Risk Stratification In Chronic Lymphocytic Leukemia Patients With IGHV3-21 Gene Usage According To Presence Of Stereotypy and Mutations In SF3B1

Abstract Introduction Chronic Lymphocytic Leukemia (CLL) patients with monoclonal IGHV3-21 gene rearrangements have been described to have adverse prognosis independent of mutational status. Heterogeneous data exists whether only patients with a stereotyped motif in the junctional region (designated as subset #2, Stamatopoulos K. et al., Blood 2007) suffer from worse prognosis. Furthermore, it was recently suggested that co-occurrence of subset #2 and mutations (mut) in SF3B1 are indicative of a shorter time to treatment (TTT). Aims 1. Determine the prognostic impact of IGHV3-21 and subset #2 rearrangements. 2. Evaluate the association with SF3B1mut and its prognostic impact. Patients and Methods IGHV3-21 positive (n=213) and independently 1,094 unselected CLL patients without prior treatment were analyzed. The whole cohort comprised 63.9% (835/1,307) males and 36.1% (472/1,307) females with a median age of 66.8 years (range: 27.5 – 90.5 years). In all cases IGHV mutation status was analyzed. IGHV unmutated (unmut) status was present in 38.6% (504/1,307) and mutated status in 61.4% (803/1,307). Stereotypy of IGHV3-21 was classified according to published criteria (Agathangelidis A. et al., Blood 2012). SF3B1 was analyzed in all and TP53 in 1,262 cases for mutations. For all patients data on immunophenotype was available. Cases were further analyzed by FISH using probes for del(17p) (n=1,305), del(11q) (n=1,303), trisomy 12 (n=1,303) and del(13q) (n=1,305). Clinical follow-up data was available in 1,040 patients with a median follow-up of 4.4 years (IGHV3-21: n=160, 4.2 years). Results Of 213 IGHV3-21 positive patients, 111 (52.1%) cases were classified as subset #2 B-cell receptor. The frequency of IGHVmut was significantly higher in subset #2 vs. non-subset #2 (78/111, 70.3% vs. 49/102, 48.0%, p=0.001). IGHV3-21 was highly associated with SF3B1mut (52/213, 24.4% vs. 92/1,094, 8.4%, p<0.001), which were particularly frequent in subset #2 cases (38/111, 34.2% vs. 14/102, 13.7%, p=0.001). Furthermore, IGHV3-21 was associated with del(11q) (35/210, 16.7% vs. 122/1,093, 11.2%, p=0.028) and was rare in patients with trisomy 12 (8/210, 3.8% vs. 168/1,093, 15.4%, p<0.001). Accordingly, del(11q) was particularly frequent in subset #2 patients (25/110, 22.7% vs. 10/100, 10.0%, p=0.016), whereas trisomy 12 (1/110, 0.9% vs. 7/100, 7.0%, p=0.029) and del(17p) (1/111, 0.9% vs. 8/101, 7.9%, p=0.015) were nearly absent. Kaplan-Meier analysis revealed no significant difference in TTT between IGHV3-21mut vs. unmutated cases. However, IGHV3-21mut cases had slightly longer TTT compared to IGHVunmut (5.3 years vs. 3.4 years, p=0.039). Taking stereotypy into account, subset #2 patients showed nearly identical TTT compared to IGHVunmut patients (3.5 vs. 3.4 years). Further stratification according to IGHV mutational status presented mutated non-subset #2 patients with a similar TTT compared to IGHVmut cases (9.2 vs. 10.2 years), whereas all other subgroups assorted together with IGHVunmut (Fig. 1A). Additionally, there was a trend to a shorter TTT in subset #2 in combination with SF3B1mut vs. SF3B1wt (1.2 vs. 4.4 years, p=0.056) (Fig. 1B). In univariate Cox regression analysis, following parameters were analyzed and showed significant impact on TTT: IGHVmut (p<0.001, HR 0.33), IGHV3-21 (p=0.002, HR 1.51), subset #2 (p=0.005, HR 2.04), SF3B1mut (p<0.001, HR 2.06). A multivariate analysis including IGHV3-21, IGHVmut and SF3B1mut revealed independent impact on TTT only for the latter two parameters: IGHVmut (p<0.001, HR 0.35) and SF3B1mut (p=0.001, HR 1.59). In contrast, analyzing subset #2, IGHVmut and SF3B1mut in a multivariate model, only subset #2 (p=0.011, HR 1.93) and SF3B1mut (p=0.023, HR 1.82) retained their prognostic effect, whereas IGHV mutational status had no independent impact. Conclusions 1. Our data suggests to prognostically stratify IGHV3-21 patients according to the presence of stereotypy, since only subset #2 patients showed shorter TTT, whereas mutated non-subset #2 cases had a TTT similar to IGHVmut cases. 2. Mutation status of SF3B1 further refines the risk stratification of subset #2 patients, as co-occurrence of subset #2 with SF3B1mut leads to shorter TTT compared to subset #2/SF3B1wt cases. Disclosures: Jeromin: MLL Munich Leukemia Laboratory: Employment. Dicker:MLL Munich Leukemia Laboratory: Employment. Bayer:MLL Munich Leukemia Laboratory: Employment. Weissmann:MLL Munich Leukemia Laboratory: Employment. Eder:MLL Munich Leukemia Laboratory: Employment. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

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Characterization and Prognostic Impact of Multiple Productive IGHV Rearrangements in CLL

Blood ◽

10.1182/blood.v128.22.3207.3207 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3207-3207

Author(s):

Sabine Jeromin ◽

Claudia Haferlach ◽

Frank Dicker ◽

Manja Meggendorfer ◽

Torsten Haferlach ◽

...

