Clinical Relevance of NOTCH1 Mutations in Ibrutinib-Treated Chronic Lymphocytic Leukemia (CLL)

Abstract Background Ibrutinib, inhibitor of Bruton's tyrosyne kinase (BTK), demonstrated exceptional activity both in untreated and relapsed/refractory CLL patients, obtaining overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) far superior to chemoimmunotherapy (Byrd, 2014). Interestingly, NOTCH1 mutations (M) were significantly correlated with CD49d overexpression which identified cases with reduced lymphocytosis and inferior nodal response (Tissino, 2018). Moreover, NOTCH1 M were characterized by remarkable expression of the NF-kB pathway genes (Benedetti, 2017) and thus may confer poor response to ibrutinib. Aims On this background, the primary aims of our research were: i) to correlate NOTCH1 M with biological and clinical prognosticators in ibrutinib-treated patients; ii) to verify the impact of NOTCH1M both on the peripheral lymphocytes redistribution and on the nodal response calculated as percentual reduction from baseline (SPD); iii) to evaluate the impact of NOTCH1 M on ORR, PFS and OS; iiii) finally, to assess NOTCH1 M as an independent prognostic factor. Patients and Methods Therefore, we evaluated the efficacy of ibrutinib as single agent, in a real-life contest, on 166 patients recruited from three independent cohorts from Italy, median age 61 years (27-85), median number of previous regimens 2 (0-4; 15% previously untreated). Noteworthy, 23/60 (38%) TP53M patients were treated in first line with ibrutinib (p<0.0001). Patients received 420 mg oral ibrutinib once daily until progression or occurrence of unacceptable side effects. Median follow up on ibrutinib was 16 months. NOTCH1 M were investigated with ARMS PCR for c.75447545delCT or by Sanger sequencing of NOTCH1 exon 34 and all cases were confirmed with next generation sequencing (NGS) method. Results Sixty-one patients were NOTCH1 M (36.75%). NOTCH1 M were significantly correlated with trisomy 12 (p=0.00045) and with CD49d >30% (p=0.001). Absolute lymphocyte counts (ALCs) were collected before treatment and at days ranging from 30 to 90 on ibrutinib. NOTCH1 M were significantly correlated with lower median ALCs measured both before (28.9 x 106/ml vs 57.0 x 106/ml; p=0.0006) and during (28.0 x 106/ml vs 54.6 x 106/ml; p=0.0005) ibrutinib therapy. Also the median SPD, calculated at 3-6 months on ibrutinib, was significantly lower in NOTCH1 M patients (51.8% vs 75.7%; p<0.0001, Figure A). ORR was 89% (complete response (CR): 21%, partial response (PR): 31%, PR with lymphocytosis (PR-L): 37%). The estimate 1-year PFS and OS were 81% and 86%, respectively. Fifty-one patients (30.7%) discontinued ibrutinib therapy due to progression (n= 25), and adverse events (n=26). Fourteen patients in progression were treated subsequently with venetoclax. With regard to clinical outcome, PR was significantly correlated with NOTCH1 M (31/61; p=0.00002). Significant shorter PFS and OS were observed in NOTCH1 M patients (39% vs 71% and 71% vs 81% at 24 months, respectively; p=0.03 and p=0.02; Figures B and C). In multivariate analysis of PFS and OS including TP53 M, IGHV mutational status and age > or <60 years, only NOTCH1 M were confirmed as an independent prognostic factor (p=0.01 and p=0.04, respectively). Conclusions NOTCH1 M patients were characterized by a reduced redistribution lymphocytosis and by a lower and/or slower nodal response under ibrutinib treatment. The clinical consequences were a significant higher number both of PR without lymphocytosis and relapses. Therefore, evaluation of NOTCH1 M in patients initiating ibrutinib may identify those cases that would benefit from combination therapy approaches, which are already underway in experimental protocols, using new molecules working through different pathways, such as venetoclax or obinutuzumab. Figure. Figure. Disclosures Del Principe: Gilead: Membership on an entity's Board of Directors or advisory committees.

