Chronic Lymphocytic Leukemia: Therapy and Outcome

A special issue of Current Oncology (ISSN 1718-7729). This special issue belongs to the section "Hematology".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 22118

Special Issue Editor


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Guest Editor
Hematology and Clinical Immunology Unit, Department of Medicine, University of Padova, 35128 Padua, Italy
Interests: chronic lymphocytic leukemia; hodgkin lymphoma; targeted therapy; lymphoma; prognostic markers;B-cell receptor signaling
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Special Issue Information

Dear Colleagues,

In the last 15 years, our understanding of chronic lymphocytic leukemia has been revolutionized thanks to significant insights into the molecular biology of the disease and the interplay between neoplastic cells and the surrounding microenvironment. The identification of molecules which are pivotal to the survival of malignant cells has allowed us to develop targeted therapies (monoclonal antibodies, kinase inhibitors and BH3-mimetics) that have become the cornerstone of chronic lymphocytic leukemia treatment. Despite these advances, the disease remains incurable and hypogammaglobulinemia, infections, and second primary malignancies still impinge upon patients’ quality of life.

For this Special Issue, we are pleased to invite you to submit original research articles and reviews on any aspect of chronic lymphocytic leukemia are welcome. Research areas may include (but are not limited to) diagnostic pitfall, prognostic factor, predictive factors, critical signaling pathways, comorbidities, targeted therapies, management of kinase inhibitors, Richter syndrome, supporting therapies, and quality of life.

We look forward to receiving your contributions.

Dr. Andrea Visentin
Guest Editor

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Keywords

  • chronic lymphocytic leukemia
  • microenvironment
  • BTK inhibitors
  • BCL2 inhibitors
  • PI3K inhibitors
  • infection
  • prognostic factors
  • predictive factors
  • Richter syndrome

Published Papers (8 papers)

