Recent Progress in Leukemia: Where Do We Stand?

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Hematology".

Deadline for manuscript submissions: closed (20 December 2023) | Viewed by 5440

Special Issue Editors


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Guest Editor
Department of Haematology, Hull University Teaching Hospitals NHS Trust, Hull, UK
Interests: CLL; prognostic factors; novel agents; lymphoproliferative disorders; clinical trials
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Guest Editor
Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
Interests: tumor immunotherapy; multiple myeloma pathogenesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Recent drug development and advances in biology have altered the therapeutic treatment of leukemia patients. Treatment options for different types of leukemias now include targeted therapies, immune-based therapeutics, and multiple novel modalities that are currently under investigation. Additionally, novel drugs approved in the last 5 years have drawn attention to new situations and treatable patient sub-groups.

Nowadays, modern leukemia therapy decisions mainly rely on the selection of patients suitable for specific targeted agents; thus, the assessment of disease- and patient-specific factors deserves special consideration.

In detail, CLL patients sequentially treated with a covalent BTK inhibitor (BTKi) and venetoclax, or vice versa, have limited therapeutic options, and their clinical management is unmet. Ongoing clinical trials assess the role of non-covalent BTKis, CAR-T cells, and bispecific monoclonal antibodies.

In AML, recent discoveries of the role of molecular drivers of leukemogenesis and disease progression have led to the development of innovative therapeutic strategies. This knowledge translates into newer algorithms, focusing on appropriate patients eligible for intensive or non-intensive treatments.

In this Special Issue in the Journal Clinical Medicine, we welcome authors to submit papers on the clinical advances of CLL and AML. We aim to discuss specific scenarios and controversial areas that prefigure unmet clinical needs in these subtypes of leukemia.

Dr. Stefano Molica
Prof. Dr. Marco Rossi
Guest Editors

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Keywords

  • leukemia
  • targeted agents
  • immunotherapy
  • CLL
  • AML
  • therapeutic algorithms

Published Papers (2 papers)

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Research

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37 pages, 5647 KiB  
Article
Vacuolar ATPase Is a Possible Therapeutic Target in Acute Myeloid Leukemia: Focus on Patient Heterogeneity and Treatment Toxicity
by Sushma Bartaula-Brevik, Calum Leitch, Maria Hernandez-Valladares, Elise Aasebø, Frode S. Berven, Frode Selheim, Annette K. Brenner, Kristin Paulsen Rye, Marie Hagen, Håkon Reikvam, Emmet McCormack, Øystein Bruserud and Tor Henrik Anderson Tvedt
J. Clin. Med. 2023, 12(17), 5546; https://doi.org/10.3390/jcm12175546 - 25 Aug 2023
Cited by 1 | Viewed by 1519
Abstract
Vacuolar ATPase (V-ATPase) is regarded as a possible target in cancer treatment. It is expressed in primary acute myeloid leukemia cells (AML), but the expression varies between patients and is highest for patients with a favorable prognosis after intensive chemotherapy. We therefore investigated [...] Read more.
Vacuolar ATPase (V-ATPase) is regarded as a possible target in cancer treatment. It is expressed in primary acute myeloid leukemia cells (AML), but the expression varies between patients and is highest for patients with a favorable prognosis after intensive chemotherapy. We therefore investigated the functional effects of two V-ATPase inhibitors (bafilomycin A1, concanamycin A) for primary AML cells derived from 80 consecutive patients. The V-ATPase inhibitors showed dose-dependent antiproliferative and proapoptotic effects that varied considerably between patients. A proteomic comparison of primary AML cells showing weak versus strong antiproliferative effects of V-ATPase inhibition showed a differential expression of proteins involved in intracellular transport/cytoskeleton functions, and an equivalent phosphoproteomic comparison showed a differential expression of proteins that regulate RNA processing/function together with increased activity of casein kinase 2. Patients with secondary AML, i.e., a heterogeneous subset with generally adverse prognosis and previous cytotoxic therapy, myeloproliferative neoplasia or myelodysplastic syndrome, were characterized by a strong antiproliferative effect of V-ATPase inhibition and also by a specific mRNA expression profile of V-ATPase interactome proteins. Furthermore, the V-ATPase inhibition altered the constitutive extracellular release of several soluble mediators (e.g., chemokines, interleukins, proteases, protease inhibitors), and increased mediator levels in the presence of AML-supporting bone marrow mesenchymal stem cells was then observed, especially for patients with secondary AML. Finally, animal studies suggested that the V-ATPase inhibitor bafilomycin had limited toxicity, even when combined with cytarabine. To conclude, V-ATPase inhibition has antileukemic effects in AML, but this effect varies between patients. Full article
(This article belongs to the Special Issue Recent Progress in Leukemia: Where Do We Stand?)
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Review

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20 pages, 714 KiB  
Review
Gilteritinib: The Story of a Proceeding Success into Hard-to-Treat FLT3-Mutated AML Patients
by Matteo Molica, Salvatore Perrone and Marco Rossi
J. Clin. Med. 2023, 12(11), 3647; https://doi.org/10.3390/jcm12113647 - 24 May 2023
Cited by 6 | Viewed by 3480
Abstract
The traditionally dismal outcome of acute myeloid leukemia (AML) patients carrying the FMS-related tyrosine kinase 3 (FLT3) mutations has been mitigated by the recent introduction of tyrosine kinase inhibitors (TKI) into clinics, such as midostaurin and gilteritinib. The present work summarizes [...] Read more.
The traditionally dismal outcome of acute myeloid leukemia (AML) patients carrying the FMS-related tyrosine kinase 3 (FLT3) mutations has been mitigated by the recent introduction of tyrosine kinase inhibitors (TKI) into clinics, such as midostaurin and gilteritinib. The present work summarizes the clinical data that led to the use of gilteritinib in clinical practice. Gilteritinib is a second-generation TKI with deeper single-agent activity than first-generation drugs against both FLT3–ITD and TKD mutations in human studies. Moreover, the phase I/II dose-escalation, dose-expansion Chrysalis trial showed an acceptable safety profile of gilteritinib (diarrhea, elevated aspartate aminotransferase, febrile neutropenia, anemia, thrombocytopenia, sepsis, and pneumonia) and a 49% overall response rate (ORR) in 191 FLT3-mutated relapsed/refractory (R/R) AML patients. In 2019, the pivotal ADMIRAL trial showed that the median overall survival was significantly longer in patients treated with gilteritinib than among those receiving chemotherapy (9.3 vs. 5.6 months, respectively) and the ORR to gilteritinib was 67.6%, outperforming the 25.8% for chemotherapy arm and leading to the license for its clinical use by the US Food and Drug Administration. Since then, several real-world experiences have confirmed the positive results in the R/R AML setting. Finally, gilteritinib-based combinations currently under investigation, with several compounds (venetoclax, azacitidine, conventional chemotherapy, etc.) and some practical tips (maintenance after allogeneic transplantation, interaction with antifungal drugs, extramedullary disease, and onset of resistance), will be analyzed in detail in this review. Full article
(This article belongs to the Special Issue Recent Progress in Leukemia: Where Do We Stand?)
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