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

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

Blood ◽

10.1182/blood.v122.21.4114.4114 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4114-4114

Author(s):

Sabine Jeromin ◽

Frank Dicker ◽

Katharina Bayer ◽

Sandra Weissmann ◽

Christiane Eder ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Risk Stratification ◽

Lymphocytic Leukemia ◽

Prognostic Impact ◽

Employment Equity ◽

Mutation Status ◽

Mutational Status ◽

Trisomy 12 ◽

Equity Ownership

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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Tumor lysis syndrome: an uncommon complication of fludarabine therapy of chronic lymphocytic leukemia.

Journal of Clinical Oncology ◽

10.1200/jco.1998.16.7.2313 ◽

1998 ◽

Vol 16 (7) ◽

pp. 2313-2320 ◽

Cited By ~ 61

Author(s):

B D Cheson ◽

J N Frame ◽

D Vena ◽

N Quashu ◽

J M Sorensen

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Disease Duration ◽

Tumor Lysis Syndrome ◽

Laboratory Data ◽

Lymphocytic Leukemia ◽

Phase Ii Trials ◽

Tumor Lysis ◽

Laboratory Features

PURPOSE To quantify the incidence and severity of tumor lysis syndrome (TLS) as a consequence of fludarabine therapy in patients with advanced chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS A retrospective review and questionnaire follow-up of clinical and laboratory data were performed on patients with intermediate or high-risk CLL on the National Cancer Institute Group C protocol or special exception mechanisms, or phase II trials of fludarabine, for whom adverse drug reports of TLS were available. Fludarabine was administered at a dose of 20 to 40 mg/m2 per day for 5 days at monthly intervals. RESULTS Among the 6,137 patients, TLS was suspected in 26 (0.42%), with clinical and laboratory features consistent with TLS present in 20 (0.33%). Prophylaxis against TLS had been administered to 60% of these patients. Clinical or laboratory features were similar to patients who did not develop TLS. Of the patients with TLS, 90% had high-risk CLL, 60 months of prior disease duration, with a median pretreatment WBC of 109 x 10(9)/L, two prior regimens, lymphadenopathy in 89%, splenomegaly and/or hepatomegaly in 90%. TLS developed on approximately day 7 and lasted a median of 9.5 days. Dialysis was required in 30% during the TLS episode; 20% of patients died during cycle one of fludarabine therapy with renal failure, and another 20% died of infection or congestive heart failure. Six patients were retreated with fludarabine without recurrent TLS. CONCLUSION TLS after fludarabine therapy is extremely uncommon, but may be associated with significant morbidity and mortality.

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Additional Genetic High-Risk Features Such As 11q Deletion, 17p Deletion, and V3-21 Usage Characterize Discordance of ZAP-70 and VH Mutation Status in Chronic Lymphocytic Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2005.03.7184 ◽

2006 ◽

Vol 24 (6) ◽

pp. 969-975 ◽

Cited By ~ 134

Author(s):

Alexander Kröber ◽

Johannes Bloehdorn ◽

Sebastian Hafner ◽

Andreas Bühler ◽

Till Seiler ◽

...

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Variable Region ◽

Multivariate Regression Analysis ◽

Lymphocytic Leukemia ◽

Prognostic Impact ◽

Mutation Status ◽

Characteristic Modes ◽

Genomic Aberrations ◽

Vh Gene

Purpose Immunoglobulin heavy chain variable-region (VH) gene mutation status and zeta-associated protein 70 (ZAP-70) expression are correlated in chronic lymphocytic leukemia (CLL), but their concordance is variable. The goal of this study was to elucidate additional factors potentially characterizing their discordance. Patients and Methods We evaluated ZAP-70 expression by flow cytometry, VH status by DNA sequencing, and genomic aberrations by fluorescence in situ hybridization in 148 CLL patients. The parameters were analyzed for their associations and their individual prognostic impact. Results ZAP-70 expression and VH mutation status were strongly associated in CLL without additional genetic high-risk-features as defined by the absence of 11q or 17p deletion and V3-21 usage (concordance 84%). In contrast, the proportion of discordant cases was significantly higher (39%), if such additional genetic high-risk features were present. Discordant cases with V3-21 usage were almost exclusively ZAP-70 positive and VH mutated (89%), whereas all but one of the discordant cases with high-risk aberrations were ZAP-70 negative and VH unmutated (92%). By multivariate regression analysis, two models were developed, which both include high-risk genomic aberrations and, alternatively, VH mutation status and V3-21 usage or ZAP-70 expression as independent outcome predictors. Conclusion There were characteristic modes of discordance between ZAP-70 and VH mutation status depending on the presence or absence of additional genetic high-risk features such as 11q and 17p deletion or V3-21 usage. Although the biologic background for these findings is yet to be determined, these data have biologic and clinical implications regarding ZAP-70 as a pathogenic factor and outcome predictor, respectively.

