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Biomedicines
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Pathogenesis and Novel Therapies of Acute Leukemias
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Pathogenesis and Novel Therapies of Acute Leukemias

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 12466

Special Issue Editors

Dr. Gwen Nichols

E-Mail Website
Guest Editor
Chief Medical Officer, The Leukemia & Lymphoma Society (LLS), Rye Brook, NY, USA
Interests: acute leukemia; leukemia pathogenesis
Dr. Alexandra Stevens

E-Mail Website
Guest Editor
Department of Pediatrics, Section of Pediatric Hematology/Oncology, Texas Children's Hospital, Houston, TX, USA
Interests: developmental therapeutics; leukemia

Special Issue Information

Dear Colleagues,

Prevention and early detection have greatly reduced age-adjusted death rates in many types of cancer. In the United States, death rates from lung, female breast and colorectal cancers have decreased by more than 40% over the last decades, in great part due to screening and early detection. However, in contrast, death rates from acute leukemia have been relatively steady over this period, with the exception of childhood ALL where survival is > 90%. Much of the progress in acute leukemia has come from improvements in classification, monitoring and modified treatment regimens. 

How can we leverage recent discoveries that have identified mutations in genes that can lead to leukemia well before leukemia occurs, or genes that are major drivers of leukemia when it occurs? Can this knowledge be used to identify individuals at risk of developing leukemia, enabling us to create diagnostic and therapeutic strategies that will prevent leukemia? Will improved subclassification of leukemia at the molecular level help novel, more targeted therapies for these diseases be successful?

This Special Issue will explore what we are learning about leukemia pathogenesis, and present progress towards new treatments that can replace “one size fits all” therapy for acute leukemia. 

Dr. Gwen Nichols
Dr. Alexandra Stevens
Guest Editors

Manuscript Submission Information

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. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short 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 thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines 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 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • acute leukemia
  • leukemia pathogenesis
  • diagnostic for leukemia
  • therapeutic strategies for leukemia
  • novel targeted therapies for leukemia
  • new leukemia treatments
  • replacing one-size-fits-all therapy

Published Papers (7 papers)

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Research

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15 pages, 3405 KiB  
Article
Addressing a Pre-Clinical Pipeline Gap: Development of the Pediatric Acute Myeloid Leukemia Patient-Derived Xenograft Program at Texas Children’s Hospital at Baylor College of Medicine
by Alexandra M. Stevens, Maci Terrell, Raushan Rashid, Kevin E. Fisher, Andrea N. Marcogliese, Amos Gaikwad, Pulivarthi Rao, Chelsea Vrana, Michael Krueger, Michael Loken, Andrew J. Menssen, Jacqueline A. Cook, Noah Keogh, Michelle Alozie, Hailey Oviedo, Alan K. Gonzalez, Tamilini Ilangovan, Julia Kim, Sohani Sandhu and Michele S. Redell
Biomedicines 2024, 12(2), 394; https://doi.org/10.3390/biomedicines12020394 - 8 Feb 2024
Viewed by 1085
Abstract
The survival rate of pediatric acute myeloid leukemia (pAML) is currently around 60%. While survival has slowly increased over the past few decades, the development of novel agents likely to further improve survival for this heterogeneous patient population has been limited by gaps [...] Read more.
The survival rate of pediatric acute myeloid leukemia (pAML) is currently around 60%. While survival has slowly increased over the past few decades, the development of novel agents likely to further improve survival for this heterogeneous patient population has been limited by gaps in the pAML pre-clinical pipeline. One of the major hurdles in evaluating new agents for pAML is the lack of pAML patient-derived xenograft (PDX) models. Unlike solid tumors and other types of leukemias, AML is notoriously hard to establish in mouse models, likely due in part to the need for specific human microenvironment elements. Our laboratory at TCH/BCM addressed this gap by establishing a systematic PDX workflow, leveraging advanced immunodeficient hosts and capitalizing on our high volume of pAML patients and close coordination between labs and clinical sections. Patients treated at TCH are offered the chance to participate in specimen banking protocols that allow blood and bone marrow collection as well as the collection of relevant clinical data. All patients who consent and have samples available are trialed for PDX development. In addition, samples from the Children’s Oncology Group (COG) are also trialed for PDX generation. Serially transplanting PDX models are validated using short tandem repeat (STR) and characterized using both targeted DNA/RNA next generation sequencing and RNAseq. As of March 2023, this systematic approach has resulted in 26 serially transplanting models. Models have been shared with requesting labs to facilitate external pAML pre-clinical studies. Available PDX models can be located through the BCM PDX Portal. We expect our growing PDX resource to make a significant contribution to expediting the testing of promising novel therapeutics for pAML. Full article
(This article belongs to the Special Issue Pathogenesis and Novel Therapies of Acute Leukemias)
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Review

