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IJMS
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Pathophysiology to Novel Therapeutic Approaches for Leukemia
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Pathophysiology to Novel Therapeutic Approaches for Leukemia

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 30 May 2024 | Viewed by 6873

Special Issue Editor

Dr. Mauro Di Ianni

E-Mail Website
Guest Editor
Department of Medicine and Sciences of Aging, University of Chieti-Pescara, 66100 Chieti, Italy
Interests: bone marrow transplantation; cellular therapy; acute leukemia; immunotherapy; GvHD/GvL

Special Issue Information

Dear Colleagues,

This Special Issue on “Pathophysiology to Novel Therapeutic Approaches for Leukemia” of the International Journal of Molecular Sciences will analyze what the possible drivers are at the basis of leukemic transformation and the innovative therapeutic strategies for acute myeloid and lymphoblastic leukemia. Advanced cell therapies that target leukemic antigen and innovative bone marrow transplantation platforms will also be explored.

The submission of original research and review articles on pathophysiology to novel therapeutic approaches for leukemia is welcomed. Since IJMS is a journal of molecular science, pure clinical or model studies will unfortunately not be suitable for this journal. However, clinical or pure model submissions which incorporate biomolecular experiments are welcomed.

The topics of this Special Issue include, but are not limited to:

  • Pathophysiology for acute leukemia;
  • Novel therapeutic approaches for leukemia;
  • Advanced cell therapy for acute leukemia;
  • Innovative allogeneic stem cell transplantation platforms.

Dr. Mauro Di Ianni
Guest Editor

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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 myeloid leukemia
  • acute lymphoblastic leukemia
  • molecular pathophysiology
  • new therapeutic approaches
  • immunotherapy
  • cellular therapy
  • allogenic bone marrow transplantation

Published Papers (5 papers)

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Research

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20 pages, 7472 KiB  
Article
CAD204520 Targets NOTCH1 PEST Domain Mutations in Lymphoproliferative Disorders
by Luca Pagliaro, Elisa Cerretani, Federica Vento, Anna Montanaro, Lucas Moron Dalla Tor, Elisa Simoncini, Mariateresa Giaimo, Andrea Gherli, Raffaella Zamponi, Isotta Tartaglione, Bruno Lorusso, Matteo Scita, Filomena Russo, Gabriella Sammarelli, Giannalisa Todaro, Enrico Maria Silini, Gian Matteo Rigolin, Federico Quaini, Antonio Cuneo and Giovanni Roti
Int. J. Mol. Sci. 2024, 25(2), 766; https://doi.org/10.3390/ijms25020766 - 7 Jan 2024
Viewed by 1206
Abstract
NOTCH1 PEST domain mutations are often seen in hematopoietic malignancies, including T-cell acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). These mutations play a key role in the [...] Read more.
NOTCH1 PEST domain mutations are often seen in hematopoietic malignancies, including T-cell acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). These mutations play a key role in the development and progression of lymphoproliferative tumors by increasing the Notch signaling and, consequently, promoting cell proliferation, survival, migration, and suppressing apoptosis. There is currently no specific treatment available for cancers caused by NOTCH1 PEST domain mutations. However, several NOTCH1 inhibitors are in development. Among these, inhibition of the Sarco-endoplasmic Ca2+-ATPase (SERCA) showed a greater effect in NOTCH1-mutated tumors compared to the wild-type ones. One example is CAD204520, a benzimidazole derivative active in T-ALL cells harboring NOTCH1 mutations. In this study, we preclinically assessed the effect of CAD204520 in CLL and MCL models and showed that NOTCH1 PEST domain mutations sensitize cells to the anti-leukemic activity mediated by CAD204520. Additionally, we tested the potential of CAD204520 in combination with the current first-line treatment of CLL, venetoclax, and ibrutinib. CAD204520 enhanced the synergistic effect of this treatment regimen only in samples harboring the NOTCH1 PEST domain mutations, thus supporting a role for Notch inhibition in these tumors. In summary, our work provides strong support for the development of CAD204520 as a novel therapeutic approach also in chronic lymphoproliferative disorders carrying NOTCH1 PEST domain mutations, emerging as a promising molecule for combination treatment in this aggressive subset of patients. Full article
(This article belongs to the Special Issue Pathophysiology to Novel Therapeutic Approaches for Leukemia)
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10 pages, 1434 KiB  
Communication
Blinatumomab Redirects Donor Lymphocytes against CD19+ Acute Lymphoblastic Leukemia without Relevant Bystander Alloreactivity after Haploidentical Hematopoietic Stem Cell Transplantation
by Antonella Mancusi, Francesco Zorutti, Loredana Ruggeri, Samanta Bonato, Sara Tricarico, Tiziana Zei, Roberta Iacucci Ostini, Valerio Viglione, Rebecca Sembenico, Sofia Sciabolacci, Valeria Cardinali, Massimo Fabrizio Martelli, Cristina Mecucci, Alessandra Carotti, Maria Paola Martelli, Andrea Velardi and Antonio Pierini
Int. J. Mol. Sci. 2023, 24(22), 16105; https://doi.org/10.3390/ijms242216105 - 9 Nov 2023
Viewed by 1029
Abstract
Blinatumomab alone or with donor leukocyte infusions (DLI) has been used after allogeneic hematopoietic stem cell transplantation (HSCT) as a salvage therapy in relapsing patients with CD19+ hematological malignancies. It was effective in a fraction of them, with low incidence of Graft-versus-Host [...] Read more.
Blinatumomab alone or with donor leukocyte infusions (DLI) has been used after allogeneic hematopoietic stem cell transplantation (HSCT) as a salvage therapy in relapsing patients with CD19+ hematological malignancies. It was effective in a fraction of them, with low incidence of Graft-versus-Host Disease (GvHD). Immunosuppressive drugs used as GvHD prophylaxis hinder T cell function and reduce the efficacy of the treatment. Because T cell-depleted haploidentical HSCT with donor regulatory and conventional T cells (Treg/Tcon haploidentical HSCT) does not require post-transplant immunosuppression, it is an ideal platform for the concomitant use of blinatumomab and DLI. However, the risk of GvHD is high because the donor is haploidentical. We treated two patients with CD19+ acute lymphoblastic leukemia (ALL) who had relapsed after Treg/Tcon haploidentical HSCT with blinatumomab and DLI. Despite the mismatch for one HLA haplotype, they did not develop GvHD and achieved complete remission with negative minimal residual disease. Consistently, we found that blinatumomab did not enhance T cell alloreactivity in vitro. Eventually, the two patients relapsed again because of their high disease risk. This study suggests that treatment with blinatumomab and DLI can be feasible to treat relapse after haploidentical transplantation, and its pre-emptive use should be considered to improve efficacy. Full article
(This article belongs to the Special Issue Pathophysiology to Novel Therapeutic Approaches for Leukemia)
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Review