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Frontline Combined Chemoimmunotherapy with Fludarabine, Cyclophosphamide, Alemtuzumab and Rituximab (CFAR) in High-Risk Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v114.22.208.208 ◽

2009 ◽

Vol 114 (22) ◽

pp. 208-208 ◽

Cited By ~ 2

Author(s):

Sameer A Parikh ◽

Michael Keating ◽

Susan O'Brien ◽

Alessandra Ferrajoli ◽

Stefan Faderl ◽

...

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Single Agent ◽

Lymphocytic Leukemia ◽

Hematologic Toxicity ◽

Frontline Therapy ◽

Grade 3 ◽

Tract Infections ◽

Cmv Reactivation

Abstract Abstract 208 Background: Combined chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has excellent clinical activity as frontline therapy for patients (pts) with chronic lymphocytic leukemia (CLL). In a subset of pts who exhibited high-risk features, such as serum beta-2 microglobulin (B2M) ≥4 mg/L; the complete remission (CR) was lower and time to progression (TTP) and overall survival (OS) were shorter; therefore characterizing these pts as high-risk. Alemtuzumab (A) has activity as a single-agent and in combination with F in pts with relapsed/refractory CLL. To improve the CR and OS for pts with high-risk CLL, we added A to the FCR regimen (CFAR) as frontline therapy in a Phase II clinical trial. Methods: All pts who met NCI-WG criteria to initiate therapy, were < 70 years and had a B2M ≥4 mg/L were eligible for the study. Frontline CFAR consisted of C-200 mg/m2 D3-5, F-20mg/m2 D3-5, A-30mg IV D1,3,5, and R-375–500 mg/m2 D2. Courses were repeated every 28 days for a total of 6 courses. All pts received pegylated filgrastim 6mg SC with each course of therapy. All pts received allopurinol for tumor lysis prophylaxis. Antibiotic prophylaxis with TMP/SMX DS and valacyclovir or valganciclovir was also given to all pts. CMV antigenemia was monitored before each course. Results: A total of 60 pts were enrolled from July 2005 through August 2008 (Table). One pt was lost to follow-up. The median age was 59 yrs (range 42–69) and 44 (75%) were male. Median B2M was 5.1 mg/L (4–11.6); HGB was 11.5gm/dL (5.5–15.1); PLT was 139 k/μL(41–446); WBC was 100k/μL (5–665); ALC was 92k/μL (4–619); and 30 pts (51%) were Rai stage III-IV. The median number of courses administered was 4 (2–6); reasons for not completing 6 courses included delayed recovery of counts (18), infection (8), AIHA (4), treatment failure (3) and pt. choice (2). CR was achieved in 70%, nPR in 3%, PR in 18%, and 7% pts did not respond, leading to an ORR of 92% (Table). There was no significant correlation between CR or OR with Rai Stage, IgVH mutation status, FISH status, ZAP70 and CD38 expression. After a median follow-up of 24 months (3–49), 19(32%) pts have progressive disease. Patients with 17p deletion and unmutated IgVH had significantly shorter TTP as shown in the >Table. Eleven (19%) pts have died: 4 with disease progression after achieving CR; 2 who did not respond; 2 with Richter's transformation; 1 transformed into AML; 1 due to metastatic lung cancer; and 1 due to severe pneumonia 8 months after achieving CR. Grade 3/4 neutropenia and thrombocytopenia occurred in 31% and 13% courses. Major infections, including pneumonia and sepsis, were reported for 10(17%) pts. Minor infectious such as bronchitis, urinary tract infections and herpes zoster were reported for 15(25%) pts. In a historic cohort of high-risk pts treated with FCR, grade 3/4 neutropenia and thrombocytopenia occurred in 31% and 10% courses; and major and minor infections were seen in 15% and 23% pts respectively, all comparable to that seen with frontline CFAR. A-associated infusion reactions occurred in 42 (71%) pts. CMV reactivation occurred in 7 (12%) pts, all of whom were on valacyclovir prophylaxis. There was 1 death due to CMV pneumonia; all other episodes of CMV reactivation were promptly treated with valaganciclovir leading to resolution of fever and/or antigenemia. The median OS for all pts has not been reached (49+mo) and the median TTP is 38 months. Conclusion: CFAR is an active frontline regimen in high-risk pts with CLL. Although CR rates in pts with other high-risk features such as 17p deletion and unmutated IgVH were >50%, TTP was significantly shorter for these pts than for pts without these features. With current follow-up, OS, TTP, infectious complications and grade 3/4 hematologic toxicity are comparable to historic high-risk pts treated with FCR. Disclosures: Keating: Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wierda:Genentech: Consultancy, Honoraria; Genzyme: Research Funding.

