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Targeted Treatment of Lymphoma, Leukaemia and Myeloma
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Targeted Treatment of Lymphoma, Leukaemia and Myeloma

A special issue of Journal of Personalized Medicine (ISSN 2075-4426). This special issue belongs to the section "Methodology, Drug and Device Discovery".

Deadline for manuscript submissions: closed (20 July 2021) | Viewed by 58745

Special Issue Editor

Prof. Stephen Opat

E-Mail Website
Guest Editor
Department of Haematology, School of Clinical Sciences at Monash Health, Monash University, Wellington Rd, Clayton, VIC 3800, Australia
Interests: lymphoma; chronic lymphocytic leukaemia; lymphoma genomics; Gaucher disease; clinical research

Special Issue Information

Dear Collegues,

Our understanding of tumor biology has led to the development of several therapies targeting specific genes and proteins involved in the growth and survival of cancer cells. This transformation is most apparent in lymphoma, leukaemia and myeloma, where therapies targeting Bruton tyrosine kinase, phosphatidylinositol 3-kinase, B-cell lymphoma 2, the proteasome and the ubiquitin E3-ligase cereblon and are already in clinics.

The role of the immune system in tumor eradication has led to the development of second-generation CD20 antibodies, bi-specific antibodies and T-cell engagers, chimeric antigen receptor T-cells, and agents acting on key immune checkpoints such as programmed cell death protein 1 (PD1). Agents acting on DNA methylation or histone protein modification are also active in certain haemopoietic malignancies.

Several of these agents are superior to conventional chemoimmunotherapy although they are not without risk. Much of the current debate centers around sequencing of therapy, identification of rational combinations, the merits of fixed duration versus continuously administered therpay and long term toxicity. The answers to these questions likely to be determined when mature trial data is available.

This Special Issue will provide a comprehensive overview of current clinical research in lymphoma, leukaemia and myeloma with special reference to targeted therapies, including the utility of specific drugs/combinations and strategies in various clinical and biological subgroups.

Prof. Stephen Opat
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. Journal of Personalized Medicine 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

  • Lymphoma
  • Chronic lymphocytic leukemia
  • Acute lymphoblastic leukaemia
  • Myeloma
  • Bruton tyrosine kinase inhibitors
  • BCL2 inhibitors/BH3 mimetics
  • Phosphatidylinositol-3-kinase (PI-3 kinase) inhibitors
  • Monoclonal antibodies
  • Antibody-drug conjugates
  • Bispecific antibodies/bispecific T cell engagers
  • Selective inhibitors of nuclear export 
  • Chimeric antigen receptor T cells
  • Hypomethylating agents
  • Histone deacetylase inhibitors
  • Histone methyltransferase inhibitors
  • Immunomodulatory Agents

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Published Papers (11 papers)

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Editorial

Jump to: Review

3 pages, 194 KiB  
Editorial
Targeted Therapy in Leukaemia, Lymphoma and Myeloma
by Stephen Samuel Opat
J. Pers. Med. 2022, 12(1), 74; https://doi.org/10.3390/jpm12010074 - 8 Jan 2022
Cited by 1 | Viewed by 1393
Abstract
Historically, most advances in cancer therapy have been pioneered by clinicians managing the blood diseases [...] Full article
(This article belongs to the Special Issue Targeted Treatment of Lymphoma, Leukaemia and Myeloma)

