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Advances in the Management of Chronic Lymphocytic Leukemia
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Advances in the Management of Chronic Lymphocytic Leukemia

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

Deadline for manuscript submissions: closed (12 May 2026) | Viewed by 5944

Editors

Dr. Alberto Fresa

E-Mail Website
Guest Editor
Hematology-Oncology and Stem-Cell Transplantation Unit, Department of Onco-Hematology and Innovative Diagnostics, Istituto Nazionale Tumori IRCCS-Fondazione G.Pascale, 80131 Naples, Italy
Interests: chronic lymphocytic leukemia; lymphoproliferative disorders; prognostic factors; targeted therapy; CAR T cell; elderly patients
Dr. Luca Laurenti

E-Mail Website
Guest Editor
Hematology Section, Department of Radiological and Hematological Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
Interests: chronic lymphocytic leukemia; lymphoproliferative disorders; prognostic factors; targeted therapy; CAR T cell; stem cell transplantation; translational medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The outcomes of patients with chronic lymphocytic leukemia (CLL) have significantly improved over the last few years due to recent advancements in therapeutic and clinical approaches. The implementation of targeted therapies has revolutionized treatment algorithms, eliminating the need for chemotherapy. Nevertheless, there is still a need for new prognostic and predictive factors, and the assessment of comorbidities, fragility, and other potential risk factors, such as infectious, cardiovascular, and metabolic risks, is of increasing importance for further personalizing treatment regimens, thereby enhancing patient outcomes.

We invite you to contribute to a Special Issue of the Journal of Clinical Medicine, focusing on the theme of Advances in the Management of Chronic Lymphocytic Leukemia. This Special Issue will explore novel diagnostic and prognostic markers, as well as recent therapeutic advancements in CLL. Authors are invited to submit original research studies and review articles on these topics. The topics of interest include, but are not limited to, the following:

  • Advances in CLL management;
  • Targeted therapies and novel therapeutic strategies in CLL;
  • Prognostic and predictive factors in CLL;
  • Measurable residual disease in CLL;
  • Drug resistance in CLL.

We look forward to receiving your contributions.

Dr. Alberto Fresa
Dr. Luca Laurenti
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 250 words) can be sent to the Editorial Office for assessment.

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-anonymized 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

  • chronic lymphocytic leukemia
  • lymphoproliferative disorders
  • prognostic factors
  • targeted therapy
  • CAR T cell
  • elderly patients
  • comorbidities

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Published Papers (3 papers)

