Multivariate transcriptome analysis identifies networks and key drivers of chronic lymphocytic leukemia relapse risk and patient survival

Abstract Background Chronic lymphocytic leukemia (CLL) is an indolent heme malignancy characterized by the accumulation of CD5+ CD19+ B cells and episodes of relapse. The biological signaling that influence episodes of relapse in CLL are not fully described. Here, we identify gene networks associated with CLL relapse and survival risk. Methods Networks were investigated by using a novel weighted gene network co-expression analysis method and examining overrepresentation of upstream regulators and signaling pathways within co-expressed transcriptome modules across clinically annotated transcriptomes from CLL patients (N = 203). Gene Ontology analysis was used to identify biological functions overrepresented in each module. Differential Expression of modules and individual genes was assessed using an ANOVA (Binet Stage A and B relapsed patients) or T-test (SF3B1 mutations). The clinical relevance of biomarker candidates was evaluated using log-rank Kaplan Meier (survival and relapse interval) and ROC tests. Results Eight distinct modules (M2, M3, M4, M7, M9, M10, M11, M13) were significantly correlated with relapse and differentially expressed between relapsed and non-relapsed Binet Stage A CLL patients. The biological functions of modules positively correlated with relapse were carbohydrate and mRNA metabolism, whereas negatively correlated modules to relapse were protein translation associated. Additionally, M1, M3, M7, and M13 modules negatively correlated with overall survival. CLL biomarkers BTK, BCL2, and TP53 were co-expressed, while unmutated IGHV biomarker ZAP70 and cell survival-associated NOTCH1 were co-expressed in modules positively correlated with relapse and negatively correlated with survival days. Conclusions This study provides novel insights into CLL relapse biology and pathways associated with known and novel biomarkers for relapse and overall survival. The modules associated with relapse and overall survival represented both known and novel pathways associated with CLL pathogenesis and can be a resource for the CLL research community. The hub genes of these modules, e.g., ARHGAP27P2, C1S, CASC2, CLEC3B, CRY1, CXCR5, FUT5, MID1IP1, and URAHP, can be studied further as new therapeutic targets or clinical markers to predict CLL patient outcomes.

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Specific Chromosomal IG Translocations Have Different Prognosis In Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v116.21.582.582 ◽

2010 ◽

Vol 116 (21) ◽

pp. 582-582

Author(s):