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14 pages, 1622 KiB  
Review
In Utero Origins of Acute Leukemia in Children
by Adam J. de Smith and Logan G. Spector
Biomedicines 2024, 12(1), 236; https://doi.org/10.3390/biomedicines12010236 - 19 Jan 2024
Cited by 1 | Viewed by 1951
Abstract
Acute leukemias, mainly consisting of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), comprise a major diagnostic group among hematologic cancers. Due to the early age at onset of ALL, particularly, it has long been suspected that acute leukemias of childhood may [...] Read more.
Acute leukemias, mainly consisting of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), comprise a major diagnostic group among hematologic cancers. Due to the early age at onset of ALL, particularly, it has long been suspected that acute leukemias of childhood may have an in utero origin. This supposition has motivated many investigations seeking direct proof of prenatal leukemogenesis, in particular, twin and “backtracking studies”. The suspected in utero origin has also focused on gestation as a critical window of risk, resulting in a rich literature on prenatal risk factors for pediatric acute leukemias. In this narrative review, we recount the circumstantial and direct evidence for an in utero origin of childhood acute leukemias. Full article
(This article belongs to the Special Issue Pathogenesis and Novel Therapies of Acute Leukemias)
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16 pages, 668 KiB  
Review
IKZF1 Alterations and Therapeutic Targeting in B-Cell Acute Lymphoblastic Leukemia
by Jonathan Paolino, Harrison K. Tsai, Marian H. Harris and Yana Pikman
Biomedicines 2024, 12(1), 89; https://doi.org/10.3390/biomedicines12010089 - 1 Jan 2024
Viewed by 2162
Abstract
IKZF1 encodes the transcription factor IKAROS, a zinc finger DNA-binding protein with a key role in lymphoid lineage development. IKAROS plays a critical role in the development of lineage-restricted mature lymphocytes. Deletions within IKZF1 in B-cell acute lymphoblastic leukemia (B-ALL) lead to a [...] Read more.
IKZF1 encodes the transcription factor IKAROS, a zinc finger DNA-binding protein with a key role in lymphoid lineage development. IKAROS plays a critical role in the development of lineage-restricted mature lymphocytes. Deletions within IKZF1 in B-cell acute lymphoblastic leukemia (B-ALL) lead to a loss of normal IKAROS function, conferring leukemic stem cell properties, including self-renewal and subsequent uncontrolled growth. IKZF1 deletions are associated with treatment resistance and inferior outcomes. Early identification of IKZF1 deletions in B-ALL may inform the intensification of therapy and other potential treatment strategies to improve outcomes in this high-risk leukemia. Full article
(This article belongs to the Special Issue Pathogenesis and Novel Therapies of Acute Leukemias)
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29 pages, 2268 KiB  
Review
Emerging and Future Targeted Therapies for Pediatric Acute Myeloid Leukemia: Targeting the Leukemia Stem Cells
by Lindsey A. Murphy and Amanda C. Winters
Biomedicines 2023, 11(12), 3248; https://doi.org/10.3390/biomedicines11123248 - 7 Dec 2023
Cited by 1 | Viewed by 1608
Abstract
Acute myeloid leukemia (AML) is a rare subtype of acute leukemia in the pediatric and adolescent population but causes disproportionate morbidity and mortality in this age group. Standard chemotherapeutic regimens for AML have changed very little in the past 3–4 decades, but the [...] Read more.
Acute myeloid leukemia (AML) is a rare subtype of acute leukemia in the pediatric and adolescent population but causes disproportionate morbidity and mortality in this age group. Standard chemotherapeutic regimens for AML have changed very little in the past 3–4 decades, but the addition of targeted agents in recent years has led to improved survival in select subsets of patients as well as a better biological understanding of the disease. Currently, one key paradigm of bench-to-bedside practice in the context of adult AML is the focus on leukemia stem cell (LSC)-targeted therapies. Here, we review current and emerging immunotherapies and other targeted agents that are in clinical use for pediatric AML through the lens of what is known (and not known) about their LSC-targeting capability. Based on a growing understanding of pediatric LSC biology, we also briefly discuss potential future agents on the horizon. Full article
(This article belongs to the Special Issue Pathogenesis and Novel Therapies of Acute Leukemias)
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20 pages, 381 KiB  
Review
CAR T-Cells in Acute Lymphoblastic Leukemia: Current Status and Future Prospects
by Abdulrahman H. Almaeen and Mohamed Abouelkheir
Biomedicines 2023, 11(10), 2693; https://doi.org/10.3390/biomedicines11102693 - 2 Oct 2023
Viewed by 2223
Abstract
The currently available treatment for acute lymphoblastic leukemia (ALL) is mainly dependent on the combination of chemotherapy, steroids, and allogeneic stem cell transplantation. However, refractoriness and relapse (R/R) after initial complete remission may reach up to 20% in pediatrics. This percentage may even [...] Read more.
The currently available treatment for acute lymphoblastic leukemia (ALL) is mainly dependent on the combination of chemotherapy, steroids, and allogeneic stem cell transplantation. However, refractoriness and relapse (R/R) after initial complete remission may reach up to 20% in pediatrics. This percentage may even reach 60% in adults. To overcome R/R, a new therapeutic approach was developed using what is called chimeric antigen receptor-modified (CAR) T-cell therapy. The Food and Drug Administration (FDA) in the United States has so far approved four CAR T-cells for the treatment of ALL. Using this new therapeutic strategy has shown a remarkable success in treating R/R ALL. However, the use of CAR T-cells is expensive, has many imitations, and is associated with some adverse effects. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are two common examples of these adverse effects. Moreover, R/R to CAR T-cell therapy can take place during treatment. Continuous development of this therapeutic strategy is ongoing to overcome these limitations and adverse effects. The present article overviews the use of CAR T-cell in the treatment of ALL, summarizing the results of relevant clinical trials and discussing future prospects intended to improve the efficacy of this therapeutic strategy and overcome its limitations. Full article
(This article belongs to the Special Issue Pathogenesis and Novel Therapies of Acute Leukemias)
25 pages, 664 KiB  
Review
Harnessing the Immune System: Current and Emerging Immunotherapy Strategies for Pediatric Acute Lymphoblastic Leukemia
by Chana L. Glasser and Jing Chen
Biomedicines 2023, 11(7), 1886; https://doi.org/10.3390/biomedicines11071886 - 3 Jul 2023
Cited by 1 | Viewed by 1476
Abstract
Treatment for relapsed acute lymphoblastic leukemia (ALL) in children and young adults continues to evolve. Despite optimization of cytotoxic chemotherapeutic approaches and risk-adapted therapy, about 12% of pediatric patients still relapse, and survival rates in this population remain poor. Salvage therapy for relapsed [...] Read more.
Treatment for relapsed acute lymphoblastic leukemia (ALL) in children and young adults continues to evolve. Despite optimization of cytotoxic chemotherapeutic approaches and risk-adapted therapy, about 12% of pediatric patients still relapse, and survival rates in this population remain poor. Salvage therapy for relapsed patients continues to be challenging as attempts to further intensify chemotherapy have resulted in excessive toxicity without improving outcomes. Immunotherapy has profoundly impacted the landscape of relapsed ALL by harnessing the patient’s immune system to target and eliminate leukemia cells. In this review, we provide an overview and summary of immunotherapy agents that have been approved and remain under investigation for children, including blinatumomab, inotuzumab, daratumomab, and chimeric antigen receptor T-cell therapy. We discuss the landmark clinical trials that have revolutionized the field and provide an update on ongoing clinical trials involving these agents for children in the relapsed and upfront setting. The incorporation of these novel immunotherapies into ALL treatment, either as monotherapy or in combination with cytotoxic chemotherapy, has demonstrated promising potential to augment outcomes while decreasing toxicity. However, we also highlight the many challenges we still face and the research critically needed to achieve our goals for cure in children. Full article
(This article belongs to the Special Issue Pathogenesis and Novel Therapies of Acute Leukemias)
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Other

