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Advances in the Treatment of Chronic Lymphocytic Leukemia
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Advances in the Treatment of Chronic Lymphocytic Leukemia

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

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 21310

Special Issue Editor

Prof. Dr. Monia Marchetti

E-Mail Website
Guest Editor
Haematology and Transplant Unit, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo,15121 Alessandria, Italy
Interests: chronic myeloproliferative neoplasms; acute myeloid leukemia; anti-cancer vaccines; immune responses to COVID-19 vaccines in patients with hematologic diseases; evidence-based medicine; clinical practice guidelines; pharmacoeconomic analysis; decision analysis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

B-cell chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder in western countries and several treatment options have been recently introduced into the clinical care for patients developing signs or symptoms of the disease. The efficacy of chemotherapy-free therapies is dramatically improving in clinical trials and prognostication of CLL has been greatly enhanced by molecular markers which are currently the major drivers of therapeutic decisions. Nevertheless, transferability of such results to the real practice is still debated and proof of sustainability is often pending. Moreover, the approval of new drugs is delayed in some countries, causing a huge heterogeneity in the treatment pathways. Finally, patients who fail pharmacologic therapies or who are forecasted to face a dismal prognosis are still recommended to undergo cellular therapies: allogeneic as well as autologous (CAR-T) therapies are rapidly evolving, therefore the selection criteria of patients need to be updated accordingly.

This special issue addresses recently approved and future treatments for CLL particularly focusing onto hurdles limiting the implementation of best therapies.

Dr. Monia Marchetti
Guest Editor

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Keywords

  • Chronic Lymphocytic Leukemia
  • BTK-Inhibitors
  • Venetoclax
  • Obinutuzumab
  • Allogeneic Stem Cell Transplant
  • CAR-T
  • Cost-Effectiveness
  • Meta-Analysis
  • Real-World Evidence

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Published Papers (7 papers)

