scholarly journals Genomic mutation profile in progressive chronic lymphocytic leukemia patients prior to first-line chemoimmunotherapy with FCR and rituximab maintenance (REM)

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257353
Author(s):  
Julia González-Rincón ◽  
José A. Garcia-Vela ◽  
Sagrario Gómez ◽  
Belén Fernández-Cuevas ◽  
Sara Nova-Gurumeta ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Somatic Mutations ◽  
Lymphocytic Leukemia ◽  
Front Line ◽  
First Line ◽  
Mutational Status ◽  
Mutation Profile ◽  
Massive Sequencing ◽  
The Impact ◽  
Generation Sequencing

Chronic Lymphocytic Leukemia (CLL) is the most prevalent leukemia in Western countries and is notable for its variable clinical course. This variability is partly reflected by the mutational status of IGHV genes. Many CLL samples have been studied in recent years by next-generation sequencing. These studies have identified recurrent somatic mutations in NOTCH1, SF3B1, ATM, TP53, BIRC3 and others genes that play roles in cell cycle, DNA repair, RNA metabolism and splicing. In this study, we have taken a deep-targeted massive sequencing approach to analyze the impact of mutations in the most frequently mutated genes in patients with CLL enrolled in the REM (rituximab en mantenimiento) clinical trial. The mutational status of our patients with CLL, except for the TP53 gene, does not seem to affect the good results obtained with maintenance therapy with rituximab after front-line FCR treatment.

Immunophenotypic Profile and Recurrent Somatic Mutations in 131 Chronic Lymphocytic Leukemia Patients: Low Expression of CD25 in NOTCH1-Mutated Cases

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3201-3201
Author(s):  
Miriam Castillo ◽  
Ana María Hurtado ◽  
Tzu Hua Chen-Liang ◽  
Julia Muñoz-Ballester ◽  
Bartlomiej P Przychodzen ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Somatic Mutations ◽  
Lymphoblastic Leukemia ◽  
Lymphocytic Leukemia ◽  
Limited Information ◽  
Male Predominance ◽  
Mutational Status ◽  
The Impact ◽  
Notch1 Mutations ◽  
Low Expression

Abstract Background: We and others have reported on the impact of recurrent somatic mutations not only in the multistep pathogenetic process, but also in the clinical heterogeneity of chronic lymphocytic leukemia (CLL) patients. Immunophenotyping, as part of the diagnostic workout, is used for assessing clonality, as a differential diagnosis tool, and to examine the expression of molecules associated with a worse prognosis. Recently, NOTCH1 mutations have been linked to low CD20 levels in CLL and with a relative resistance to anti-CD20 immunotherapy in vitro. But to date, there is limited information on the correlation between cell surface marker expression and the presence of somatic mutations in CLL. The aim of this study was to evaluate potential associations between an extended phenotypic panel and the mutational status of 13 recurrently mutated genes in CLL detected by deep sequencing. Patients and Methods: To this end, we performed targeted NGS sequencing of blood samples, collected at diagnosis, from 131 CLL patients. Every patient underwent, at baseline, a flow cytometry characterization with a panel including (sIg)λ, (sIg)κ, CD19, CD5, CD11b, CD81, CD10, CD79b, CD29, CD38, FMC7, CD22, CD45, CD103, CD11c, CD25, ZAP70, CD11a, and CD24. We designed a TruSeq Custom Amplicon panel (Illumina, Inc. San Diego, CA, USA) containing 13 genes and covering 28.099 bases. The average amplicon size was 238 base pairs and ~ 99.1% of the regions were covered on both strands. Paired-end sequencing (2x250 bp) was performed with MiSeq v2.2 chemistry, and a mean depth of 998 reads/base within the regions of interest was obtained. Raw data were analyzed with IlluminaonJboard Real Time Analysis (RTA v.2.4.60.8) software and MiSeq Reporter. Results: With a median age of 68 y.o. (range, 33-95) and a slight male predominance, the median follow up time of our cohort was 43 months (24-104). We found that 47/131 (35%) patients harbored at least one mutation, with NOTCH1 (n = 13, 10%), ATM (n = 10, %), TP53 (n = 8, %), and SF3B1 (n = 8, 5.5%), as the most frequently mutated genes. Those patients with a NOTCH1 mutation showed a lower CD25 expression (25 mean fluorescence intensity units (MFIu)) than those without a mutation (45 MFIu), p=0.001. In addition, a higher expression of CD5 (265 vs. 219 MFIu, p= 0.02), of the monoclonal light chain (90.5 vs. 58.6 MFIu, p=0.03), and a higher percentage of CD38+ cells in the CD19+CD5+ compartment (37% vs. 19%, p=0.006) were significantly associated with the presence of, at least, one somatic mutation. We could not validate the recently reported association between the presence of NOTCH1 mutations and a low expression of CD20. In our cohort, the MFI expression in NOTCH1 mutated and non-mutated patients was 176 and 135 units, respectively (p=0.2) In the multivariate Cox analysis, the presence of a somatic variant in TP53 and a higher percentage of positive CD38 cells in the tumour population showed both a worse overall survival and shorter time to first treatment. The independence of these two variables was also supported by not finding a significative difference percentage of CD38 positive cells between TP53 mutated and non mutated cases (p=0.5). Conclusions: The associations described herein suggest potential pathogenic pathways in CLL, in particular the CD25-NOTCH1 axis, with a significative inferior expression of CD25 when activating NOTCH1 mutations are present. The relationship found between these two variables, with an inversed direction to that found in physiological conditions, has also been shown in the setting of NOTCH1-mutated acute lymphoblastic leukemia, emerging as a potential targetable pathway in this subset of CLL patients. Disclosures Maciejewski: Apellis Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau.