Keyword(s):

Prognostic Factors ◽

Lymphocytic Leukemia ◽

Prognostic Impact ◽

Employment Equity ◽

Mutational Status ◽

Treatment Naïve ◽

Trisomy 12 ◽

Equity Ownership ◽

The Impact

Abstract Background: In chronic lymphocytic leukemia (CLL) one of the strongest prognostic factors is IGHV mutational status. Infrequently, patients present not only with a single IGHV rearrangement but with multiple productive rearrangements. In about 2% of all CLL patients analyzed on cDNA level multiple rearrangements display the same mutational status and are categorized accordingly following ERIC recommendations. In another 1% rearrangements with discordant IGHV mutational status are detected and preclude a definite risk assignment. Only limited data exist on these rare subgroups. Aim: To characterize treatment-naive CLL patients with multiple productive IGHV rearrangements and determine the impact on prognosis. Patients and Methods: Out of 8,016 treatment-naive CLL patients between 2005 and 2015 and with data on IGHV mutational status we identified 204 (3%) with multiple productive rearrangements. IGHV mutational status was analyzed on cDNA and in all cases according to ERIC recommendations. IGHV mutated status (M) was defined by sequence identity <98% and unmutated status (U) by ≥98%. Chromosome banding analysis was available in 102 cases and interphase FISH with probes for 17p13, 13q14, 11q22 and centromeric region of chromosome 12 in 191. Male:female ratio was 3:1 and median age 68 years (range: 38-89). Additionally, data on SF3B1 and TP53 mutations was present in all cases. Follow-up data on time to first treatment (TTT) and overall survival (OS) was available in 105 cases with a median follow-up of 4 years. For statistical comparison we used a cohort of 1,262 untreated CLL patients with single IGHV rearrangement (median age: 67 years; range: 30-91, median follow-up: 6 years). Results: Out of 204 patients with multiple, productive rearrangements 199 (98%) presented with two and 5 patients (2%) with three IGHV rearrangements. Concordant IGHV mutated status (MM) was present in 120 cases (59%), whereas concordant unmutated status (UU) was seen in 34 patients (17%). In 50 cases (25%) a mixed IGHV status (UM) was detected. We analyzed frequencies of complex karyotype by CBA, biclonality according to immunophenotype (concurrent kappa restricted and lambda restricted subpopulations) and/or CBA, TP53 disruption (TP53mut and/or del(17p)), SF3B1mut, del(11q), trisomy 12, and del(13q). Overall, a higher frequency of biclonality was detected in patients with multiple vs. single IGHV rearrangements (16% vs. 1%, p<0.001). However, association to neither MM, UU nor UM existed. MM presented with molecular and cytogenetic characteristics similar to M. Correspondingly, UU showed similar frequencies of mutations and aberrations to U, except for higher frequency of trisomy 12 in UU vs. U (42% vs. 19%, p=0.003). Interestingly, UM presented with characteristics similar to U and UU. UM was associated with TP53 disruption vs. M (16% vs. 5%, p=0.003) and vs. MM (5%, p=0.035) as well as with SF3B1mut vs. M (16% vs. 5%, p=0.008). Furthermore, UM cases showed high frequency of del(11q) vs. M (29% vs. 3%, p<0.001) and vs. MM (1%, p<0.001) and less frequently del(13q) sole vs. M (41% vs. 60%, p=0.011) and MM (41% vs. 69%, p=0.001). No significantly differences in TTT were observed between MM and M (median: 13 vs. 14 years) and between UU and U (6 vs. 4 years), respectively. However, the difference between MM vs. UU (p=0.022) and M vs. U (p<0.001) was significant. The UM subgroup presented with a TTT (median: 4 years) similar to U and UU, whereas it was significantly shorter vs. M (p=0.003) and MM (p=0.006), respectively. A similar picture emerged for survival. 5-year OS of MM was not different vs. M (94% vs. 90%) but vs. U (78%, p=0.001). The statistical analysis of OS in UU was hampered by low case numbers. UM presented again with similar 5-year OS vs. U (81% vs. 78%, n.s.) and significantly worse OS vs. M (90%, p=0.049) and vs. MM (94%, p=0.014). Conclusions: (1) Patients with multiple productive IGHV rearrangements and concordant IGHV status show similar prognosis and characteristics to patients with single rearrangement with the respective IGHV status. (2) Cases with mixed IGHV status show similar prognosis to patients with IGHV unmutated status and accordingly are characterized by high frequencies of adverse prognostic factors like TP53 disruption, SF3B1mut, and del(11q), whereas del(13q) sole is less frequent. Disclosures Jeromin: MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Dicker:Munich Leukemia Laboratory: Employment. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

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Frequency and Prognostic Impact of CD8 Expression In 5,523 Patients with Chronic Lymphocytic Leukemia (CLL) In Relation to Chromosomal Aberrations, IGHV Mutational Status and ZAP-70 Expression.

Blood ◽

10.1182/blood.v116.21.4616.4616 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4616-4616

Author(s):

Wolfgang Kern ◽

Claudia Haferlach ◽

Susanne Schnittger ◽

Torsten Haferlach

Keyword(s):