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Global Methylation Provides Independent Prognostic Information in Chronic Lymphocytic Leukemia and Is Associated with a Microrna Signature

Blood ◽

10.1182/blood.v120.21.3873.3873 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3873-3873

Author(s):

Alfons Navarro ◽

Gerardo Ferrer ◽

Marina Díaz-Beyá ◽

Carmen Muñoz ◽

Rut Tejero ◽

...

Keyword(s):

Dna Methylation ◽

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Mirna Expression ◽

Clinical Stage ◽

Prognostic Significance ◽

Surrogate Marker ◽

Lymphocytic Leukemia ◽

Prognostic Impact ◽

Global Methylation

Abstract Abstract 3873 Introduction: Disruption of normal DNA methylation, including both gene specific hypermethylation and genome-wide hypomethylation, is found in most malignant tumors. Most epigenetic studies in chronic lymphocytic leukemia (CLL) have been focused in CpG islands and gene promoter regions, and have identified hypomethylated genes, such as BCL2 or TCL1, and hypermethylated genes, such as GRM7. However, the quantification of overall methylation measured as levels of 5-methylCytosine (5mC) has been poorly explored. As compared to their normal counterparts (CD19+ B cells), overall hypomethylation has been observed in CLL neoplastic cells. Importantly, the overall methylation varies among patients but its clinical significance has not been widely investigated. In addition, it is known that microRNA (miRNA) expression is altered in CLL, and that and epigenetic mechanisms, such as methylation, can affect miRNA expression. Aim: To investigate the prognostic impact of overall methylation in patients with CLL and to analyze the correlation of 5mC levels with miRNAs expression. Methods: We analyzed 73 CLL patients (median age, 69 [range, 34–86]; 43% males) diagnosed in our institution between 1992 and 2007. The median follow up was 10.5 years. The level of global methylation in total DNA was estimated after determination of percentage of 5mC using anti-5mC monoclonal antibodies (MethylFlash Methylated DNA Quantification Kit, Epigentek). The expression of 377 mature miRNAs was analyzed using TaqMan Array Human MicroRNA A Card v2.0 (Applied Biosystems). Statistical analysis was performed with SPSS version 15.0.1 and R software version 2.9.0. MaxStat package of R were used to determine the optimal cutoffs and Quantitative trail function in BRB array tools to correlate miRNA expression and methylation levels. Results: The analysis of methylation levels showed a wide distribution of methylation degree among patients (median: 3.02%, range: 0.58–6.14%). From the clinical standpoint, methylation levels were only correlated with Binet clinical stage, patients with C stage showing a higher degree of methylation (p=0.015). Using MaxStat, we identified two cutoffs which classified patients as having low, medium or high degree of methylation. Mean progression-free survival (PFS) was 8.4 years (95% CI: 6.4–10.4), 6.2 years (95% CI: 4.7–7.7) and 3.2 years (95% CI: 2.4–4.8) for patients with low, medium, and high methylation levels, respectively (p=0.013). In the multivariate analysis for PFS (including ZAP70, IGHV, Age≤65, cytogenetics and global methylation), high ZAP70 expression (HR: 3; 95%CI: 1.1–7.9; p=0.026) and high global methylation (HR: 5.4 95%CI: 1.7–17.1; p=0.004) were independent unfavorable prognostic factors, while a significant trend was observed for high-risk cytogenetics (17p-, 11q-, +12) (p=0.054). Interestingly, methylation levels retained its prognostic significance in subgroup analysis: clinical stage A (p=0.06) and B/C (p=0.009); mutated (p=0.008) and unmutated IGHV (p=0.028); low (p=0.028) and high ZAP70 (p=0.001); and low-risk (normal karyotype, 13q-)(p=0.008) and high-risk (17p-, 11q-, +12) cytogenetics (p=0.001). Finally, we identified a 4-miRNA signature associated with global methylation levels: miR-103 (Spearman correlation [SC]: −0.821;p=0.03), miR-132 (SC: 0.786;p=0.05), miR-494 (SC: −0.786; p=0.02), and miR-193a-5p (SC: 0.786; p=0.05). Interestingly, miR-103, miR-132 and miR-494 are located in subtelomeric regions, which are known to be more susceptible to overall methylation changes. Conclusions: In this study, the degree of global DNA methylation was an independent prognostic factor for PFS in patients with CLL. The analysis of overall methylation could be useful not only for the prognosis of patients with CLL but also in the monitoring of clinical trials in which hypomethylating agents (e.g., decitabine) are being investigated as CLL therapy. The correlation between overall methylation levels and certain miRNAs may be a surrogate marker of epigenetic lesions and deserves further investigation. Disclosures: No relevant conflicts of interest to declare.