scholarly journals Lenalidomide and Rituximab Maintenance Therapy after Front-Line Induction Chemoimmunotherapy in Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5470-5470
Author(s):  
Julie E Chang ◽  
Vaishalee P. Kenkre ◽  
Christopher D. Fletcher ◽  
Aric C. Hall ◽  
Natalie Scott Callander ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Maintenance Therapy ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Second Malignancies ◽  
Front Line ◽  
First Line ◽  
11Q Deletion ◽  
Line Chemotherapy

Introduction: Chronic lymphocytic leukemia (CLL) is incurable with standard therapy. With first-line chemotherapy, some patients (pts) may achieve durable remissions of many months/years. Lenalidomide (LEN) has improved progression-free survival (PFS) when given as maintenance (MNT) therapy after front-line chemotherapy (CALGB10404, CLLM1). The combination of LEN + rituximab (LR) has activity in relapsed CLL, hypothesizing benefit as MNT therapy after first-line chemotherapy. Methods: Adult pts ≥18 years with previously untreated CLL received induction bendamustine (B) 90 mg/m2 IV days 1 & 2 and rituximab (R) IV day 1 (375 mg/m2 cycle 1, then 500 mg/m2 cycles 2-6) for 6 treatment cycles (as few as 4 cycles allowed). MNT therapy with LR was initiated within 12 weeks after cycle 6, day 1 of BR. Criteria to start LR MNT included: neutrophils ≥1000/microliter (uL), platelets ≥75 K/uL, and creatinine clearance ≥40 mL/min. LEN was administered in 28-day cycles for 24 cycles, initially 5-10 mg daily continuous dosing, later modified to 5-10 mg on days 1-21 of each 28-day cycle in 6/2018 due to neutropenia and second malignancy risk. LEN was reduced to 5 mg every other day for toxicities at 5 mg/day. R 375 mg/m2 IV was given every odd cycle (total of 12 doses). Patients discontinuing LEN for any reason were allowed to continue R MNT per protocol. The primary endpoint is PFS with LR MNT therapy, calculated from the first day of MNT therapy until progressive disease (PD), death, or start of a new therapy. Secondary endpoints are response rate and overall survival. Results: Thirty-four pts have enrolled beginning 11/2013, with follow-up through 6/2019. Median age is 64 years, with 8 pts ≥70 years; 8 women and 26 men. CLL FISH panel is available on all pts: 14 with 13q (as sole abnormality), 9 with 11q deletion, 6 with trisomy 12, 4 with normal FISH panel and 1 with 17p deletion. Heavy chain mutation analysis is available on 11 pts: 8 unmutated, 2 mutated, 1 indeterminate. Thirty-one pts completed 4 (n=2) or 6 cycles of induction BR; 3 pts are receiving induction BR. Twenty-four pts have received MNT LR; 7 did not receive LR for reasons of PD during induction (n=2), infection (n=1), pt preference (n=2), renal insufficiency (n=1), and new carcinoma (n=1). MNT LR was completed in 7 pts; 9 pts are still receiving LR. Fourteen subjects have discontinued protocol therapy, 3 during induction due to PD (n=2) and infection (n=1), and 8 during MNT. Toxicities that led to discontinuation of LR were recurrent infections in 7 pts, including 2 events of PJP pneumonia; 4 pts had recurrent neutropenia with infections; 1 pt had neutropenia without infections. Response is assessable in 31 patients using the International Working Group Consensus Criteria. Best responses to treatment were: partial response 65% (22/34), complete response (CR)/unconfirmed CR 24% (8/34). The median number of MNT cycles received is 16. The dose intensity of LEN across total cycles received (n=278): 5 mg every other day (52.5%), 5 mg/day (43.9%), and 10 mg/day (3.6%). The most common reason for dose reduction or dose holding was neutropenia. Most common Gr 3/4 toxicities (reported as events Gr3/Gr4) during MNT therapy were: neutropenia (20/20), leukopenia (19/4), febrile neutropenia (3/1), and infections (11/-). The majority of Gr3 infections were pneumonia/respiratory (n=5). One event of disseminated herpes zoster occurred. Second malignancies during MNT included: basal cell CA (n=1), squamous cell carcinoma (n=5), and colon cancer (n=1). No unexpected second malignancies were observed in pts receiving LR. Two-year PFS (defined from day 1 of MNT therapy) is 90% (95% confidence interval [CI] 0.78-1), and the median follow-up for 24 patient who started maintenance therapy is 1.79 years (95% CI 1.53-2.7). There have been no deaths. Conclusion: The combination of LR is effective in sustaining remissions after a BR induction in previously untreated CLL, but with frequent neutropenia and infections even at low doses of LEN. Most patients discontinuing MNT did so due to neutropenia and/or infections. A shorter planned interval of MNT LR (i.e., 6-12 months) may confer similar benefit to extended dosing that is more tolerable. Pts at high risk for short remissions after front-line chemotherapy (e.g., unmutated heavy chain status, 11q deletion and/or failure to achieve minimal residual disease after induction) may be the populations for which LR MNT therapy is most appropriate. Disclosures Chang: Genentech: Research Funding; Adaptive Biotechnologies: Research Funding; Celgene: Research Funding. OffLabel Disclosure: Lenalidomide administered as maintenance therapy for first treatment of CLL/SLL.

