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Updates in Chronic Lymphocytic Leukemia: 10 Years of Paradigm Change...
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Updates in Chronic Lymphocytic Leukemia: 10 Years of Paradigm Change and Outlook for the Future

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: 30 July 2025 | Viewed by 9188

Special Issue Editor

Dr. Alan Skarbnik

E-Mail Website
Guest Editor
Novant Health Cancer Institute, Lymphoma and CLL Program, Charlotte, NC, USA
Interests: chronic lymphocytic loeukemia; lymphoma; malignant hematology; CAR-T; cellular therapy

Special Issue Information

Dear Colleagues,

Chronic lymphocytic leukemia (CLL) is the most prevalent blood cancer in the Western world. Up to a decade ago, patients in need of therapy only had chemotherapy and monoclonal antibodies available. The year 2014 marked a watershed moment in the history of CLL, with the approval of ibrutinib. The availability of targeted drugs changed the landscape of CLL and, since the approval of ibrutinib, seven other novel drugs were approved for the treatment of CLL (with some currently removed from use).

This Special Issue marks 10 years since novel agents for CLL have been available for use outside of clinical trials. Much knowledge has been acquired during the past decade and now we look to the future with the following aims: understanding mechanisms of resistance, evaluating treatments for patients with disease that is refractory to the currently available drugs, and focusing on minimizing toxicity and improving quality of life for our patients.

We invite you to submit an article to this Special Issue, where we aim to highlight where we stand in the treatment of CLL and what our path is moving forward. We thank you in advance for your contribution.

Dr. Alan Skarbnik
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 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. Cancers 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 2900 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

  • chronic lymphocytic leukemia
  • treatment
  • targeted therapy
  • chemotherapy
  • treatment resistance
  • quality of life

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Published Papers (6 papers)