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8 pages, 1603 KiB  
Case Report
ALK Fusion in an Adolescent with Acute Myeloid Leukemia: A Case Report and Review of the Literature
by Meghan Shekar, Gabriela Llaurador Caraballo, Jyotinder N. Punia, Choladda V. Curry, Kevin E. Fisher and Michele S. Redell
Biomedicines 2023, 11(7), 1842; https://doi.org/10.3390/biomedicines11071842 - 27 Jun 2023
Viewed by 1181
Abstract
Activating mutations and fusions of the ALK oncogene have been identified as drivers in a number of malignancies. Crizotinib and subsequent ALK tyrosine kinase inhibitors have improved treatment outcomes for these patients. In this paper, we discuss the case of an adolescent patient [...] Read more.
Activating mutations and fusions of the ALK oncogene have been identified as drivers in a number of malignancies. Crizotinib and subsequent ALK tyrosine kinase inhibitors have improved treatment outcomes for these patients. In this paper, we discuss the case of an adolescent patient with acute myeloid leukemia, who was identified to have an activating ALK fusion, which is a rare finding and has never been reported in cases of AML without monosomy 7. Crizotinib was added to this patient’s frontline therapy and was well tolerated. In cases of more common gene alterations, existing data supports the use of targeted agents as post-HSCT maintenance therapy; however, crizotinib was not able to be used post-HSCT for this patient due to the inability to obtain insurance coverage. Full article
(This article belongs to the Special Issue Pathogenesis and Novel Therapies of Acute Leukemias)
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