Florence Nguyen-Khac ◽

CLaude Lesty ◽

Elise Chapiro ◽

Aurore Grelier ◽

Isabelle Luquet ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Sex Ratio ◽

Conflicts Of Interest ◽

Lymphocytic Leukemia ◽

Rank Test ◽

Exact Test ◽

Kaplan Meier ◽

Trisomy 12 ◽

Binet Stage ◽

The Individual

Abstract Abstract 582 Chromosomal translocations (t) are usually analyzed as one group, and are associated with poor prognosis in chronic lymphocytic leukemia (CLL). Translocations involving immunoglobulin (IG) genes are recurrent, but uncommon (< 5%) in CLL. The two most frequent IG-partners are BCL2 (18q21) and BCL3 (19q13). On the behalf of the Groupe Francophone de Cytogenetique Hematologique (GFCH), we report an extensive analysis of 75 t(14;18)-CLLs, and a comparison to our previously published series of 29 t(14;19)-CLLs (Chapiro et al, Leukemia 2008). The 75 t(14;18)-CLLs or variant BCL2-t have been collected between 1985 and 2009. The morphological and immunological reviews were performed by KM, CS, and HM-B. All karyotypes were reviewed by the GFCH. Fluorescence in situ hybridization analyses were performed to detect IG and BCL2 rearrangements, trisomy 12, and deletions of 11q22 (ATM), 17p13 (TP53), 6q21, 13q14 (D13S319). IGHV mutation analyses were performed by referring laboratories. Statistical analyses were carried out using the Fisher's exact test, and continuous data using the Mann-Whitney test. Overall survival (OS) and treatment free survival (TFS) calculated from diagnosis were estimated using the Kaplan-Meier method, and the statistic significance was determined using log-rank test. Among BCL2-CLL, the sex ratio was 57M/18F, the median age at diagnosis was 66 years; of 68 patients with available data, 63 (93%) presented with Binet stage A; median lymphocytosis was 14.6×109/l. There were 47/75 (63%) “classical” CLL and 28/75 (37%) “atypical” CLL, with more than 10% of lymphoplasmacytoid cells and/or large cells. All tested cases (58/58) were CD10-, 69/73 (94%) were CD5+, and 44/63 (70%) were CD38-; 57/68 (84%) had a Matutes score > 4, 7/68 (10%) a score = 3, 4/68 (6%) a score < 3. We observed 62 t(14;18) and 13 variant translocations [11 t(18;22), 2 t(2;18)]. The karyotype was complex (> 3 abnormalities) in 15/74 (20%) cases, and the BCL2-t was isolated in 25/74 (34%) cases. There were 33/75 (44%) tri12, 32/68 (47%) del13q14, 1/72 (1%) delTP53, 0/72 (0%) delATM, 0/59 (0%) del6q21. Of 42 analyzed cases, 33 (78%) were mutated. Finally, the median time from diagnosis to first therapy was 24 months (m). Comparisons with the BCL3-CLL showed no difference in sex ratio, age, and Binet stages. The lymphocytosis was lower in BCL2-CLL (14.6 vs 24.4 x109/l, p<0.008), and splenomegaly was less frequent (3/61 (5%) vs 13/28 (46%), p<0.0001). There were more “classical” morphologies in BCL2-CLL group (63% vs 9/29 (31%), p<0.005), more Matutes score > 4 (84% vs 5/20 (25%), p<0.001), and more CD38- (70% vs 1/5 (20%), p<0.05). BCL2-t were more frequently single (35% vs 1/28 (3%), p<0.0008). There were less complex karyotypes (20% vs 13/28 (46%), p<0.02), more del13q14 (47% vs 4/27 (15%), p<0.005), and less tri12 (44% vs 20/29 (69%), p<0.03), del6q (0% vs 5/25 (20%), p<0.002) and delTP53 (1% vs 4/23 (17%), p<0.02) in BCL2-CLLs. The IGHV status of BCL2-CLLs was more frequently mutated (78% vs 2/20 (10%), p<0.0001). Finally, the TFS interval was longer in BCL2-CLLs (p<0.0001, median 48 vs 1.2 m,); and the median OS was longer (not reached with 75% alive at 204 m) (p<0.0001). Comparison to common CLL showed that BCL2-CLLs had more tri12 (p<0.00001), and lacked delATM (p<0.0001) and del6q (p<0.05). The majority were CD38-, and mutated (p<0.0001). Finally, even if the median TFS was 48m, the median OS was more than 204m, which is longer than the median OS of the prognostically most favorable subgroup reported by Döhner et al (group with isolated del13q, 133m) (Döhner et al, N Eng J Med, 2000). The presence of BCL2-t remains a favorable marker even in patients who also exhibit markers of intermediate prognosis such as tri12. Compared to BCL3-CLLs, BCL2-CLLs have a much less aggressive behavior, indicating that distinguishing the individual translocations and the cytogenetic partners would allow a better patients' stratification. Disclosures: No relevant conflicts of interest to declare.

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Efficacy and Safety of Frontline Therapy with "FCR" Regimen for Chronic Lymphocytic Leukemia Outside Clinical Trials: Israeli CLL Study Group Experience

Blood ◽

10.1182/blood.v124.21.5659.5659 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5659-5659 ◽

Cited By ~ 1

Author(s):

Yair Herishanu ◽

Neta Goldschmidt ◽

Osnat Bairey ◽

Rosa Ruchlemer ◽

Riva Fineman ◽

...

Keyword(s):