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Research

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15 pages, 1765 KiB  
Article
Real-World Effectiveness of Frontline Treatments Among Patients with Chronic Lymphocytic Leukemia: Results from ConcertAI
by Lindsey E. Roeker, John M. Burke, Joanna M. Rhodes, Nnadozie Emechebe, Dureshahwar Jawaid, Beenish S. Manzoor, Christopher E. Jensen, Lindsay Ryland, Yangyang Liu, Steve E. Marx, Wendy Sinai, Jordan Roser and Mazyar Shadman
Cancers 2025, 17(5), 799; https://doi.org/10.3390/cancers17050799 - 26 Feb 2025
Viewed by 948
Abstract
Background: The long-term follow-up of clinical trials of novel first-line (1L) therapies for chronic lymphocytic leukemia (CLL) demonstrates 6–10-year progression-free survival. We describe the effectiveness of 1L CLL treatments in real-world settings, with an emphasis on the important real-world outcome of time to [...] Read more.
Background: The long-term follow-up of clinical trials of novel first-line (1L) therapies for chronic lymphocytic leukemia (CLL) demonstrates 6–10-year progression-free survival. We describe the effectiveness of 1L CLL treatments in real-world settings, with an emphasis on the important real-world outcome of time to next treatment or death (TTNT-D). Methods: This retrospective, observational study utilized de-identified electronic health records from the ConcertAI RWD360™ database with linked administrative open claims. Adults with CLL who initiated an approved 1L CLL therapy (June 2019–March 2023) were included. Duration of therapy (DoT), TTNT-D, and overall survival were assessed. Results: At 1L, 39.8% of 1843 patients received first-generation covalent Bruton tyrosine kinase inhibitors (cBTKis), 23.0% second-generation cBTKis, 12.4% venetoclax-obinutuzumab (VenO), 7.4% chemotherapy/chemoimmunotherapy (CT/CIT), and 17.4% anti-CD20 monotherapy. Median (range) follow-up in months was 24.9 (13.1–36.6) for first-generation cBTKis, 13.4 (7.3–21.7) for second-generation cBTKis, 16.0 (8.4–27.8) for VenO, 21.8 (11.2–32.7) for CT/CIT, and 19.7 (10.0–33.4) for anti-CD20 monotherapy. Median (range) DoT was 11.5 (4.2–25.0) and 8.6 (3.0–16.1), 9.1 (5.9–12.2), 5.6 (3.2–5.8), and 1.6 (1.6–4.5) months for first- and second-generation cBTKis, VenO, CT/CIT, and anti-CD20 monotherapy, respectively. Regarding TTNT-D, at 2 years’ follow-up, 69.1%, 82.5%, 86.3%, 79.1%, and 53.0% of patients treated with first- and second-generation cBTKis, VenO, CT/CIT, and anti-CD20 monotherapy, respectively, had not initiated subsequent treatment or experienced death. Conclusions: TTNT-D is an important real-world outcome in CLL. Our findings demonstrated the utility of time-limited VenO, with potentially more time off treatment, relative to continuous 1L cBTKi therapies. Full article
(This article belongs to the Special Issue Updates in Chronic Lymphocytic Leukemia: 10 Years of Paradigm Change and Outlook for the Future)
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17 pages, 1132 KiB  
Article
The Economic Impact of Treatment Sequencing in Chronic Lymphocytic Leukemia in Canada Using Venetoclax plus Obinutuzumab
by Kimberly Guinan, Karine Mathurin, Jean Lachaine, Nancy Paul Roc, Sarah-Jane Bull, Dipti Tankala, Stephane Barakat, Beenish S. Manzoor, Christopher Hillis and Versha Banerji
Cancers 2024, 16(18), 3182; https://doi.org/10.3390/cancers16183182 - 17 Sep 2024
Viewed by 1531
Abstract
Background: Bruton tyrosine kinase inhibitors (BTKis) represent an advancement in chronic lymphocytic leukemia; however, these agents are administered continuously until disease progression or unacceptable toxicity, raising concerns about their affordability. Venetoclax in combination with obinutuzumab (VO) is a fixed-duration (12-month) treatment, approved in [...] Read more.
Background: Bruton tyrosine kinase inhibitors (BTKis) represent an advancement in chronic lymphocytic leukemia; however, these agents are administered continuously until disease progression or unacceptable toxicity, raising concerns about their affordability. Venetoclax in combination with obinutuzumab (VO) is a fixed-duration (12-month) treatment, approved in Canada in 2020. This study estimated the total cumulative cost of different treatment sequences and evaluated the economic impact of introducing treatment sequences with/without VO, from a Canadian health care system perspective. Methods: A 10-year partitioned survival model was developed, considering key clinical parameters and direct medical costs. Results were stratified by TP53 aberration. Results: Treatment sequences starting with first-line (1L) VO resulted in lower 10-year cumulative costs compared to sequences starting with BTKis administered until disease progression, across both TP53 aberration subgroups. With a maximum of three lines of treatment over a 10-year period, cumulative costs were largely determined by the first two lines of treatment. When comparing sequences with the same 1L treatment, sequences with BTKis in second-line incurred greater costs compared to fixed-duration regimens. Conclusions: Overall, the economic impact of treating all patients with VO led to 10-year cumulative savings of CAD 169,341 and CAD 293,731 per patient, without and with TP53 aberration, respectively. These savings are mainly due to reductions in treatment costs associated with fixed treatment duration. Full article
(This article belongs to the Special Issue Updates in Chronic Lymphocytic Leukemia: 10 Years of Paradigm Change and Outlook for the Future)
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Review