Review

Jump to: Editorial

18 pages, 3106 KiB  
Review
Molecular Mechanisms of Cereblon-Interacting Small Molecules in Multiple Myeloma Therapy
by Matteo Costacurta, Jackson He, Philip E. Thompson and Jake Shortt
J. Pers. Med. 2021, 11(11), 1185; https://doi.org/10.3390/jpm11111185 - 11 Nov 2021
Cited by 12 | Viewed by 5900
Abstract
Thalidomide analogues (or immunomodulatory imide drugs, IMiDs) are cornerstones in the treatment of multiple myeloma (MM). These drugs bind Cereblon (CRBN), a receptor for the Cullin-ring 4 ubiquitin-ligase (CRL4) complex, to modify its substrate specificity. IMiDs mediate CRBN-dependent engagement and proteasomal degradation of [...] Read more.
Thalidomide analogues (or immunomodulatory imide drugs, IMiDs) are cornerstones in the treatment of multiple myeloma (MM). These drugs bind Cereblon (CRBN), a receptor for the Cullin-ring 4 ubiquitin-ligase (CRL4) complex, to modify its substrate specificity. IMiDs mediate CRBN-dependent engagement and proteasomal degradation of ‘neosubstrates’, Ikaros (IKZF1) and Aiolos (IKZF3), conveying concurrent antimyeloma activity and T-cell costimulation. There is now a greater understanding of physiological CRBN functions, including endogenous substrates and chaperone activity. CRISPR Cas9-based genome-wide screening has further elucidated the complex cellular machinery implicated in IMiD sensitivity, including IKZF1/3-independent mechanisms. New-generation IMiD derivatives with more potent anti-cancer properties—the CELMoDs (Cereblon E3 ligase modulators)—are now being evaluated. Rational drug design also allows ‘hijacking’ of CRL4CRBN utilising proteolysis targeting chimeras (PROTACs) to convey entirely distinct substrate repertoires. As all these chemotypes—thalidomide, IMiDs, CELMoDs and PROTACs—engage CRBN and modify its functions, we describe them here in aggregate as ‘CRBN-interacting small molecules’ (CISMs). In this review, we provide a contemporary summary of the biological consequences of CRBN modulation by CISMs. Detailed molecular insight into CRBN–CISM interactions now provides an opportunity to more effectively target previously elusive cancer dependencies, representing a new and powerful tool for the implementation of precision medicine. Full article
(This article belongs to the Special Issue Targeted Treatment of Lymphoma, Leukaemia and Myeloma)
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14 pages, 632 KiB  
Review
New Drugs Bringing New Challenges to AML: A Brief Review
by Zhi Han Yeoh, Ashish Bajel and Andrew H. Wei
J. Pers. Med. 2021, 11(10), 1003; https://doi.org/10.3390/jpm11101003 - 3 Oct 2021
Cited by 6 | Viewed by 3030
Abstract
The better understanding of the genomic landscape in acute myeloid leukaemia (AML) has progressively paved the way for precision medicine in AML. There is a growing number of drugs with novel mechanisms of action and unique side-effect profiles. This review examines the impact [...] Read more.
The better understanding of the genomic landscape in acute myeloid leukaemia (AML) has progressively paved the way for precision medicine in AML. There is a growing number of drugs with novel mechanisms of action and unique side-effect profiles. This review examines the impact of evolving novel therapies on survival in AML and the challenges that ensue. Full article
(This article belongs to the Special Issue Targeted Treatment of Lymphoma, Leukaemia and Myeloma)
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12 pages, 1188 KiB  
Review
Non-Covalent BTK Inhibitors—The New BTKids on the Block for B-Cell Malignancies
by Katharine L Lewis and Chan Y Cheah
J. Pers. Med. 2021, 11(8), 764; https://doi.org/10.3390/jpm11080764 - 3 Aug 2021
Cited by 39 | Viewed by 7414
Abstract
The B-cell receptor signalling pathway plays a critical role in development of B-cell malignancies, and the central role of Bruton’s tyrosine kinase (BTK) activation in this pathway provides compelling rationale for BTK inhibition as a therapeutic strategy for these conditions. Covalent BTK inhibitors [...] Read more.