Chromosomal Aberration ◽

Chromosomal Aberrations ◽

Lymphocytic Leukemia ◽

Prognostic Impact ◽

Employment Equity ◽

Mutational Status ◽

Trisomy 12 ◽

Equity Ownership ◽

Wbc Count

Abstract Abstract 4616 Chronic lymphocytic leukemia (CLL) is an indolent lymphoma with largely heterogeneous clinical course. Identifying patients which benefit from early therapy is one of the most important issues in the management of CLL. Besides patient-specific characteristics and applicability of different treatment approaches the decision on therapy is based on conventional prognostic parameters as well as on chromosomal aberrations, IgVH mutational status and expression of ZAP-70, which all have been shown to be independently associated with outcome. The expression of CD8 has been rarely observed in CLL and its prognostic impact is unclear yet. In order to clarify the frequency of CD8 expression, its correlation to established prognostic parameters as well as its prognostic impact we analyzed a total of 5,523 patients with CLL by multiparameter flow cytometry including the expression of CD8 between August 2005 and August 2010. Fluorescence in situ hybridization (FISH) applying a standard set of probes for the detection of del(6q), del(11q22.3) (ATM), trisomy 12, del(13q14) (D13S25, D13S319), and del(17p13) (TP53) was performed in 3,407 patients. IGHV mutational status was determined and evaluable in 2,845 patients. Clinical follow-up data was available in 1,021 patients (median follow-up: 21.3 months). 61 patients (1.1%) showed an expression of CD8 (antibody clone B9.11, Immunotech, France) as compared to isotype used as negative control. CD8+ vs. CD8- cases did not differ in age (mean±SD: 70.3±9.7 vs. 68.3±10.4 years, n.s.) and the male/female ratio was 1.11 vs. 1.61 (n.s.). There were no significant differences in WBC count (mean±SD, 31.7±33.9 vs. 36.1±53.1 × 10e9/l) and hemoglobin level (Hb, mean±SD, 13.6±2.0 vs. 13.2±2.1 g/dl), while platelet counts were higher in CD8+ vs. CD8- cases (229±72 vs. 194±99 × 10e9/l, p=0.021). In CD8+ vs. CD8- cases chromosomal aberrations were detected by FISH analysis with the following frequencies: del(6q), 5.9% vs. 3.1%, n.s.; del(11q22.3), 17.1% vs. 10.7% (n.s.); trisomy 12, 20.0% vs. 14.5% (n.s.); del(13q14), 66.7% vs. 59.8% (n.s.); del(13q14) as sole chromosomal aberration, 41.2% vs. 45.5% (n.s.); del(17q13), 2.9% vs. 5.7% (n.s.). The IGHV status was mutated in 79.3% vs. 60.4% (p=0.054) in CD8+ vs. CD8- cases. Patients with CD8 expression had a significantly shorter time to therapy (TTT) as compared to CD8- patients (median TTT, 12.0 vs. 77.1 months, p=0.008). The following parameters showed a significant relation to a shorter TTT in univariate Cox analyses: CD8 positivity, p=0.011, relative risk (RR)=2.87; higher WBC count, p=0.008, RR=1.01 per 10 × 10e9 increase; del(11q22.3), p<0.001, RR=1.97; del(17p13), p=0.005, RR=1.72; higher % of CLL cells with ZAP-70 expression (antibody clone SBZAP, Immunotech, France), p=0.011, RR=1.04 per 10% increase. Parameters significantly related to a longer TTT in univariate Cox analyses were: higher Hb level, p<0.001, RR=0.86 per 1 g/dl; higher platelet count, p=0.021, RR=0.98 per 10 × 10e9 increase; and del(13q14) as sole chromosomal aberration, p<0.001, RR=0.58. Multivariate analysis identified two parameters to be independently related to a shorter TTT: higher ZAP-70 expression (p=0.002) and CD8 positivity (p=0.036), while a higher Hb level (p<0.001) and del(13q14) as sole chromosomal aberration (p=0.011) were identified to be independently related to a longer TTT. This data supports the further evaluation of the prognostic impact of CD8 expression in CLL in order to define its role in identifying the most appropriate timepoint for therapy and the most appropriate treatment modality for patients with CLL. Disclosures: Kern: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

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Translocations Involving the IGH@locus Occur In 3.7% of Chronic Lymphocytic Leukemia and Are Associated with Unmutated IGHV Status and a Shorter Time to Treatment: A Study on 2,135 Cases

Blood ◽

10.1182/blood.v116.21.3596.3596 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3596-3596

Author(s):

Claudia Haferlach ◽

Frank Dicker ◽

Susanne Schnittger ◽

Wolfgang Kern ◽

Torsten Haferlach

Keyword(s):

Multivariate Analysis ◽

Regression Analysis ◽

Chronic Lymphocytic Leukemia ◽

Cox Regression ◽

Lymphocytic Leukemia ◽

Employment Equity ◽

Mutation Status ◽

Cox Regression Analysis ◽

Igh Locus ◽

Equity Ownership

Abstract Abstract 3596 Introduction: Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable clinical course and a large spectrum of treatment options. Based on FISH data, a prognostic classification system has been established with 13q deletions as sole abnormality associated with a favorable prognosis and 17p and 11q deletions correlating with an unfavorable outcome. Recently, the combined evaluation of FISH data, IGHV mutation status and chromosome banding analysis (CBA) revealed that the impact of distinct genetic parameters differs with respect to overall survival (OS) and time to treatment (TTT). Thus far only few data is available on less frequent genetic abnormalities such as 14q deletions and translocations involving the IGH@ locus (tIGH). Therefore, we analyzed CLL with tIGH in detail with respect to frequency, partner genes and impact on prognosis. Methods/Patients: 78 CLL cases with tIGH were identified from 2,135 CLL sent to our laboratory for diagnostic work-up. All cases had been evaluated by immunphentotyping, FISH and CBA. Result: The most frequent tIGH was t(14;19)(q32;q13) (BCL3, n=21) followed by t(14;18)(q32;q21) (BCL2, n=19), t(8;14)(q24;q32) (CMYC, n=7) and t(11;14)(q13;q32) (CCND1, n=6). In the remaining 25 cases 5 recurrent translocations (t(2;14)(p13;q32), n=3; t(4;14)(p16;q32), FGFR3, n=2; t(11;14)(p15;q32), n=2; t(14;17)(q32;q25), n=2; and t(7;14)(q21;q32), n=2) were observed while the remaining 14 translocations were identified in single cases only. In 9/78 cases (11.5%) the tIGH was the sole abnormality. Recurrent additional chromosome abnormalities were +12 (n=7), del(13q) (n=9), del(11q) (n=3). A 17p deletion was observed in 1 case. In two cases tIGH was present only in a subclone and was a secondary abnormality occurring in addition to an del(11q) and a +12, respectively. CLL with tIGH were compared to 401 CLL without tIGH comprising all other genetic subgroups (subdivided according to Döhner et al.: del(17p) n=26, del(11q) n=42, +12 n=42, “normal” n=88, del(13q) sole n=177 and del(14q) n=26). An unmutated IGHV status was more frequent in CLL with tIGH as compared to all others (26/46 (54.3%) vs 128/353 (36.3%); p=0.023). For 53 cases with tIGH and all cases of the non-tIGH cohort clinical follow-up data was available. Median OS was 143.8 months (mo) in CLL with tIGH and 72.9 mo in patients with del(17p) while it was not reached in all other subgroups. In Cox regression analysis only del(17p) and mutated IGHV status were significantly associated with OS (p<0.0001, relative risk (RR)=7.0; p=0.014, RR=0.38). Median TTT was as follows: total cohort: 60.9 mo; tIGH: 27.8 mo; del(17p): 58.9 mo; del(11q): 19.7 mo; +12: n.r.; “normal” 63.9 mo; del(13q) sole: 83.0 mo and del(14q): 21.0 mo. In univariate Cox regression analysis the following parameters were significantly associated with shorter TTT: tIGH (p=0.004, RR=1.82), del(11q) (p<0.0001, RR=2.55), and del(14q) (p=0.007, RR=2.1), while del(13q) sole and mutated IGHV status were associated with longer TTT (p<0.0001, RR=0.40; p<0.0001, RR=0.23). In multivariate analysis including tIGH, del(11q), del(14q) and del(13q) sole all parameters retained their impact on TTT. However, if IGHV mutation status was included in the model only the mutated IGHV mutation status retained an impact on TTT (p<0.0001, RR=0.26). Next, patients with tIGH were subdivided according to their partner genes. Median OS was not reached in all subgroups, while median TTT was as follows: t(11;14): 101.2 mo, t(14;18): 47.9 mo, t(14;19): 11.0 mo, t(8;14): 18.5 mo and other partner genes: 27.8 mo. In univariate Cox regression analysis only t(14;19) was significantly associated with shorter TTT (p<0.001, RR=3.1). Including t(14;19) into multivariate analysis revealed a significant impact of both mutated IGHV mutation status and t(14;19) on TTT (p<0.0001, RR=0.286; p=0.004, RR=3.60). Conclusion: Translocations involving the IGH@ locus occur at low frequency in CLL. They are associated with unmutated IGHV status and a shorter TTT. TTT is especially short in cases with t(14;19). The prognostic impact of t(14;19) is independent of IGHV mutation status. In contrast CLL with t(11;14) and t(14;18) are neither associated with shorter OS nor shorter TTT. This data supports the application of CBA in CLL in order to identify all clinically relevant chromosomal aberrations, including those not detected by routine FISH analysis. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Dicker:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