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Renal Disease In Patients With Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v122.21.5302.5302 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5302-5302 ◽

Cited By ~ 4

Author(s):

Tait D Shanafelt ◽

Kari G. Rabe ◽

Curtis A Hanson ◽

Timothy G. Call ◽

Susan Schwager ◽

...

Keyword(s):

Renal Function ◽

Chronic Lymphocytic Leukemia ◽

Renal Insufficiency ◽

Serum Creatinine ◽

Research Funding ◽

Univariate Analysis ◽

Lymphocytic Leukemia ◽

Disease Course ◽

To Receive

Abstract Background Chronic lymphocytic leukemia (CLL) can effect renal function in a variety of ways including direct infiltration of the kidney, ureteral obstruction by lymphadenopathy, and treatment related tumor lysis syndrome (uric acid nephropathy). Rarely, CLL has also been reported to be associated with light chain nephropathy, renal amyloidosis, membranoproliferative glomerulonephritis (MPGN), granulomatous interstitial nephritis (GIN), and minimal change disease (MCD). Nearly all the data on the effects of CLL on renal function is at the case report level. We systematically evaluated the prevalence of renal insufficiency at diagnosis as well the incidence of acquired renal insufficiency during follow-up in a large cohort of patients with newly diagnosed CLL to more accurately define the effects of CLL on the kidney and its impact on clinical outcomes. Methods Between January 1995 -February 2013, previously untreated CLL patients seen in the Division of Hematology at Mayo Clinic at diagnosis (<12 months) and who had baseline assessment of serum creatinine were included in this analysis. Patients with serum creatinine (Cr) ≥1.5 mg/dL at baseline were classified as having renal insufficiency at diagnosis. Patients who initially had baseline creatinine <1.5 mg/dL but who developed a Cr≥1.5 mg/dL during the course of their disease were considered to have acquired renal insufficiency. Results Existing renal insufficiency at the time of CLL diagnosis: Of 2047 patients who met the eligibility criteria, 153 (7.5%) patients had renal insufficiency (Cr≥1.5 mg/dL) at the time of CLL diagnosis including 15 (0.7%) with a Cr≥3 mg/dL. Renal insufficiency was also more common among men (9.3% vs. 3.9%; p<0.00001), those with advanced stage disease (Rai 0=7.0%; Rai I-II=6.4%, Rai III-IV=20.2%; p<0.0001), and CD49d positive patients (6.8% vs. 3.8%; p<0.038). Patients with renal insufficiency at diagnosis were also older (median age 72.2 vs. 63.9; p<0.0001). No difference in the prevalence of renal insufficiency at diagnosis was observed based on cytogenetic abnormalities detected by FISH or CD38, ZAP-70 or IGHV gene mutation status. Although renal insufficiency at diagnosis was strongly associated with OS on univariate analysis (p<0.001), no association was observed between renal insufficiency and TTT or OS on multi-variate analysis adjusting for age, sex, and Rai stage. Acquired renal insufficiency during CLL disease course: Among the 1894 patients with normal renal function at diagnosis, 304 (16.1%) acquired renal insufficiency (Cr≥1.5 mg/dL) during the course of their CLL disease course including 43 (2.3%) with peak Cr≥3 mg/dL. In addition to age (older) and male sex, a number of CLL disease characteristics were associated with a higher likelihood of acquired renal insufficiency including: IGHV UM (OR=2.0; p=0.0001), unfavorable FISH (del17p- or 11q-; OR=2.0; p=0.001), and being CD49d+ (OR=1.8; p=0.002), ZAP-70+ (OR=1.6; p=0.004), or CD38+ (OR=1.4; p=0.0.032),. Shorter TTT (p<0.001) and OS (P<0.001) was observed among patients with initially normal creatinine who acquired renal insufficiency (Figure 1A and 1B). On MV analysis adjusting for age, sex, and stage at diagnosis, acquired renal insufficiency remained an independent predictor of TTT (OR=1.77; p=0.001) and OS (OR=2.67; p<0.001). Renal insufficiency and therapy selection After median follow-up of 4.5 years (range 0-18.0), 620 of 2047 (30.3%) patients have progressed to require treatment. Patients with renal insufficiency prior to treatment were less likely to receive purine nucleoside analogue based therapy and more likely to receive single agent alkylator based treatment. Conclusions Approximately 1 in every 13 patients (7.5%) with CLL has renal insufficiency at the time of diagnosis and an additional 16.1% acquire renal insufficiency during the course of the disease. The risk of developing renal insufficiency is associated with a variety of CLL B-cell characteristics and is associated with TTT and OS. Data on causes of acquired renal insufficiency is being abstracted and will be presented at the meeting. Disclosures: Shanafelt: Genentech: Research Funding; Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding. Off Label Use: MK2206 in a phase 1 trial of CLL.