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Research

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10 pages, 965 KiB  
Article
Long-Term Efficacy and Safety of Ibrutinib in the Treatment of CLL Patients: A Real Life Experience
by Alessandro Broccoli, Lisa Argnani, Alice Morigi, Laura Nanni, Beatrice Casadei, Cinzia Pellegrini, Vittorio Stefoni and Pier Luigi Zinzani
J. Clin. Med. 2021, 10(24), 5845; https://doi.org/10.3390/jcm10245845 - 13 Dec 2021
Cited by 9 | Viewed by 2804
Abstract
Ibrutinib has demonstrated a significant clinical impact in patients with de novo and relapsed/refractory chronic lymphocytic leukemia (CLL), even in cases with unfavorable cytogenetics and molecular markers. All CLL patients’ data treated at our Institute with ibrutinib have been retrospectively reviewed. Forty-six patients [...] Read more.
Ibrutinib has demonstrated a significant clinical impact in patients with de novo and relapsed/refractory chronic lymphocytic leukemia (CLL), even in cases with unfavorable cytogenetics and molecular markers. All CLL patients’ data treated at our Institute with ibrutinib have been retrospectively reviewed. Forty-six patients received ibrutinib either as frontline (10) or second or more advanced treatment (36). Five patients presented with TP53 mutations; 11 had the deletion of chromosome 17p; 17 displayed an unmutated immunoglobulin variable heavy chain status. The median number of cycles administered was 26. Among patients treated frontline, the best overall response rate (ORR) was 90.0%. In patients receiving ibrutinib as a second or later line ORR was 97.2%. Median progression-free survival was 28.8 and 21.1 months for patients treated frontline and as second/later line, respectively. Median overall survival was not reached for those treated frontline and resulted in 4.9 years for patients treated as second/later line. Grade 3–4 hematological toxicities were neutropenia, thrombocytopenia, and anemia. Grade 3–4 extrahematological toxicities included diarrhea, cutaneous rash, utero-vesical prolapse, vasculitis, and sepsis. Ibrutinib is effective and well tolerated in CLL. Responses obtained in a real-life setting are durable and the safety profile of the drug is favorable. Full article
(This article belongs to the Special Issue Advances in the Treatment of Chronic Lymphocytic Leukemia)
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8 pages, 736 KiB  
Article
Driver Mutations and Single Copy Number Abnormalities Identify Binet Stage A Patients with Chronic Lymphocytic Leukemia with Aggressive Progression
by Ana P. Gonzalez-Rodriguez, Angel R. Payer, Juan J. Menendez-Suarez, Christian Sordo-Bahamonde, Seila Lorenzo-Herrero, Joud Zanabili, Ariana Fonseca, Ana Julia Gonzalez-Huerta, Pilar Palomo and Segundo Gonzalez
J. Clin. Med. 2020, 9(11), 3695; https://doi.org/10.3390/jcm9113695 - 17 Nov 2020
Cited by 2 | Viewed by 2454
Abstract
The correlation between progression and the genetic characteristics of Binet stage A patients with chronic lymphocytic leukemia (CLL) detected by whole exome sequencing (WES) was analyzed in 55 patients. The median follow-up for the patients was 102 months. During the follow-up, 24 patients [...] Read more.
The correlation between progression and the genetic characteristics of Binet stage A patients with chronic lymphocytic leukemia (CLL) detected by whole exome sequencing (WES) was analyzed in 55 patients. The median follow-up for the patients was 102 months. During the follow-up, 24 patients (43%) progressed. Univariate Cox analysis showed that the presence of driver mutations, the accumulation of two or more mutations, the presence of adverse mutations, immunoglobulin heavy chain genes (IGHV) mutation status and unfavorable single copy number abnormalities (SCNAs) were associated with a higher risk of progression. Particularly, the occurrence of an adverse mutation and unfavorable SCNAs increased the risk of progression nine-fold and five-fold, respectively. Nevertheless, only the occurrence of adverse mutations retained statistical significance in the multivariate analysis. All patients carrying an unfavorable mutation progressed with a median progression-free survival (PFS) of 29 months. The accumulation of two or more mutations also increased the risk of progression with a median PFS of 29 months. The median PFS of patients with unfavorable SCNAs was 38 months. Combining mutations and SCNAs, patients may be stratified into three groups with different prognostic outcomes: adverse (17% probability of five-year PFS), protective (86% probability of five-year PFS) and neither (62% probability of five-year PFS, p < 0.001). Overall, the analysis of the mutational status of patients with CLL at an early stage of the disease may allow the identification of patients with a high risk of progression. The feasibility of an early therapeutic intervention in these particular patients requires further investigation. Full article
(This article belongs to the Special Issue Advances in the Treatment of Chronic Lymphocytic Leukemia)
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Review