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Sensitivity of Ibrutinib Exposed Chronic Lymphocytic Leukemia B-Cells to Inhibition of Axl Receptor Tyrosine Kinase

Blood ◽

10.1182/blood.v128.22.2020.2020 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2020-2020

Author(s):

Sutapa Sinha ◽

Justin C Boysen ◽

Kari G. Chaffee ◽

Brian F Kabat ◽

Susan L. Slager ◽

...

Keyword(s):

B Cells ◽

Board Of Directors ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Employment Equity ◽

Advisory Committees ◽

Mutation Status ◽

Axl Receptor Tyrosine Kinase ◽

Equity Ownership

Abstract Introduction: The use of B-cell receptor (BCR) signal inhibitors-based therapies (e.g., Ibrutinib) for B-chronic lymphocytic leukemia (CLL) was initiated just a few years ago but has rapidly escalated due to their clinical efficacy and relative ease of use. However newer therapeutic approaches are needed due to multiple issues including the continued need to improve complete responses and reduce toxicity profiles. To that end our group has discovered a novel membrane target in the ubiquitous presence of Axl receptor tyrosine kinase (Axl RTK) on CLL B-cells and has reported that the Axl RTK inhibitor TP-0903 is able to induce apoptosis of CLL B-cells at nanomolar doses (Sinha, Clin Cancer Res, 2015). Given this we assessed if TP-0903 would be effective in the induction of apoptosis of leukemic B-cells from CLL patients who are currently on Ibrutinib therapy or whom have relapsed while on Ibrutinib treatment. Methods: Relapsed/refractory CLL patients (n=22) who were placed on Ibrutinib for progressive disease provided blood samples at a median of 3.2 months after Ibrutinib therapy initiation for these studies. We also obtained sequential samples on 8 patients from initial start of ibrutinib therapy and then over a 6 month follow-up period. CLL B-cells from these blood samples were subject to Ficoll separation, purified by using a Rosette Sep B-cell enrichment kit and then studied by flow cytometry to determine Axl RTK expression levels by flow cytometric analysis. Purified CLL B-cells (CD19+/CD5+) were cultured with TP-0903 in vitroat increasing doses (0.01µM - 0.50µM) for 24 hours and the LD50 dose was determined. In addition, 3 CLL patients who had been on Ibrutinib therapy and had a documented relapse were studied in similar fashion using TP-0903. LD50-sensitivity was measured. "LD50-sensitivity" was defined as an LD50 ≤0.50µM and "insensitive" was defined as an LD50 dose >0.50µM. CLL prognostic factors (e.g., FISH, IGHV mutation status, Rai stage, CD38, and CD49d) were evaluated at the time of ibrutinib treatment. Differences in factors between sensitive and insensitive cases were computed using the Kruskal-Wallis test for continuous variables and Chi-square test for categorical variables. Results: Twenty-two CLL patients (5 female, 17 male) were included in the analysis. Fourteen (64%) patients were found to be TP-0903 LD50-sensitive. Axl expression on CLL B-cells for this cohort was heterogeneous with a median of CD19+/CD5+ cells positive for Axl at 69.9% (range of 2.7-91.3%). The sensitive subjects tended to be younger with a median age at Ibrutinib treatment initiation of 62 vs 75.5 years (p=0.004). There were no significant differences in gender, FISH, IGHV mutation status, CD38, CD49d, or Rai stage between the sensitive and insensitive LD50 groups. There were no significant differences in relation to median Axl expression on CLL B-cells (sensitive: 72.6%, range: 2.7-91.3%; insensitive: 41.5%, range: 16.5-83.1%; p=0.35). The median number of treatments prior to initiation of ibrutinib did not differ between sensitivity groups (sensitive: 2.53, range: 8-10; insensitive: 43.5, range 12-20; p=0.2833). Association for ZAP70+ CLL B-cells tended to have more apoptosis induction by TP-0903 (sensitive: 84.6% ZAP70+; insensitive: 42.9% ZAP70+; p=0.052). In 8 CLL patients that were studied sequentially while on Ibrutinib continued to express Axl or increased their Axl expression (n=2) over a 3-6 month follow-up period. Three CLL patients who had relapsed on Ibrutinib were sensitive to TP-0903 with LD50 values of ≤0.50µM. Summary: Here we find that CLL B-cells from over 60% of relapsed CLL patients on Ibrutinib therapy were highly sensitive to the high-affinity Axl inhibitor TP-0903 with induction of apoptosis at nanomolar doses (≤0.50µM). The sensitivity of CLL B-cells to TP-0903 appears to be independent of Axl expression levels and of the known CLL prognostic factors but more evident for younger patients and for ZAP70+ expression status. Given this level of activity for apoptosis induction of CLL B-cells by TP-0903 encourages the further testing of this drug in clinical trials for CLL patients. Disclosures Parikh: Pharmacyclics: Honoraria, Research Funding. Shanafelt:Pharmacyclics: Research Funding; Janssen: Research Funding; Genentech: Research Funding; GlaxoSmithKline: Research Funding; Celgene: Research Funding; Cephalon: Research Funding; Hospira: Research Funding. Warner:Tolero Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties. Bearss:Tolero Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties. Kay:Pharmacyclics: Research Funding; Tolero Pharmaceuticals: Research Funding; Acerta: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Morpho-Sys: Membership on an entity's Board of Directors or advisory committees; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

