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Molecular-Biology-Driven Frontline Treatment for Chronic Lymphocytic Leukemia: A Network Meta-Analysis of Randomized Clinical Trials

The treatment of chronic lymphocytic leukemia (CLL) currently relies on the use of chemo-immunotherapy, Bruton’s tyrosine kinase inhibitors, or BCL2 inhibitors alone or combined with an anti-CD20 monoclonal antibody. However, the availability of multiple choices for the first-line setting and a lack...

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Autores principales: Rizzuto, Andrea, Pirrera, Angelo, Gigliotta, Emilia, Mancuso, Salvatrice, Vullo, Candida, Camarda, Giulia Maria, Rotolo, Cristina, Roppolo, Arianna, Spoto, Corinne, Gentile, Massimo, Botta, Cirino, Siragusa, Sergio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10298034/
https://www.ncbi.nlm.nih.gov/pubmed/37373078
http://dx.doi.org/10.3390/ijms24129930
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author Rizzuto, Andrea
Pirrera, Angelo
Gigliotta, Emilia
Mancuso, Salvatrice
Vullo, Candida
Camarda, Giulia Maria
Rotolo, Cristina
Roppolo, Arianna
Spoto, Corinne
Gentile, Massimo
Botta, Cirino
Siragusa, Sergio
author_facet Rizzuto, Andrea
Pirrera, Angelo
Gigliotta, Emilia
Mancuso, Salvatrice
Vullo, Candida
Camarda, Giulia Maria
Rotolo, Cristina
Roppolo, Arianna
Spoto, Corinne
Gentile, Massimo
Botta, Cirino
Siragusa, Sergio
author_sort Rizzuto, Andrea
collection PubMed
description The treatment of chronic lymphocytic leukemia (CLL) currently relies on the use of chemo-immunotherapy, Bruton’s tyrosine kinase inhibitors, or BCL2 inhibitors alone or combined with an anti-CD20 monoclonal antibody. However, the availability of multiple choices for the first-line setting and a lack of direct head-to-head comparisons pose a challenge for treatment selection. To overcome these limitations, we performed a systematic review and a network meta-analysis on published randomized clinical trials performed in the first-line treatment setting of CLL. For each study, we retrieved data on progression-free survival (according to del17/P53 and IGHV status), overall response rate, complete response, and incidence of most frequent grade 3–4 adverse event. We identified nine clinical trials encompassing 11 different treatments, with a total of 5288 CLL patients evaluated. We systematically performed separated network meta-analyses (NMA) to evaluate the efficacy/safety of each regimen in the conditions previously described to obtain the surface under the cumulative ranking curve (SUCRA) score, which was subsequently used to build separated ranking charts. Interestingly, the combination of obinutuzumab with acalabrutinib reached the top of the chart in each sub-analysis performed, with the exception of the del17/P53mut setting, where it was almost on par with the aCD20 mAbs/ibrutinib combination (SUCRA aCD20-ibrutinib and O-acala: 93.5% and 91%, respectively) and of the safety evaluation, where monotherapies (acalabrutinib in particular) gave better results. Finally, considering that NMA and SUCRA work for single endpoints only, we performed a principal component analysis to recapitulate in a cartesian plane the SUCRA profiles of each schedule according to the results obtained in each sub-analysis, confirming again the superiority of aCD20/BTKi or BCL2i combinations in a first-line setting. Overall, here we demonstrated that: (1) a chemotherapy-free regimen, such as the combination of aCD20 with a BTKi or BCL2i, should be the preferred treatment choice despite biological/molecular characteristics (preferred regimen O-acala); (2) there is less and less room for chemotherapy in the first line treatment of CLL.