Overall Survival ◽

Clinical Trials ◽

Chronic Lymphocytic Leukemia ◽

Dose Reduction ◽

Lymphocytic Leukemia ◽

Fish Analysis ◽

Efficacy And Safety ◽

Reduced Dose ◽

Binet Stage ◽

Frontline Therapy

Abstract The combination of fludarabine, cyclophosphamide and rituximab (FCR) is still currently regarded as the standard regimen for treatment of physically fit patients with chronic lymphocytic leukemia (CLL). This therapy can be associated with significant toxicity, and patient adherence to the protocol may often be difficult outside of clinical trials. This retrospective study aimed to evaluate the efficacy and safety of FCR therapy in the real life setting, with particular focus on the influence of dose reduction on treatment outcome. A total of 132 CLL patients (≤70 years of age) treated with FCR as frontline therapy from 10 medical centers, were reviewed. The majority of patients were males (73.5%, n=97) and younger than 60 years (78%, n=103). Eleven patients had Binet stage A (8.3%), 72 (54.5%) were stage B and 49 (37.1%) had Binet stage C. Results of FISH analysis were available for 99 patients, with high risk cytogenetics of del(11q) in 21 patients (21.2%) and del(17p) in 9 cases (9.1%). The majority (56.5%, n=74) received rituximab at a dose of 500mg/m2 and the rest 375mg/m2. Almost half of the patients (49.2%, n=65) were given a reduced dose of chemotherapy (<90% of the indicated dosage), while 23% (n=30) received 2/3 or less. Primary chemotherapy dose reduction was most commonly in accordance with the treating physician's judgment, while secondary dose modifications and less chemotherapy cycles were initiated mainly because of hematological toxicity. Most patients had a clinical complete response (69.8%, n=90) while only 10 (7.8%) failed to respond. Partial or non- responders were more commonly associated with lower pretreatment hemoglobin levels and platelet counts, Binet stage C, and presence of del(17p) and had also received lower doses of chemotherapy (p=0.024). The rituximab dose administered was not associated with differences in response rates (p=0.7). Reducing the dose of chemotherapy (≤2/3) was associated with an increase in risk of disease progression (HR 4.1, 95% CI 2.3-7.0, p<0.0001), resulting in a decrease in median progression free survival (PFS) from 46.9 months (for those receiving the full dose), to 15.8 months for patients given a reduced dose. In a multivariate analysis of PFS only a reduced dose of chemotherapy (≤2/3) and del(17) retained statistical significance, p=0.004 and p<0.0001, respectively. The median overall survival for the entire cohort was 99.5 months (95% CI 78.5-120.5). Del(17p) and failure to respond to treatment were independently associated with a worse overall survival (HR=9.2, 95% CI 2.0-41.8, p=0.004 and HR=15.1, 95% CI 3.2-72.0, p-0.001, respectively). The most commonly recorded severe adverse events included, at least one episode of infection or neutropenia in 25.8% and 24.2% of patients, respectively. Treatment related DAT+ autoimmune hemolysis occurred in 6.0% of the cases, late-onset neutropenia in 8.1%, Richter's transformation in 3% and therapy related MDS/AML in 2.3% of patients. In conclusion, it is apparent that outside of clinical trials treating physicians tend more readily to reduce doses of chemotherapy. Reduced doses of fludarabine and cyclophosphamide but not of rituximab, is significantly associated with a shorter PFS. Disclosures No relevant conflicts of interest to declare.

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Prognostic Value of Myocardial Enzymes and Therapeutic Potential of Cardioprotective Agents in Chronic Lymphocytic Leukemia Patients with Cardiovascular Comorbidities

Blood ◽

10.1182/blood-2021-149236 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4689-4689

Author(s):

Xiaoya Yun ◽

Zixun Yin ◽

Juan Fan ◽

Na Chen ◽

Mei Ding ◽

...

Keyword(s):