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Patients with TP53 Disruption and IGHV Mutated Status Show Indolent Clinical Course: A Study on 1,327 Treatment-Naive CLL Cases

Blood ◽

10.1182/blood.v128.22.4378.4378 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4378-4378

Author(s):

Sabine Jeromin ◽

Claudia Haferlach ◽

Frank Dicker ◽

Torsten Haferlach ◽

Wolfgang Kern

Keyword(s):

Disease Course ◽

Complex Karyotype ◽

Employment Equity ◽

Mutational Status ◽

Treatment Naïve ◽

Trisomy 12 ◽

Binet Stage ◽

Equity Ownership ◽

Indolent Disease

Abstract Background: Treatment-naive CLL patients displaying TP53 disruption (TP53 mutation and/or del(17p)) show heterogeneity in their clinical course. A few studies have proposed a mutated IGHV status and Rai 0 as potential factors for an indolent disease course in these cases. Aim: To determine the prognostic impact of TP53 disruption in a treatment-naive CLL cohort and the factors associated with an indolent disease course. Patients and Methods: 1,327 CLL patients at diagnosis or without prior treatment were screened both for TP53 mutations (mut) and del(17p). IGHV mutational status was analyzed in all cases. IGHV mutated status (IGHV-M) was defined by sequence identity <98%. Chromosome banding analysis and interphase FISH with probes for 13q14, 11q22 and centromeric region of chromosome 12 were performed in all cases. Additionally, data on mutations in SF3B1 (n=1,183) and NOTCH1 (n=967) was present. Male:female ratio was 2:1 and median age was 67 years (range: 30 - 91 years). Data on Binet stage was available in 711 cases. Follow-up data on time to first treatment (TTT) and overall survival (OS) was available in 1,123 (TP53 disruption: 84) and 1,143 (TP53 disruption: 88) cases, respectively, with a median follow-up of 6 years, each. Results: Overall in 7% (97/1,327) of patients a TP53 disruption was present. TP53mut was detected in 89 (7%) of cases and del(17p) in 51 (4%). Three different combinations were determined: TP53mut with del(17p) in 43 (44%) cases, TP53mut sole in 46 (48%) patients and del(17p) sole in 8 (8%) cases. TP53 disruption was associated with IGHV-U vs. IGHV-M (12% vs. 5%, p<0.001), NOTCH1mut vs. NOTCH1wt (14% vs. 8%, p=0.027), complex karyotype (≥ 3 abnormalities) vs. non-complex karyotype (27% vs. 6%, p<0.001), and Binet B/C vs. A (10% vs. 5%, p=0.010). In contrast, TP53 disruption was rare in del(11q) vs. others (3% vs. 8%, p=0.046). Next, we analyzed patients with TP53 disruption for differences in TTT and OS according to IGHV mutational status, SF3B1mut, NOTCH1mut, del(11q), trisomy 12, del(13q), complex karyotype and Binet stage. We detected a significantly longer TTT in IGHV-M cases (median: 10 vs. 2 years, p<0.001) and in patients without trisomy 12 (median: 6 vs. 2 years, p=0.046). A better 5-year OS was seen in cases with IGHV-M (76% vs. 57%, p=0.006) and in patients with Binet A vs. B/C (80% vs. 46%, p=0.049). Interestingly, in TP53 disruption/IGHV-M patients as compared to IGHV-M without TP53 disruption no significant difference in TTT was detected. In contrast, TP53 disruption/IGHV-M cases showed an intermediate 5-year OS comparable to IGHV-U without TP53 disruption, whereas patients with IGHV-U/TP53 disruption showed the most adverse OS (see Table). A cox regression analysis in TP53 disrupted cases including all the above mentioned factors showed significant impact only for IGHV-M both on TTT (HR: 0.24, p<0.001) and OS (HR: 0.38, p=0.008). Therefore, we further focused on the characterization of patients with TP53 disruption/IGHV-M vs. TP53 disruption/IGHV-U. TP53 disruption/IGHV-M showed higher frequencies of del(13q) (71% vs. 45%, p=0.013), whereas del(17p) (39% vs. 63%, p=0.025) and trisomy 12 (2% vs. 23%, p=0.003) were less frequent. NOTCH1mut were mutually exclusive of TP53 disruption/IGHV-M (0% vs. 36%, p<0.001). Thus, within the cohort of TP53 disruption cases the subgroup with IGHV-M is characterized by the occurrence of adverse prognostic factors to a lesser extent. Conclusions: Treatment-naive patients with TP53 disruption and IGHV-M show a more indolent disease course: (1) TTT was not significantly altered in comparison to IGHV-M cases without TP53 disruption; (2) for OS an additive effect of IGHV-U and TP53 disruption was detected with patients presenting with both factors showing the most adverse OS. Thus, in treatment-naive CLL patients TP53 disruption should always be evaluated on the background of IGHV mutational status and as recommended only at progression and before treatment is required. Disclosures Jeromin: MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Dicker:Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

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Mutations of NOTCH1 Are An Independent Predictor of Survival in Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v118.21.283.283 ◽

2011 ◽

Vol 118 (21) ◽

pp. 283-283

Author(s):

Davide Rossi ◽

Silvia Rasi ◽

Giulia Fabbri ◽

Valeria Spina ◽

Marco Fangazio ◽

...