Extensive Intraclonal Diversification in a Subgroup of Chronic Lymphocytic Leukemia Patients with Stereotyped IGHV4-34/IGKV2-30 B cell Receptors: Implications for Ongoing Interactions with Antigen.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2337-2337
Author(s):  
Lesley-Ann Sutton ◽  
Efterpi Kostareli ◽  
Anastasia Hadzidimitriou ◽  
Nikos Darzentas ◽  
Athanasios Tsaftaris ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Heavy Chain ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
B Cell Receptors ◽  
Valuable Insight ◽  
Cell Receptors ◽  
Mutational Status ◽  
The Impact

Abstract Abstract 2337 Poster Board II-314 Several studies indicate that the development of chronic lymphocytic leukemia (CLL) may be influenced by antigen (Ag) recognition through the clonotypic B cell receptors (BCRs). However, it is still unclear whether Ag involvement is restricted to the malignant transformation phase or whether the putative Ag(s) may continuously trigger the CLL clone. Valuable insight into these issues may be gleaned from the study of intraclonal diversification (ID) within the immunoglobulin (IG) genes through ongoing somatic hypermutation (SHM). Definitive data regarding ID within IG genes in CLL remains limited and conflicting. In the present study we systematically explored the presence of ID within IG genes of CLL, not only at cohort level but also in subgroups defined by BCR stereotypy and IG gene mutational status. We thus conducted a large-scale subcloning study of both IG heavy and light variable genes, in a total of 1496 and 1008 subcloned sequences from 71 and 56 CLL cases, respectively. The analysis was intentionally biased to cases expressing IGHV4-34/IGKV2-30 IGs (subset #4) and IGHV3-21/IGLV3-21 IGs (subset #2) that exhibit distinctive, subset-biased SHM patterns. PCR reactions were run using the high-fidelity Accuprime Pfx polymerase and at least 14 colonies/case were analyzed. All “non-ubiquitous” sequence changes from the germline were evaluated and recorded as follows: (i) unconfirmed mutation (UCM) - a mutation observed in only one subcloned sequence from the same sample (ii) confirmed mutation (CM) - a mutation observed more than once among subcloned sequences from the same sample. Analysis of heavy chain sequences revealed that 40% (28/71) of cases carried intraclonally diversified IGHV-D-J genes with CMs amongst subclones, whilst 32% (23/71) of cases carried only UCMs. The remaining 28% (20/71) of cases carried sets of identical IGHV-D-J subcloned sequences. Although most cases showed no or low levels of ID, an intense and, likely, functionally driven ID was evident in selected cases, especially those belonging to subset #4. The distinct ID in subset #4 was statistically significant when compared to all other groups defined by IGHV gene usage and mutation status, BCR stereotypy or heavy chain isotype. Subsequent analysis of the clonotypic light chains revealed that the impact of ID was generally low, with the outstanding exception again relating to subset #4. In fact, of 22 IGKV-J rearrangements exhibiting CMs, 11 (50%) utilized the IGKV2-30 gene and notably 10/11 (91%) of these were expressed by subset #4 cases. In such cases, the expressed IGKV2-30 gene was affected by an active and precisely targeted ID, analogous to their partner IGHV4-34 gene. These findings suggest that the SHM mechanism may continuously operate in certain subsets of CLL patients, particularly those cases expressing stereotyped IGHV4-34/IGKV2-30 BCRs typical of subset #4. In such cases, the observed ID patterns attest to the very precise targeting of the SHM process and may be considered as evidence for a “stereotyped response” to an active, ongoing interaction with Ag(s). Disclosures: No relevant conflicts of interest to declare.