Cell Proliferation ◽

Creatine Kinase ◽

Chronic Lymphocytic Leukemia ◽

Therapeutic Potential ◽

Lymphocytic Leukemia ◽

Prognostic Biomarkers ◽

Cardiac Biomarkers ◽

Logistic Analysis ◽

Kaplan Meier ◽

Binet Stage

Abstract Introduction: Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults in the western world. Cardiovascular disease (CVD), with a high incidence among comorbidities, is associated with significant morbidity and inferior quality of life in cancer patients. In CLL, comorbidities are associated with increased mortality from infections, second cancers and CVD. However, previous studies have not uncovered the relationships between cardiac biomarkers and the prognosis of CLL patients. In addition, whether cardioprotective drugs affect the effect of therapy in CLL patients remains undefined. Methods: Five hundred and ten CLL patients diagnosed in Shandong Provincial Hospital affiliated to Shandong University from October 2010 to July 2020 were enrolled in our study. The Kaplan-Meier curves were used to estimate survival rates, while the log-rank tests were used for comparison. Univariate and multivariate logistic regression analysis was used to verify prognostic independence. The available expression data and survival information of CLL samples and normal samples were extracted from 2 databases. The expression level of genes involved in the KEGG lipid and atherosclerosis pathway was analyzed to evaluate the prognosis of CLL patients. GSEA enrichment analysis was performed to explore the potential function of TNFRSF1A. Cell proliferation assay with the Cell Counting Kit-8 (CCK-8) was performed to detect the therapeutic potential of the common cardioprotective drugs atorvastatin, metoprolol and losartan in CLL. Results: Among the cohort, 30% CLL patients were complicated with CVD. Compared with those without CVD, CLL patients with CVD were of significantly advanced age (p<0.001), larger proportion with diabetes (p=0.003), as well as higher levels of N-terminal brain natriuretic peptide precursor (NTpro-BNP; p=0.016) and myohemoglobin (MYO; p=0.005). The Kaplan-Meier curves revealed that Binet stage (χ2=3.863, p=0.049), creatine kinase isoenzyme (CK-MB; χ2=4.335, p=0.037) and MYO (χ2=4.010, p=045) were related to the OS time of CLL patients with CVD (shown in Figure 1). The univariate logistic analysis showed that sex (p=0.031), Rai stage (p=0.036), Binet stage (p=0.017), β2-MG (p=0.004), creatine kinase (CK; p=0.017), α-hydroxybutyrate dehydrogenase (α-HBDH; p=0.017), MYO (p=0.025) and C-reactive protein (p=0.007) were associated with the outcomes of CLL patients with CVD. The multivariate logistic analysis confirmed that α-HBDH (p=0.046) and MYO (p=0.013) were independent prognostic biomarkers for the outcomes of CLL patients with CVD. To further evaluate the prognosis of CLL patients and CVD, the expression of genes involved in the KEGG lipid and atherosclerosis pathway were assessed. Most of them were dysregulated (shown in Figure 2A-B). The genes which were differential expression were performed with Kaplan-Meier analysis and univariate and multivariate Cox analysis subsequently. TNFRSF1A was upregulated among CLL cells and was independent prognostic biomarkers of both OS (shown in Figure 2C) and time to first treatment (TTFT) in CLL patients (shown in Figure 2D). GSEA enrichment illuminated that TNFRSF1A was related to the lipid catabolic and metabolic process, as well as other metabolic processes (shown in Figure 2E-F). To investigate the effect of cardioprotective drugs on chronic lymphocytic leukemia patients, cell proliferation assays were performed. Atorvastatin, metoprolol and losartan decreased the proliferation of CLL cell lines with IC50 values of 94.19 uM, 123.60 uM and 411.80 uM in EHEB cells, and 79.20 uM, 138.60 uM and 318.5 uM in MEC-1 cells, respectively (shown in Figure 3). Conclusions: In conclusion, we demonstrated CLL patients with CVD were of older age, larger proportion of patients with diabetes, higher levels of NTpro-BNP and MYO compared those without CVD for the first time. α-HBDH and MYO were independent prognostic biomarkers for survival in CLL patients with CVD. TNFRSF1A was an independent prognostic biomarker of OS and TTFT in CLL patients. Furthermore, atorvastatin, metoprolol and losartan exhibited inhibitory effects in CLL cell lines. The evaluation of cardiac biomarkers is beneficial to predict the clinical outcomes of CLL patients. CLL patients may benefit from the application of cardioprotective agents. Strengthening the evaluation of CVD risk and preventing CVD may improve the prognosis of CLL patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Analysis of Major Infection Risk in 706 Patients with Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v124.21.3321.3321 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3321-3321

Author(s):

Andrea Visentin ◽

Nicolò Compagno ◽

Monica Castelli ◽

Francesco Cinetto ◽

Renato Zambello ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Replacement Therapy ◽