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Research

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10 pages, 601 KiB  
Article
A Retrospective Study on the Efficacy of Subcutaneous Immunoglobulin as Compared to Intravenous Formulation in Patients with Chronic Lymphocytic Leukemia and Secondary Antibody Deficiency
by Andrea Visentin, Maria Chiara Molinari, Stefano Pravato, Alessandro Cellini, Francesco Angotzi, Chiara Adele Cavaretta, Valeria Ruocco, Silvia Imbergamo, Francesco Piazza, Giulia Proietti, Francesca Romana Mauro and Livio Trentin
Curr. Oncol. 2023, 30(1), 274-283; https://doi.org/10.3390/curroncol30010022 - 25 Dec 2022
Cited by 5 | Viewed by 2232
Abstract
Secondary antibody deficiency (SAD) is a common complication in chronic lymphocytic leukemia (CLL) which favors the development of life-threatening infections. Subcutaneous immunoglobulins (IG) (SCIG) have been proven to be as effective as intravenous immunoglobulin (IVIG) in primary immunodeficiencies. Since only a few studies [...] Read more.
Secondary antibody deficiency (SAD) is a common complication in chronic lymphocytic leukemia (CLL) which favors the development of life-threatening infections. Subcutaneous immunoglobulins (IG) (SCIG) have been proven to be as effective as intravenous immunoglobulin (IVIG) in primary immunodeficiencies. Since only a few studies investigated SCIG in secondary antibody deficiency, the aim of this study was to assess the efficacy and safety of SCIG or IVIG in CLL patients with secondary antibody deficiency. One hundred and sixteen CLL patients were recruited, 63% were males, and the median age was 68 years; 44% had bronchiectasis and 76% never smoked. Forty-nine patients received IVIG and 88 SCIG, including 28 patients who shifted from IVIG to SCIG. Despite similar baseline IgG levels, patients receiving SCIG achieved higher IgG after at least +6 months (p = 0.0009). We observed that SCIG can decrease the cumulative incidence of first (HR 0.39 p < 0.0001) and second (HR 0.56 p = 0.0411) infection more than IVIG. The effect was remarkable in that patients were able to reach at least 6 g/L of IgG after 6 months of treatments (p < 0.0001). Replacement therapies were well tolerated with less adverse events and a lower discontinuation rate in patients was managed with SCIG than IVIG. In this study we describe the clinical features of a large cohort of CLL with secondary antibody deficiency receiving IG. We demonstrated that SCIG are active and well tolerated drugs that allows to reach higher IgG levels and decrease the rate of infections better than IVIG, in particular when IgG levels reach 6 g/L. Full article
(This article belongs to the Special Issue Chronic Lymphocytic Leukemia: Therapy and Outcome)
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15 pages, 984 KiB  
Article
Effect of Lenalidomide Maintenance in Chronic Lymphocytic Leukemia: A Meta-Analysis and Trial-Sequential Analysis
by Tsung-Ying Yu, Hong-Jie Jhou, Po-Huang Chen and Cho-Hao Lee
Curr. Oncol. 2022, 29(6), 4245-4259; https://doi.org/10.3390/curroncol29060339 - 14 Jun 2022
Viewed by 2034
Abstract
Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disease in adults. Despite durable responses and sustained remission rates to frontline therapy, CLL is still incurable within standard therapy and eventually relapses. Maintenance therapies aim to achieve deep remission. However, the efficacy and [...] Read more.
Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disease in adults. Despite durable responses and sustained remission rates to frontline therapy, CLL is still incurable within standard therapy and eventually relapses. Maintenance therapies aim to achieve deep remission. However, the efficacy and safety of lenalidomide maintenance are still debated. Randomized controlled trials published before March 2022 were retrieved from databases. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Trial sequential analysis examined analytical power in primary outcomes. Secondary outcomes were Grade 3–4 neutropenia, treatment discontinuation (TD), serious adverse events (SAE), and fatal adverse events (FAE). Hazard (HR) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Four articles (733 patients) met the selection criteria. Lenalidomide maintenance was associated with a statistically significant effect in prolonging PFS (HR, 0.43; 95% CI, 0.28–0.68; I2 = 57%) and higher proportion of SAE (OR 4.64; 95% CI 2.96–7.26; I2 = 0%) and exhibited no difference in OS (HR, 0.62; 95% CI, 0.29–1.30; I2 = 52%) observation/placebo. It showed no significant difference compared with observation/placebo regarding Grade 3–4 neutropenia (OR 2.30; 95% CI 0.84–6.28; I2 = 81%), TD (OR 0.76; 95% CI 0.29–1.99; I2 = 84%), and FAE (OR 0.86; 95% CI 0.28–2.63; I2 = 0%). Lenalidomide maintenance can prolong PFS in CLL. Further studies should verify its effect on OS. Full article
(This article belongs to the Special Issue Chronic Lymphocytic Leukemia: Therapy and Outcome)
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10 pages, 778 KiB  
Article
Invasive Fungal Disease in Patients with Chronic Lymphocytic Leukemia in Japan: A Retrospective Database Study
by Takeo Yasu, Kotono Sakurai and Manabu Akazawa
Curr. Oncol. 2022, 29(5), 3242-3251; https://doi.org/10.3390/curroncol29050264 - 4 May 2022
Cited by 1 | Viewed by 1952
Abstract
Invasive fungal disease (IFD) is an important cause of morbidity and mortality in patients with hematological malignancies. As chronic lymphocytic leukemia (CLL) is a rare hematological malignancy in Japan, IFD incidence in Japanese patients with CLL is unclear. This study aimed to investigate [...] Read more.
Invasive fungal disease (IFD) is an important cause of morbidity and mortality in patients with hematological malignancies. As chronic lymphocytic leukemia (CLL) is a rare hematological malignancy in Japan, IFD incidence in Japanese patients with CLL is unclear. This study aimed to investigate IFD incidence in Japanese patients with CLL. This retrospective cohort study used data of patients with CLL registered between April 2008 and December 2019 in the Medical Data Vision database (n = 3484). IFD incidence after CLL diagnosis in the watch-and-wait (WW) and drug therapy (DT) groups was 1.5% and 9.2%, respectively. The most common type of IFD was invasive aspergillosis (28.1%). Cox proportional hazards multivariate analysis revealed that DT (hazard ratio [HR]: 2.13) and steroid use (HR: 4.19) were significantly associated with IFD occurrence. IFD incidence was significantly higher in the DT group than in the WW group (log-rank p < 0.001); however, there was no significant between-group difference in the time to IFD onset or the type of IFD (p = 0.09). This study determined the incidence of IFD in patients with CLL during WW. Physicians should monitor for IFD, even among patients with CLL undergoing the WW protocol. Full article
(This article belongs to the Special Issue Chronic Lymphocytic Leukemia: Therapy and Outcome)
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13 pages, 1561 KiB  
Article
Overcoming of Microenvironment Protection on Primary Chronic Lymphocytic Leukemia Cells after Treatment with BTK and MDM2 Pharmacological Inhibitors
by Erika Rimondi, Elisabetta Melloni, Arianna Romani, Veronica Tisato, Fabio Casciano, Gian Matteo Rigolin, Daniela Milani, Claudio Celeghini, Giorgio Zauli, Paola Secchiero and Rebecca Voltan
Curr. Oncol. 2021, 28(4), 2439-2451; https://doi.org/10.3390/curroncol28040223 - 1 Jul 2021
Cited by 3 | Viewed by 2612
Abstract
In B-chronic lymphocytic leukemia (B-CLL), the interaction between leukemic cells and the microenvironment promotes tumor cell survival. The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib is one of the first-in-class molecules for the treatment of B-CLL patients; however, the emerging mechanisms of resistance to [...] Read more.
In B-chronic lymphocytic leukemia (B-CLL), the interaction between leukemic cells and the microenvironment promotes tumor cell survival. The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib is one of the first-in-class molecules for the treatment of B-CLL patients; however, the emerging mechanisms of resistance to ibrutinib call for new therapeutic strategies. The purpose of the current study was to investigate the ability of ibrutinib plus the MDM2-inhibitor nutlin-3 to counteract the tumor microenvironment protective effect. We observed that primary B-CLL cells cultivated in microenvironment mimicking conditions were protected from apoptosis by the up-regulation of c-MYC and of p53. In the same setting, combined treatments with ibrutinib plus nutlin-3 led to significantly higher levels of apoptosis compared to the single treatments, counteracting the c-MYC up-regulation. Moreover, the combination induced high p53 levels and a significant dissipation of the mitochondrial membrane potential, together with BAX cleavage in the more active p18 form and phospho-BAD down-regulation, that are key components of the mitochondrial apoptotic pathway, enhancing the apoptosis level. Our findings propose a new therapeutic strategy to overcome the tumor microenvironment protection involved in B-CLL resistance to drugs, with possible clinical implications also for other hematologic and solid tumors for which ibrutinib is considered a therapeutic option. Full article
(This article belongs to the Special Issue Chronic Lymphocytic Leukemia: Therapy and Outcome)
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Review