Keyword(s):

Multivariate Analysis ◽

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Univariate Analysis ◽

Lymphocytic Leukemia ◽

Prognostic Impact ◽

Prognostic Role ◽

Trisomy 12 ◽

Notch1 Mutations

Abstract Abstract 283 The clinical course of chronic lymphocytic leukemia (CLL) ranges from very indolent, with a nearly normal life expectancy, to rapidly progressive leading to death and occasionally undergoing transformation to Richter syndrome (RS). TP53 disruption identifies a fraction of high risk CLL destined to experience a very short survival. High risk CLL, however, cannot be fully recapitulated by TP53 disruption and other lesions of cancer genes may be implicated in this aggressive phenotype. Analysis of the CLL coding genome has recently disclosed that the NOTCH1 proto-oncogene is recurrently mutated at CLL presentation. Here we assessed the prognostic role of NOTCH1 mutations in CLL. Two series of previously untreated CLL were utilized as training (n=309, median follow-up 6 years) and validation (n=230, median follow-up 7 years) cohorts. NOTCH1 mutations were analyzed by DNA Sanger sequencing in blind with respect to clinical data. In the training series, NOTCH1 mutations occurred in 34/309 (11.0%) patients, being mostly represented (26/34, 76.5%) by a recurrent two bp frameshift deletion (c.7544_7545delCT). The remaining NOTCH1 mutations (8/34, 23.5%) were frameshift deletions other than c.7544_7545delCT (n=7) and frameshift insertions (n=1). All mutations were predicted to disrupt the NOTCH1 PEST domain. CLL with NOTCH1 mutations preferentially carried unmutated IGHV genes (76.5%, p<.001). Other characteristics at presentation associated with NOTCH1 mutations were advanced Rai stage (26.5%, p=.006) and trisomy 12 (44.1%, p<.001). By univariate analysis, NOTCH1 mutations associated with an increase in the hazard of death (HR: 3.77; 95% CI: 2.14–6.66) and a significant overall survival OS shortening (p<.001) (Fig. 1A). Multivariate analysis selected NOTCH1 mutations as an independent risk factor of OS (HR: 4.22; 95% CI: 2.15–8.28; p<.001), after adjusting for age (p<.001), Rai stage (p=.005), IGHV mutation status (p=.465), 11q22-q23 deletion (p=.128), trisomy 12 (p=.183) and TP53 disruption (p<.001). The poor prognosis conferred by NOTCH1 mutations was attributable, at least in part, to a shorter time to progression requiring treatment (p<.001), and a higher cumulative probability of RS development (p=.026). Although NOTCH1 mutated patients were devoid of TP53 disruption in 31/34 (91.2%) cases, the OS predicted by NOTCH1 mutations was similar to that of TP53 mutated/deleted CLL (Fig. 1C). Analysis of the validation series confirmed: i) the prevalence of NOTCH1 mutations at CLL presentation (26/230, 11.3%); ii) the spectrum of NOTCH1 mutations at CLL presentation (c.7544_7545delCT: 21/26, 80.7%; other mutations: 5/26, 19.3%) iii) the adverse prognostic impact of NOTCH1 mutations in CLL both by univariate analysis (Fig. 1B) and by multivariate analysis (HR: 2.08; 95% CI: 1.10–3.93; p=.023); iv) the preferential mutually exclusive distribution of NOTCH1 mutations and TP53 disruption (25/26, 96.2%); v) that OS of NOTCH1 mutated CLL is similarly poor as that of TP53 disrupted CLL (Fig. 1D). The current study on 539 CLL documents that NOTCH1 mutations: i) represent one of the most frequent cancer gene mutations known to be involved at CLL presentation; ii) identify a subgroup of patients showing poor OS similar to that of TP53 disrupted cases; iii) exert a prognostic role independent of widely accepted clinical and genetic risk factors; iv) predict OS in series from different institutions, as documented by the training-validation approach chosen for the design of this study. Disclosures: No relevant conflicts of interest to declare.

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Flow Cytometric Identification of Biclonal Disease Among 5,523 Patients with Chronic Lymphocytic Leukemia and Its Genetic Characterization

Blood ◽

10.1182/blood.v116.21.3608.3608 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3608-3608

Author(s):

Wolfgang Kern ◽

Susanne Schnittger ◽

Frank Dicker ◽

Torsten Haferlach ◽

Claudia Haferlach

Keyword(s):