The B-cell receptor signalling pathway plays a critical role in development of B-cell malignancies, and the central role of Bruton’s tyrosine kinase (BTK) activation in this pathway provides compelling rationale for BTK inhibition as a therapeutic strategy for these conditions. Covalent BTK inhibitors (BTKi) have transformed the treatment landscape of B-cell malignancies, but adverse events and treatment resistance have emerged as therapeutic challenges, with the majority of patients eventually discontinuing treatment due to toxicity or disease progression. Non-covalent BTKi have alternative mechanisms of binding to BTK than covalent BTKi, and therefore offer a therapeutic alternative for patients with B-cell malignancies, including those who have been intolerant to, or experienced disease progression during treatment with a covalent BTKi. Here, we summarise the clinical data, adverse events and mechanisms of resistance observed with covalent BTKi and describe the emerging data for non-covalent BTKi as a novel treatment for B-cell malignancies. Full article
(This article belongs to the Special Issue Targeted Treatment of Lymphoma, Leukaemia and Myeloma)
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24 pages, 741 KiB  
Review
Targeted Therapy in Acute Lymphoblastic Leukaemia
by Ross Salvaris and Pasquale Luke Fedele
J. Pers. Med. 2021, 11(8), 715; https://doi.org/10.3390/jpm11080715 - 25 Jul 2021
Cited by 13 | Viewed by 5124
Abstract
The last decade has seen a significant leap in our understanding of the wide range of genetic lesions underpinning acute lymphoblastic leukaemia (ALL). Next generation sequencing has led to the identification of driver mutations with significant implications on prognosis and has defined entities [...] Read more.
The last decade has seen a significant leap in our understanding of the wide range of genetic lesions underpinning acute lymphoblastic leukaemia (ALL). Next generation sequencing has led to the identification of driver mutations with significant implications on prognosis and has defined entities such as BCR-ABL-like ALL, where targeted therapies such as tyrosine kinase inhibitors (TKIs) and JAK inhibitors may play a role in its treatment. In Philadelphia positive ALL, the introduction of TKIs into frontline treatment regimens has already transformed patient outcomes. In B-ALL, agents targeting surface receptors CD19, CD20 and CD22, including monoclonal antibodies, bispecific T cell engagers, antibody drug conjugates and chimeric antigen receptor (CAR) T cells, have shown significant activity but come with unique toxicities and have implications for how treatment is sequenced. Advances in T-ALL have lagged behind those seen in B-ALL. However, agents such as nelarabine, bortezomib and CAR T cell therapy targeting T cell antigens have been examined with promising results seen. As our understanding of disease biology in ALL grows, as does our ability to target pathways such as apoptosis, through BH3 mimetics, chemokines and epigenetic regulators. This review aims to highlight a range of available and emerging targeted therapeutics in ALL, to explore their mechanisms of action and to discuss the current evidence for their use. Full article
(This article belongs to the Special Issue Targeted Treatment of Lymphoma, Leukaemia and Myeloma)
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16 pages, 562 KiB  
Review
Targeted Approaches to T-Cell Lymphoma
by Sean Harrop, Chathuri Abeyakoon, Carrie Van Der Weyden and H. Miles Prince
J. Pers. Med. 2021, 11(6), 481; https://doi.org/10.3390/jpm11060481 - 27 May 2021
Cited by 1 | Viewed by 3828
Abstract
The T-cell lymphomas are a rare group of Non-Hodgkin’s lymphomas derived from mature T-lymphocytes. They are divided broadly into the Peripheral T-cell lymphomas and the Cutaneous T-cell lymphomas. Clinical outcomes vary widely but are generally unsatisfactory with current treatments. The development of an [...] Read more.
The T-cell lymphomas are a rare group of Non-Hodgkin’s lymphomas derived from mature T-lymphocytes. They are divided broadly into the Peripheral T-cell lymphomas and the Cutaneous T-cell lymphomas. Clinical outcomes vary widely but are generally unsatisfactory with current treatments. The development of an understanding of the various critical pathways in T-cell lymphogenesis and subsequent identification of therapeutic targets has led to a rapid expansion of the previously underwhelming T-cell lymphoma armament. This review aims to provide an up-to-date overview of the current state of targeted therapies in the T-cell lymphomas, including novel antibody-based treatments, small molecule inhibitors and immune-based therapies. Full article
(This article belongs to the Special Issue Targeted Treatment of Lymphoma, Leukaemia and Myeloma)
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14 pages, 452 KiB  
Review
Review of Venetoclax in CLL, AML and Multiple Myeloma
by Masa Lasica and Mary Ann Anderson
J. Pers. Med. 2021, 11(6), 463; https://doi.org/10.3390/jpm11060463 - 24 May 2021
Cited by 52 | Viewed by 7540