Conflicts Of Interest ◽

Lymphocytic Leukemia ◽

Categorical Variables ◽

Fisher Exact Test ◽

Risk Of Death ◽

Kaplan Meier

Abstract Background Chronic lymphocytic leukemia (CLL) is the most common leukemia in western country. Although the prognosis is improved in the last years, CLL is still an incurable disease and infections are the major cause of morbidity and mortality. Susceptibility to infections in CLL patients can be an intrinsic characteristic of the disease or due to chemo-immunotherapy. Immunoglobulin (Ig) replacement therapy is a safe and effective way to prevent infectious events in CLL patients, but indications to their use are not strictly defined. The aim of this study was to determine risk factors to serious bacterial infections in CLL patients and to identify a clinical phenotype of patients characterized by a high infectious risk, in which Ig replacement therapy (IgRT) is appropriate. Methods We retrospectively analyzed clinical and biochemical data of 706 patients, referred to the Hematology and Clinical Immunology Unit of Padua University Hospital since 1982. In this series, we identify patients with at least one episode of major infections (MI), defined as pneumonia, sepsis, meningitis, and endocarditis. We considered only non neutropenic MI. FISH analyses (n=450), CD38 expression (n=529), ZAP70 (n=502), IGHV (n=473), TP53, NOTCH1, BIRC3, SF3B1 (176 genes tested) mutational status, were evaluated before at diagnosis or before starting treatment. Staging and Ig levels were collected at the time of the MI; for patients who didnÕt complain any MI we recorded the last available data. Inferior normal values for IgG, IgA and IgM were 7.0, 0.70 and 0.40g/dL, respectively. Continuous variables were compared by Mann-Whiney test, while categorical variables by Fisher exact test or Chi-square test, when appropriated. Overall survival (OS) was calculated from the date of initial presentation to death for any cause (event) or last known follow-up (censored). Survival analyses were performed by Kaplan-Meier method. Log-rank test was used to compare overall survival curves between groups and Cox regression models to estimate hazard ratios. The proportional hazard assumption was tested in all cox models. p values <0.05 were considered significant and <0.0005 as highly significant. 95% confidential intervals (CI), positive predictive value (PPV) and negative predictive valure (NPV) were also reported. Results 69 patients (9.8%) had 89 MI, among these 62 were pneumonia (3 pulmonary aspergillosis), 21 sepsis, 1 meningitides, 1 cerebral abscess, 1 uveitis and 1 endocarditis. We observed a higher risk of MI in subject with at least 2 Ig isotypes deficiencies (Figure 1, Odds Ratio 10.1 (CI 5.78-17.6), p<0.0001); PPV and NPV were 29% and 96%, respectively. By contrast, patients with only 1 Ig deficiency did not show a higher risk of MI. Clinical-biological characteristics between patients with MI (PwI) and without MI (PwoI) were skewed, in particular the formers harbored a high-risk cytogenetic (i.e. del17p and del11q, p<0.0001), unmutated IGHV (homology>98%, p=0.0043), CD38+ (>30%, p=0.0205), were at a more advance stage (Rai III-IV, p<0.0001) and experienced treatment (p<0.0001). No differences were found neither for ZAP70 expression (>20%, p=0.6775), nor TP53, NOTCH1, BIRC3, SF3B1 gene mutations (p=0.9998), nor chemotherapy regiments (p=0.1587). Considering PwI and at least 2 Ig isotypes deficiencies (n=47), 21 patients treated with IgRT showed a reduction of the incidence of MI (0.70 MI/patient/year in the 12 months before IgRT and 0.27 MI/patient/year during replacement therapy). Kaplan-Meier analysis showed that PwI had a shorter OS than PwoI with a median OS of 196 months vs not reached, respectively (Figure 2, p<0.0001). 10-years OS were 64.7% and 83.4% for PwI and PwoI, respectively. In multivariate analysis highly significant variables were history of MI, del17p and U-IGHV. In particular PwI had 2.3 (CI 1.5-3.6, p<0.0001) higher risk of death than PwoI patients. Discussion In our work, we described the prognostic role of MI in CLL patients, superimposable to other main prognostic factors. Moreover, we identified the clinical profile of patients at high risk of major infections: low levels of at least 2 Ig isotypes, aggressive disease (U-IGHV, del17p) and previous treatment. We also described the reduction of the incidence of MI in a small cohort of 21 patients after IgRT. Taking advantage from this study, we will investigate safety and usefulness of Ig prophylaxis in a bigger subset of patients. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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Telomere length predicts progression and overall survival in chronic lymphocytic leukemia: data from the UK LRF CLL4 trial

Leukemia ◽

10.1038/leu.2015.217 ◽

2015 ◽

Vol 29 (12) ◽

pp. 2411-2414 ◽

Cited By ~ 28

Author(s):

J C Strefford ◽

L Kadalayil ◽

J Forster ◽

M J J Rose-Zerilli ◽

A Parker ◽

...