Clinical Impact of Clonal and Subclonal TP53, SF3B1, BIRC3, and ATM Mutations in Chronic Lymphocytic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4138-4138
Author(s):  
Ferran Nadeu ◽  
Julio Delgado ◽  
Cristina Royo ◽  
Tycho Bauman ◽  
Tatjana Stankovic ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Allele Frequency ◽  
Lymphocytic Leukemia ◽  
Molecular Characteristics ◽  
Prognostic Impact ◽  
Driver Genes ◽  
Germline Variants ◽  
Tp53 Mutations ◽  
Mutational Status ◽  
The Impact

Abstract Genomic studies have provided a complete profile of somatic mutations in chronic lymphocytic leukemia (CLL). These comprehensive approaches have revealed a relatively large number of mutated genes, the adverse prognostic value of some of which has been demonstrated in a number of reports. Recent studies have shown the clinical relevance of TP53 mutations at very low allele frequency. The presence and prognostic impact of minor mutated clones of other CLL driver genes and their clonal dynamics in the evolution of the disease is not well known. The goal of this study was to explore the presence of clonal and subclonal mutations of TP53, SF3B1, BIRC3, and ATM using an ultra-deep next-generation sequencing (NGS) strategy, to define the evolution of these subclones in different time-points of the disease, and to determine their influence in the outcome of the patients. Samples from 363 untreated CLL cases were included in this study. Copy number alterations were investigated by high density SNP-arrays or by quantitative PCR in 341 and 16 cases, respectively. Targeted ultra-deep NGS of TP53 (exons 4-10), ATM (exons 2-63), BIRC3 (exons 2-9), and SF3B1 (exons 14-16 and 18), including splicing sites, was performed using the Access-Array system (Fluidigm) and sequenced in a MiSeq equipment (Illumina). This methodology combined with a robust bioinformatic analysis based on well-known available tools allowed the identification of mutations down to 0.3% of variant allele frequency (VAF). Results obtained were fully verified by orthogonal techniques. Twelve per cent of VAF was used as threshold for the classification of clonal or subclonal mutations since 12% was the cut-off for detection of mutations by Sanger sequencing. Deletions of 11q comprising ATM or BIRC3 were found in 7% of the cases and were associated with mutations of the other ATM allele in 19/26 (73%) cases and BIRC3 in 3/23 (13%). Deletions of 17p were found in 19 (5%) cases and co-existed with TP53 mutations in 15 (79%) of them. Regarding the mutational status of the studied genes, TP53 mutations were present in 11.6% of patients (7.2% clonal, 4.4% subclonal), ATM mutations in 10% (7% clonal, 1% subclonal, 2% germline mutations considered pathogenic), SF3B1 mutations in 12% (7% clonal, 5% subclonal), and BIRC3 mutations in 4% (2% clonal, 2% subclonal). These subclonal mutations had similar molecular characteristics to their respective high-allele frequency mutations supporting a comparable pathogenic effect. In this regard, clonal and subclonal SF3B1 mutations were associated with shorter time to first treatment (TTT) independently of IGHV mutations. Clonal and subclonal TP53 mutations predicted for shorter overall survival (OS) together with the IGHV mutational status, although the impact of isolated TP53 mutations (i.e. without 17p deletion) on OS was not so evident, as has been the case in other studies. In addition, the outcome of patients with clonal and subclonal BIRC3 mutations showed a similar significant shorter OS. Regarding ATM, the effect of isolated subclonal ATM mutations could not be evaluated because of their low number, but ATM mutations as a whole had a significant impact on TTT even in the absence of 11q deletions. This study also reinforces the need to study the germline of the patients to fully characterize the ATM mutations observed in the tumors. Of note, germline variants previously described as pathogenic were associated with 11q deletions, confirming the hypothesis already suggested that these germline variants may influence disease progression through loss of the otherallele. Clonal dynamics was examined in longitudinal samples of 45 CLL patients. We confirmed the expansion of most TP53 mutated clones after therapy. However, both TP53 and SF3B1 mutations expanded also before any therapy in some patients, indicating that progressive dynamics of these clones is not only dependent on therapy selection. On the contrary, small ATM mutated clones seemed to be more stable. Although the number of cases is limited, we observed that clonal evolution in longitudinal samples had an unfavorable impact on OS. In conclusion, this study shows the presence of a high number of subclonal mutations of different driver genes in CLL and provides insights on the impact of these mutations on the outcome of the patients. These findings suggest that the characterization of the subclonal architecture may be relevant for a better management of CLL patients. Disclosures No relevant conflicts of interest to declare.