Abstract
Venetoclax is a highly selective and effective B-cell lymphoma-2 (BCL-2) inhibitor, which is able to reinstate the apoptotic potential of cancer cells. With its full repertoire yet to be explored, it has changed the therapeutic landscape in haematological malignancies, and most particularly chronic [...] Read more.
Venetoclax is a highly selective and effective B-cell lymphoma-2 (BCL-2) inhibitor, which is able to reinstate the apoptotic potential of cancer cells. With its full repertoire yet to be explored, it has changed the therapeutic landscape in haematological malignancies, and most particularly chronic lymphocytic leukaemia (CLL), acute myeloid leukaemia (AML) and multiple myeloma (MM). In CLL, it has shown remarkable efficacy both as monotherapy and in combination therapy. Based on data from MURANO and CLL14 studies, fixed-duration combination therapy of venetoclax with anti-CD20 antibody is now the standard of care in numerous countries. In AML, although of limited efficacy as a single agent, venetoclax combination therapy has demonstrated encouraging outcomes including rapid, durable responses and acceptable toxicity, particularly in the older, unfit patient population. Multiple myeloma with translocation (t)(11;14) harbours high BCL-2/ myeloid cell leukaemia sequence-1 (MCL-1) and BCL-2/BCL-XL ratio and is, therefore, particularly suited for venetoclax-based therapy. Despite a wide ranging and evolving clinical role in these diseases, venetoclax treatment is not curative and, over time, clonal evolution and disease relapse appear to be the norm. While a variety of distinct resistance mechanisms have been identified, frequently emerging in a sub-clonal pattern, the full picture is yet to be characterised. Further illumination of the complex interplay of various factors is needed to pave the way for rational combination therapies aimed at circumventing resistance and improving durability of disease control. Serial molecular studies can aid in identification of new prognostically significant and/or targetable mutations. Full article
(This article belongs to the Special Issue Targeted Treatment of Lymphoma, Leukaemia and Myeloma)
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15 pages, 1022 KiB  
Review
Bispecific Antibodies: A Review of Development, Clinical Efficacy and Toxicity in B-Cell Lymphomas
by Ross Salvaris, Jeremy Ong and Gareth P. Gregory
J. Pers. Med. 2021, 11(5), 355; https://doi.org/10.3390/jpm11050355 - 29 Apr 2021
Cited by 49 | Viewed by 7927
Abstract
The treatment landscape of B-cell lymphomas is evolving with the advent of novel agents including immune and cellular therapies. Bispecific antibodies (bsAbs) are molecules that recognise two different antigens and are used to engage effector cells, such as T-cells, to kill malignant B-cells. [...] Read more.
The treatment landscape of B-cell lymphomas is evolving with the advent of novel agents including immune and cellular therapies. Bispecific antibodies (bsAbs) are molecules that recognise two different antigens and are used to engage effector cells, such as T-cells, to kill malignant B-cells. Several bispecific antibodies have entered early phase clinical development since the approval of the CD19/CD3 bispecific antibody, blinatumomab, for relapsed/refractory acute lymphoblastic leukaemia. Novel bsAbs include CD20/CD3 antibodies that are being investigated in both aggressive and indolent non-Hodgkin lymphoma with encouraging overall response rates including complete remissions. These results are seen even in heavily pre-treated patient populations such as those who have relapsed after chimeric antigen receptor T-cell therapy. Potential toxicities include cytokine release syndrome, neurotoxicity and tumour flare, with a number of strategies existing to mitigate these risks. Here, we review the development of bsAbs, their mechanism of action and the different types of bsAbs and how they differ in structure. We will present the currently available data from clinical trials regarding response rates, progression free survival and outcomes across a range of non-Hodgkin lymphoma subtypes. Finally, we will discuss the key toxicities of bsAbs, their rates and management of these adverse events. Full article
(This article belongs to the Special Issue Targeted Treatment of Lymphoma, Leukaemia and Myeloma)
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19 pages, 784 KiB  
Review
Targeted Therapies for Multiple Myeloma
by Christopher Chang-Yew Leow and Michael Sze Yuan Low
J. Pers. Med. 2021, 11(5), 334; https://doi.org/10.3390/jpm11050334 - 23 Apr 2021
