The impact of increasing karyotypic complexity and evolution on survival in patients with CLL treated with ibrutinib

Kittai, Adam; Miller, Cecelia; Goldstein, Daniel; Huang, Ying; Abruzzo, Lynne V.; Beckwith, Kyle A.; Bhat, Seema A.; Bond, David A.; Grever, Michael R.; Heerema, Nyla A.; Rogers, Kerry A.; Ruppert, Amy S.; Byrd, John C.; Woyach, Jennifer A.

doi:10.1182/blood.2020010536

Cited by 43 publications

(44 citation statements)

References 40 publications

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“…Nevertheless, the low number of high-CK (5%) at least at front-line treatment underscores the need for large population-studies, since it will be difficult to recruit the required number of patients with high-CK in the context of a clinical trial in order to reach statistical significance. Following this approach, it was recently reported that increasing cytogenetic complexity was an independent predictor of shorter PFS [HR1.07 (95% CI 1.04–1.10), p <0.0001] and overall survival [HR 1.09 (95% CI 1.05–1.12), p <0.0001] for patients treated with ibrutinib ( 46 ).…”

Section: Discussionmentioning

confidence: 99%

Biology and Treatment of High-Risk CLL: Significance of Complex Karyotype

2021

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Several reports highlight the clinical significance of cytogenetic complexity, namely, complex karyotype (CK) identified though the performance of chromosome banding analysis (CBA) in chronic lymphocytic leukemia. Indeed, apart from a number of studies underscoring the prognostic and predictive value of CK in the chemo(immune)therapy era, mounting evidence suggests that CK could serve as an independent prognosticator and predictor even in patients treated with novel agents. In the present review, we provide an overview of the current knowledge regarding the clinical impact of CK in CLL, touching upon open issues related to the incorporation of CK in the clinical setting.

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Section: Discussionmentioning

confidence: 99%

Biology and Treatment of High-Risk CLL: Significance of Complex Karyotype

2021

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“…Analysis of the sequenced capture genes identified mutations in 35 patients (Figure 3). Thirty nine TP53 mutations were detected in 16 patients (16%) with a median of 1 mutation per patient (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) and a median allele frequency of 4% (1-90). The patient who had 15 TP53 mutations did not display CNA for this gene.…”

Section: Oncogene Variants Analysismentioning

confidence: 99%

Reliable one-step assessment of IGHV mutational status and gene mutations in Chronic Lymphocytic Leukemia by capture-based high throughput sequencing

Bris

Thonier

Menard

et al. 2022

Preprint

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Proper management of chronic lymphocytic leukemia (CLL) patients requiring therapy relies on two important prognostic and theranostic molecular features: respectively, the mutational status of tumoral cells immunoglobulin heavy chain variable domain (IGHV) and the characteristics of TP53. Both these (immuno)genetic analyses require multiple time-consuming amplification and sequencing techniques by Sanger or HTS. The capture-HTS technology, allowing to select regions of interest, represents an attractive alternative and has already been applied for the detection of clonality in lymphoproliferative disorders. Here, a single-step capture design was developed to concomitantly investigate for IGHV and TP53. This was applied to a training retrospective (n=14) and a validation prospective (n=91) cohorts of CLL patients. The training cohort demonstrated the robustness of the method by comparison with the classical Sanger sequencing technology (100% identical results) for the IGHV mutational status. This consistency was confirmed for the first 59 patients of the validation cohort. Overall, the IGHV status of whole population (n=103) was accurately identified. Simultaneously, deletion or mutations of TP53 were identified from the same capture-library and HTS-sequencing run for each patient. This novel approach provides, in a single assay, useful answers about the molecular landscape of CLL patients, allowing for a documented choice of therapy.

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“…55 However, when considering predicting PFS, the model reported by Ahn et al, which included del(17p)/TP53 mutations, was more accurate than the BALL score. 56 More recently, in an attempt to better define clinical implications of karyotype complexity in the setting of patients treated with ibrutinib, Kittai et al 57 analyzed a patient cohort including both treatment naïve (TN) or relapsed/refractory (R/R) CLL patients treated at Ohio State University. In a multivariable analysis, increasing karyotypic complexity was an independent predictor of shorter PFS and OS.…”

Section: Prognostic Models In the Era Of Targeted Agentsmentioning

confidence: 99%

“…Importantly, this study demonstrated for the first time that karyotypic complexity, which acts as a continuous variable, should be incorporated in future models predicting clinical outcomes of CLL patients, especially if treated with BTK inhibitors. 57 In the era of targeted therapy, the development of prognostic models is still an ongoing process and will undoubtedly lead us to new questions that will need to be solved. Another area for further study relates to using these models in the context of combination therapy versus monotherapy.…”

Section: Prognostic Models In the Era Of Targeted Agentsmentioning

confidence: 99%

A perspective on prognostic models in chronic lymphocytic leukemia in the era of targeted agents

Molica

Seymour

Polliack

2021

Hematological Oncology

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Despite the increase in the number of prognostic models currently available for evaluating patients with chronic lymphocytic leukemia (CLL), their current application and utilization in clinical practice in the era of targeted agents is unclear. A critical reappraisal of recently developed prognostic models is presented in this review. The underlying CLL's genetic instability and changes in the host's health and comorbidities can all contribute to the acquisition of additional risk factors for adverse outcomes during the course of the disease. Therefore, available risk models solely based on pretreatment variables only partially predict patients' clinical outcome. A dynamic prognostic model that takes into account changes in the risk profile over time could indeed be useful in routine clinical practice. The next generation of risk assessment models should incorporate post-treatment and response biomarkers such as minimal residual disease. Finally, recent advances in the field of machine learning present novel opportunities to generate models capable of providing an individualized estimation of clinical outcomes in CLL. However, in the era of improved prognostic models, it is important to remember that these indices should supplement but not replace clinical expertise and medical decision-making.

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The impact of increasing karyotypic complexity and evolution on survival in patients with CLL treated with ibrutinib

Cited by 43 publications

References 40 publications

Biology and Treatment of High-Risk CLL: Significance of Complex Karyotype

Biology and Treatment of High-Risk CLL: Significance of Complex Karyotype

Reliable one-step assessment of IGHV mutational status and gene mutations in Chronic Lymphocytic Leukemia by capture-based high throughput sequencing

A perspective on prognostic models in chronic lymphocytic leukemia in the era of targeted agents

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