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The Amount of Apoptosis Predicts Outcome in Ibrutinib-Treated Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood-2018-99-113060 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4397-4397

Author(s):

Giovanni Del Poeta ◽

Massimiliano Postorino ◽

Federico Pozzo ◽

Maria Ilaria Del Principe ◽

Enrico Santinelli ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factor ◽

Clinical Outcome ◽

Real Life ◽

Response To Therapy ◽

Independent Prognostic Factor ◽

Lymphocytic Leukemia ◽

Apoptosis Resistance ◽

Serious Adverse Events ◽

The Impact

Abstract Background Altough the inhibitor of Bruton's tyrosyne kinase (BTK) ibrutinib has transformed the management of patients with CLL obtaining decreased tumor burden and improved progression free survival (PFS), it does not induce substantial apoptosis in vitro (Ponader, 2012). Dysregulation of the mitchondrial pathway of apoptosis is one of the hallmarks of CLL cell pathophysiology and thus targeting the anti-apoptotic protein bcl-2 with venetoclax is a promising new therapeutic strategy (Souers, 2013; Roberts, 2016). Moreover ibrutinib increases bcl-2 dependence (Deng, 2017) enhancing sensitivity to venetoclax in CLL. Therefore the basal level of apoptosis measured through bax/bcl-2 ratio before therapy may be crucial to test sensitivity to ibrutinib. Aims The primary aims of our research were: i) to verify the correlations of bax/bcl-2 ratio with other well-known biological and clinical prognosticators in patients treated with ibrutinib; ii) to evaluate the impact of bax/bcl-2 ratio on overall response rate (ORR), PFS and overall survival (OS); iii) to test bax/bcl-2 ratio as an independent prognostic factor. Patients and Methods Therefore, we evaluated the efficacy of ibrutinib, in a real-life contest, on 100 patients, median age 60 years (38-85), median number of previous regimens 2 (0-4; 14% previously untreated). Patients received 420 mg oral ibrutinib once daily until progression or occurrence of unacceptable side effects. Median follow up on ibrutinib was 16 months. ORR was 92% [complete response (CR): 27%, partial response (PR): 32%, PR with lymphocytosis (PR-L): 33%]. The estimate 1-year PFS and OS were 74% and 77%, respectively. Twenty-nine patients (29%) discontinued ibrutinib therapy due to progression (n=11) and serious adverse events (n=18). Five out of 6 patients with Richter's syndrome (RS) had baseline del(17p)/TP53 mutations (M). Interestingly, PFS was significantly better for patients in first/second lines (n=38) vs later lines of therapy (n=55; p=0.022). Bax/bcl-2 ratio was calculated by flow cytometry, dividing mean florescence intensity (MFI) of bax by MFI of bcl-2 on peripheral CLL cells before treatment with ibrutinib. The threshold of positivity was set at the median value higher than 1.5 (range 0.38-5.10). Results Sixty-four patients had bax/bcl-2 ratio <1.5 (64%). Bax/bcl-2 ratio <1.5 was strongly correlated with ZAP-70 >20% (40/64; p=0.005), but not with CD49d or CD38 >30%. There was only a slight significant correlation between bax/bcl-2 ratio <1.5 and NOTCH1 mutations (M) (25/32; p=0.030). On the other hand, no significant correlations were found between bax/bcl-2 ratio and del(17)p/TP53 M or IGHV status or cytogenetic subsets. With regard to clinical outcome, lack of response/progression and PR/PR-L were significantly correlated both with bax/bcl-2<1.5 (p=0.001) and NOTCH1 M (p=0.0005), but not with del(17)p/TP53 M. Noteworthy, 20/37 del(17)p/TP53 M patients were treated in first/second lines (p=0.001). Significant shorter PFS was observed in patients with bax/bcl-2 ratio <1.5 (65% vs 92% at 24 months, p=0.015, Figure A). Moreover, patients with lower bax/bl-2 ratio showed significant shorter OS (68% vs 96% at 24 months, p=0.006, Figure B). In multivariate analysis of PFS, only bax/bcl-2 ratio < 1.5 (p=0.030), analysed together with NOTCH1 M, TP53 M, number of therapeutic lines and age, was confirmed as an independent prognostic factor. With regard to multivariate analysis of OS, bax/bcl-2 ratio (p=0.016) and number of therapeutic lines (p=0.035) remained significant. Conclusions In our hands, bax/bcl-2 ratio was a powerful prognosticator for patients treated with ibrutinib, particularly useful to identify subsets of CLL patients with different levels of spontaneus apoptosis and consequent different clinical outcome under ibrutinib treatment. At the light of these our recent observations, bcl-2 antagonists, such as ABT-199, should be reasonably combined with BTK inhibitors, as it is already underway in clinical protocols, in order to overcome apoptosis resistance in patients treated with ibrutinib, particularly within the CLL subset characterized by lower bax/bcl-2 ratio e poor response to therapy with ibrutinib. Figure. Figure. Disclosures Del Principe: Gilead: Membership on an entity's Board of Directors or advisory committees.

