Dataset Information

Analysis of Data on Fludarabine, Cyclophosphamide, and Rituximab Chemoimmunotherapy for Chronic Lymphocytic Leukemia Shows High Patient Heterogeneity and the Need for More Consideration of Individualized Treatment.

ABSTRACT:

Methods

Data from single-cell RNA sequencing (RNA-seq) of CLL patients were obtained from the Gene Expression Omnibus database. The R package was utilized to analyze the data, and the relation of results was predicted via the GeneMANIA website. The information of 7 samples covered three stages: observation stage, pretreatment by CIT with rituximab, fludarabine, and cyclophosphamide (pre-CIT), and post-CIT. The differentially expressed genes (DEGs) were identified, and functional enrichment analyses were performed. B cell subpopulations and pseudotime trajectories analysis was conducted.

Results

A total of 70,659 DEGs were identified. Each patient's DEGs presented their own characteristics, with low similarity. Therefore, it is difficult to identify potential hub genes. Similarly, pathway enrichment analysis showed significant tumor heterogeneity among CLL patients. Analysis of relapsed post-CIT compared to the observation stage suggested that the TP53 pathway should be taken seriously as it is closely related to treatment strategy and patient prognosis.

Conclusions

Tumor heterogeneity may be a more common manifestation of CLL. Individualized treatment should be considered for CLL. TP53 abnormality and its regulatory factors should still be the focus of CLL diagnosis and treatment.

SUBMITTER: Xu X

PROVIDER: S-EPMC9550475 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Analysis of Data on Fludarabine, Cyclophosphamide, and Rituximab Chemoimmunotherapy for Chronic Lymphocytic Leukemia Shows High Patient Heterogeneity and the Need for More Consideration of Individualized Treatment.

Xu Xiaoli X Zhao Ying Y Ye Haiyan H Qi Yonglei Y Xu Wenning W Ling Yiwen Y Yang Shaojiang S

Computational and mathematical methods in medicine 20221003

<h4>Methods</h4>Data from single-cell RNA sequencing (RNA-seq) of CLL patients were obtained from the Gene Expression Omnibus database. The R package was utilized to analyze the data, and the relation of results was predicted via the GeneMANIA website. The information of 7 samples covered three stages: observation stage, pretreatment by CIT with rituximab, fludarabine, and cyclophosphamide (pre-CIT), and post-CIT. The differentially expressed genes (DEGs) were identified, and functional enrichme ...[more]

PMID: 36226246

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Project description:BackgroundFludarabine, cyclophosphamide, and rituximab (FCR) has become a gold-standard chemoimmunotherapy regimen for patients with chronic lymphocytic leukaemia. However, the question remains of how to treat treatment-naive patients with IGHV-unmutated chronic lymphocytic leukaemia. We therefore aimed to develop and validate a gene expression signature to identify which of these patients are likely to achieve durable remissions with FCR chemoimmunotherapy.MethodsWe did a retrospective cohort study in two cohorts of treatment-naive patients (aged ≥18 years) with chronic lymphocytic leukaemia. The discovery and training cohort consisted of peripheral blood samples collected from patients treated at the University of Texas MD Anderson Cancer Center (Houston, TX, USA), who fulfilled the diagnostic criteria of the International Workshop on Chronic Lymphocytic Leukemia, had received at least three cycles of FCR chemoimmunotherapy, and had been treated between Oct 10, 2000, and Oct 26, 2006 (ie, the MDACC cohort). We did transcriptional profiling on samples obtained from the MDACC cohort to identify genes associated with time to progression. We did univariate Cox proportional hazards analyses and used significant genes to cluster IGHV-unmutated samples into two groups (intermediate prognosis and unfavourable prognosis). After using cross-validation to assess robustness, we applied the Lasso method to standardise the gene expression values to find a minimum gene signature. We validated this signature in an external cohort of treatment-naive patients with IGHV-unmutated chronic lymphocytic leukaemia enrolled on the CLL8 trial of the German Chronic Lymphocytic Leukaemia Study Group who were treated between July 21, 2003, and April 4, 2006 (ie, the CLL8 cohort).FindingsThe MDACC cohort consisted of 101 patients and the CLL8 cohort consisted of 109 patients. Using the MDACC cohort, we identified and developed a 17-gene expression signature that distinguished IGHV-unmutated patients who were likely to achieve a long-term remission following front-line FCR chemoimmunotherapy from those who might benefit from alternative front-line regimens (hazard ratio 3·83, 95% CI 1·94-7·59; p<0·0001). We validated this gene signature in the CLL8 cohort; patients with an unfavourable prognosis versus those with an intermediate prognosis had a cause-specific hazard ratio of 1·90 (95% CI 1·18-3·06; p=0·008). Median time to progression was 39 months (IQR 22-69) for those with an unfavourable prognosis compared with 59 months (28-84) for those with an intermediate prognosis.InterpretationWe have developed a robust, reproducible 17-gene signature that identifies a subset of treatment-naive patients with IGHV-unmutated chronic lymphocytic leukaemia who might substantially benefit from treatment with FCR chemoimmunotherapy. We recommend testing the value of this gene signature in a prospective study that compares FCR treatment with newer alternative therapies as part of a randomised clinical trial.FundingChronic Lymphocytic Leukaemia Global Research Foundation and the National Institutes of Health/National Cancer Institute.