Serum BAFF (B-CELL Activating Factor Of The TNF Family) predicts time to First Treatment in Early B-CELL Chronic Lymphocytic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4158-4158
Author(s):  
Stefano Molica ◽  
Gaetano Vitelli ◽  
Giovanna Cutrona ◽  
Giovanna Digiesi ◽  
Rosanna Mirabelli ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Serum Concentration ◽  
B Cell ◽  
Serum Levels ◽  
Lymphocytic Leukemia ◽  
B Cell Activating Factor ◽  
Mutational Status ◽  
Time To First Treatment ◽  
The Impact ◽  
Cell Chronic Lymphocytic Leukemia

Abstract We analyzed the correlation between well-established biological parameters of prognostic relevance in B-cell chronic lymphocytic leukemia [CLL] (i.e, mutational status of the immunoglobulin heavy chain variable region [IgVH], ZAP-70− and CD38− expression) and serum levels of BAFF (B-cell activating factor of the TNF family) by evaluating the impact of these variables on the time to first treatment [TFT] in a series of 125 previously untreated Binet stage A B-cell CLL patients. By using a commercial ELISA (R & D Systems, USA) we found that higher levels of BAFF characterized more frequently females (P=0.01), patients with Rai stage 0 (P=0.03), mutated IgVH disease (P=0.008) and low ZAP-70 expression (P=0.04). In contrast, age (P=0.35), peripheral blood lymphocytosis (PBL)(P=0.09), hemoglobin (Hb) level (P=0.64), platelet (PLT) count (P=0.12), serum β2-m (P=0.49), LDH (P=0.85) and percentage of CD38-positive B-CLL cells (P=0.63) did not reflect circulating levels of BAFF. We used an optimal cut-point search to determine how to best split soluble BAFF data. Maximally selected log-rank statistics plots identified a BAFF serum concentration of 311 ng/mL as the best cut-off (P<0.0001). Accordingly, patients who had BAFF levels higher than 311 ng/mL experienced a longer TFT (median 108 months) in comparison to patients whose BAFF levels were lower than 311 ng/mL (median 30 months; P<0.0001). Along with serum concentration of BAFF, the univariate Cox proportional hazard model identified Rai substage I–II (P=0.003), lower PLT count (P=0.04), higher PBL count (P=0.01), increased LDH (P=0.01), ZAP-70 expression > 20% (P=0.02) and absence of mutation of IgVH (P<0.0001) as predictor of shorter TFT. In multivariate analysis only soluble BAFF (Hazard ratio [HR], 6.13; CI 95%, 2.31–16.25) and mutational status of IgVH, (HR= 2.99; CI 95% 1.33–6.76, P=0.008) maintained their discriminating power. The effects of BAFF on TFT were masked by mutational status of IgVH in patients with unmutated IgVH. However, serum levels of BAFF and mutational status of IgVH had a joint effect on TFT in patients with mutated IgVH which translates into a segregation of patients with mutated IgVH in two groups with different TFT according to BAFF levels (HR= 8.9; P<0.0001). Our results indicate that in early B-cell CLL biological profile including among other parameters soluble BAFF may provide a useful insight into the complex interrelationship of prognostic variables. Furthermore, BAFF along with mutational status of IgVH can be adequately used to predict clinical behaviour of patients with low biological risk.