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Detection Rate of Integrated Molecular and Cytogenetic Biomarker Testing for Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2021-152717 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4691-4691

Author(s):

Ramadevi Prathapam ◽

Najuma Maharjan ◽

Sheila B Powers ◽

Tracey Allen K Freitas ◽

Guoli Sun ◽

...

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Prognostic Model ◽

Lymphocytic Leukemia ◽

Low Risk ◽

Intermediate Risk ◽

Clinical Value ◽

Trisomy 12 ◽

Biomarker Testing ◽

Testing Approach

Abstract Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in western countries and typically occurs in elderly individuals. There will be an estimated 21,250 newly diagnosed cases in the United States this year and 4,320 deaths. Due to the highly variable clinical course of this disease, prognostication and risk stratification methods are necessary for guiding decisions on clinical management. Integrated prognostic models incorporating laboratory testing for multiple molecular, cytogenetic, and other biomarkers have recently been proposed by major clinical guidelines to classify patients into risk subgroups. The current NCCN Guidelines for Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia describe such an integrated prognostic model known as the Rossi model that includes TP53, NOTCH1, SF3B1, and BIRC3 mutations along with the cytogenetic abnormalities detected by fluorescence in situ hybridization (FISH) to classify CLL patients into 4 distinct prognostic subgroups: high-risk (TP53 and/or BIRC3 abnormalities), intermediate-risk (NOTCH1 and/or SF3B1 mutations and/or deletion 11q), low-risk (trisomy 12 and wild-type for all genetic lesions), and very low-risk (deletion 13q only). The 10-year survival rates for these subgroups are 29%, 37%, 57%, and 69%, respectively. To assess the clinical value of an integrated biomarker testing approach, we analyzed results of 651 consecutive cases submitted to our clinical diagnostic laboratory for testing on our integrated panel of molecular and cytogenetic biomarkers for CLL. Our panel includes detection of genomic alterations by FISH (deletion 6q, 13q, 11q, 17p, trisomy 12, IGH rearrangement, and IGH/CCND1 translocation) and detection of sequence variants in BIRC3, BTK, MYD88, NOTCH1, PCLG2, SF3B1, and TP53 by next-generation sequencing (NGS). In total, 472 cases had positive findings by either FISH (90%) or NGS (46%) for a detection rate of 72.5%. Using the Rossi integrated prognostic model, 17.5% of cases fell into the high-risk subgroup, 20% of cases fell into the intermediate-risk subgroup, 43.5% of cases fell into the low-risk subgroup, and 19% of cases fell into the very low-risk subgroup. Importantly, among cases with positive FISH findings, 40.1% of cases also had positive molecular findings. In approximately 84% of cases belonging to the low-risk cytogenetic subgroups by FISH assessment alone, the incorporation of molecular findings resulted in reclassification into a higher-risk subgroup. Among the FISH-negative cases, 17% were classified as high-risk or intermediate-risk based on the molecular findings. Together, these findings support the clinical value of an integrative biomarker testing approach that includes both molecular and cytogenetic biomarkers to stratify CLL patients into risk subgroups to help guide decisions on clinical management. Disclosures Prathapam: Quest Diagnostics: Current Employment. Maharjan: Quest Diagnostics: Current Employment. Powers: Quest Diagnostics: Current Employment. Freitas: Quest Diagnostics: Current Employment. Sun: Quest Diagnostics: Current Employment. Tan: Quest Diagnostics: Current Employment. Gupta: Quest Diagnostics: Current Employment. Hucthagowder: Quest Diagnostics: Current Employment. Graham: Quest Diagnostics: Current Employment. Whitman: Quest Diagnostics: Current Employment. Khadgi: Quest Diagnostics: Current Employment. Daniel: Quest Diagnostics: Current Employment. Racke: Quest Diagnostics: Current Employment. Champion: Quest Diagnostics: Current Employment.