Light Chain ◽

Chromosomal Aberrations ◽

Molecular Genetic ◽

Lymphocytic Leukemia ◽

Fish Analysis ◽

Employment Equity ◽

Mutational Status ◽

Trisomy 12 ◽

Genetic Level ◽

Equity Ownership

Abstract Abstract 3608 Chronic lymphocytic leukemia (CLL) is an indolent disease with largely heterogeneous clinical course. While the diagnosis is made based on the characteristic immunophenotype as determined by multiparameter flow cytometry (MFC) another aspect of major clinical importance is the estimation of the prognosis which includes the analysis of chromosomal aberrations, the IGHV mutational status as well as the expression of CD38 and ZAP-70. In general, the methods used to determine these parameters are applied in the assumption of analyzing one homogeneous leukemic population and are evaluated accordingly. The potential presence of subpopulations and even subclones may not always be considered adequately in this regard. We identified 76 out of 5,523 patients (1.4%) in whom MFC identified biclonal disease based on the presence of both kappa- and lambda-light chain restricted leukemic subpopulations. In 45 of these cases fluorescence in situ hybridization (FISH) analysis was performed applying a standard set of probes for the detection of del(6q), del(11q22.3) (ATM), trisomy 12, del(13q14) (D13S25, D13S319), and del(17p13) (TP53). In 17 of the 76 patients a chromosome banding analysis (CBA) was performed and the IGHV mutational status was determined in 38 of 76 patients. The patients` ages ranged from 47.7 to 88.0 years (median, 71.3 years), 50 patients were male. The median WBC count amounted to 19 ×10e9/l (range, 0.6–237 ×10e9/l). In most cases the kappa-light chain restricted subpopulation was larger than the lambda-light chain restricted one. The median values and ranges for the respective percentages of subpopulations amounted to: kappa, 24%, 1%-88%; lambda, 12%, 1%-85%. The respective peripheral blood concentrations amounted to: kappa, 3.68 ×10e9/l, 0.12–142 ×10e9/l; lambda, 2.37 ×10e9/l, 0.01–128 ×10e9/l. The median ratio kappa population/lambda population amounted to 1.9 (range, 0.05–76). FISH analysis identified del(6q) in 2/44 (4.5%) cases, del(11q) in 2/44 (4.5%), trisomy 12 in 7/44 (15.9%), del(13q) in 28/45 (62.2%), del(13q) as sole aberration detected by FISH in 23/43 (53.5%), and del(17p) in 1/45 (2.2%). In three cases more than one aberration was detected by FISH: two cases with del(11q) and del(13q) and one case with trisomy 12 and del(13q). While in two of these three cases the size-ratios of the respective subpopulations were similar in MFC and FISH analysis (1.7:1 vs. 4.3:1 and 2.0:1 vs. 1.5:1) this was not true for the third case (15.5:1 vs. 1.1:1). The further two cases could be considered in line with both methods detecting independent clones. In the latter case the chromosomal aberrations were present in 54% and 59% of the cells and the subpopulations detected by MFC amounted to 62% and 4%. Thus, both chromosomal aberrations must be considered to coexist in one population and not related to the two subpopulations detected by MFC. Overall, however, no clear-cut conclusions can be drawn from FISH results regarding the presence of independent subpopulations and therefore we next focused on the results of CBA. Within the 17 patients analyzed by CBA 12 cases showed an aberrant karyotype (70.6%). In four of these cases more than one clone was identified by differences in the chromosomal aberrations, respectively. In three cases chromosomal evolution was suggested by shared aberrations in both clones and additional aberrations in one of both clones only, respectively. Conversely, in the fourth case two completely different aberration patterns were observed. In 14 out of the 38 patients (36.8%) in whom an IGHV mutational analysis was performed two independent clones were identified by the presence of two different B-cell receptor rearrangements. The presence of biclonal disease had no impact on the clinical outcome of the patients as assessed by time to therapy and overall survival. This data indicates that subpopulations can be identified in a significant number of patients with CLL based on the immunophenotype as well as on the cytogenetic and molecular genetic level. These subpopulations at least in part must be considered as subclones with differing genetic background. These subclones may be associated with differing clinical courses. This data therefore suggests to vigorously screen patients with CLL for subpopulations by MFC and to comprehensively characterize positive cases cytogenetically by CBA and FISH analysis as well as on the molecular genetic level. Disclosures: Kern: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Dicker:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

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The prognostic impact of autologous stem cell transplantation in patients with chronic lymphocytic leukemia: a risk-matched analysis based on the VH gene mutational status

Blood ◽

10.1182/blood-2003-05-1549 ◽

2004 ◽

Vol 103 (7) ◽

pp. 2850-2858 ◽

Cited By ~ 81

Author(s):

Peter Dreger ◽

Stephan Stilgenbauer ◽

Axel Benner ◽

Matthias Ritgen ◽

Alexander Kröber ◽

...

Keyword(s):

Stem Cell ◽

Chronic Lymphocytic Leukemia ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Autologous Stem Cell Transplantation ◽

Lymphocytic Leukemia ◽

Study Entry ◽

Prognostic Impact ◽

Cox Regression Analysis ◽

Mutational Status

Abstract To assess the therapeutic value of sequential high-dose therapy (SHDT) including autologous stem cell transplantation in chronic lymphocytic leukemia (CLL) we performed a risk-matched comparison between 66 patients who had undergone a uniform SHDT regimen and a database of 291 patients treated conventionally. Matching variables were age, Binet stage, IgVH (variable region of the immunoglobulin heavy chain) gene mutational status, and lymphocyte count. Forty-four pairs fully matched for all 4 variables were identified. Patient groups were well balanced for additional risk factors including adverse genomic abnormalities and CD38 expression. With an overall median follow-up time of 70 and 86 months, respectively, survival was significantly longer for the SHDT patients than for the conventionally treated patients when calculated from diagnosis (hazard ratio [HR] 0.39; P = .03 [log rank]) or from study entry (HR 0.32; P = .006). The benefit for the SHDT group remained significant when the analyses were restricted to those 58 patients who had an unmutated VH status. Cox regression analysis confirmed SHDT as independent favorable prognostic factor for survival from diagnosis (HR 0.38, P = .04) as well as from study entry (HR 0.38, P = .03). These data suggest a survival benefit for patients with poor-risk CLL receiving SHDT during the course of their disease. (Blood. 2004;103:2850-2858)

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Improvements in Health-Related Quality of Life and Symptoms in Patients with Previously Untreated Chronic Lymphocytic Leukemia: Final Results from the Phase II GIBB Study of the Combination of Obinutuzumab and Bendamustine

Blood ◽

10.1182/blood-2019-123630 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3491-3491 ◽

Cited By ~ 1

Author(s):

Alexey Danilov ◽

Habte A Yimer ◽

Michael Boxer ◽

John M Burke ◽

Sunil Babu ◽

...

Keyword(s):

Quality Of Life ◽

Health Status ◽

Chronic Lymphocytic Leukemia ◽

Global Health ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Future Health ◽