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16 pages, 472 KiB  
Review
BTK Is the Target That Keeps on Giving: A Review of BTK-Degrader Drug Development, Clinical Data, and Future Directions in CLL
by Ross T. Salvaris, Jamie Brennan and Katharine L. Lewis
Cancers 2025, 17(3), 557; https://doi.org/10.3390/cancers17030557 - 6 Feb 2025
Viewed by 1500
Abstract
Effective available treatment options for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who relapse after becoming refractory to both a covalent Bruton Tyrosine Kinase inhibitor (cBTKi) and a B cell leukemia/lymphoma 2 inhibitor (BCL2i) remain limited, and prognosis is very poor. Emerging [...] Read more.
Effective available treatment options for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who relapse after becoming refractory to both a covalent Bruton Tyrosine Kinase inhibitor (cBTKi) and a B cell leukemia/lymphoma 2 inhibitor (BCL2i) remain limited, and prognosis is very poor. Emerging areas of drug development include cellular therapies such as chimeric antigen receptor T-cell therapy and bispecific antibodies. However, cost, accessibility, toxicity, and the need for either prolonged or repeated hospitalization prevent universal application of these therapies. Given this area of unmet clinical need, we present this review article on Bruton Tyrosine Kinase (BTK) degraders in patients with CLL/SLL. We focus on their development as a drug class, the up-to-date clinical data available, as well as future directions. BTK protein degraders are a novel drug class with an alternate mechanism of action (MOA), compared to cBTKis and non-covalent BTKis (ncBTKis), causing ubiquitination of BTK, thereby leading to its degradation through the proteasome. Encouraging pre-clinical data show that this MOA allows BTK protein degraders to overcome common BTK mutations. We focus on four agents which are under investigation in B-cell malignancies in early clinical trials: BGB-16673, NX-2127, NX-5948, and AC676. Preliminary data suggest a comparable safety and toxicity profile between agents across this drug class with many patients on phase 1 trials deriving durable clinical benefit. Optimal sequencing of BTK degraders in the therapeutic landscape of CLL/SLL treatment is yet to be established. Further trials investigating these agents in combination with other targeted CLL agents may help to further understand their applicability. An effective, tolerable oral class of drugs would be invaluable in the treatment of patients with multiply relapsed CLL/SLL. Full article
(This article belongs to the Special Issue Updates in Chronic Lymphocytic Leukemia: 10 Years of Paradigm Change and Outlook for the Future)
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18 pages, 406 KiB  
Review
Improving Treatment Options for Patients with Double Refractory CLL
by Ryan Jacobs and William Wierda
Cancers 2025, 17(3), 430; https://doi.org/10.3390/cancers17030430 - 27 Jan 2025
Viewed by 1480
Abstract
The proliferation and survival of chronic lymphocytic leukemia (CLL) cells are heavily dependent on B-cell receptor (BCR) signaling and resistance to apoptosis. Approvals of multiple covalent Bruton’s tyrosine kinas inhibitors (cBTKis) as well as the B-cell lymphoma-2 inhibitor (BCL2i) venetoclax targeting these pathways [...] Read more.
The proliferation and survival of chronic lymphocytic leukemia (CLL) cells are heavily dependent on B-cell receptor (BCR) signaling and resistance to apoptosis. Approvals of multiple covalent Bruton’s tyrosine kinas inhibitors (cBTKis) as well as the B-cell lymphoma-2 inhibitor (BCL2i) venetoclax targeting these pathways have revolutionized the treatment of CLL and small lymphocytic lymphoma (SLL). The superiority of these treatments over chemoimmunotherapy has been proven in phase III studies in both treatment-naïve and relapsed refractory settings, leading to the majority of patients with CLL being treated sequentially with cBTKis and the BCL2i venetoclax as their first- and second-line therapies. While most patients with CLL respond for many years to these sequenced treatments, they are unfortunately not curative. There remains an unmet need for effective treatment options for patients who progressed after treatment with both cBTKis and BCL2i, also referred to as double refractory patients. Treatment options for double refractory CLL has improved recently with the approval of the non-covalent BTK inhibitor (ncBTKi) pirtobrutinib as well as the CD19 targeted chimeric antigen receptor T-cell (CAR T-cell) therapy lisocabtagene maraleucel (liso-cel). These recently approved treatment options for patients with CLL with at