Influence of clone and deletion size on outcome in chronic lymphocytic leukemia patients with an isolated deletion 13q in a population-based analysis in British Columbia, Canada.

Deletion of the long arm of chromosome 13 (del(13q)) as the sole abnormality in chronic lymphocytic leukemia (CLL) portends a good prognosis; however, there is great outcome heterogeneity within this subgroup. The percentage of cells with a del(13q) (clone size) and the extent of the deletion are two factors that may affect outcome in CLL patients with isolated del(13q). We analyzed 248 CLL patients from the BC Provincial CLL database identified as having isolated del(13q) detected pretreatment by interphase fluorescence in situ hybridization to determine what impact clone and deletion size had on overall survival (OS) and treatment free survival (TFS). Patients with 60% or more of nuclei with a del(13q) had shorter TFS and shorter OS. A large deletion, encompassing the RB1 gene locus, was detected in half of the 90 cases with available specimens for testing, and there was no significant difference in OS and TFS between RB1-deleted and RB1-not-deleted cases. Further study in a larger sample size is required to determine the clinical interest of RB1 locus testing; however, clone size of del(13q) does predict TFS and OS and may better refine prognosis in this clinically heterogeneous population.

Population-level impact of ibrutinib for chronic lymphocytic leukemia in British Columbia, Canada.

Ibrutinib has dramatically changed the treatment landscape for chronic lymphocytic leukemia (CLL) since its availability in British Columbia (BC), Canada in 2014. We analyzed patterns of use and real-world survival outcomes in 370 patients who received ibrutinib for first-line (1 L, n = 35) and relapsed/refractory (R/R, n = 335) CLL between 2014-2018 in BC. Dose reductions and interruptions were frequent in 32% and 27%, respectively. With a median follow-up of 27.6 months, 35% of patients discontinued ibrutinib, primarily for adverse events (AEs) rather than progressive disease. Over the course of treatment, 87% of patients experienced at least one adverse event. The 2-year overall survival (OS) and event-free survival (EFS) were excellent at 83.9% and 76.1%, respectively, with medians not reached. However, patients who discontinued ibrutinib had a median OS of 32.5 months and median EFS of only 3.8 months from time of discontinuation, highlighting the need to minimize toxicity in the real-world.

Impact of age and treatment institution type on outcomes of patients treated for chronic lymphocytic leukemia in British Columbia, Canada.

Older age has been shown to adversely impact overall survival (OS) in chronic lymphocytic leukemia (CLL) however, prior population-based studies did not analyze the impact of cytogenetic abnormalities or were prior to the availability of ibrutinib. OBJECTIVES: i) We sought to compare outcomes of patients based on their age at treatment to examine if older age has an impact on OS in patients who were treated during the period when fludarabine-rituximab was the standard upfront therapy and when ibrutinib was first introduced and ii) compare outcomes based on whether the patient received primary treatment at an academic or community-based centre. METHODS: The BC Provincial CLL Database, a population-based databasewas used to include patients who have received treatment in British Columbia (BC), Canada between 2004 and 2016. RESULTS: A total of 1122 patients were included (<70 years at treatment, n = 589) with median age at diagnosis 66 years. Younger patients had higher Rai stage (55% vs. 44% stage I-II, p < 0.001), higher lymphocyte count at diagnosis (13 × 109/L vs. 10 × 109/L, p = 0.004), greater proportion with B-symptoms at diagnosis (15% vs 10%, p = 0.004), shorter time from diagnosis to treatment (13.9 months vs. 21.4 months, p = 0.001), higher proportion treated at an academic centre (79% vs. 69%, p < 0.001) and more were treated with fludarabine-rituximab or FCR (69% vs. 42%, p < 0.001) compared to older patients. Older patients had both a significantly (p < 0.001) shorter OS from treatment start (4.7 years) and disease specific survival (8.1 years) than younger patients (median OS and DSS not reached). Of interest, there was no difference in OS between patients treated at an academic centre or community centre (p = 0.087). First-line treatment with chemoimmunotherapy improved OS (HR 0.465, 95% CI: 0.381-.567). CONCLUSIONS: Older age but not treatment-institution type adversely impacts overall survival and CLL survival in treated patients in BC.

Comparison of real-world treatment patterns in chronic lymphocytic leukemia management before and after availability of ibrutinib in the province of British Columbia, Canada.