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Telomere Length ◽

Lymphocytic Leukemia ◽

The Uk ◽

Leukemia Data

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Reduced Intensity Conditioning Yields Superior Overall Survival Rates Compared to Myeloablative Regimens for Allogeneic HCT in Chronic Lymphocytic Leukemia: A Side-By-Side Systematic Review/Meta-Analysis

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2016.12.170 ◽

2017 ◽

Vol 23 (3) ◽

pp. S269 ◽

Cited By ~ 1

Author(s):

Jessica El-Asmar ◽

Tea Reljic ◽

Ambuj Kumar ◽

Mohamed A. Kharfan-Dabaja

Keyword(s):

Systematic Review ◽

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Meta Analysis ◽

Survival Rates ◽

Lymphocytic Leukemia ◽

Reduced Intensity Conditioning ◽

Allogeneic Hct ◽

Reduced Intensity ◽

Overall Survival Rates

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Impact of Idelalisib Treatment Interruption with or without Dose Reduction on Outcomes in Relapsed / Refractory Indolent Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2019-124541 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5468-5468

Author(s):

Shuo Ma ◽

Rebecca J Chan ◽

Lin Gu ◽

Guan Xing ◽

Nishan Rajakumaraswamy ◽

...

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Dose Reduction ◽

Clinical Outcomes ◽

Research Funding ◽

Treatment Interruption ◽

Lymphocytic Leukemia ◽

Hodgkin's Lymphoma ◽

Advisory Committees

Introduction: Idelalisib (IDELA) is the first-in-class PI3Kδ inhibitor and is approved as a monotherapy for relapsed or refractory (R/R) follicular lymphoma and in combination with rituximab for R/R chronic lymphocytic leukemia (CLL). We previously evaluated IDELA treatment interruption as a mechanism to mitigate treatment-emergent adverse events (TEAEs) and found that limited interruption with clinically appropriate re-challenging resulted in superior clinical outcomes. These findings did not comprehensively address the potential confound of interruptions inherently being associated with longer duration of therapy (DoT). Furthermore, the compound effect of IDELA dose reduction together with treatment interruption on IDELA efficacy was not assessed. Objectives: 1) To evaluate whether the benefit of IDELA interruption is retained in patients on therapy >180 days, a duration previously found to be associated with longer overall survival among patients who discontinued IDELA due to an AE; and 2) To compare clinical outcomes of patients who reduced IDELA dosing in addition to interrupting IDELA with those of patients who interrupted IDELA without additional dose reduction. Methods: Using data from Gilead-sponsored trials of patients with R/R indolent non-Hodgkin's lymphoma (iNHL) treated with IDELA monotherapy (N=125, Gopal et al., N. Engl. J. Med., 2014) or with R/R CLL treated with IDELA + anti-CD20 (N=110, Furman et al., N. Engl. J. Med., 2014; and N=173, Jones et al., Lancet Haematol., 2017), DoT, progression-free survival (PFS), and overall survival (OS) were compared between patients on IDELA therapy >180 days with vs. without interruption and between patients who experienced Interruption and Dose Reduction (IDR) vs. patients who experienced Interruption but NoDose Reduction (INoDR) at any point during IDELA treatment. Interruption was defined as missing at least one IDELA treatment day due to an AE and dose reduction could have occurred before or after the first interruption. PFS and OS were estimated using the