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Lymphomas: Current Approaches and Future Perspectives towards More Personalized Treatments
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Lymphomas: Current Approaches and Future Perspectives towards More Personalized Treatments

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

Deadline for manuscript submissions: closed (25 June 2023) | Viewed by 15913

Special Issue Editors

Dr. Afua Adjeiwaa Mensah

E-Mail Website
Guest Editor
Institute of Oncology Research, Faculty of Biomedical Sciences, USI, 6500 Bellinzona, Switzerland
Interests: lymphoma; lymphoma genomics; epigenetics; diffuse large B-cell lymphoma; marginal zone lymphoma; histone deacetylase inhibitors; anti-lymphoma agents; pre-clinical studies
Special Issues, Collections and Topics in MDPI journals
Dr. Patrizia Mondello

E-Mail Website
Guest Editor
Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA
Interests: epigenetics; genomics; intracellular signaling; immunotherapy; lymphoma; diffuse large B cell lymphoma; follicular lymphoma; tumor microenvironment; germinal center research; precision therapy

Special Issue Information

Dear Colleagues,

Lymphomas are one of the most prevalent types of cancer and the most frequently occurring of all hematological tumors. Physiologically, the regulation of lymphoid cell differentiation is governed by finely tuned networks of signaling proteins, epigenetic enzymes and transcription factors. The combined action of these different molecules enables the rapid and timely regulation of specific genes during different stages of lymphocyte development. As revealed by large sequencing efforts, many of the proteins involved in these processes are targets of genetic and structural aberrations in lymphomas. Individual aberrations as well as sets of recurrently aberrant genes are characteristic of certain lymphomas and can distinguish specific subtypes of lymphomas with different clinical outcomes and therapeutic responses. Additionally, mechanisms that reduce antitumor immunity including loss of major histocompatibility complex expression, and amplifications and rearrangements of immune checkpoint genes are also frequently observed in lymphomas. Targeted agents against lymphoma-associated proteins and immunotherapies such as antibody–drug conjugates, checkpoint inhibitors and CAR-T cells are currently the focus of efforts towards pharmacological approaches tailored to individual patients’ lymphoma molecular subtype. It is likely that combination or sequential approaches comprising these two classes of agents will lead to more durable responses in more patients than either class alone. This Special Issue of the Journal of Clinical Medicine is focused on current approaches and future perspectives towards more personalized treatments for lymphomas, with the aim of bringing together novel research findings and recent advances in this rapidly developing field.

We warmly invite you to submit an original research paper or review article to this Special Issue.

Dr. Afua Adjeiwaa Mensah
Dr. Patrizia Mondello
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. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly 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

  • lymphoma
  • diffuse large B-cell lymphoma
  • follicular lymphoma
  • genomics
  • lymphoma molecular subtypes
  • targeted therapy
  • precision therapy
  • immunotherapy
  • novel anti-lymphoma drugs
  • preclinical testing
  • combination treatments

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Published Papers (7 papers)

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Editorial

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5 pages, 183 KiB  
Editorial
Harnessing the Molecular Fingerprints of B Cell Lymphoma for Precision Therapy
by Afua Adjeiwaa Mensah and Patrizia Mondello
J. Clin. Med. 2022, 11(19), 5834; https://doi.org/10.3390/jcm11195834 - 1 Oct 2022
Viewed by 1589
Abstract
The last two decades have brought ground-breaking advances in genetics, culminating in deep profiling of the human genome and high resolution detection of genetic variants [...] Full article
(This article belongs to the Special Issue Lymphomas: Current Approaches and Future Perspectives towards More Personalized Treatments)