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37 pages, 900 KB  
Review
The Development of Novel Therapies for Chronic Lymphocytic Leukaemia in the Era of Targeted Drugs
by Tadeusz Robak, Elżbieta Iskierka-Jażdżewska, Anna Puła, Pawel Robak and Bartosz Puła
J. Clin. Med. 2025, 14(22), 8247; https://doi.org/10.3390/jcm14228247 - 20 Nov 2025
Cited by 4 | Viewed by 4366
Abstract
Over the past decade, chronic lymphocytic leukaemia (CLL) treatment has shifted from chemoimmunotherapy to targeted oral agents, predominantly Bruton’s tyrosine kinase inhibitors (BTKis) and the BCL-2 inhibitor venetoclax. These therapies have significantly improved outcomes and are now established as first-line treatment options. However, [...] Read more.
Over the past decade, chronic lymphocytic leukaemia (CLL) treatment has shifted from chemoimmunotherapy to targeted oral agents, predominantly Bruton’s tyrosine kinase inhibitors (BTKis) and the BCL-2 inhibitor venetoclax. These therapies have significantly improved outcomes and are now established as first-line treatment options. However, CLL remains incurable, and resistance or intolerance to both drug classes (double-refractory disease) is an emerging challenge. This has driven the development of novel therapeutic strategies, including non-covalent BTKis such as pirtobrutinib and nemtabrutinib, which retain activity in BTK C481-mutated disease. Next-generation BCL-2 inhibitors (sonrotoclax, lisaftoclax) and BTK degraders are promising in early clinical trials. Immunotherapeutic approaches, such as bispecific T-cell engagers, CD20/CD3 antibodies, and CAR-T cell therapies, provide additional options for high-risk patients. Although PI3K inhibitors remain under investigation, their role is yet to be defined due to safety concerns. Minimal residual disease (MRD)-guided, fixed-duration regimens represent a significant paradigm shift toward personalised treatment and potentially deeper remissions. Ongoing clinical studies are expected to introduce new effective therapies that may further transform the management of CLL in the coming years. Full article
(This article belongs to the Special Issue Advances in the Management of Chronic Lymphocytic Leukemia)
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6 pages, 398 KB  
Case Report
Refractory Thrombocytopenia in TP53—Aberrant Chronic Lymphocytic Leukemia: A Multimechanistic Case with Response to Idelalisib and Romiplostim
by Serkan Guven, Hulya Kacar, Omer Seker and Fatih Demirkan
J. Clin. Med. 2026, 15(12), 4483; https://doi.org/10.3390/jcm15124483 - 10 Jun 2026
Viewed by 203
Abstract
Background/Objectives: Thrombocytopenia in chronic lymphocytic leukemia (CLL) is a heterogeneous and multifactorial complication that often reflects the combined effects of immune dysregulation, impaired megakaryopoiesis, bone marrow microenvironmental disruption, and disease-related factors. In patients with high-risk molecular features, particularly TP53 abnormalities, management becomes increasingly [...] Read more.
Background/Objectives: Thrombocytopenia in chronic lymphocytic leukemia (CLL) is a heterogeneous and multifactorial complication that often reflects the combined effects of immune dysregulation, impaired megakaryopoiesis, bone marrow microenvironmental disruption, and disease-related factors. In patients with high-risk molecular features, particularly TP53 abnormalities, management becomes increasingly challenging and frequently refractory to conventional therapies. Methods: We report a 57-year-old male with long-standing CLL characterized by a highly aggressive and treatment-refractory course. The patient developed persistent severe thrombocytopenia despite multiple lines of therapy, including corticosteroids, intravenous immunoglobulin, rituximab, splenectomy, and thrombopoietin receptor agonists. Subsequent treatments with ibrutinib and a venetoclax-based regimen failed to improve platelet counts and were discontinued due to worsening cytopenia. Bone marrow evaluation, molecular/cytogenetic analyses, and subsequent treatment responses were thoroughly evaluated. Results: Bone marrow evaluation revealed hypercellularity with significant CLL infiltration, dysplastic megakaryopoiesis, and reticulin fibrosis, indicating impaired platelet production in addition to immune-mediated destruction. Molecular and cytogenetic analyses demonstrated high-risk disease with deletion of 17p and dual TP53 mutations (p.His179Tyr and p.Arg282Trp), consistent with biallelic TP53 disruption. Romiplostim monotherapy did not result in a meaningful hematologic response. However, following the addition of idelalisib, a rapid and sustained increase in platelet counts was observed, allowing tapering of romiplostim and stabilization of hematologic parameters. Conclusions: This case highlights the complex and dynamic pathophysiology of thrombocytopenia in CLL, where immune-mediated destruction and defective thrombopoiesis coexist within a profoundly altered marrow microenvironment. TP53 disruption appears to play a central role not only in driving treatment resistance but also in promoting immune dysregulation and disease aggressiveness. Although a delayed therapeutic effect of romiplostim cannot be entirely excluded, the distinct temporal association following idelalisib initiation suggests a potential collaborative interaction or disease-directed clearance that may facilitate platelet recovery in this setting. Refractory thrombocytopenia in CLL should be approached as a manifestation of complex disease biology rather than an isolated complication. This single observation indicates that in TP53 aberrant cases with multi-mechanism thrombocytopenia, disease-directed targeted therapy may contribute significantly to platelet recovery. Full article
(This article belongs to the Special Issue Advances in the Management of Chronic Lymphocytic Leukemia)
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25 pages, 2464 KB  
Case Report
Efficacy and Long-Term Remission Following Haploidentical HSCT for Therapy-Related Acute Myelomonocytic Leukemia with Plasmacytoid Dendritic Cells Post-FCR Therapy for CLL: A Case Report
by Alina Camelia Catana, Lidia-Maria Mondoc, Maria-Gabriela Vladoiu, Zsofia Varady, Camelia Dobrea, Horia Mihail Sandu, Liliana Mocanu, Ariela Olteanu, Geanina Mera and Minodora Teodoru
J. Clin. Med. 2026, 15(4), 1559; https://doi.org/10.3390/jcm15041559 - 16 Feb 2026
Viewed by 831
Abstract
Introduction: Chronic lymphocytic leukemia (CLL) is a common adult leukemia often treated with fludarabine, cyclophosphamide, and rituximab (FCR). While effective, FCR can lead to therapy-related myeloid neoplasms (t-MN), including aggressive therapy-related acute myeloid leukemia (t-AML). Stem cell transplantation offers the best chance for [...] Read more.
Introduction: Chronic lymphocytic leukemia (CLL) is a common adult leukemia often treated with fludarabine, cyclophosphamide, and rituximab (FCR). While effective, FCR can lead to therapy-related myeloid neoplasms (t-MN), including aggressive therapy-related acute myeloid leukemia (t-AML). Stem cell transplantation offers the best chance for long-term remission in these cases. Here, we report a rare case of t-AML with plasmacytoid dendritic cells (pDC-AML) developing after FCR treatment for CLL that was successfully treated with haplotransplantation. Case Presentation: A 57-year-old woman with CLL-B was treated with six cycles of FCR, achieving a complete response. Six years later, at age 63, she developed t-AML with a rare morphophenotypic subtype: acute myelomonocytic leukemia with plasmacytoid dendritic cells (pDC-AML) and monosomy 8. Diagnostic challenges included distinguishing this subtype from blastic plasmacytoid dendritic cell neoplasm (BPDCN). She was treated with high-dose cytarabine followed by haploidentical stem cell transplantation from her son. Haploidentical transplantation was prioritized due to the urgent clinical need in a patient with high-risk acute leukemia (therapy-related leukemia secondary to prior chemoimmunotherapy and failure to achieve complete remission following the standard 3 + 7 induction protocol). In this critical setting, the patient’s son was immediately available as an HLA-haploidentical donor. Prior to the performance of the haploidentical stem cell transplant from her son, no HLA-matched unrelated donor (MUD) could be identified. Another viable alternative would have been the utilization of umbilical cord blood-derived stem cells harvested from the patient’s twin granddaughters. She was closely monitored post-transplant for potential complications, including graft-versus-host disease (GVHD), post-transplant lymphoproliferative disorder, and thyroid dysfunction, all of which were ruled out during follow-up. The patient remains in complete remission 15 years after her initial CLL diagnosis and 8 years after the t-AML diagnosis and haplotransplantation. Notably, no residual CLL clone was detected at the time of t-AML development, and a benign polyclonal lymphocytosis observed between 2018 and 2020 spontaneously resolved without intervention. Conclusions: This case illustrates the potential for long-term survival in high-risk patients with therapy-related AML developed after cytotoxic treatment for lymphoid malignancies. Haplotransplantation from a semi-identical Human Leukocyte Antigen (HLA) donor proved to be a viable and effective treatment option despite the patient’s age and dual hematologic malignancies. Full article
(This article belongs to the Special Issue Advances in the Management of Chronic Lymphocytic Leukemia)
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