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23 pages, 826 KiB  
Review
Old and New Drugs for Chronic Lymphocytic Leukemia: Lights and Shadows of Real-World Evidence
by Monia Marchetti, Candida Vitale, Gian Matteo Rigolin, Alessandra Vasile, Andrea Visentin, Lydia Scarfò, Marta Coscia and Antonio Cuneo
J. Clin. Med. 2022, 11(8), 2076; https://doi.org/10.3390/jcm11082076 - 7 Apr 2022
Cited by 7 | Viewed by 2956
Abstract
Several novel treatments for chronic lymphocytic leukemia (CLL) have been recently approved based on the results of randomized clinical trials. However, real-world evidence (RWE) is also requested before and after drug authorization in order to confirm safety and to provide data for health [...] Read more.
Several novel treatments for chronic lymphocytic leukemia (CLL) have been recently approved based on the results of randomized clinical trials. However, real-world evidence (RWE) is also requested before and after drug authorization in order to confirm safety and to provide data for health technology assessments. We conducted a scoping review of the available RWE for targeted treatments of CLL, namely ibrutinib, acalabrutinib, idelalisib, and venetoclax, as well as for chemoimmunotherapy (CIT). In particular, we searched studies published since 1 January 2010 and reported outcomes of the above treatments based on health databases, registries, or phase IV studies, including named-patient programs. We included both full papers and abstracts of studies presented at major meetings. Overall, 110 studies were selected and analyzed: 28,880 patients were treated with ibrutinib, 1424 with idelalisib, 751 with venetoclax, 496 with acalabrutinib, and 14,896 with CIT. Reported discontinuation rates were higher than in clinical trials, while effectiveness could not be indirectly compared with clinical trials since a detailed case mix, including cytogenetic risk factors, was partially available and propensity scores rarely applied. RWE on CLL can help to set realistic outcomes with novel treatments, however, real-world studies should be fostered, and available data shared. Full article
(This article belongs to the Special Issue Advances in the Treatment of Chronic Lymphocytic Leukemia)
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13 pages, 549 KiB  
Review
Comparative Clinical Value of Pharmacologic Therapies for B-Cell Chronic Lymphocytic Leukemia: An Umbrella Analysis
by Monia Marchetti, Paolo Rivela, Claudia Bertassello and Manuela Canicattì
J. Clin. Med. 2022, 11(7), 1868; https://doi.org/10.3390/jcm11071868 - 28 Mar 2022
Cited by 1 | Viewed by 2635
Abstract
Several new drugs are progressively improving the life span of patients with B-cell chronic lymphocytic leukemia (CLL). However, the rapidly evolving standard of care precludes robust assessments of the incremental clinical value of further innovative drugs. Therefore, we systematically reviewed comparative evidence on [...] Read more.
Several new drugs are progressively improving the life span of patients with B-cell chronic lymphocytic leukemia (CLL). However, the rapidly evolving standard of care precludes robust assessments of the incremental clinical value of further innovative drugs. Therefore, we systematically reviewed comparative evidence on newly authorized CLL drugs, as reported by standard and network meta-analyses (MA) published since 2016. Overall, 17 MAs addressed the relative survival or safety of naïve and/or refractory/relapsed (R/R) CLL patients. In R/R patients, therapies including BTK- and BCL2-inhibitors reported progression free survival (PFS) hazard ratios ranging from 0.08 to 0.24 (versus chemotherapy) and a significant advantage in overall survival (OS). In naïve patients, the PFS hazard ratios associated with four recent chemo-free therapies (obinutuzumab- and/or acalabrutinib-based) ranged from 0.11 to 0.61 versus current standard treatments (STs), without a significant OS advantage. Ten MAs addressed the risk of cardiovascular, bleeding, and infective events associated with BTK inhibitors, with some reporting a different relative safety in naïve and R/R patients. In conclusion, last-generation therapies for CLL consistently increase PFS, but not OS, and minimally decrease safety, as compared with STs. Based on available evidence, the patient-customized adoption of new therapies, rather than universal recommendations, seems desirable in CLL patients. Full article
(This article belongs to the Special Issue Advances in the Treatment of Chronic Lymphocytic Leukemia)
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17 pages, 302 KiB  
Review
Treatment Options for Elderly/Unfit Patients with Chronic Lymphocytic Leukemia in the Era of Targeted Drugs: A Comprehensive Review
by Alberto Fresa, Francesco Autore, Eugenio Galli, Annamaria Tomasso, Luca Stirparo, Idanna Innocenti and Luca Laurenti
J. Clin. Med. 2021, 10(21), 5104; https://doi.org/10.3390/jcm10215104 - 30 Oct 2021
Cited by 4 | Viewed by 2992
Abstract
Chronic lymphocytic leukemia (CLL) incidence increases with age reaching 37.9/100,000 in patients over 85 years. Although there is no standardized geriatric tool specifically validated for CLL, a correct framing of the fitness status is of critical importance to individualize treatment strategies. Based on [...] Read more.