scholarly journals Developmental subtypes assessed by DNA methylation-iPLEX forecast the natural history of chronic lymphocytic leukemia

Blood ◽  
2019 ◽  
Vol 134 (8) ◽  
pp. 688-698 ◽  
Author(s):  
Brian Giacopelli ◽  
Qiuhong Zhao ◽  
Amy S. Ruppert ◽  
Akwasi Agyeman ◽  
Christoph Weigel ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Chronic Lymphocytic Leukemia ◽  
Risk Stratification ◽  
Kinase Inhibitor ◽  
Lymphocytic Leukemia ◽  
Biological Traits ◽  
Elegant Method ◽  
Mutational Status ◽  
Methylation Patterns ◽  
The Impact

Abstract Alterations in global DNA methylation patterns are a major hallmark of cancer and represent attractive biomarkers for personalized risk stratification. Chronic lymphocytic leukemia (CLL) risk stratification studies typically focus on time to first treatment (TTFT), time to progression (TTP) after treatment, and overall survival (OS). Whereas TTFT risk stratification remains similar over time, TTP and OS have changed dramatically with the introduction of targeted therapies, such as the Bruton tyrosine kinase inhibitor ibrutinib. We have shown that genome-wide DNA methylation patterns in CLL are strongly associated with phenotypic differentiation and patient outcomes. Here, we developed a novel assay, termed methylation-iPLEX (Me-iPLEX), for high-throughput quantification of targeted panels of single cytosine guanine dinucleotides from multiple independent loci. Me-iPLEX was used to classify CLL samples into 1 of 3 known epigenetic subtypes (epitypes). We examined the impact of epitype in 1286 CLL patients from 4 independent cohorts representing a comprehensive view of CLL disease course and therapies. We found that epitype significantly predicted TTFT and OS among newly diagnosed CLL patients. Additionally, epitype predicted TTP and OS with 2 common CLL therapies: chemoimmunotherapy and ibrutinib. Epitype retained significance after stratifying by biologically related biomarkers, immunoglobulin heavy chain mutational status, and ZAP70 expression, as well as other common prognostic markers. Furthermore, among several biological traits enriched between epitypes, we found highly biased immunogenetic features, including IGLV3-21 usage in the poorly characterized intermediate-programmed CLL epitype. In summary, Me-iPLEX is an elegant method to assess epigenetic signatures, including robust classification of CLL epitypes that independently stratify patient risk at diagnosis and time of treatment.

Select High-Risk Genetic Features Predict Earlier Progression Following Chemoimmunotherapy With Fludarabine and Rituximab in Chronic Lymphocytic Leukemia: Justification for Risk-Adapted Therapy

2006 ◽  
Vol 24 (3) ◽  
pp. 437-443 ◽  
Author(s):  
John C. Byrd ◽  
John G. Gribben ◽  
Bercedis L. Peterson ◽  
Michael R. Grever ◽  
Gerard Lozanski ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Prognostic Factors ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Progression Free Survival ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Interphase Cytogenetics ◽  
Mutational Status ◽  
The Impact

Purpose Several new prognostic factors predicting rapid disease progression in chronic lymphocytic leukemia (CLL) have been identified, including unmutated Ig VH mutational status, del(11)(q23), del(17)(p13.1), and p53 mutations. To date, the impact of these same prognostic factors have not been examined relative to treatment outcome with chemoimmunotherapy. Methods We examined the impact of these new prognostic factors on predicting treatment outcome in symptomatic, untreated CLL patients who received chemoimmunotherapy with fludarabine and rituximab as part of a completed, randomized phase II study, Cancer and Leukemia Group B (CALGB) 9712. Results Eighty-eight patients treated as part of CALGB 9712 had detailed prognostic factor assessment performed. Using Ig VH mutational status to classify risk, there was no association between complete response rate with either unmutated Ig VH mutational status or high-risk interphase cytogenetics. However, the median progression-free survival (PFS; P = .048) and overall survival (OS; P = .01) were shorter among the Ig VH unmutated patients as compared with the Ig VH mutated patients. Using the hierarchical classification of Döhner, PFS (P = .005) and OS (P = .004) were significantly longer as the classification moved from high risk [del (11)(q22.3) or del (17)(p13.1)] to low risk. Conclusion These data demonstrate that high-risk CLL patients characterized by Ig VH unmutated (≥ 98%) or high-risk interphase cytogenetics, including either del(17p) or del(11q), appear to have a shorter PFS and OS with chemoimmunotherapy. Larger prospective studies will be required to determine the independent influence of Ig VH mutational status and interphase cytogenetics on treatment outcome.