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Impaired Nodal Shrinkage and Apoptosis Lacking Define the Adverse Independent Clinical Outcome of NOTCH1 mutated Chronic Lymphocytic Leukemia (CLL) Patients in the Age of Targeted Agents (TA)

Blood ◽

10.1182/blood-2019-122481 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1744-1744

Author(s):

Giovanni Del Poeta ◽

Annalisa Biagi ◽

Annalisa Chiarenza ◽

Luca Laurenti ◽

Federico Pozzo ◽

...

Keyword(s):

Flow Cytometry ◽

Multivariate Analysis ◽

Prognostic Factor ◽

Clinical Outcome ◽

Conflicts Of Interest ◽

Single Agent ◽

Real Life ◽

Independent Prognostic Factor ◽

Prognostic Impact ◽

The Impact

The advent of agents inhibiting the BCR-associated kinases (ibrutinib and idelalisib) and the antiapoptotic protein Bcl-2 (venetoclax) has dramatically changed treatments algorithms of CLL as well as the role of different adverse prognosticators. The marked benefit of these new drugs has been investigated in the context of NOTCH1 mutations (M). In fact, NOTCH1 M were significantly correlated with CD49d overexpression identifying CLL with reduced lymphocytosis and inferior nodal response (Tissino, 2018). Moreover, NOTCH1 M were characterized by overexpression and increased activity of the NF-kB pathway genes, promoting tumor cell proliferation and survival (Benedetti, 2017). The primary aims of our clinical research were: i) to correlate NOTCH1 M with CD49d expression and bax/bcl-2 ratio in ibrutinib-treated patients; ii) to verify the impact of NOTCH1M on the peripheral lymphocytes redistribution and on the nodal response calculated as percentual reduction from baseline (SPD); iii) to evaluate the impact of NOTCH1 M on overall response rate (ORR), progression free survival (PFS) and overall survival (OS); iiii) finally, to assess NOTCH1 M as an independent prognostic factor. Therefore, we evaluated the efficacy of ibrutinib as single agent, in a real-life contest, on 180 patients recruited from three independent cohorts from Italy, median age 69 years (36-90), median number of previous regimens 2 [range 0-4; 26 patients (14.4%) previously untreated]. Noteworthy, 24/64 (37.5%) TP53 mutated patients were treated in first line with ibrutinib (p<0.0001). Patients received 420 mg oral ibrutinib once daily until progression or occurrence of unacceptable side effects. Median follow up on TA was 25 months. NOTCH1 M were investigated with next generation sequencing (NGS) method. CD49d antigen was evaluated by flow cytometry and the threshold of positivity was set >30%. Bax/bcl-2 ratio, evaluated in 113 patients, was calculated by flow cytometry, dividing mean florescence intensity (MFI) of bax by MFI of bcl-2 on CLL cells. The threshold of positivity was set at the median value >1.5 (range 0.41-5.10). Sixty-five patients were NOTCH1 M (36.11%). NOTCH1 M were strongly correlated both with CD49d >30% (51/65; p=0.0001) and bax/bcl-2 ratio <1.5 (34/38; p=0.00007). Absolute lymphocyte counts (ALCs) were collected at days ranging from 30 to 90 on ibrutinib. NOTCH1 M were correlated with significant lower median ALCs than all other patients (10.7 x 106/ml vs 31.0 x 106/ml; p=0.0003). Moreover, the median SPD, calculated at 3-6 months on ibrutinib, was lower in NOTCH1 M patients (53% vs 80%; p<0.0001), confirming a significant poor nodal response. ORR was 90% [complete response (CR): 18%, partial response (PR): 28%, PR with lymphocytosis (PR-L): 44%]. The estimate 2-year PFS and OS were 80% and 84%, respectively. Sixty nine patients (39%) discontinued ibrutinib either for progression (n=38) or for adverse events (n=31). With regard to clinical outcome, NOTCH1 M were significantly correlated with PR and PR-L (30/65 and 22/65, respectively; p=0.00002). Moreover, NOTCH1M were significantly associated with disease recurrence (23/38; p=0.0005). Significant shorter PFS and OS were observed in NOTCH1 M patients (36% vs 84% and 58% vs 84% at 3 years, respectively; p<0.0001 and p=0.00075; Figure 1A and 1B). Thirty-seven patients underwent subsequently venetoclax [13 for toxicity (grade 3 or 4 WHO) and 24 for progression]. OS for this subgroup was 70% at 3 years (Figure 1C). In multivariate analysis of PFS, including previous chemotherapy regimens, NOTCH1, TP53 and IGHV status, NOTCH1 was confirmed as an independent prognostic factor (p=0.0002) together with TP53 (p=0.003). On the other hand, in multivariate analysis of OS, NOTCH1 remained as an independent prognostic factor (p=0.009) together with previous therapy (p=0.013) and TP53 (p=0.019). In conclusion, NOTCH1M are characterized by resistance to apoptosis, lower peripheral lymphocytosis and lower nodal shrinkage, all responsible for partial responses, subsequent relapses, shorter PFS and OS under ibrutinib treatment. The prognostic impact of NOTCH1 M on patients treated subsequently with venetoclax is unclear due to the low number of our cases (Roberts, 2019). Probably the therapeutic answer for NOTCH1 M patients could come either from TA combination approaches or from new gamma-secretase inhibitors or also from new antibodies targeting NOTCH1. Disclosures No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood.v128.22.3201.3201 ◽