Cited by 11 | Viewed by 5136
Abstract
Multiple myeloma continues to be a challenging disorder to treat despite improved therapies and the widespread use of proteasome inhibitors and immunomodulatory drugs. Although patient outcomes have improved, the disease continues to invariably relapse, and in the majority of cases, a cure remains [...] Read more.
Multiple myeloma continues to be a challenging disorder to treat despite improved therapies and the widespread use of proteasome inhibitors and immunomodulatory drugs. Although patient outcomes have improved, the disease continues to invariably relapse, and in the majority of cases, a cure remains elusive. In the last decade, there has been an explosion of novel drugs targeting cellular proteins essential for malignant plasma cell proliferation and survival. In this review, we focus on novel druggable targets leading to the development of monoclonal antibodies and cellular therapies against surface antigens (CD38, CD47, CD138, BCMA, SLAMF7, GPRC5D, FcRH5), inhibitors of epigenetic regulators such as histone deacetylase (HDAC), and agents targeting anti-apoptotic (BCL-2), ribosomal (eEF1A2) and nuclear export (XPO1) proteins. Full article
(This article belongs to the Special Issue Targeted Treatment of Lymphoma, Leukaemia and Myeloma)
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15 pages, 475 KiB  
Review
Management of Hepatitis B Virus Reactivation in Malignant Lymphoma Prior to Immunosuppressive Treatment
by Yu-Fen Tsai, Chin-Mu Hsu and Hui-Hua Hsiao
J. Pers. Med. 2021, 11(4), 267; https://doi.org/10.3390/jpm11040267 - 2 Apr 2021
Cited by 11 | Viewed by 3671
Abstract
Hepatitis B reactivation is a common complication in lymphoma patients under immunosuppressive treatment with potentially serious and life-threating consequences. In this review, we discuss the basis of chronic Hepatitis B virus (HBV) infection, the definition and risk factors for HBV reactivation. We overview [...] Read more.
Hepatitis B reactivation is a common complication in lymphoma patients under immunosuppressive treatment with potentially serious and life-threating consequences. In this review, we discuss the basis of chronic Hepatitis B virus (HBV) infection, the definition and risk factors for HBV reactivation. We overview the management of HBV reactivation based on virological status and immunosuppressive regimen risk stratification. We also highlight and update information about the HBV reactivation in lymphoma patients under novel agent treatment, including newer monoclonal antibodies, small molecule inhibitors, and even chimeric antigen receptor T-cell immunotherapy. Full article
(This article belongs to the Special Issue Targeted Treatment of Lymphoma, Leukaemia and Myeloma)
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19 pages, 1186 KiB  
Review
Targeted Treatment of Follicular Lymphoma
by Karthik Nath and Maher K. Gandhi
J. Pers. Med. 2021, 11(2), 152; https://doi.org/10.3390/jpm11020152 - 22 Feb 2021
Cited by 4 | Viewed by 6551
Abstract
Follicular lymphoma (FL) is the most common indolent B-cell lymphoma. Advanced stage disease is considered incurable and is characterized by a prolonged relapsing/remitting course. A significant minority have less favorable outcomes, particularly those with transformed or early progressive disease. Recent advances in our [...] Read more.
Follicular lymphoma (FL) is the most common indolent B-cell lymphoma. Advanced stage disease is considered incurable and is characterized by a prolonged relapsing/remitting course. A significant minority have less favorable outcomes, particularly those with transformed or early progressive disease. Recent advances in our understanding of the unique genetic and immune biology of FL have led to increasingly potent and precise novel targeted agents, suggesting that a chemotherapy-future may one day be attainable. The current pipeline of new therapeutics is unprecedented. Particularly exciting is that many agents have non-overlapping modes of action, offering potential new combinatorial options and synergies. This review provides up-to-date clinical and mechanistic data on these new therapeutics. Ongoing dedicated attention to basic, translational and clinical research will provide further clarity as to when and how to best use these agents, to improve efficacy without eliciting unnecessary toxicity. Full article
(This article belongs to the Special Issue Targeted Treatment of Lymphoma, Leukaemia and Myeloma)
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