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Diseases
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Targeted Therapies for Acute Leukemias
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Targeted Therapies for Acute Leukemias

A special issue of Diseases (ISSN 2079-9721).

Deadline for manuscript submissions: closed (31 May 2025) | Viewed by 2884

Special Issue Editor

Dr. Eleftheria Hatzimichael

E-Mail Website
Guest Editor
Department of Hematology, Faculty of Medicine, University of Ioannina, Stavros Niarchos Avenue, 45110 Ioannina, Greece
Interests: acute leukemia; myelodysplastic syndromes; chronic lymphocytic leukemia; lymphomas; multiple myeloma; clinical trials; biomarkers

Special Issue Information

Dear Colleagues,

Targeted therapies aim to interfere with the molecular pathways that drive the growth and survival of leukemia cells, while simultaneously mitigating any adverse effects on healthy cells. Several such agents have revolutionized treatment approaches and improved outcomes for many patients with acute leukemias. They have been used as single agents, in combination with conventional chemotherapy or stem cell transplantation to attain the most favorable results. Treatment choices are determined by various criteria, including the specific subtype of leukemia, genetic or molecular alterations, the age of the patient, and/or their previous responsiveness to therapeutic interventions.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Recent advances have significantly impacted treatment options. Targeted agents approved and commonly used in AML are gemtuzumab ozogamicin, FLT3 inhibitors, bcl-2 inhibitors, IDH1/2 inhibitors and Hedgehog pathway inhibitors, both in first line and the relapsed/refractory (R/R) setting.

Acute lymphoblastic leukemia (ALL) is the most common acute leukemia in children. The targeted agents used in B-ALL are tyrosine kinase inhibitors when Philadelphia-positive, rituximab, blinatumomab, inotuzumab ozogamicin and, most recently, chimeric antigen receptor (CAR)-T cell therapies, such as tisagenlecleucel and axicabtagene ciloleucel that have shown promising results in treating R/R disease.

Nevertheless, questions remain about optimal sequencing, effective combinations, maintenance therapy post-remission, especially in AML, and treatment options post-CAR-T cell therapy failure in ALL. Moreover, certain AML subtypes, such as those with TP53 mutations or KMT2A rearrangements, still need better solutions. This Special Issue focuses on known or developing targeted treatments in acute leukemias to provide clinicians a comprehensive perspective on not only established, but also new and innovative findings in the field.

Dr. Eleftheria Hatzimichael
Guest Editor

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Keywords

  • acute leukemia
  • acute myeloid leukemia
  • acute lymphoblastic leukemia
  • bi-specific antibodies
  • FLT3 inhibitors
  • bcl-2 inhibitors
  • IDH1/2 inhibitors
  • hedgehog pathway inhibitors
  • CAR-T cell therapy

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Published Papers (2 papers)

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13 pages, 3163 KiB  
Article
Valproic Acid Enhances Venetoclax Efficacy in Targeting Acute Myeloid Leukemia
by Renshi Kawakatsu, Kenjiro Tadagaki, Kenta Yamasaki, Yasumichi Kuwahara and Tatsushi Yoshida
Diseases 2025, 13(1), 10; https://doi.org/10.3390/diseases13010010 - 8 Jan 2025
Cited by 1 | Viewed by 1403
Abstract
Background: Acute myeloid leukemia (AML) is a common and aggressive form of leukemia, yet current treatment strategies remain insufficient. Venetoclax, a BH3-mimetic approved for AML treatment, induces Bcl-2-dependent apoptosis, though its therapeutic efficacy is still limited. Therefore, new strategies to enhance the effect [...] Read more.
Background: Acute myeloid leukemia (AML) is a common and aggressive form of leukemia, yet current treatment strategies remain insufficient. Venetoclax, a BH3-mimetic approved for AML treatment, induces Bcl-2-dependent apoptosis, though its therapeutic efficacy is still limited. Therefore, new strategies to enhance the effect of venetoclax are highly sought. Valproic acid (VPA), commonly used for epilepsy, has also been studied for potential applications in AML treatment. Methods: AML cells were treated with venetoclax, with or without VPA. Cell viability was assessed using the trypan blue dye exclusion assay, while cell cycle progression was analyzed by flow cytometry. The expression of pro-apoptotic proteins Bax and Bak was measured by RT-qPCR. Results: Venetoclax and VPA individually had only mild effects on AML cell proliferation. However, their combination significantly inhibited cell growth and triggered pronounced cell death. This combination also led to the cleavage of poly (ADP-ribose) polymerase (PARP), a substrate of caspases, indicating activation of apoptosis. VPA treatment upregulated the expression of Bax and Bak, further supporting apoptosis induction. The cell death induced by the venetoclax–VPA combination was predominantly apoptotic, as confirmed by the near-complete blockade of cell death by a pan-caspase inhibitor. Conclusions: Our study demonstrates that VPA enhances venetoclax-induced apoptosis in AML cell lines, providing a novel role for VPA and suggesting a promising combinatory strategy for AML treatment. These findings offer valuable insights into potential clinical applications of venetoclax and VPA in AML management. Full article
(This article belongs to the Special Issue Targeted Therapies for Acute Leukemias)
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Review