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14 pages, 584 KiB  
Review
Venetoclax and Hypomethylating Agent Combination in Myeloid Malignancies: Mechanisms of Synergy and Challenges of Resistance
by Rahul Mishra, Maedeh Zokaei Nikoo, Sindhusha Veeraballi and Abhay Singh
Int. J. Mol. Sci. 2024, 25(1), 484; https://doi.org/10.3390/ijms25010484 - 29 Dec 2023
Viewed by 1193
Abstract
There has been a widespread adoption of hypomethylating agents (HMA: 5-Azacytidine (5-Aza)/decitabine) and venetoclax (Ven) for the treatment of acute myeloid leukemia (AML); however, the mechanisms behind the combination’s synergy are poorly understood. Monotherapy often encounters resistance, leading to suboptimal outcomes; however, the [...] Read more.
There has been a widespread adoption of hypomethylating agents (HMA: 5-Azacytidine (5-Aza)/decitabine) and venetoclax (Ven) for the treatment of acute myeloid leukemia (AML); however, the mechanisms behind the combination’s synergy are poorly understood. Monotherapy often encounters resistance, leading to suboptimal outcomes; however, the combination of HMA and Ven has demonstrated substantial improvements in treatment responses. This study elucidates multiple synergistic pathways contributing to this enhanced therapeutic effect. Key mechanisms include HMA-mediated downregulation of anti-apoptotic proteins, notably MCL-1, and the priming of cells for Ven through the induction of genes encoding pro-apoptotic proteins such as Noxa. Moreover, Ven induces sensitization to HMA, induces overcoming resistance by inhibiting the DHODH enzyme, and disrupts antioxidant pathways (Nrf2) induced by HMA. The combination further disrupts oxidative phosphorylation in leukemia stem cells, amplifying the therapeutic impact. Remarkably, clinical studies have revealed a favorable response, particularly in patients harboring specific mutations, such as IDH1/2, NPM1, CEBPA, or ASXL1. This prompts future studies to explore the nuanced underpinnings of these synergistic mechanisms in AML patients with these molecular signatures. Full article
(This article belongs to the Special Issue Pathophysiology to Novel Therapeutic Approaches for Leukemia)
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19 pages, 673 KiB  
Review
Novel Approaches to Treatment of Acute Myeloid Leukemia Relapse Post Allogeneic Stem Cell Transplantation
by Carmine Liberatore and Mauro Di Ianni
Int. J. Mol. Sci. 2023, 24(19), 15019; https://doi.org/10.3390/ijms241915019 - 9 Oct 2023
Cited by 2 | Viewed by 2087
Abstract
The management of patients with acute myeloid leukemia (AML) relapsed post allogeneic hematopoietic stem cell transplantation (HSCT) remains a clinical challenge. Intensive treatment approaches are limited by severe toxicities in the early post-transplantation period. Therefore, hypomethylating agents (HMAs) have become the standard therapeutic [...] Read more.
The management of patients with acute myeloid leukemia (AML) relapsed post allogeneic hematopoietic stem cell transplantation (HSCT) remains a clinical challenge. Intensive treatment approaches are limited by severe toxicities in the early post-transplantation period. Therefore, hypomethylating agents (HMAs) have become the standard therapeutic approach due to favorable tolerability. Moreover, HMAs serve as a backbone for additional anti-leukemic agents. Despite discordant results, the addition of donor lymphocytes infusions (DLI) generally granted improved outcomes with manageable GvHD incidence. The recent introduction of novel targeted drugs in AML gives the opportunity to add a third element to salvage regimens. Those patients harboring targetable mutations might benefit from IDH1/2 inhibitors Ivosidenib and Enasidenib as well as FLT3 inhibitors Sorafenib and Gilteritinib in combination with HMA and DLI. Conversely, patients lacking targetable mutations actually benefit from the addition of Venetoclax. A second HSCT remains a valid option, especially for fit patients and for those who achieve a complete disease response with salvage regimens. Overall, across studies, higher response rates and longer survival were observed in cases of pre-emptive intervention for molecular relapse. Future perspectives currently rely on the development of adoptive immunotherapeutic strategies mainly represented by CAR-T cells. Full article
(This article belongs to the Special Issue Pathophysiology to Novel Therapeutic Approaches for Leukemia)
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Other