Research

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9 pages, 1075 KiB  
Article
Efficacy of Residual Site Radiation Therapy (ISRT) in Patients with Primary Mediastinal Lymphoma with Deauville Score 4 Following R-CHT: Results of a Retrospective Mono Institutional Study
by Giuseppe Facondo, Mattia Serio, Gianluca Vullo, Maria Paola Bianchi, Sabrina Pelliccia, Alice Di Rocco, Tiziana Lanzolla, Maurizio Valeriani, Arianna Di Napoli, Agostino Tafuri, Maurizio Martelli, Mattia Falchetto Osti and Vitaliana De Sanctis
J. Clin. Med. 2023, 12(11), 3777; https://doi.org/10.3390/jcm12113777 - 31 May 2023
Viewed by 1813
Abstract
Background: In order to evaluate the efficacy of residual site radiation therapy (RSRT) in terms of progression-free survival (PFS) and overall survival (OS) in patients with primary mediastinal lymphoma (PMBCL) with Deauville Score 4 (DS 4) following rituximab and chemotherapy treatment (R-ICHT). Methods: [...] Read more.
Background: In order to evaluate the efficacy of residual site radiation therapy (RSRT) in terms of progression-free survival (PFS) and overall survival (OS) in patients with primary mediastinal lymphoma (PMBCL) with Deauville Score 4 (DS 4) following rituximab and chemotherapy treatment (R-ICHT). Methods: Thirty-one patients with PMBCL were recruited. After completion of R-ICHT, patients were staged with 18F-fluorodeoxyglucose positron-emission tomography, showing DS 4, and were treated with adjuvant RSRT. The chosen techniques for RT delivery were intensity-modulated radiation therapy (IMRT) or three-dimensional conformal RT (3D-CRT). Most patients underwent the first one using cone-beam computed tomography (CBCT). All patients were evaluated every 3 months for the first 2 years and every 6 months afterwards for a period of at least 5 years, with clinical and radiological procedures as required. Results: All patients received RSRT with a dose of 30 Gy in 15 fractions. The median follow-up time of 52.7 months (IQR: 26–64.1 months). The 5-year OS rate was 100%. The 2-year and 5-year PFS rates were 96.7% and 92.5%, respectively. Patients with relapsed disease had been treated with high-dose chemotherapy (HDC) and autologous stem cell transplantation (auto-SCT). Conclusion: RSRT in patients with PMBCL treated with ICHT and DS 4 did not impact unfavorably on patient survival. Full article
(This article belongs to the Special Issue Lymphomas: Current Approaches and Future Perspectives towards More Personalized Treatments)
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12 pages, 683 KiB  
Article
BeEAM Conditioning including High-Dose Bendamustine before Autologous Stem Cell Transplantation Is Safe and Effective in Patients with Waldenstrom’s Macroglobulinemia
by Alexander D. Heini, Philipp Beck, Ulrike Bacher, Katja Seipel, Thilo Zander, Michael Daskalakis and Thomas Pabst
J. Clin. Med. 2023, 12(6), 2378; https://doi.org/10.3390/jcm12062378 - 19 Mar 2023
Cited by 1 | Viewed by 1596
Abstract
High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) is an option to consolidate remission in Waldenstrom’s macroglobulinemia (WM), particularly in selected younger patients with chemosensitive disease. BEAM, consisting of BCNU, etoposide, cytarabine, and melphalan, is often used as a conditioning regimen. However, [...] Read more.
High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) is an option to consolidate remission in Waldenstrom’s macroglobulinemia (WM), particularly in selected younger patients with chemosensitive disease. BEAM, consisting of BCNU, etoposide, cytarabine, and melphalan, is often used as a conditioning regimen. However, problems with BCNU, including pneumotoxicity, tolerance, and availability, necessitate the search for alternatives. In this pilot study, we investigated high-dose chemotherapy with BeEAM, in which BCNU is replaced with high-dose bendamustine as an alternative conditioning regimen in six subsequent patients with WM. Bendamustine treatment was well tolerated without unexpected toxicities. The overall response rate was 6/6 patients (2 very good partial responses (VGPR) and 4 PR). After a median follow-up of 72 months, two (33%) patients relapsed. Median progression-free and overall survivals were not reached, and no severe late-onset toxicities were observed so far. In this pilot study, BeEAM conditioning before ASCT seems feasible, safe, and effective in patients with WM. Full article
(This article belongs to the Special Issue Lymphomas: Current Approaches and Future Perspectives towards More Personalized Treatments)
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13 pages, 4363 KiB  
Article
Targeting IRAK4 with Emavusertib in Lymphoma Models with Secondary Resistance to PI3K and BTK Inhibitors
by Francesca Guidetti, Alberto J. Arribas, Giulio Sartori, Filippo Spriano, Laura Barnabei, Chiara Tarantelli, Reinhard Von Roemeling, Elizabeth Martinez, Emanuele Zucca and Francesco Bertoni
J. Clin. Med. 2023, 12(2), 399; https://doi.org/10.3390/jcm12020399 - 4 Jan 2023
Cited by 9 | Viewed by 3662
Abstract
Inhibitors of phosphatidylinositol 3-kinase (PI3K) and Bruton tyrosine kinase (BTK) represent a recognized option for the treatment of patients affected by indolent B cell lymphomas. However, small molecules as single agents show limited success in their ability in inducing complete responses, with only [...] Read more.