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Lymphocyte Doubling Time As A Key Prognostic Factor To Predict Time To First Treatment In Early-Stage Chronic Lymphocytic Leukemia

Frontiers in Oncology ◽

10.3389/fonc.2021.684621 ◽

2021 ◽

Vol 11 ◽

Author(s):

Fortunato Morabito ◽

Giovanni Tripepi ◽

Riccardo Moia ◽

Anna Grazia Recchia ◽

Paola Boggione ◽

...

Keyword(s):

Prognostic Factors ◽

Chronic Lymphocytic Leukemia ◽

Doubling Time ◽

Lymphocytic Leukemia ◽

Prognostic Impact ◽

Newly Diagnosed ◽

Prognostic Role ◽

Mutational Status ◽

Binet Stage ◽

Time To First Treatment

The prognostic role of lymphocyte doubling time (LDT) in chronic lymphocytic leukemia (CLL) was recognized more than three decades ago when the neoplastic clone’s biology was almost unknown. LDT was defined as the time needed for the peripheral blood lymphocyte count to double the of the initial observed value. Herein, the LDT prognostic value for time to first treatment (TTFT) was explored in our prospective O-CLL cohort and validated in in two additional CLL cohorts. Specifically, newly diagnosed Binet stage A CLL patients from 40 Italian Institutions, representative of the whole country, were prospectively enrolled into the O-CLL1-GISL protocol (clinicaltrial.gov identifier: NCT00917540). Two independent cohorts of newly diagnosed CLL patients recruited respectively at the Division of Hematology in Novara, Italy, and at the Hospital Clinic in Barcelona, Spain, were utilized as validation cohorts. In the training cohort, TTFT of patients with LDT >12 months was significantly longer related to those with a shorter LDT. At Cox multivariate regression model, LDT ≤ 12 months maintained a significant independent relationship with shorter TTFT along with IGHV unmutated (IGHVunmut) status, 11q and 17p deletions, elevated β2M, Rai stage I-II, and NOTCH1 mutations. Based on these statistics, two regression models were constructed including the same prognostic factors with or without the LDT. The model with the LTD provided a significantly better data fitting (χ2 = 8.25, P=0.0041). The risk prediction developed including LDT had better prognostic accuracy than those without LDT. Moreover, the Harrell’C index for the scores including LDT were higher than those without LDT, although the accepted 0.70 threshold exceeded in both cases. These findings were also confirmed when the same analysis was carried out according to TTFT’s explained variation. When data were further analyzed based on the combination between LDT and IGHV mutational status in the training and validation cohorts, IGHVunmut and LDT>12months group showed a predominant prognostic role over IGHVmut LTD ≤ 12 months (P=0.006) in the O-CLL validation cohort. However, this predominance was of borden-line significance (P=0.06) in the Barcelona group, while the significant prognostic impact was definitely lost in the Novara group. Overall, in this study, we demonstrated that LDT could be re-utilized together with the more sophisticated prognostic factors to manage the follow-up plans for Binet stage A CLL patients.

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Risk Factors Associated with Richter's Transformation in Patients with Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2018-99-112442 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1697-1697 ◽

Cited By ~ 1

Author(s):

Yasmin Ben-Dali ◽

Mariam Hussein Hleuhel ◽

Michael Asger Andersen ◽

Christian Brieghel ◽

Erik Clasen-Linde ◽

...

Keyword(s):