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.

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

Journal of Clinical Oncology ◽

10.1200/jco.2005.03.1021 ◽

2006 ◽

Vol 24 (3) ◽

pp. 437-443 ◽

Cited By ~ 184

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.

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

Blood ◽

10.1182/blood.2020010536 ◽

2021 ◽

Author(s):

Adam S Kittai ◽

Cecelia R Miller ◽

Daniel Goldstein ◽

Ying Huang ◽

Lynne V. Abruzzo ◽

...

Keyword(s):

Overall Survival ◽

Clonal Evolution ◽

Single Agent ◽

Multivariable Analysis ◽

Progression Free Survival ◽

Continuous Variable ◽

Lymphocytic Leukemia ◽

Karyotypic Analysis ◽

Cytogenetic Abnormalities ◽

The Impact

Complex karyotype defined as ≥3 cytogenetic abnormalities is prognostic of survival in patients treated with ibrutinib or venetoclax in relapsed/refractory (RR) chronic lymphocytic leukemia (CLL). Recent studies re-evaluating this dichotomous variable have shown that higher numbers of cytogenetic abnormalities (i.e. ≥5) have a worse overall survival in patients treated with chemoimmunotherapy. We sought to determine if increasing karyotypic complexity, treated as a continuous variable, was prognostic of survival for patients treated with ibrutinib for CLL. We conducted a retrospective analysis of all patients with CLL treated with single-agent ibrutinib or in combination with an anti-CD20 antibody at our institution. We included 456 patients with both treatment-naïve (TN) and RR disease. Median number of prior therapies was 2 (range 0-13), 30% of patients had del(17p), and 75% were IGHV unmutated. 50% had ≥3 cytogenetic abnormalities including 30% with ≥5. In a multivariable analysis, increasing karyotypic complexity was an independent predictor of shorter progression-free survival (HR 1.07 (95% CI 1.04-1.10), p<0.0001) and overall survival (HR 1.09 (95% CI 1.05-1.12), p<0.0001). Furthermore, we found that presence of clonal evolution determined by cytogenetic analysis at progression was prognostic of subsequent survival (p=0.02). This solidifies karyotypic complexity as an important prognostic factor for CLL patients treated with ibrutinib. Further research should consider sequential karyotypic analysis as a determination of risk of progression and death in patients with CLL.

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Real Life Use of Bendamustine in Elderly Patients with Lymphoid Neoplasia

Journal of Personalized Medicine ◽

10.3390/jpm11040249 ◽

2021 ◽

Vol 11 (4) ◽

pp. 249

Author(s):

Irene Dogliotti ◽

Simone Ragaini ◽

Francesco Vassallo ◽

Elia Boccellato ◽

Gabriele De Luca ◽

...

