonly seen in children or young adults; however, it has been described in multiple age groups. MS can be seen in patients with acute myeloid leukemia (AML), chronic myeloid leukemia and other myeloproliferative disorders. This entity has the potential to be underdiagnosed if the MS appearance precedes the first diagnosis of leukemia. The main reason is that their appearance on CT and MRI has a broad differential diagnosis, and proper diagnosis of MS can only be made if the imaging findings are correlated with the clinical history and laboratory findings. Herein, we describe the intracranial CNS manifestations of MS in patients with AML on CT and MRI involving the brain and/or meninges. This study is based on a systematic review of the literature. In addition, three case reports from the author’s institution with AML and intracranial involvement of MS are included. Our aim is to enhance the awareness of this entity among both clinicians and radiologists. Full article
(This article belongs to the Special Issue AML in the Molecular Age: From Biology to Clinical Management)
Open AccessReview Rational Combinations of Targeted Agents in AML
J. Clin. Med. 2015, 4(4), 634-664; doi:10.3390/jcm4040634
Received: 10 October 2014 / Revised: 31 December 2014 / Accepted: 6 January 2015 / Published: 10 April 2015
Cited by 4 | PDF Full-text (458 KB) | HTML Full-text | XML Full-text
Abstract
Despite modest improvements in survival over the last several decades, the treatment of AML continues to present a formidable challenge. Most patients are elderly, and these individuals, as well as those with secondary, therapy-related, or relapsed/refractory AML, are particularly difficult to treat, [...] Read more.
Despite modest improvements in survival over the last several decades, the treatment of AML continues to present a formidable challenge. Most patients are elderly, and these individuals, as well as those with secondary, therapy-related, or relapsed/refractory AML, are particularly difficult to treat, owing to both aggressive disease biology and the high toxicity of current chemotherapeutic regimens. It has become increasingly apparent in recent years that coordinated interruption of cooperative survival signaling pathways in malignant cells is necessary for optimal therapeutic results. The modest efficacy of monotherapy with both cytotoxic and targeted agents in AML testifies to this. As the complex biology of AML continues to be elucidated, many “synthetic lethal” strategies involving rational combinations of targeted agents have been developed. Unfortunately, relatively few of these have been tested clinically, although there is growing interest in this area. In this article, the preclinical and, where available, clinical data on some of the most promising rational combinations of targeted agents in AML are summarized. While new molecules should continue to be combined with conventional genotoxic drugs of proven efficacy, there is perhaps a need to rethink traditional philosophies of clinical trial development and regulatory approval with a focus on mechanism-based, synergistic strategies. Full article
(This article belongs to the Special Issue AML in the Molecular Age: From Biology to Clinical Management)
Figures

Open AccessReview Current Approaches in the Treatment of Relapsed and Refractory Acute Myeloid Leukemia
J. Clin. Med. 2015, 4(4), 665-695; doi:10.3390/jcm4040665
Received: 16 January 2015 / Revised: 19 March 2015 / Accepted: 20 March 2015 / Published: 10 April 2015
Cited by 6 | PDF Full-text (246 KB) | HTML Full-text | XML Full-text
Abstract
The limited sensitivity of the historical treatment response criteria for acute myeloid leukemia (AML) has resulted in a different paradigm for treatment compared with most other cancers presenting with widely disseminated disease. Initial cytotoxic induction chemotherapy is often able to reduce tumor [...] Read more.
The limited sensitivity of the historical treatment response criteria for acute myeloid leukemia (AML) has resulted in a different paradigm for treatment compared with most other cancers presenting with widely disseminated disease. Initial cytotoxic induction chemotherapy is often able to reduce tumor burden to a level sufficient to meet the current criteria for “complete” remission. Nevertheless, most AML patients ultimately die from their disease, most commonly as clinically evident relapsed AML. Despite a variety of available salvage therapy options, prognosis in patients with relapsed or refractory AML is generally poor. In this review, we outline the commonly utilized salvage cytotoxic therapy interventions and then highlight novel investigational efforts currently in clinical trials using both pathway-targeted agents and immunotherapy based approaches. We conclude that there is no current standard of care for adult relapsed or refractory AML other than offering referral to an appropriate clinical trial. Full article
(This article belongs to the Special Issue AML in the Molecular Age: From Biology to Clinical Management)
Open AccessReview The Potential of Vitamin D-Regulated Intracellular Signaling Pathways as Targets for Myeloid Leukemia Therapy
J. Clin. Med. 2015, 4(4), 504-534; doi:10.3390/jcm4040504
Received: 20 September 2014 / Revised: 6 January 2015 / Accepted: 6 March 2015 / Published: 25 March 2015
Cited by 2 | PDF Full-text (763 KB) | HTML Full-text | XML Full-text
Abstract
The current standard regimens for the treatment of acute myeloid leukemia (AML) are curative in less than half of patients; therefore, there is a great need for innovative new approaches to this problem. One approach is to target new treatments to the [...] Read more.