Risk Factors ◽

Chronic Lymphocytic Leukemia ◽

Incidence Rate ◽

Cumulative Incidence ◽

Research Funding ◽

Univariate Analysis ◽

Lymphocytic Leukemia ◽

Increased Risk ◽

Binet Stage

Abstract Background Richter's transformation (RT) refers to the development of an aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL). Roughly, 2-10 % of patients with CLL develop RT most often as diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma (HL). Aim This study aimed to assess the incidence rate and risk factors for RT for patients with CLL in a nationwide cohort. Furthermore, we want to assess prognostic risk factors for patients with RT. Methods All patients diagnosed with CLL in Denmark between 2008 and 2016 were included in this study. Clinical data was retrieved from the Danish National CLL Registry (DCLLR), whereas all histologically verified DLBCL, HL and/or transformation diagnoses for patients with CLL were retrieved from the Danish National Pathology Registry. Patients were followed from date of CLL diagnosis until date of RT, death or end of follow-up, whichever came first. The time to RT was estimated as cumulative incidence considering death as a competing risk. Stepwise Cox analysis with backward elimination was applied to identify independent risk factors for RT in patients with CLL. Results A total of 3771 CLL patients were identified, and followed for 14165 person-years. With a median follow-up of 4.3 (IQR (2.4;6.6)) years, 120 (3%) CLL patients had a transformation diagnosis, of which 4 patients were excluded due to misdiagnosis. DLBCL accounted for 78/116 (67%) cases, HL for 15/116 (13%) cases and one patient presented with both DLBCL and HL. In the remaining 22/116 (19%) cases the subtype of the transformation was either unspecified or unclassified RT. The median time to RT was 3.4 (IQR (1.8;5.7)) years from CLL diagnosis and the median overall survival (OS) after development of RT was 4.9 (IQR (0.7;8.4)) years. The cumulative incidence of RT, calculated by Aalen-Johansen estimator, at 5 and 8 years post-CLL diagnosis were 3.3% and 7.9% respectively (Figure 1). The annual crude incidence rate of RT was approximately 0.7% per year for all CLL patients. In all, 918 (24%) patients received CLL-related treatment, of whom 59 (6.4%) patients developed RT, resulting in a cumulative incidence of RT of 7% after 5 years and 11% after 8 years. At the time of CLL diagnosis, patients treated for CLL prior to RT diagnosis had a worse median OS (1.49 years) compared to RT patients who were untreated for CLL (6.16 years). In the univariate analysis, RT was significantly associated with male gender, advanced Binet stage (B or C), unmutated IGHV status (CLL-U), elevated beta-2-microglobulin (>3.5 mg/L) and elevated lactate dehydrogenase (>205 U/L). Of cytogenic aberration, deletion 13q (del(13q)) had a protective effect on the risk of RT, whereas deletion 11q (del(11q)) and deletion 17p (del(17p)) increased the risk. In the multivariable model, advanced Binet stage (HR 2.86 (1.82;4.51), p<0.001), del(17p) ((HR 3.74 (2.12;6.61), p<0.001) and CLL-U ((HR 2.30 (1.46;3.63), p<0.001) showed an independent correlation with development of RT. ZAP70 and CD38 were excluded from statistical analyses due to incomplete data and high inter-laboratory variation. Among RT patients, CLL-U, trisomy 12 and del(17p) at CLL diagnosis as well as ECOG Performance Status (PS) (i.e. PS≥1) at time of RT diagnosis correlated with poor OS in univariate analysis. Both del(17p) and PS≥1 were independently associated with an increased risk of death in a multivariable analysis (HR 2.9, (1.1;7.7), p=0.04 and HR 3.0, (1.0;3.1), p=0.05, respectively). Conclusions To the best of our knowledge, we here report the largest study on RT assessing nationwide data of consecutive patients diagnosed with CLL. The incidence of RT in this unselected population was 3.3% after 5 years while the median OS for patients from time of RT was 4.9 years. Advanced Binet stage, del(17p) and CLL-U were significantly and independently associated with an increased risk of RT. Del(17p) at CLL diagnosis and PS≥1 at RT diagnosis were significant predictors for death for patients with RT. For patients diagnosed with RT prior to any CLL treatment, a less severe disease course with a median OS of 6.16 years was demonstrated. Contrary, the median OS for patients receiving prior CLL treatment was 1.49 years. Thus, assessment of different treatment options for patients developing RT based on whether they have received prior CLL treatment or not is warranted. Figure 1. Figure 1. Disclosures Ben-Dali: Rigshospitalet: Research Funding. Hleuhel:Rigshospitalet: Research Funding. Brieghel:Arvid Nilson's Fund: Research Funding; Rigshospitalet, Denmark: Research Funding. Niemann:Danish Cancer Society: Research Funding; Novo Nordisk Foundation: Research Funding; Janssen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy; CSL Behring: Consultancy.

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Other Cancers in Long-Term Survivors of Chronic Lymphocytic Leukemia: Incidence and Prognostic Relevance

Blood ◽

10.1182/blood.v124.21.3323.3323 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3323-3323 ◽

Cited By ~ 2

Author(s):

Lorenzo Falchi ◽

Michael Keating ◽

Susan Lerner ◽

Xuemei Wang ◽

Kplola Y Elhor Gbito ◽

...