Kaplan-Meier method and were compared using a log-rank test. Results: Sixty-nine of 125 patients with R/R iNHL (55.2%) and 222 of 283 patients with R/R CLL (78.4%) remained on IDELA therapy >180 days with 29 (42.0%) and 103 (46.4%) of them, respectively, experiencing interruption on or after day 180 (Table 1). The proportions of patients with interruption before day 180 were similar within each of these populations. Among patients on therapy >180 days, those with treatment interruption on or after 180 days had a longer median (m) DOT than patients without interruption (Table 1). Both PFS and OS were longer in CLL patients who interrupted compared to those who did not interrupt (mPFS=28.9 mos. vs. 17.3 mos. and mOS=not reached [NR] vs. 40.4 mos. for with interruption vs. without interruption, respectively, Table 1 and Figure 1). In patients with iNHL, no difference was observed in PFS or OS between patients who interrupted vs. those who did not (Table 1). Of patients who experienced at least one AE-induced interruption at any point during IDELA therapy (n=63 iNHL and n=157 CLL), 47 iNHL patients (74.6%) and 84 CLL patients (53.5%) also had dose reduction. Two iNHL patients (1.6%) and 5 CLL patients (1.8%) had IDELA dose reduction but no interruption. Both iNHL and CLL patients with IDR experienced a similar PFS compared to patients with INoDR (mPFS=16.5 mos. vs. 14.2 mos. for iNHL and 21.8 mos. vs. 22.1 mos. for CLL with IDR vs. INoDR, respectively, Table 2). However, OS was longer in both iNHL and CLL patients with IDR compared to INoDR (mOS=61.2 mos. vs. 35.3 mos. for iNHL and NR vs. 42.4 mos. for CLL, respectively, Table 2; CLL patients shown in Figure 2). Discussion: IDELA treatment interruption is not associated with rapid clinical deterioration, as observed with some B-cell receptor signaling pathway inhibitors. No clear relationship between IDELA DoT and frequency of interruption was observed. When normalized for DoT >180 days, IDELA treatment interruption retained its clinical benefit in the CLL population. When utilized together with IDELA interruption, dose reduction did not lead to inferior clinical outcomes but instead extended OS in both iNHL and CLL populations. Adherence to treatment interruption and dose reduction guidance as outlined in the IDELA USPI may optimize IDELA tolerability and efficacy for patients with iNHL and CLL. Disclosures Ma: Janssen: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Gilead: Research Funding; Abbvie: Research Funding; Juno: Research Funding; Incyte: Research Funding; Xeme: Research Funding; Beigene: Research Funding; Novartis: Research Funding; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Kite: Consultancy; Acerta: Research Funding; Bioverativ: Consultancy; Genentech: Consultancy. Chan:Gilead Sciences, Inc.: Employment, Equity Ownership. Gu:Gilead Sciences, Inc.: Employment. Xing:Gilead Sciences, Inc.: Employment. Rajakumaraswamy:Gilead Sciences, Inc.: Employment. Ruzicka:Gilead Sciences, Inc.: Employment. Wagner-Johnston:Gilead: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees.

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Prognostic Impact of NOTCH1 Hotspot Mutation in TP53-Mutated Patients with Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v124.21.3283.3283 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3283-3283

Author(s):

Barbara Kantorova ◽

Jitka Malcikova ◽

Veronika Navrkalova ◽

Jana Smardova ◽

Kamila Brazdilova ◽

...