The current standard regimens for the treatment of acute myeloid leukemia (AML) are curative in less than half of patients; therefore, there is a great need for innovative new approaches to this problem. One approach is to target new treatments to the pathways that are instrumental to cell growth and survival with drugs that are less harmful to normal cells than to neoplastic cells. In this review, we focus on the MAPK family of signaling pathways and those that are known to, or potentially can, interact with MAPKs, such as PI3K/AKT/FOXO and JAK/STAT. We exemplify the recent studies in this field with specific relevance to vitamin D and its derivatives, since they have featured prominently in recent scientific literature as having anti-cancer properties. Since microRNAs also are known to be regulated by activated vitamin D, this is also briefly discussed here, as are the implications of the emerging acquisition of transcriptosome data and potentiation of the biological effects of vitamin D by other compounds. While there are ongoing clinical trials of various compounds that affect signaling pathways, more studies are needed to establish the clinical utility of vitamin D in the treatment of cancer. Full article
(This article belongs to the Special Issue AML in the Molecular Age: From Biology to Clinical Management)
Figures

Open AccessReview Effects of T-Cell Depletion on Allogeneic Hematopoietic Stem Cell Transplantation Outcomes in AML Patients
J. Clin. Med. 2015, 4(3), 488-503; doi:10.3390/jcm4030488
Received: 7 September 2014 / Revised: 19 January 2015 / Accepted: 19 January 2015 / Published: 19 March 2015
Cited by 1 | PDF Full-text (131 KB) | HTML Full-text | XML Full-text
Abstract
Graft versus host disease (GVHD) remains one of the leading causes of morbidity and mortality associated with conventional allogeneic hematopoietic stem cell transplantation (HCT). The use of T-cell depletion significantly reduces this complication. Recent prospective and retrospective data suggest that, in patients [...] Read more.
Graft versus host disease (GVHD) remains one of the leading causes of morbidity and mortality associated with conventional allogeneic hematopoietic stem cell transplantation (HCT). The use of T-cell depletion significantly reduces this complication. Recent prospective and retrospective data suggest that, in patients with AML in first complete remission, CD34+ selected grafts afford overall and relapse-free survival comparable to those observed in recipients of conventional grafts, while significantly decreasing GVHD. In addition, CD34+ selected grafts allow older patients, and those with medical comorbidities or with only HLA-mismatched donors to successfully undergo transplantation. Prospective data are needed to further define which groups of patients with AML are most likely to benefit from CD34+ selected grafts. Here we review the history of T-cell depletion in AML, and techniques used. We then summarize the contemporary literature using CD34+ selection in recipients of matched or partially mismatched donors (7/8 or 8/8 HLA-matched), and provide a summary of the risks and benefits of using T-cell depletion. Full article
(This article belongs to the Special Issue AML in the Molecular Age: From Biology to Clinical Management)
Open AccessReview Molecular Genetic Markers in Acute Myeloid Leukemia
J. Clin. Med. 2015, 4(3), 460-478; doi:10.3390/jcm4030460
Received: 5 January 2015 / Revised: 15 January 2015 / Accepted: 3 February 2015 / Published: 12 March 2015
Cited by 10 | PDF Full-text (200 KB) | HTML Full-text | XML Full-text
Abstract
Genetics play an increasingly important role in the risk stratification and management of acute myeloid leukemia (AML) patients. Traditionally, AML classification and risk stratification relied on cytogenetic studies; however, molecular detection of gene mutations is playing an increasingly important role in classification, [...] Read more.