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11 pages, 1669 KiB  
Review
CAR T Cell Therapy for Chronic Lymphocytic Leukemia: Successes and Shortcomings
by Zeljko Todorovic, Dusan Todorovic, Vladimir Markovic, Nevena Ladjevac, Natasa Zdravkovic, Predrag Djurdjevic, Nebojsa Arsenijevic, Marija Milovanovic, Aleksandar Arsenijevic and Jelena Milovanovic
Curr. Oncol. 2022, 29(5), 3647-3657; https://doi.org/10.3390/curroncol29050293 - 18 May 2022
Cited by 19 | Viewed by 4269
Abstract
Chimeric antigen receptor T (CAR T) cell therapy achieved remarkable success in B-cell leukemia and lymphoma which led to its incorporation in treatment protocols for these diseases. CAR T cell therapy for chronic lymphocytic leukemia (CLL) patients showed less success compared to other [...] Read more.
Chimeric antigen receptor T (CAR T) cell therapy achieved remarkable success in B-cell leukemia and lymphoma which led to its incorporation in treatment protocols for these diseases. CAR T cell therapy for chronic lymphocytic leukemia (CLL) patients showed less success compared to other malignant tumors. In this review, we discuss the published results regarding CAR T cell therapy of CLL, possible mechanisms of failures and expected developments. Full article
(This article belongs to the Special Issue Chronic Lymphocytic Leukemia: Therapy and Outcome)
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Other