Chronic lymphocytic leukemia (CLL) incidence increases with age reaching 37.9/100,000 in patients over 85 years. Although there is no standardized geriatric tool specifically validated for CLL, a correct framing of the fitness status is of critical importance to individualize treatment strategies. Based on the evidence available to date, frontline chemoimmunotherapy has an increasingly narrowing application, being eligible for candidacy only in elderly fit patients without or with minimal geriatric syndromes. On the other hand, treatment with BCR inhibitors, monotherapy, or in combination with anti-CD20 antibodies (e.g., obinutuzumab), must be preferred both for frontline and relapsed CLL not only in unfit patients, but also in fit patients with unmutated IGHV or harboring del(17p) and/or TP53 mutations/deletions. Second-generation inhibitors (e.g., acalabrutinib, zanubrutinib, pirtobrutinib) are novel compounds that, due to their better safety profile and different specificity, will help physicians overcome some of the safety issues and treatment resistances. In the era of targeted therapies, treatment decisions in elderly and/or unfit patients with CLL must be a balance between efficacy and safety, carefully evaluating comorbidities and geriatric syndromes to ensure the best approach to improve both quality of life and life expectancy. Full article
(This article belongs to the Special Issue Advances in the Treatment of Chronic Lymphocytic Leukemia)
11 pages, 786 KiB  
Review
Perspectives on Precision Medicine in Chronic Lymphocytic Leukemia: Targeting Recurrent Mutations—NOTCH1, SF3B1, MYD88, BIRC3
by Maciej Putowski and Krzysztof Giannopoulos
J. Clin. Med. 2021, 10(16), 3735; https://doi.org/10.3390/jcm10163735 - 22 Aug 2021
Cited by 8 | Viewed by 4126
Abstract
Chronic lymphocytic leukemia (CLL) is highly heterogeneous, with extremely variable clinical course. The clinical heterogeneity of CLL reflects differences in the biology of the disease, including chromosomal alterations, specific immunophenotypic patterns and serum markers. The application of next-generation sequencing techniques has demonstrated the [...] Read more.
Chronic lymphocytic leukemia (CLL) is highly heterogeneous, with extremely variable clinical course. The clinical heterogeneity of CLL reflects differences in the biology of the disease, including chromosomal alterations, specific immunophenotypic patterns and serum markers. The application of next-generation sequencing techniques has demonstrated the high genetic and epigenetic heterogeneity in CLL. The novel mutations could be pharmacologically targeted for individualized approach in some of the CLL patients. Potential neurogenic locus notch homolog protein 1 (NOTCH1) signalling targeting mechanisms in CLL include secretase inhibitors and specific antibodies to block NOTCH ligand/receptor interactions. In vitro studies characterizing the effect of the splicing inhibitors resulted in increased apoptosis of CLL cells regardless of splicing factor 3B subunit 1 (SF3B1) status. Several therapeutic strategies have been also proposed to directly or indirectly inhibit the toll-like receptor/myeloid differentiation primary response gene 88 (TLR/MyD88) pathway. Another potential approach is targeting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and inhibition of this prosurvival pathway. Newly discovered mutations and their signalling pathways play key roles in the course of the disease. This opens new opportunities in the management and treatment of CLL. Full article
(This article belongs to the Special Issue Advances in the Treatment of Chronic Lymphocytic Leukemia)
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8 pages, 443 KiB  
Review
Will New Drugs Replace Transplants for Chronic Lymphocytic Leukaemia?
by Shenmiao Yang, Xiaojun Huang and Robert Peter Gale
J. Clin. Med. 2021, 10(11), 2516; https://doi.org/10.3390/jcm10112516 - 7 Jun 2021
Viewed by 2185
Abstract
Transplants have been used to treat chronic lymphocytic leukemia (CLL) for more than 35 years. Use has been restricted to <1 percent of highly selected persons typically failing concurrent conventional therapies. As therapies of CLL have evolved, so have indications for transplantation and [...] Read more.
Transplants have been used to treat chronic lymphocytic leukemia (CLL) for more than 35 years. Use has been restricted to <1 percent of highly selected persons typically failing concurrent conventional therapies. As therapies of CLL have evolved, so have indications for transplantation and transplant techniques. The data that we review indicate that transplants can result in long-term leukemia-free survival in some persons but are associated with substantial transplant-related morbidity and mortality. We discuss the mechanisms underlying the anti-leukemia effects of transplants including drugs, ionizing radiations, immune-mediated mechanisms and/or a combination. We discuss prognostic and predicative covariates for transplant outcomes. Importantly, we consider whether there is presently a role of transplants in CLL and who, if anyone, is an appropriate candidate in the context of new drugs. Full article
(This article belongs to the Special Issue Advances in the Treatment of Chronic Lymphocytic Leukemia)
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