Genetics play an increasingly important role in the risk stratification and management of acute myeloid leukemia (AML) patients. Traditionally, AML classification and risk stratification relied on cytogenetic studies; however, molecular detection of gene mutations is playing an increasingly important role in classification, risk stratification, and management of AML. Molecular testing does not take the place of cytogenetic testing results, but plays a complementary role to help refine prognosis, especially within specific AML subgroups. With the exception of acute promyelocytic leukemia, AML therapy is not targeted but the intensity of therapy is driven by the prognostic subgroup. Many prognostic scoring systems classify patients into favorable, poor, or intermediate prognostic subgroups based on clinical and genetic features. Current standard of care combines cytogenetic results with targeted testing for mutations in FLT3, NPM1, CEBPA, and KIT to determine the prognostic subgroup. Other gene mutations have also been demonstrated to predict prognosis and may play a role in future risk stratification, although some of these have not been confirmed in multiple studies or established as standard of care. This paper will review the contribution of cytogenetic results to prognosis in AML and then will focus on molecular mutations that have a prognostic or possible therapeutic impact. Full article
(This article belongs to the Special Issue AML in the Molecular Age: From Biology to Clinical Management)
Figures

Open AccessReview Treatment of Acute Myeloid Leukemia in Adolescent and Young Adult Patients
J. Clin. Med. 2015, 4(3), 441-459; doi:10.3390/jcm4030441
Received: 5 September 2014 / Accepted: 3 February 2015 / Published: 11 March 2015
Cited by 2 | PDF Full-text (154 KB) | HTML Full-text | XML Full-text
Abstract
The objectives of this review were to discuss standard and investigational treatment strategies for adolescent and young adult with acute myeloid leukemia, excluding acute promyelocytic leukemia. Acute myeloid leukemia (AML) in adolescent and young adult patients (AYAs) may need a different type [...] Read more.
The objectives of this review were to discuss standard and investigational treatment strategies for adolescent and young adult with acute myeloid leukemia, excluding acute promyelocytic leukemia. Acute myeloid leukemia (AML) in adolescent and young adult patients (AYAs) may need a different type of therapy than those currently used in children and older patients. As soon as AML is diagnosed, AYA patient should be offered to participate in well-designed clinical trials. The standard treatment approach for AYAs with AML is remission induction chemotherapy with an anthracycline/cytarabine combination, followed by either consolidation chemotherapy or stem cell transplantation, depending on the ability of the patient to tolerate intensive treatment and cytogenetic features. Presently, continuing progress of novel drugs targeting specific pathways in acute leukemia may bring AML treatment into a new era. Full article
(This article belongs to the Special Issue AML in the Molecular Age: From Biology to Clinical Management)
Open AccessReview Pediatric AML: From Biology to Clinical Management
J. Clin. Med. 2015, 4(1), 127-149; doi:10.3390/jcm4010127
Received: 17 October 2014 / Accepted: 28 November 2014 / Published: 9 January 2015
Cited by 5 | PDF Full-text (971 KB) | HTML Full-text | XML Full-text
Abstract
Pediatric acute myeloid leukemia (AML) represents 15%–20% of all pediatric acute leukemias. Survival rates have increased over the past few decades to ~70%, due to improved supportive care, optimized risk stratification and intensified chemotherapy. In most children, AML presents as a de [...] Read more.
Pediatric acute myeloid leukemia (AML) represents 15%–20% of all pediatric acute leukemias. Survival rates have increased over the past few decades to ~70%, due to improved supportive care, optimized risk stratification and intensified chemotherapy. In most children, AML presents as a de novo entity, but in a minority, it is a secondary malignancy. The diagnostic classification of pediatric AML includes a combination of morphology, cytochemistry, immunophenotyping and molecular genetics. Outcome is mainly dependent on the initial response to treatment and molecular and cytogenetic aberrations. Treatment consists of a combination of intensive anthracycline- and cytarabine-containing chemotherapy and stem cell transplantation in selected genetic high-risk cases or slow responders. In general, ~30% of all pediatric AML patients will suffer from relapse, whereas 5%–10% of the patients will die due to disease complications or the side-effects of the treatment. Targeted therapy may enhance anti-leukemic efficacy and minimize treatment-related morbidity and mortality, but requires detailed knowledge of the genetic abnormalities and aberrant pathways involved in leukemogenesis. These efforts towards future personalized therapy in a rare disease, such as pediatric AML, require intensive international collaboration in order to enhance the survival rates of pediatric AML, while aiming to reduce long-term toxicity. Full article
(This article belongs to the Special Issue AML in the Molecular Age: From Biology to Clinical Management)
Open AccessReview Clinical Results of Hypomethylating Agents in AML Treatment
J. Clin. Med. 2015, 4(1), 1-17; doi:10.3390/jcm4010001
Received: 18 September 2014 / Accepted: 2 December 2014 / Published: 25 December 2014
Cited by 1 | PDF Full-text (197 KB) | HTML Full-text | XML Full-text
Abstract
Epigenetic changes play an important role in the development of acute myeloid leukemia (AML). Unlike gene mutations, epigenetic changes are potentially reversible, which makes them attractive for therapeutic intervention. Agents that affect epigenetics are the DNA methyltransferase inhibitors, azacitidine and decitabine. Because [...] Read more.