Single-Agent Rituximab as First-Line and Maintenance Treatment for Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma: A Phase II Trial of the Minnie Pearl Cancer Research Network

2003 ◽  
Vol 21 (9) ◽  
pp. 1746-1751 ◽  
Author(s):  
John D. Hainsworth ◽  
Sharlene Litchy ◽  
John H. Barton ◽  
Gerry Ann Houston ◽  
Robert C. Hermann ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Response Rate ◽  
Single Agent ◽  
Objective Response ◽  
Lymphocytic Leukemia ◽  
Research Network ◽  
Small Lymphocytic Lymphoma ◽  
First Line ◽  
The Impact

Purpose: To assess the efficacy and toxicity of first-line single-agent rituximab, followed by re-treatment with rituximab at 6-month intervals, in previously untreated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Patients and Methods: Forty-four previously untreated patients with CLL/SLL received rituximab 375 mg/m2 weekly for 4 consecutive weeks. All patients were required to have one or more indications for treatment. Patients with objective response or stable disease continued to receive identical 4-week rituximab courses at 6-month intervals, for a total of four courses. Results: The objective response rate after the first course of rituximab was 51% (4% complete responses). Twenty-eight patients received one or more additional courses of rituximab. At present, the overall response rate is 58%, with 9% complete responses. After a median follow-up of 20 months, the median progression-free survival (PFS) time was 18.6 months, and the 1- and 2-year PFS rates were 62% and 49%, respectively. Treatment was well tolerated, with only two episodes of grade 3 to 4 infusion-related toxicity. No cumulative toxicity or opportunistic infections occurred. Conclusion: Single-agent rituximab, used at a standard dose and schedule, is active in the first-line treatment of patients with CLL/SLL, producing substantially higher response rates than previously reported in relapsed or refractory patients (51% v 13%, respectively). Re-treatment with rituximab at 6-month intervals is well tolerated. The PFS time of 18.6 months in patients with CLL/SLL seems shorter than the 36- to 40-month median PFSs previously reported with first-line plus maintenance rituximab in patients with follicular lymphoma. Additional follow-up is required to fully assess the impact of this treatment strategy.

scholarly journals Next-Generation Sequencing Targeted Chronic Lymphocytic Leukemia Panel: A Pilot Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 19-19
Author(s):  
Mariia Mikhaleva ◽  
Irina Martynkevich ◽  
Sergey Petrov ◽  
Ilya Buldakov ◽  
Alexey Kuvshinov ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Pilot Study ◽  
Chronic Lymphocytic Leukemia ◽  
Clinical Significance ◽  
Lymphocytic Leukemia ◽  
Next Generation ◽  
Mutational Status ◽  
Prognostic Groups ◽  
Treatment Naïve ◽  
Generation Sequencing