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7 pages, 1533 KiB  
Case Report
Therapeutic Management of Chronic Lymphocytic Leukemia Presenting with Recurrent Massive Ascites
by Ugochi Ebinama, Nathaniel R. Wilson, Anindita Ghosh and Binsah S. George
Curr. Oncol. 2022, 29(10), 6787-6793; https://doi.org/10.3390/curroncol29100534 - 22 Sep 2022
Cited by 2 | Viewed by 2031
Abstract
Chronic lymphocytic leukemia (CLL) is a lymphoproliferative malignancy that is categorized by the production and accumulation of CD5+ monoclonal B cell lymphocytes, commonly in the spleen, bone marrow, and peripheral blood; these are morphologically mature lymphocytes with abnormal immune function. Ascites, although common [...] Read more.
Chronic lymphocytic leukemia (CLL) is a lymphoproliferative malignancy that is categorized by the production and accumulation of CD5+ monoclonal B cell lymphocytes, commonly in the spleen, bone marrow, and peripheral blood; these are morphologically mature lymphocytes with abnormal immune function. Ascites, although common in solid organ malignancies such as ovarian, breast, and gastrointestinal, is a rare clinical manifestation in hematological malignancies. The case presented herein describes an elderly male patient with CLL who presented with transudative ascites 7 years after the completion of chemotherapy. Microscopic analysis and flow cytometry of the patient’s ascitic fluid were consistent with CLL, and he was treated with six cycles of obinutuzumab immunotherapy with the addition of acalabrutinib, resulting in near resolution of malignant ascites. A few cases have reported CLL manifesting as transudative or exudative ascites in elderly patients. A few previous cases have reported the development of ascites between 12 and 21 months after the initial treatment of CLL with chemotherapy. A unique feature of our patient is the presentation with malignant ascites nearly 7 years after the initial CLL treatment with chemotherapy. The intent of this case report is to bring awareness of ascites as a possible initial presenting symptom of CLL in patients with isolated abdominal distention with or without common clinical features of leukemia (i.e., splenomegaly, lymphadenopathy, and B-symptoms) and the therapeutic management thereafter. Malignant ascites may be associated with relapse or the transformation of leukemia; thus, prompt diagnosis and treatment should not be delayed. Full article
(This article belongs to the Special Issue Chronic Lymphocytic Leukemia: Therapy and Outcome)
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6 pages, 696 KiB  
Case Report
Two Distinct Clinical Patterns of Ibrutinib-to-Venetoclax Transition in Relapsed Chronic Lymphocytic Leukemia Patients
by Isacco Ferrarini, Francesca Gandini, Ettore Zapparoli and Antonella Rigo
Curr. Oncol. 2022, 29(4), 2792-2797; https://doi.org/10.3390/curroncol29040227 - 15 Apr 2022
Cited by 3 | Viewed by 2408
Abstract
Patients with chronic lymphocytic leukemia (CLL) relapsing on ibrutinib are often treated with the Bcl-2 inhibitor venetoclax. However, the transition from one agent to another poses some clinical challenges due to disease flares sometimes occurring right after ibrutinib interruption. Here, we describe three [...] Read more.
Patients with chronic lymphocytic leukemia (CLL) relapsing on ibrutinib are often treated with the Bcl-2 inhibitor venetoclax. However, the transition from one agent to another poses some clinical challenges due to disease flares sometimes occurring right after ibrutinib interruption. Here, we describe three clinical vignettes highlighting two distinct patterns of ibrutinib-to-venetoclax transition. While patients following the favorable pattern transited to venetoclax without experiencing disease flare, the one patient who took the unfavorable path showed rapid disease rebound, with large-cell transformation occurring one week after ibrutinib interruption. A high burden of BTK and PLCG2 mutations was found only in patients with the favorable transition pattern, suggesting that removing BTK inhibition might be particularly harmful if CLL cells are progressing through mechanisms external to the BTK axis. Full article
(This article belongs to the Special Issue Chronic Lymphocytic Leukemia: Therapy and Outcome)
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6 pages, 2263 KiB  
Case Report
Primary Myelofibrosis Occurring during Targeted Therapy for Chronic Lymphocytic Leukemia: A Report of Two Cases
by Francesco Angotzi, Andrea Visentin, Federico Scarmozzino, Alessandro Cellini, Roberta Bertorelle, Marco Pizzi, Gianni Binotto, Angelo Paolo Dei Tos and Livio Trentin
Curr. Oncol. 2022, 29(3), 1455-1460; https://doi.org/10.3390/curroncol29030122 - 27 Feb 2022
Viewed by 2866
Abstract
The disease course of chronic lymphocytic leukemia (CLL) is frequently characterized by the occurrence of various complications, such as second primary cancer, which can impact patients’ prognoses. While therapies for CLL have evolved tremendously in the past decades, overlooking the possibility of rare [...] Read more.
The disease course of chronic lymphocytic leukemia (CLL) is frequently characterized by the occurrence of various complications, such as second primary cancer, which can impact patients’ prognoses. While therapies for CLL have evolved tremendously in the past decades, overlooking the possibility of rare neoplasms that arise along with CLL may hinder the benefit that these therapies grant to patients. Moreover, the ability of newer therapies to alter the landscape of these complications is still largely unknown. Primary myelofibrosis (PMF) is not commonly associated with CLL, with only a few cases reported in the literature, with little information regarding the clinico-biological features and the optimal management for these associated conditions. Here, we report two unusual cases of PMF that occurred a few months after the start of therapy for CLL with targeted agents (ibrutinib and venetoclax). Both cases represented a diagnostic and therapeutic challenge, underscoring the need for clinicians to remain vigilant about the possible co-occurrence of these two hematological malignancies, especially in the era of targeted therapy for CLL. Full article
(This article belongs to the Special Issue Chronic Lymphocytic Leukemia: Therapy and Outcome)
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