Epigenetic changes play an important role in the development of acute myeloid leukemia (AML). Unlike gene mutations, epigenetic changes are potentially reversible, which makes them attractive for therapeutic intervention. Agents that affect epigenetics are the DNA methyltransferase inhibitors, azacitidine and decitabine. Because of their relatively mild side effects, azacitidine and decitabine are particularly feasible for the treatment of older patients and patients with co-morbidities. Both drugs have remarkable activity against AML blasts with unfavorable cytogenetic characteristics. Recent phase 3 trials have shown the superiority of azacitidine and decitabine compared with conventional care for older AML patients (not eligible for intensive treatment). Results of treatment with modifications of the standard azacitidine (seven days 75 mg/m2 SC; every four weeks) and decitabine (five days 20 mg/m2 IV; every four weeks) schedules have been reported. Particularly, the results of the 10-day decitabine schedule are promising, revealing complete remission (CR) rates around 45% (CR + CRi (i.e., CR with incomplete blood count recovery) around 64%) almost comparable with intensive chemotherapy. Application of hypomethylating agents to control AML at the cost of minimal toxicity is a very promising strategy to “bridge” older patients with co-morbidities to the potential curative treatment of allogeneic hematopoietic cell transplantation. In this article, we discuss the role of DNA methyltransferase inhibitors in AML. Full article
(This article belongs to the Special Issue AML in the Molecular Age: From Biology to Clinical Management)
Open AccessReview Targeted Therapy of FLT3 in Treatment of AML—Current Status and Future Directions
J. Clin. Med. 2014, 3(4), 1466-1489; doi:10.3390/jcm3041466
Received: 21 September 2014 / Revised: 27 November 2014 / Accepted: 28 November 2014 / Published: 15 December 2014
Cited by 2 | PDF Full-text (203 KB) | HTML Full-text | XML Full-text
Abstract
Internal tandem duplications (ITDs) of the gene encoding the Fms-Like Tyrosine kinase-3 (FLT3) receptor are present in approximately 25% of patients with acute myeloid leukemia (AML). The mutation is associated with poor prognosis, and the aberrant protein product has been hypothesized as [...] Read more.
Internal tandem duplications (ITDs) of the gene encoding the Fms-Like Tyrosine kinase-3 (FLT3) receptor are present in approximately 25% of patients with acute myeloid leukemia (AML). The mutation is associated with poor prognosis, and the aberrant protein product has been hypothesized as an attractive therapeutic target. Various tyrosine kinase inhibitors (TKIs) have been developed targeting FLT3, but in spite of initial optimism the first generation TKIs tested in clinical studies generally induce only partial and transient hematological responses. The limited treatment efficacy generally observed may be explained by numerous factors; extensively pretreated and high risk cohorts, suboptimal pharmacodynamic and pharmacokinetic properties of the compounds, acquired TKI resistance, or the possible fact that inhibition of mutated FLT3 alone is not sufficient to avoid disease progression. The second-generation agent quizartinb is showing promising outcomes and seems better tolerated and with less toxic effects than traditional chemotherapeutic agents. Therefore, new generations of TKIs might be feasible for use in combination therapy or in a salvage setting in selected patients. Here, we sum up experiences so far, and we discuss the future outlook of targeting dysregulated FLT3 signaling in the treatment of AML. Full article
(This article belongs to the Special Issue AML in the Molecular Age: From Biology to Clinical Management)

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