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Tp53 Mutation ◽

Direct Sequencing ◽

Lymphocytic Leukemia ◽

The Other ◽

Wild Type ◽

Tp53 Mutations ◽

Time To First Treatment ◽

Hotspot Mutation

Abstract Introduction A presence of activating mutations in NOTCH1 gene has been recently associated with reduced survival and chemo-immunotherapy resistance in chronic lymphocytic leukemia (CLL). However, a prognostic significance of the NOTCH1 mutations with respect to TP53mutation status has not been fully explained yet. Methods An examined cohort included 409 patients with CLL enriched for high risk cases; in 121 patients consecutive samples were investigated. To determine the TP53 mutation status, a functional analysis of separated alleles in yeast (FASAY, exons 4-10) combined with direct sequencing was performed; the ambiguous cases were retested using an ultra-deep next generation sequencing (MiSeq platform; Illumina). The presence of NOTCH1 hotspot mutation (c.7544_7545delCT) was analyzed using direct sequencing complemented by allele-specific PCR in the selected samples. In several patients harboring concurrent NOTCH1 and TP53 mutations, single separated cancer cells were examined using multiplex PCR followed by direct sequencing. A correlation between mutation presence and patient overall survival, time to first treatment and other molecular and cytogenetic prognostic markers was assessed using Log-rank (Mantel-cox) test and Fisher's exact test, respectively. Results The NOTCH1 and TP53 mutations were detected in 16% (65/409) and 27% (110/409) of the examined patients, respectively; a coexistence of these mutations in the same blood samples was observed in 11% (19/175) of the mutated patients. The detected increased mutation frequency attributes to more unfavorable profile of the analyzed cohort; in the TP53-mutated patients missense substitutions predominated (75% of TP53 mutations). As expected, a significantly reduced overall survival in comparison to the wild-type cases (147 months) was observed in the NOTCH1-mutated (115 months; P = 0.0018), TP53-mutated (79 months; P < 0.0001) and NOTCH1-TP53-mutated patients (101 months; P = 0.0282). Since both NOTCH1 and TP53 mutations were strongly associated with an unmutated IGHV gene status (P < 0.0001 and P = 0.0007), we reanalyzed the IGHV-unmutated patients only and interestingly, the impact of simultaneous NOTCH1 and TP53 mutation presence on patient survival was missed in this case (P = 0.1478). On the other hand, in the NOTCH1 and/or TP53-mutated patients significantly reduced time to first treatment was identified as compared to the wild-type cases (41 months vs. 25 months in NOTCH1-mutated, P = 0.0075; 17 months in TP53-mutated, P < 0.0001; and 18 months in NOTCH1-TP53-mutated patients, P = 0.0003). The similar results were observed also in the subgroup of the IGHV-unmutated patients, with the exception of patients carrying sole NOTCH1 mutation (P = 0.2969). Moreover, in the NOTCH1-TP53-mutated patients an increased frequency of del(17p)(13.1) was found in comparison to the TP53-mutated patients only (72% vs. 56%); this cytogenetic defect was not detected in the patients with sole NOTCH1 mutation. Our results might indicate, that NOTCH1 mutation could preferentially co-selected with particular, less prognostic negative type of TP53 defects. Notably, in our cohort the NOTCH1 mutation predominated in the patients harboring truncating TP53 mutations localized in a C-terminal part of the TP53 gene behind the DNA-binding domain (P = 0.0128). Moreover, in one of the NOTCH1-TP53-mutated patients the analysis of separated cancer cells revealed a simultaneous presence of NOTCH1 mutation and TP53 in-frame deletion in the same CLL cell. In contrast, in the other examined NOTCH1-TP53-mutated patient the concurrent NOTCH1 mutation and TP53 missense substitution (with presumed negative impact on patient prognosis) were found in different CLL cells. Conclusions The parallel presence of NOTCH1 hotspot mutation might be detected in a significant proportion of TP53-mutated patients and it seems to be associated with less prognostic unfavorable TP53 mutations. Nevertheless, these preliminary data should be further confirmed in a large cohort of patients. This study was supported by projects VaVPI MSMT CR CZ.1.05/1.1.00/02.0068 of CEITEC, IGA MZ CR NT13493-4/2012, NT13519-4/2012 and CZ.1.07/2.3.00/30.0009. Disclosures Brychtova: Roche: Travel grants Other. Doubek:Roche: Travel grants Other.

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CARD11 is a novel target of miR-181b that is upregulated in chronic lymphocytic leukemia

Biomarkers in Medicine ◽

10.2217/bmm-2020-0601 ◽

2021 ◽

Author(s):

Zhen Kou ◽

Min Mao ◽

Hong Liu ◽

Xiaomin Wang ◽

Zengsheng Wang ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Target Gene ◽

Target Genes ◽

Prognostic Indicator ◽

Lymphocytic Leukemia ◽

Poor Survival ◽

Kaplan Meier ◽

Poor Prognostic Indicator ◽

Novel Target

Aim: To investigate the targets of miR-181b in patients with chronic lymphocytic leukemia (CLL). Materials & methods: The bioinformatic softwares were used to indicate the key target genes associated with miR-181b, and the results were verified in CLL patient samples and 293T cells. Results: CARD11 is a potential target gene of miR-181b, an inverse relationship was revealed between the expression of CARD11 and miR-181b in 104 CLL patients, and it was confirmed in vitro with luciferase assays and western blotting. Kaplan–Meier analysis showed that CLL patients with high CARD11 expression demonstrated poor survival. Conclusion: CARD11 is a novel target of miR-181b that is upregulated, which could be a poor prognostic indicator for CLL patients.

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