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9 pages, 828 KiB  
Case Report
Clofarabine Preconditioning followed by Allogeneic Transplant Using TBI and Post-Transplant Cyclophosphamide for Relapsed Refractory Leukemia
by Seema Naik, Kevin Rakszawski, Hong Zheng, David Claxton, Kentaro Minagawa and Shin Mineishi
Int. J. Mol. Sci. 2024, 25(2), 957; https://doi.org/10.3390/ijms25020957 - 12 Jan 2024
Viewed by 818
Abstract
Acute myeloid leukemia patients with induction failure or relapsed refractory disease have minimal chance of achieving remission with subsequent treatments. Several trials have shown the feasibility of clofarabine-based conditioning in allogeneic stem cell transplants (allo-HSCT) for non-remission AML patients. Pre-transplant conditioning with clofarabine [...] Read more.
Acute myeloid leukemia patients with induction failure or relapsed refractory disease have minimal chance of achieving remission with subsequent treatments. Several trials have shown the feasibility of clofarabine-based conditioning in allogeneic stem cell transplants (allo-HSCT) for non-remission AML patients. Pre-transplant conditioning with clofarabine followed by reduced-intensity allo-HSCT has also demonstrated a potential benefit in those patients with human leukocyte antigen (HLA)-identical donors, but it is not commonly used in haploidentical and mismatched transplants. In this case report, we describe our experience of seven cases of non-remission AML who received clofarabine preconditioning followed by an allo-HSCT with PTCy. The 2-year overall survival and disease-free survival was 83.3% (95% confidence interval (CI): 27.3–97.9%) and 85.7% (95% CI: 33.4–97.9%). Median days of neutrophil and platelet recovery were 16 (range of 13–23) and 28 (range of 17–75), respectively. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) at day 100 and chronic GVHD at 1-year showed 28.6% (95% CI: 8–74.2%) and 28.6% (95% CI: 3–63.9%), respectively. The two-year relapse rate was 14.3% (95% CI: 2.14–66.6%). One-year GVHD-free relapse-free survival (GFRS) at 1-year was 71.4% (95% CI: 25.8–92%). Our patients showed successful outcomes with clofarabine preconditioning to reduce the leukemic burden at the pre-transplant period followed by PTCy to reduce GVHD resulting in lower relapsed rate and better GFRS in these patients. Full article
(This article belongs to the Special Issue Pathophysiology to Novel Therapeutic Approaches for Leukemia)
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