Inhibitors of phosphatidylinositol 3-kinase (PI3K) and Bruton tyrosine kinase (BTK) represent a recognized option for the treatment of patients affected by indolent B cell lymphomas. However, small molecules as single agents show limited success in their ability in inducing complete responses, with only partial remission achieved in most patients, suggesting the need for combination therapies. IRAK4 is a protein kinase downstream of the Toll-like receptor signaling (TLR), a driver pathway of secondary tumor° resistance in both hematological and solid tumor malignancies. Activation of IRAK4 upon TLRs and IL-1 receptor (IL-1R) stimulation and through the adaptor protein MYD88 initiates a signaling cascade that induces cytokine and survival factor expression mediated by the transcription factor NF-κB. MYD88-L265P encoding mutations occur in diffuse large B-cell lymphomas, in lymphoplasmacytic lymphomas and in few marginal zone lymphomas (MZL). The IRAK4 inhibitor emavusertib (CA-4948) has shown early safety and clinical activity in lymphoma and leukemia patients. In this preclinical study, we assessed emavusertib effectiveness in MZL, both as single agent and in combination with targeted agents, with a particular focus on its capability to overcome resistance to BTK and PI3K inhibitors. We showed that the presence of MYD88 L265P mutation in bona fide MZL cell lines confers sensitivity to the IRAK4 inhibitor emavusertib as single agent. Emavusertib-based combinations improved the sensitivity of MZL cells to BTK and PI3K inhibitors, including cells with a secondary resistance to these agents. Emavusertib exerted its activity via inhibition of NF-κB signaling and induction of apoptosis. Considering the early safety data from clinical trials, our study identifies the IRAK4 inhibitor emavusertib as a novel compound to be explored in trials for patients with MYD88-mutated indolent B cell lymphomas as single agent and as combination partner with BTK or PI3K inhibitors in unselected populations of patients. Full article
(This article belongs to the Special Issue Lymphomas: Current Approaches and Future Perspectives towards More Personalized Treatments)
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12 pages, 432 KiB  
Article
Combining BeEAM with Brentuximab Vedotin for High-Dose Therapy in CD30 Positive Lymphomas before Autologous Transplantation—A Phase I Study
by Christian Rausch, Ulrike Bacher, Manuela Rabaglio, Corinne Vorburger, Anke Klingenberg, Yara Banz, Michael Daskalakis and Thomas Pabst
J. Clin. Med. 2022, 11(18), 5378; https://doi.org/10.3390/jcm11185378 - 13 Sep 2022
Cited by 1 | Viewed by 1607
Abstract
The prognosis for patients with CD30+ lymphomas (Hodgkin lymphoma and various T-cell lymphomas) relapsing after autologous stem cell transplantation (ASCT) is critical. Brentuximab vedotin (BV), an ADC targeting CD30, is an obvious candidate for inclusion into high-dose chemotherapy (HDCT) regimens to improve outcomes. [...] Read more.
The prognosis for patients with CD30+ lymphomas (Hodgkin lymphoma and various T-cell lymphomas) relapsing after autologous stem cell transplantation (ASCT) is critical. Brentuximab vedotin (BV), an ADC targeting CD30, is an obvious candidate for inclusion into high-dose chemotherapy (HDCT) regimens to improve outcomes. This single center phase I trial investigated 12 patients with CD30+ lymphoma (AITL: n = 5; relapsed HL: n = 7; median of two previous treatment lines) undergoing ASCT. In a 3 + 3 dose escalation design, 12 patients received a single BV dose at three dose levels (DL) (0.9/1.2/1.8 mg/kg b.w.) prior to standard BeEAM. All patients were treated as planned; no dose limiting toxicities (DLTs) occurred at DL 1 and 2. At DL 3, one DLT (paralytic ileus, fully recovering) occurred. Grade III febrile neutropenia occurred in one patient, and two others had septic complications, all fully recovering. Median hospitalization was 23 days. Hematologic recovery was normal. Six of twelve (50%) patients achieved CR. PFS and OS at 1 year were 67% (n = 8/12) and 83% (n = 10/12), respectively. The addition of brentuximab to standard BeEAM HDCT seems to be safe. We observed a CR rate of 75% post-ASCT in a highly pretreated population. The efficacy of this novel HDCT combination with BV at a 1.8 mg/kg dose level needs to be explored in larger studies. Full article
(This article belongs to the Special Issue Lymphomas: Current Approaches and Future Perspectives towards More Personalized Treatments)
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16 pages, 2469 KiB  
Article
Targeting CD38 with Daratumumab Plus Chemotherapy for Patients with Advanced-Stage Plasmablastoid Large B-Cell Lymphoma
by Yun Kyoung Ryu, Edd C. Ricker, Craig R. Soderquist, Mark A. Francescone, Andrew H. Lipsky and Jennifer E. Amengual
J. Clin. Med. 2022, 11(16), 4928; https://doi.org/10.3390/jcm11164928 - 22 Aug 2022
Cited by 6 | Viewed by 2533
Abstract
Plasmablastic lymphoma (PBL) is a rare and aggressive form of large B-cell lymphoma (LBCL) most commonly seen in the setting of chronic immunosuppression or autoimmune disease. The prognosis is poor and CHOP-like regimens often fail to produce durable remission; therefore, there is no [...] Read more.
Plasmablastic lymphoma (PBL) is a rare and aggressive form of large B-cell lymphoma (LBCL) most commonly seen in the setting of chronic immunosuppression or autoimmune disease. The prognosis is poor and CHOP-like regimens often fail to produce durable remission; therefore, there is no established standard of care treatment. However, PBL demonstrates substantial morphologic and immunophenotypic overlap with multiple myeloma (MM), suggesting that MM therapeutics might prove useful in treating PBL. We studied the effects of treatment using the first-in-class monoclonal antibody directed against CD38, daratumumab, in combination with chemotherapy in seven patients with advanced-stage LBCL with plasmablastic features. Treatment was safe and well-tolerated. Among six evaluable patients, six patients had complete response after treatment, and four patients who met strict WHO criteria for PBL had durable response (12–31 months and ongoing). Full article
(This article belongs to the Special Issue Lymphomas: Current Approaches and Future Perspectives towards More Personalized Treatments)
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Review