Keyword(s):

Elderly Patients ◽

Rating Scale ◽

Single Agent ◽

Multivariable Analysis ◽

Real Life ◽

Lymphocytic Leukemia ◽

Factors Affecting ◽

Lymphoid Neoplasia ◽

Baseline Factors ◽

Grade 3

Background. Bendamustine is a cytotoxic alkylating drug with a broad range of indications as a single agent or in combination therapy in lymphoid neoplasia patients. However, its tolerability in elderly patients is still debated. Methods: An observational, retrospective study was carried out; patients with chronic lymphocytic leukemia (CLL) or lymphoma, aged ≥ 65 years old, treated with bendamustine-based regimens in first or subsequent lines between 2010 and 2020 were considered eligible. Results: Overall, 179 patients aged ≥ 65 years were enrolled, 53% between 71 and 79 years old. Cumulative Illness Rating Scale (CIRS) comorbidity score was ≥6 in 54% patients. Overall survival (OS) at 12 months was 95% (95% confidence interval [CI]: 90–97%); after a median follow up of 50 months, median OS was 84 months. The overall response rate was 87%, with 56% complete responses; the median time to progression (TTP) was 61 months. The baseline factors affecting OS by multivariable analysis were sex, histological diagnosis, renal function, and planned bendamustine dose, while only type of lymphoma and bendamustine dose impacted on TTP. Main adverse events were neutropenia (grade ≥ 3: 43%) and infections (any grade: 36%), with 17% of patients requiring hospital admission. Conclusions: The responses to bendamustine, as well as survival, are relevant even in advanced age patients, with a manageable incidence of acute toxicity.

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Primary and Secondary Kinase Genotypes Correlate With the Biological and Clinical Activity of Sunitinib in Imatinib-Resistant Gastrointestinal Stromal Tumor

Journal of Clinical Oncology ◽

10.1200/jco.2007.15.7461 ◽

2008 ◽

Vol 26 (33) ◽

pp. 5352-5359 ◽

Cited By ~ 463

Author(s):

Michael C. Heinrich ◽

Robert G. Maki ◽

Christopher L. Corless ◽

Cristina R. Antonescu ◽

Amy Harlow ◽

...

Keyword(s):

Growth Factor Receptor ◽

Progression Free Survival ◽

Clinical Results ◽

Clinical Activity ◽

Wild Type ◽

Mutational Status ◽

Imatinib Resistant ◽

Exon 9 ◽

Exon 11 ◽

The Impact

PurposeMost gastrointestinal stromal tumors (GISTs) harbor mutant KIT or platelet-derived growth factor receptor α (PDGFRA) kinases, which are imatinib targets. Sunitinib, which targets KIT, PDGFRs, and several other kinases, has demonstrated efficacy in patients with GIST after they experience imatinib failure. We evaluated the impact of primary and secondary kinase genotype on sunitinib activity.Patients and MethodsTumor responses were assessed radiologically in a phase I/II trial of sunitinib in 97 patients with metastatic, imatinib-resistant/intolerant GIST. KIT/PDGFRA mutational status was determined for 78 patients by using tumor specimens obtained before and after prior imatinib therapy. Kinase mutants were biochemically profiled for sunitinib and imatinib sensitivity.ResultsClinical benefit (partial response or stable disease for ≥ 6 months) with sunitinib was observed for the three most common primary GIST genotypes: KIT exon 9 (58%), KIT exon 11 (34%), and wild-type KIT/PDGFRA (56%). Progression-free survival (PFS) was significantly longer for patients with primary KIT exon 9 mutations (P = .0005) or with a wild-type genotype (P = .0356) than for those with KIT exon 11 mutations. The same pattern was observed for overall survival (OS). PFS and OS were longer for patients with secondary KIT exon 13 or 14 mutations (which involve the KIT-adenosine triphosphate binding pocket) than for those with exon 17 or 18 mutations (which involve the KIT activation loop). Biochemical profiling studies confirmed the clinical results.ConclusionThe clinical activity of sunitinib after imatinib failure is significantly influenced by both primary and secondary mutations in the predominant pathogenic kinases, which has implications for optimization of the treatment of patients with GIST.

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KRASandBRAFMutations in Advanced Colorectal Cancer Are Associated With Poor Prognosis but Do Not Preclude Benefit From Oxaliplatin or Irinotecan: Results From the MRC FOCUS Trial

Journal of Clinical Oncology ◽

10.1200/jco.2009.22.4295 ◽

2009 ◽

Vol 27 (35) ◽

pp. 5931-5937 ◽

Cited By ~ 377

Author(s):

Susan D. Richman ◽

Matthew T. Seymour ◽

Philip Chambers ◽

Faye Elliott ◽

Catherine L. Daly ◽

...