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15 pages, 427 KiB  
Review
Therapeutic Implications of Menin Inhibitors in the Treatment of Acute Leukemia: A Critical Review
by Martina Canichella, Cristina Papayannidis, Carla Mazzone and Paolo de Fabritiis
Diseases 2025, 13(7), 227; https://doi.org/10.3390/diseases13070227 - 19 Jul 2025
Viewed by 270
Abstract
Menin inhibitors are a class of targeted agents that exemplify how a deeper understanding of leukemia pathogenesis can unify seemingly distinct genetic acute leukemia subgroups under a common therapeutic strategy. In particular, acute leukemia with NPM1 mutations (NPM1m) and KMT2A rearrangements ( [...] Read more.
Menin inhibitors are a class of targeted agents that exemplify how a deeper understanding of leukemia pathogenesis can unify seemingly distinct genetic acute leukemia subgroups under a common therapeutic strategy. In particular, acute leukemia with NPM1 mutations (NPM1m) and KMT2A rearrangements (KMT2Ar) represent the primary targets of this emerging drug class. Acute myeloid leukemia (AML) with NPM1m—which accounts for approximately 30% of AML cases and AML or acute lymphoblastic leukemia (ALL) with KMT2Ar—and is present in 5–10% of cases, shares a common pathogenetic mechanism: the aberrant activation of the MEIS1–HOXA axis. These leukemic subsets are associated with poor prognosis, particularly in the relapsed/refractory (R/R) setting. For KMT2Ar AML, the prognosis is especially dismal, with a median overall survival (OS) of 2.4 months and a complete remission (CR) rate of only 5%. In NPM1m AML, intensive chemotherapy achieves remission in approximately 80% of cases, but relapse remains a major challenge, occurring in nearly 50% of patients. Relapsed NPM1m AML is linked to a poor prognosis, with a median OS of 6.1 months (12-month OS: 30%) and a median relapse-free survival (RFS) of 5.5 months (12-month RFS: 34%). Menin inhibitors directly target the leukemogenic transcriptional program driven by HOX and MEIS1, disrupting oncogenic signaling and offering a promising therapeutic approach for these high-risk patients. This class of agents has rapidly progressed through clinical development, showing promising antileukemic activity in both treatment-naïve and R/R AML. Currently, six menin inhibitors are in clinical evaluation as monotherapy or in combination regimens: revumenib, ziftomenib, bleximenib (previously JNJ-75276617), enzomenib (previously DSP-5336), DS-1594, and BMF-219. In this review, we critically analyze the clinical development and therapeutic potential of the four most extensively studied menin inhibitors—revumenib, ziftomenib, bleximenib, and enzomenib. We discuss their efficacy, safety profiles, and potential roles within the current treatment algorithm. The continued clinical evaluation of menin inhibitors may redefine treatment paradigms for NPM1m and KMT2Ar AML and other acute leukemia with the aberrant MEIS1-HOXA axis, offering new hope for patients with limited therapeutic options. Full article
(This article belongs to the Special Issue Targeted Therapies for Acute Leukemias)
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