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spelling pubmed-102980342023-06-28 Molecular-Biology-Driven Frontline Treatment for Chronic Lymphocytic Leukemia: A Network Meta-Analysis of Randomized Clinical Trials Rizzuto, Andrea Pirrera, Angelo Gigliotta, Emilia Mancuso, Salvatrice Vullo, Candida Camarda, Giulia Maria Rotolo, Cristina Roppolo, Arianna Spoto, Corinne Gentile, Massimo Botta, Cirino Siragusa, Sergio Int J Mol Sci Article The treatment of chronic lymphocytic leukemia (CLL) currently relies on the use of chemo-immunotherapy, Bruton’s tyrosine kinase inhibitors, or BCL2 inhibitors alone or combined with an anti-CD20 monoclonal antibody. However, the availability of multiple choices for the first-line setting and a lack of direct head-to-head comparisons pose a challenge for treatment selection. To overcome these limitations, we performed a systematic review and a network meta-analysis on published randomized clinical trials performed in the first-line treatment setting of CLL. For each study, we retrieved data on progression-free survival (according to del17/P53 and IGHV status), overall response rate, complete response, and incidence of most frequent grade 3–4 adverse event. We identified nine clinical trials encompassing 11 different treatments, with a total of 5288 CLL patients evaluated. We systematically performed separated network meta-analyses (NMA) to evaluate the efficacy/safety of each regimen in the conditions previously described to obtain the surface under the cumulative ranking curve (SUCRA) score, which was subsequently used to build separated ranking charts. Interestingly, the combination of obinutuzumab with acalabrutinib reached the top of the chart in each sub-analysis performed, with the exception of the del17/P53mut setting, where it was almost on par with the aCD20 mAbs/ibrutinib combination (SUCRA aCD20-ibrutinib and O-acala: 93.5% and 91%, respectively) and of the safety evaluation, where monotherapies (acalabrutinib in particular) gave better results. Finally, considering that NMA and SUCRA work for single endpoints only, we performed a principal component analysis to recapitulate in a cartesian plane the SUCRA profiles of each schedule according to the results obtained in each sub-analysis, confirming again the superiority of aCD20/BTKi or BCL2i combinations in a first-line setting. Overall, here we demonstrated that: (1) a chemotherapy-free regimen, such as the combination of aCD20 with a BTKi or BCL2i, should be the preferred treatment choice despite biological/molecular characteristics (preferred regimen O-acala); (2) there is less and less room for chemotherapy in the first line treatment of CLL. MDPI 2023-06-09 /pmc/articles/PMC10298034/ /pubmed/37373078 http://dx.doi.org/10.3390/ijms24129930 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Rizzuto, Andrea
Pirrera, Angelo
Gigliotta, Emilia
Mancuso, Salvatrice
Vullo, Candida
Camarda, Giulia Maria
Rotolo, Cristina
Roppolo, Arianna
Spoto, Corinne
Gentile, Massimo
Botta, Cirino
Siragusa, Sergio
Molecular-Biology-Driven Frontline Treatment for Chronic Lymphocytic Leukemia: A Network Meta-Analysis of Randomized Clinical Trials
title Molecular-Biology-Driven Frontline Treatment for Chronic Lymphocytic Leukemia: A Network Meta-Analysis of Randomized Clinical Trials
title_full Molecular-Biology-Driven Frontline Treatment for Chronic Lymphocytic Leukemia: A Network Meta-Analysis of Randomized Clinical Trials
title_fullStr Molecular-Biology-Driven Frontline Treatment for Chronic Lymphocytic Leukemia: A Network Meta-Analysis of Randomized Clinical Trials
title_full_unstemmed Molecular-Biology-Driven Frontline Treatment for Chronic Lymphocytic Leukemia: A Network Meta-Analysis of Randomized Clinical Trials
title_short Molecular-Biology-Driven Frontline Treatment for Chronic Lymphocytic Leukemia: A Network Meta-Analysis of Randomized Clinical Trials
title_sort molecular-biology-driven frontline treatment for chronic lymphocytic leukemia: a network meta-analysis of randomized clinical trials
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10298034/
https://www.ncbi.nlm.nih.gov/pubmed/37373078
http://dx.doi.org/10.3390/ijms24129930
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