Project description:BackgroundData regarding the efficacy of treatment with ibrutinib-rituximab, as compared with standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, in patients with previously untreated chronic lymphocytic leukemia (CLL) have been limited.MethodsIn a phase 3 trial, we randomly assigned (in a 2:1 ratio) patients 70 years of age or younger with previously untreated CLL to receive either ibrutinib and rituximab for six cycles (after a single cycle of ibrutinib alone), followed by ibrutinib until disease progression, or six cycles of chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. The primary end point was progression-free survival, and overall survival was a secondary end point. We report the results of a planned interim analysis.ResultsA total of 529 patients underwent randomization (354 patients to the ibrutinib-rituximab group, and 175 to the chemoimmunotherapy group). At a median follow-up of 33.6 months, the results of the analysis of progression-free survival favored ibrutinib-rituximab over chemoimmunotherapy (89.4% vs. 72.9% at 3 years; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.22 to 0.56; P<0.001), and the results met the protocol-defined efficacy threshold for the interim analysis. The results of the analysis of overall survival also favored ibrutinib-rituximab over chemoimmunotherapy (98.8% vs. 91.5% at 3 years; hazard ratio for death, 0.17; 95% CI, 0.05 to 0.54; P<0.001). In a subgroup analysis involving patients without immunoglobulin heavy-chain variable region (IGHV) mutation, ibrutinib-rituximab resulted in better progression-free survival than chemoimmunotherapy (90.7% vs. 62.5% at 3 years; hazard ratio for progression or death, 0.26; 95% CI, 0.14 to 0.50). The 3-year progression-free survival among patients with IGHV mutation was 87.7% in the ibrutinib-rituximab group and 88.0% in the chemoimmunotherapy group (hazard ratio for progression or death, 0.44; 95% CI, 0.14 to 1.36). The incidence of adverse events of grade 3 or higher (regardless of attribution) was similar in the two groups (in 282 of 352 patients [80.1%] who received ibrutinib-rituximab and in 126 of 158 [79.7%] who received chemoimmunotherapy), whereas infectious complications of grade 3 or higher were less common with ibrutinib-rituximab than with chemoimmunotherapy (in 37 patients [10.5%] vs. 32 [20.3%], P<0.001).ConclusionsThe ibrutinib-rituximab regimen resulted in progression-free survival and overall survival that were superior to those with a standard chemoimmunotherapy regimen among patients 70 years of age or younger with previously untreated CLL. (Funded by the National Cancer Institute and Pharmacyclics; E1912 ClinicalTrials.gov number, NCT02048813.).

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Dataset Information

Analysis of Data on Fludarabine, Cyclophosphamide, and Rituximab Chemoimmunotherapy for Chronic Lymphocytic Leukemia Shows High Patient Heterogeneity and the Need for More Consideration of Individualized Treatment.

Methods

Results

Conclusions

Publications

Analysis of Data on Fludarabine, Cyclophosphamide, and Rituximab Chemoimmunotherapy for Chronic Lymphocytic Leukemia Shows High Patient Heterogeneity and the Need for More Consideration of Individualized Treatment.

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