Keyword(s):

Bladder Cancer ◽

Chronic Lymphocytic Leukemia ◽

Conflicts Of Interest ◽

Observation Time ◽

Lymphocytic Leukemia ◽

P Value ◽

Prognostic Impact ◽

Long Term Survivors

Abstract Introduction. The clinical course of chronic lymphocytic leukemia (CLL) is mostly indolent. About one third of the patients are managed with lifelong watch-and-wait (WW) and those who receive therapy often achieve a durable remission. As a result, the majority of patients with CLL will live with their disease for long periods of time, and be exposed to several complications, including the occurrence of other cancers (OC). Patients with CLL may have an increased incidence in OC. Published reports indicate an incidence of 3-27%, mostly in treated patients, however, very little is known on OC in patients with CLL not requiring therapy. Furthermore, observation time in published studies is limited to <5 years, and the incidence of OC in patients followed for longer than 10 years is unknown. We, therefore, studied the incidence and prognostic impact of OC in treatment-naïve patients with CLL followed for ≥10 years. Methods. We reviewed our database and identified all patients with CLL untreated at the time of referral. We selected long-term survivors (LTS), defined as patients with a follow-up ≥10 years, and analyzed the incidence and prognostic impact of OC in this population. Non-melanoma skin cancers were excluded since these were diagnosed and treated promptly in virtually all cases and felt not to have prognostic impact. Standardized incidence ratios (SIR) were calculated for OC occurring after the diagnosis of CLL that were reportable to the Surveillance, Epidemiology and End Results program.The estimated overall survival (OS) according to the presence of OC was plotted considering OC as a time-dependent covariate. Results. We identified 797 LTS of CLL seen at our institution between 1957 and 2003. Median age was 56 years (24-88). 57% of patients were males. Median follow-up for the entire population is 154 months (120-485). We recorded 383 OC in 286 (36%) patients. 76/286 (26%) patients had >1 OC (62 had 2 OC, 10 had 3, 2 had 4, 1 had 5 and 1 had 6).The firstOC preceded or was diagnosed concomitantly with CLL in 100 patients (35%), while in the remaining 186 (65%) it occurred later during the course of the disease. 570 patients (71%) required treatment for CLL. Median time to treatment was 18 months (0-454). In treated patients, the cumulative frequency of OC was 205/570 (36%) and in WW patients 81/227 (36%). The SIR for all OC was 1.2 (p = .034). Males and patients younger than 60 years had a significantly higher incidence of OC (SIR 1.31 and 1.27, respectively). Among OC types, secondary leukemia, melanoma and head and neck cancers had the highest observed-to-expected ratio. Surprisingly, lung, digestive tract, and bladder cancer had a lower-than-expected incidence (table). 474 patients (59%) are alive. 222/570 (39%) treated patients and 101/227 (44%) WW patients have died. The median OS was longer in patients without OC (279 months) vs. those with OC (189 months). Independent predictors of shorter survival in multivariate analysis included higher creatinine, the presence of OC, and older age. Discussion. This is the first study to address the incidence of OC in LTS of CLL, including WW patients. In our population, the frequency of OC is similar in treated and WW patients. Although the incidence of OC in LTS of CLL is higher compared to matched general population, the incidence of lung, digestive and bladder cancer is lower than expected. Reasons of this finding remain to be identified.The occurrence of OC is an independent predictor of shorter survival, thus constituting a relevant competing risk of mortality in LTS of CLL. Variable Observed Expected Person-years SIR (O/E) 95% CI for O/E P -value Overall 148 123.34 10956 1.20 1.01 – 1.40 0.034 Male 96 73.4 5885 1.31 1.06 – 1.58 0.013 Female 52 49.93 5071 1.04 0.78 – 1.36 0.67 Age ≥60 years 60 54.33 3416 1.10 0.84 – 1.42 0.44 Age <60 years 88 69.02 7540 1.27 1.02 – 1.57 0.027 OC type Prostate 28 25.92 11809 1.08 0.72 – 1.56 0.64 Lung 20 29.08 11942 0.69 0.42 – 1.06 0.04 Breast 19 18.60 11855 1.02 0.62 – 1.59 0.96 Melanoma 16 4.23 11926 3.78 2.16 – 6.14 0.00 Leukemia 15 4.27 12009 3.51 1.96 – 5.79 0.00 Non-Hodgkin lymphoma 6 6.38 11996 0.94 0.34 – 2.05 1.00 Digestive 16 40.4 11937 0.40 0.23 – 0.64 0.00 Colon 8 19.42 11972 0.41 0.18 – 0.81 0.006 Pancreas 2 4.83 12024 0.41 0.05 – 1.49 0.18 Rectal 3 8.69 12011 0.34 0.07 – 1.00 0.05 Bladder 3 11.18 11993 0.27 0.05 – 0.78 0.009 Multiple Myeloma 2 1.98 12012 1.01 0.12 – 3.64 1.00 Lip 3 0.02 12015 150 31.00 – 438.5 0.00 Salivary gland 2 0.03 12026 66.66 8.00 – 240.06 0.00 Disclosures No relevant conflicts of interest to declare.

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