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13 pages, 2201 KiB  
Review
T-Cell Engaging Antibodies in Diffuse Large B Cell Lymphoma—An Update
by Shalini Balendran, Constantine Tam and Matthew Ku
J. Clin. Med. 2023, 12(21), 6737; https://doi.org/10.3390/jcm12216737 - 25 Oct 2023
Cited by 2 | Viewed by 2208
Abstract
Novel cellular immunotherapies such as T-cell engaging antibodies (TCEAbs) are changing the landscape of treatment for diffuse large B cell lymphoma (DLBCL), especially in the relapsed/refractory (R/R) setting. TCEAbs harness the power of the host immune system to induce killing of tumor cells [...] Read more.
Novel cellular immunotherapies such as T-cell engaging antibodies (TCEAbs) are changing the landscape of treatment for diffuse large B cell lymphoma (DLBCL), especially in the relapsed/refractory (R/R) setting. TCEAbs harness the power of the host immune system to induce killing of tumor cells by binding to both the tumor antigen and the T-cell receptor. Since the approval of blinatumomab for R/R acute lymphoblastic leukemia, there has been significant development in novel TCEAbs. Many of these novel TCEAbs have shown promising effectiveness in R/R DLBCL, with favorable response rates including complete remissions, even in heavily pretreated patients. There are unique therapy-related toxicities with TCEAbs, namely cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS), and it is important to both recognize and manage these side effects appropriately. This review examines the development and mechanism of action of these TCEAbs, and the available published data from clinical trials. Their role in the treatment of DLBCL, the management of therapy-related adverse events, and the mechanisms of resistance will also be discussed. Full article
(This article belongs to the Special Issue Lymphomas: Current Approaches and Future Perspectives towards More Personalized Treatments)
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