Keyword(s):

Colorectal Cancer ◽

Prognostic Factor ◽

Braf Mutation ◽

Poor Prognosis ◽

Advanced Colorectal Cancer ◽

Progression Free Survival ◽

Predictive Biomarker ◽

Poor Prognostic Factor ◽

Minimal Impact ◽

The Impact

PurposeActivating mutation of the KRAS oncogene is an established predictive biomarker for resistance to anti–epidermal growth factor receptor (anti-EGFR) therapies in advanced colorectal cancer (aCRC). We wanted to determine whether KRAS and/or BRAF mutation is also a predictive biomarker for other aCRC therapies.Patients and MethodsThe Medical Research Council Fluorouracil, Oxaliplatin and Irinotecan: Use and Sequencing (MRC FOCUS) trial compared treatment sequences including first-line fluorouracil (FU), FU/irinotecan or FU/oxaliplatin in aCRC. Tumor blocks were obtained from 711 consenting patients. DNA was extracted and KRAS codons 12, 13, and 61 and BRAF codon 600 were assessed by pyrosequencing. Mutation (mut) status was assessed first as a prognostic factor and then as a predictive biomarker for the benefit of adding irinotecan or oxaliplatin to FU. The association of BRAF-mut with loss of MLH1 was assessed by immunohistochemistry.ResultsThree hundred eight (43.3%) of 711 patients had KRAS-mut and 56 (7.9%) of 711 had BRAF-mut. Mutation of KRAS, BRAF, or both was present in 360 (50.6%) of 711 patients. Mutation in either KRAS or BRAF was a poor prognostic factor for overall survival (OS; hazard ratio [HR], 1.40; 95% CI, 1.20 to 1.65; P < .0001) but had minimal impact on progression-free survival (PFS; HR, 1.16; 95% CI, 1.00 to 1.36; P = .05). Mutation status did not affect the impact of irinotecan or oxaliplatin on PFS or OS. BRAF-mut was weakly associated with loss of MLH1 staining (P = .012).ConclusionKRAS/BRAF mutation is associated with poor prognosis but is not a predictive biomarker for irinotecan or oxaliplatin. There is no evidence that patients with KRAS/BRAF mutated tumors are less likely to benefit from these standard chemotherapy agents.

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Mutational Status of the TP53 Gene As a Predictor of Response and Survival in Patients With Chronic Lymphocytic Leukemia: Results From the LRF CLL4 Trial

Journal of Clinical Oncology ◽

10.1200/jco.2010.32.0838 ◽

2011 ◽

Vol 29 (16) ◽

pp. 2223-2229 ◽

Cited By ~ 170

Author(s):

David Gonzalez ◽

Pilar Martinez ◽

Rachel Wade ◽

Sarah Hockley ◽

David Oscier ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Survival Data ◽

Prognostic Value ◽

Gene Mutations ◽

Progression Free Survival ◽

Tp53 Gene ◽

Lymphocytic Leukemia ◽

Tp53 Mutations ◽

Mutational Status ◽

Gene Tp53

Purpose TP53 mutations have been described in chronic lymphocytic leukemia (CLL) and have been associated with poor prognosis in retrospective studies. We aimed to address the frequency and prognostic value of TP53 abnormalities in patients with CLL in the context of a prospective randomized trial. Patients and Methods We analyzed 529 CLL samples from the LRF CLL4 (Leukaemia Research Foundation Chronic Lymphocytic Leukemia 4) trial (chlorambucil v fludarabine with or without cyclophosphamide) at the time of random assignment for mutations in the TP53 gene. TP53 mutation status was correlated with response and survival data. Results Mutations of TP53 were found in 40 patients (7.6%), including 25 (76%) of 33 with 17p deletion and 13 (3%) of 487 without that deletion. There was no significant correlation between TP53 mutations and age, stage, IGHV gene mutations, CD38 and ZAP-70 expression, or any other chromosomal abnormality other than 17p deletion, in which concordance was high (96%). TP53 mutations were significantly associated with poorer overall response rates (27% v 83%; P < .001) and shorter progression-free survival (PFS) and overall survival (OS; 5-year PFS: 5% v 17%; 5-year OS: 20% v 59%; P < .001 for both). Multivariate analysis that included baseline clinical variables, treatment, and known adverse genetic factors confirmed that TP53 mutations have added prognostic value. Conclusion TP53 mutations are associated with impaired response and shorter survival in patients with CLL. Analysis of TP53 mutations should be performed in patients with CLL who have progressive disease before starting first-line treatment, and those with mutations should be selected for novel experimental therapies.

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