Equity Ownership

Introduction: Longitudinal changes in health-related quality of life (HRQoL) are important in patients with chronic lymphocytic leukemia (CLL). GIBB (NCT02320487) is an open-label, single-arm phase II study of obinutuzumab (GA101; G) in combination with bendamustine (G-Benda) in patients with previously untreated CLL. A previous report from the GIBB study demonstrated an investigator-assessed objective response rate of 89.2%, a complete response rate of 49.0%, and no unexpected safety signals with G-Benda (Sharman et al. J Clin Oncol 2017). Here we report the final HRQoL data over 3 years from the GIBB study. Methods: Enrolled patients received G-Benda by intravenous infusion over six 28-day cycles: G 100mg on Day (D)1, 900mg on D2, and 1000mg on D8 and D15 of Cycle (C)1, then 1000mg on D1 of C2-6; benda 90mg/m2 on D2-3 of C1, and on D1-2 of C2-6. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) includes a global health status measure, 5 functional scales (physical, emotional, cognitive, social, and role functioning), 8 symptom scales/items (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, and diarrhea), and an item on financial difficulties (Aaronson et al. J Natl Cancer Inst 1993). The EORTC Quality of Life Questionnaire-Chronic Lymphocytic Leukemia 16 (QLQ-CLL16) is a 16-item module, specific to CLL, containing 4 multi-item scales (fatigue, treatment side effects, disease symptoms, and infection) and 2 single items (social activities and future health worries). Both questionnaires were completed by patients on C1D1 (baseline), C3D1, and C6D1, at the end of induction (EOI) treatment (defined as +28 days from C6D1 or early treatment termination visit), at the response visit (defined as 2-3 months after the EOI treatment for all patients who received study treatment and had not experienced disease progression), and every 3 months thereafter at follow-up visits for up to 2 years. In total, there were 14 timepoints where data were collected. HRQoL scores were linear transformed to a 0-100-point scale. Mean baseline scores and mean score changes from baseline at each visit were evaluated. A threshold of ≥10-point change in score represents a clinically meaningful difference. For symptoms, negative change scores from baseline reflect an improvement in symptom burden. For global health status and functioning, positive change scores from baseline reflect improvements. Results: The trial enrolled 102 patients. Median age was 61 years and 68.4% of patients were male. Ninety-eight patients (96%) completed a questionnaire at baseline and at least 1 other questionnaire during a follow-up visit. Questionnaire completion rates at 14 time points ranged from 96% at baseline to 66% at 27 months follow-up (Table 1). According to the EORTC QLQ-C30 (Figure 1), improvements were observed for global health status at all follow-up visits, and clinically meaningful improvements were observed at the response visit, 3 months follow-up, and 27 months follow-up. Clinically meaningful improvements in role functioning were observed at EOI and persisted throughout the 27-month follow-up. For fatigue, clinically meaningful improvements were observed at every visit starting from the end of treatment (EOT) visit. Improvements were also observed for insomnia with mean reductions from baseline ≥10 points at various time points during follow-up. There was no worsening in other patient-reported symptoms or functional status over time. Similarly, with the EORTC QLQ-CLL16 (Figure 2), clinically meaningful improvements in symptoms were observed for fatigue, disease symptoms, and future health worries during treatment, at the EOT and/or throughout the follow-up. The largest improvement was observed for fatigue (-24.7) at the 24-month follow-up and future health worries (-25.4) at the 27-month follow-up. Conclusions: We previously reported that G-Benda is an effective regimen for first-line treatment of CLL with no unexpected safety signals. The HRQoL data from the GIBB trial suggest that G-Benda treatment consistently improved patient HRQoL over time. Several clinically meaningful improvements were observed in HRQoL, including global health status, functioning, symptoms, and future health worries. Disclosures Danilov: AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; MEI: Research Funding; Bristol-Meyers Squibb: Research Funding; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Takeda Oncology: Research Funding; Genentech: Consultancy, Research Funding; Bristol-Meyers Squibb: Research Funding; Takeda Oncology: Research Funding; Aptose Biosciences: Research Funding; Aptose Biosciences: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Consultancy; Janssen: Consultancy; Curis: Consultancy; Seattle Genetics: Consultancy; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Gilead Sciences: Consultancy, Research Funding; Bayer Oncology: Consultancy, Research Funding; Curis: Consultancy; Seattle Genetics: Consultancy; MEI: Research Funding; TG Therapeutics: Consultancy; Celgene: Consultancy; Gilead Sciences: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Abbvie: Consultancy; Abbvie: Consultancy. Yimer:AstraZeneca: Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Honoraria; Celgene: Honoraria; Clovis Oncology: Equity Ownership; Puma Biotechnology: Equity Ownership; Amgen: Consultancy. Boxer:Gerson Lerman: Consultancy; Best Doctors: Consultancy; Takeda: Honoraria, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau. Burke:Celgene: Consultancy; Gilead: Consultancy; Roche/Genentech: Consultancy. Babu:Genentech: Research Funding. Li:Genentech: Employment; Roche: Equity Ownership. Mun:Genentech: Employment, Equity Ownership. Trask:Genentech: Employment, Equity Ownership. Masaquel:Roche: Equity Ownership; Genentech: Employment. Sharman:Acerta: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated: in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia; in combination with bendamustine followed by GAZYVA monotherapy, for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab-containing regimen

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The mutational landscape of chronic lymphocytic leukemia and its impact on prognosis and treatment

Hematology ◽

10.1182/asheducation-2017.1.329 ◽

2017 ◽

Vol 2017 (1) ◽

pp. 329-337 ◽

Cited By ~ 19

Author(s):

Gianluca Gaidano ◽

Davide Rossi

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Predictive Biomarkers ◽

Predictive Biomarker ◽

Treatment Choice ◽

Lymphocytic Leukemia ◽

Prognostic Scores ◽

Mutation Status ◽

Biological Variables ◽

Trisomy 12 ◽

Innovative Drugs

Abstract The typical genome of chronic lymphocytic leukemia (CLL) carries ∼2000 molecular lesions. Few mutations recur across patients at a frequency >5%, whereas a large number of biologically and clinically uncharacterized genes are mutated at lower frequency. Approximately 80% of CLL patients carry at least 1 of 4 common chromosomal alterations, namely deletion 13q14, deletion 11q22-23, deletion 17p12, and trisomy 12. Knowledge of the CLL genome has translated into the availability of molecular biomarkers for prognosis and treatment prediction. Prognostic biomarkers do not affect treatment choice, and can be integrated into prognostic scores that are based on both clinical and biological variables. Molecular predictive biomarkers affect treatment choice, and currently include TP53 disruption by mutation and/or deletion and IGHV mutation status. TP53 disruption by gene mutation and/or deletion associates with chemoimmunotherapy failure and mandates treatment with innovative drugs, including ibrutinib, idelalisib, or venetoclax. The mutation status of IGHV genes represents a predictive biomarker for identifying patients that may benefit the most from chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. Assessment of these biomarkers at the time of treatment requirement is recommended by most current guidelines for CLL management. Other molecular predictors are under investigation, but their application in clinical practice is premature.

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