least two prior lines of therapy have fortunately demonstrated efficacy for double refractory CLL. Additionally, there are several novel treatment options in clinical development, including bi-specific antibodies, second-generation BCL2is, new ncBTKis, and BTK degraders. Understanding resistance mechanisms to existing cBTKis and venetoclax can potentially inform us of the best utilization of available treatment options for double refractory CLL and provide a personalized approach for these patients. In this review, a challenging example of a double refractory patient with CLL will serve as the basis for a review of available literature on the treatment of double refractory CLL/SLL. Full article
(This article belongs to the Special Issue Updates in Chronic Lymphocytic Leukemia: 10 Years of Paradigm Change and Outlook for the Future)
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28 pages, 1242 KiB  
Review
Chimeric Antigen Receptor-T Cells in the Modern Era of Chronic Lymphocytic Leukemia Treatment
by Alycia Hatashima, Mazyar Shadman and Vikram Raghunathan
Cancers 2025, 17(2), 268; https://doi.org/10.3390/cancers17020268 - 15 Jan 2025
Viewed by 1161
Abstract
Pathway inhibitors targeting Bruton tyrosine kinase (BTK) and B-cell lymphoma-2 (BCL-2) have dramatically changed the treatment landscape for both treatment-naïve and relapsed/refractory chronic lymphocytic leukemia (CLL). However, with increased utilization, a growing number of patients will experience progressive disease on both agents. This [...] Read more.
Pathway inhibitors targeting Bruton tyrosine kinase (BTK) and B-cell lymphoma-2 (BCL-2) have dramatically changed the treatment landscape for both treatment-naïve and relapsed/refractory chronic lymphocytic leukemia (CLL). However, with increased utilization, a growing number of patients will experience progressive disease on both agents. This subgroup of “double refractory” patients has limited treatment options and poor prognosis. Chimeric antigen receptor (CAR)-T cells have transformed the treatment of relapsed/refractory B-cell malignancies. Although the earliest success of CAR-T cell therapy was in CLL, the clinical application of this modality has lagged until the recent approval of the first CAR-T cell product for CLL. In this review, we describe the current treatment options for upfront and subsequent therapies and the unmet need for novel agents highlighted by the burgeoning role and challenges of CAR-T cell therapy. Full article
(This article belongs to the Special Issue Updates in Chronic Lymphocytic Leukemia: 10 Years of Paradigm Change and Outlook for the Future)
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17 pages, 1042 KiB  
Review
Updates in the Management of Richter Transformation
by Noa Rippel, Richard Sheppard and Adam S. Kittai
Cancers 2025, 17(1), 95; https://doi.org/10.3390/cancers17010095 - 31 Dec 2024
Viewed by 1817
Abstract
Richter transformation (RT) is a rare albeit devastating complication of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). RT is defined as an aggressive lymphoma, typically diffuse large B-cell lymphoma, in the setting of CLL. A clonal relationship to the preceding CLL clone is detected [...] Read more.
Richter transformation (RT) is a rare albeit devastating complication of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). RT is defined as an aggressive lymphoma, typically diffuse large B-cell lymphoma, in the setting of CLL. A clonal relationship to the preceding CLL clone is detected in the majority of RT cases and confers more aggressive clinicopathologic kinetics, resistance to standard chemoimmunotherapy regimens, and inferior survival. Taken together, these considerations precipitate a significant unmet need for novel therapeutic strategies that improve the outcomes of patients with RT. Through this review, we will explore current data on emerging regimens targeting BTK, BCL-2, CD79, CD20, PI3K, and PD-1—both as single agents and as combination therapies with or without concurrent chemoimmunotherapy. Furthermore, we will review the role of bispecific T-cell engagers, anti-CD19 chimeric antigen receptor T-cell therapies, and hematopoietic stem cell transplantation in RT. To guide therapeutic decision-making, we will outline an algorithmic approach to the management of RT, with particular emphasis on prioritization of clinical trial enrollment and utilization of an ever-evolving array of novel therapies. Full article
(This article belongs to the Special Issue Updates in Chronic Lymphocytic Leukemia: 10 Years of Paradigm Change and Outlook for the Future)
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