Background: Rapid progress in next-generation sequencing (NGS) technologies make it possible to spell out the mutational status, the genetic and epigenetic variability of chronic lymphocytic leukemia (CLL). The identification of driver mutations allows us to expand understanding of the pathogenesis of CLL, to identify prognostic groups and to select potential targets for therapy, contributing to the development and implementation of new targeted drugs and its combinations. Nevertheless, the course of CLL does not always correspond to the existing prognostic risk groups, assessed by "standard" cytogenetic and molecular genetic methods. The NGS technology admits establishing markers of an unfavorable course of the disease. Aim: To assess the mutational status of patients (pts) with CLL using the developed Lymphoid Targeted NGS Panel and to study the possible correlation of the mutational status with the clinical characteristics of the disease. Method: In this prospective study were included 24 pts with CLL: treatment-naïve (n=8) and relapsed/refractory (n=16). The diagnosis of CLL was established according to iwCLL criteria (iwCLL, Hallek et al., 2018) and show only typical immunophenotype. The pts were divided into three prognostic groups according to cytogenetic assay: favorable (n=14), neutral (n=2), and unfavorable (n=8). Although, 20/24 pts were divided into two prognostic groups taking into account the data on the mutational status of the immunoglobulin heavy-chain variable (IGHV) region: favorable (n=8) and unfavorable (n=12). Four patients have no available data on IGHV mutational status. All patients had indications for starting treatment: FCR (n=7), RB (n=6), ibrutinib (n=3), venetoclax (n=1), acalabrutinib (n=5), combination of venetoclax and acalabrutinib (n=2). DNA samples were extracted from peripheral B-cell lymphocytes via the standard phenol-chloroform method. Average reading depth of 1000x is produced on a MiSeq platform (Illumina, USA). The 2% threshold of allele frequency (VAF) was used. The clinical significance of mutations was established using the following databases: COSMIC, ClinVar, gnomAD with application in silico analysis (Cscape, Cancer Genome Interpreter, SNPs&Go). The Lymphoid Panel includes 117 genes, part of which is involved in the main 8 cellular signaling pathways underlying the pathogenesis of CLL. We have completed a pilot NGS study using the developed Lymphoid Targeted Gene Panel on DNA samples of six treatment-naïve pts. Results: Genetic aberrations were identified in all DNA samples using NGS. Somatic mutations were detected in 82.9% of cases, in an amount from 15 to 37. In four pts (4/6) with an unfavorable prognosis (cytogenetics and unmutated IGHV), known pathogenic variants of mutations were identified: JAK3 V722L, NOTCH1 P2514fs*4, IDH2 T352P, TP53 Lys120Glu, BRAF D594G. The existing approach to the interpretation of the results does not allow making an unambiguous conclusion about the clinical significance of variants in the IDH2 and JAK3 genes, despite the known pathogenic effect of the variants. The detected variant of the mutation (Lys120Glu) in the TP53 gene is often associated with the presence of a 17p13 deletion, which was confirmed by the FISH assay and correlated with the unfavorable clinical course of the disease in patient CLL-024. Twenty-two mutations were identified, the pathogenicity of which has not yet been determined, in the amount of 2 to 5 (median=3.5) mutations per patient. It should be noted that two patients (CLL-023, CLL-024) with unfavorable prognosis had mutations both in BCR gene and in NOTCH2 gene of unknown significance. Conclusion: The data obtained from a pilot study demonstrate the possibility of using NGS technology in clinical practice. The assessment of the mutational status of pts with CLL using NGS correlates with the clinical parameters of pts. Considering that there is currently no information about prognostic significances of identified mutations, additional research is required. Disclosures Martynkevich: Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Shuvaev:Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Voloshin:Novartis: Honoraria, Speakers Bureau.

Clinical Prognostic Biomarkers in Chronic Lymphocytic Leukemia and Diffuse Large B-Cell Lymphoma

2014 ◽  
Vol 139 (5) ◽  
pp. 602-607 ◽  
Author(s):  
Elizabeth C. Chastain ◽  
Eric J. Duncavage
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Somatic Mutations ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Large B Cell Lymphoma ◽  
Mutational Status ◽  
Igvh Mutational Status ◽  
Large B Cell

Context Diffuse large B-cell lymphoma and chronic lymphocytic leukemia are 2 of the most common B-cell lymphomas in adults. Both diffuse large B-cell lymphoma and chronic lymphocytic leukemia share heterogeneous outcomes, and the use of prognostic biomarkers to better stratify risk in these patients has now become commonplace. Objective To review chronic lymphocytic leukemia and diffuse large B-cell lymphoma biomarkers commonly used in the clinical laboratory, which can be divided into the following 3 main groups by testing methodology: chromosomal based (including fluorescence in situ hybridization and cytogenetics), expression based (including immunohistochemistry and flow cytometry), and DNA based (including gene sequencing for somatic mutations and IGVH mutational status). Data Sources Review of recent literature. Conclusions In chronic lymphocytic leukemia, important biomarkers include expression of CD38 and ZAP-70, IGVH mutational status, somatic mutations in TP53 and NOTCH1, and abnormalities in chromosomes 11, 12, 13q, and 17. In diffuse large B-cell lymphoma, important biomarkers include chromosomal rearrangement of BCL2, BCL6, and MYC and expression of CD5, BCL2, and CD43, as well as somatic mutations in TP53 and BCL6.

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