We performed a retrospective study comparing treatment patterns and overall survival (OS) in chronic lymphocytic leukemia (CLL) patients with the advent of ibrutinib to provide current real-world data. METHODS: Using a provincial population-based database, we analyzed CLL patients who received upfront treatment in British Columbia before ibrutinib availability (1984-2014), during ibrutinib access for: relapse only (2014-2015) and for upfront treatment of patients (with 17p deletion or unfit for chemotherapy) (2015-2016). Analysis included up to third-line treatment. RESULTS: Of 1729 patients meeting inclusion criteria (median age, 66 years; 1466, period 1; 140, period 2; 123, period 3), FR was the most common first-line therapy (35.8 %, 54.3 % and 40.7 %, periods 1-3, respectively) and 18.7 % received ibrutinib upfront in period 3. The most common therapies in relapse were chemoimmunotherapy (36.1 % and 55.6 %, periods 1 and 2, second-line; 29.2 %, period 1, third-line) and ibrutinib (69.8 %, period 3, second-line; 46.4 % and 70.3 %, periods 2 and 3, third-line). OS improved for patients treated in periods 2-3 over period 1 (median OS not reached vs. 11.9 years, p < 0.001; no difference in OS for periods 2-3, p = 0.385). CONCLUSION: Ibrutinib has replaced chemoimmunotherapy as the preferred therapy in relapse. Overall survival has improved over time with access to ibrutinib.

Ultrasensitive Detection of NOTCH1 c.7544_7545delCT Mutations in Chronic Lymphocytic Leukemia by Droplet Digital PCR Reveals High Frequency of Subclonal Mutations and Predicts Clinical Outcome in Cases with Trisomy 12.

NOTCH1 is recurrently mutated in chronic lymphocytic leukemia (CLL), most commonly as a 2-bp frameshift deletion (c.7541_7542delCT). This mutated allele encodes a truncated form of the receptor (p.P2514Rfs∗4) lacking the C-terminal proline, glutamic acid, serine, and threonine (PEST) degradation domain that increases NOTCH1 signaling duration. NOTCH1 mutation has been associated with poor clinical outcomes in CLL. We validated a highly sensitive and quantitative droplet digital PCR assay for the NOTCH1 delCT mutation, which was anticipated to perform well compared with Sanger sequencing and allele-specific PCR. Performance characteristics of this assay were tested on 126 samples from an unselected CLL cohort and a separate cohort of 85 samples from patients with trisomy 12 CLL. The delCT mutation was detected at allele frequencies as low as 0.024%; 25% of unselected cases and 55% of trisomy 12 cases were positive at the 0.024% detection threshold. Mutational burdens ≥1% were significantly associated with shorter overall survival (OS) in patients with trisomy 12+ disease in multivariate analysis (median OS, 9.1 versus 13 years, with hazard ratio of 2.34; P = 0.031). Mutational burdens <1% correlated with shorter OS in univariate, but not multivariate, analyses. These results suggest that droplet digital PCR testing for NOTCH1 delCT mutation may aid in risk stratification and/or disease monitoring in certain subsets of patients with CLL.

Chronic lymphocytic leukemia patients with HLA-B27 referred for allogeneic hematopoietic stem cell transplantation do not have worse outcomes: Results of a population-based case series analysis in British Columbia, Canada.

Human leukocyte antigen B27 (HLA-B27), associated with spondyloarthritis, was suggested to be protective against chronic lymphocytic leukemia (CLL). It is hypothesized that HLA-B27 patients may have worse outcome in part related to their other comorbidities. OBJECTIVES: We sought to compare the clinical characteristics and outcomes of CLL and small lymphocytic lymphoma (SLL) patients referred for allogeneic hematopoietic stem cell transplantation (allo-HSCT) based on their HLA-B27 status. METHODS: This retrospective population-based case series analyzed CLL/SLL patients who were HLA-typed for potential allo-HSCT in British Columbia, Canada. RESULTS: of 279 CLL/SLL patients referred for potential allo-HSCT, 34 patients were HLA-B27 positive. For HLA-B27 patients, median age at CLL diagnosis was 53.5 years (range, 27-67) and 71% were male. Seven patients had 11q deletion and nine patients had 17p deletion detected prior to first CLL therapy or at relapse. Eleven HLA-B27 patients received allo-HSCT. Two patients developed acute myeloid leukemia. One patient with ankylosing spondylitis had Richter's transformation prior to any CLL therapy. Spondyloarthritis-related disorders were diagnosed in 12 HLA-B27 patients but there was no temporal correlation with development of CLL. Overall survival (OS) and treatment-free survival (TFS) were not significantly different between HLA-B27 patients with or without spondyloarthritis-related disorders. There were no significant differences in clinical characteristics at CLL diagnosis or OS/TFS between HLA-B27 positive and negative patients referred for allo-HSCT. CONCLUSIONS: HLA-B27 positivity does not appear to influence outcome for CLL/SLL patients referred for allo-HSCT. Further studies are needed to evaluate the clinical significance of HLA-B27 in a general CLL population.

Improved survival outcomes with the addition of rituximab to initial therapy for chronic lymphocytic leukemia: a comparative effectiveness analysis in the province of British Columbia, Canada.

Chemoimmunotherapy with rituximab improves survival in clinical trials in upfront chronic lymphocytic leukemia (CLL) treatment. This study compared clinical outcomes with and without rituximab added to first-line chemotherapy in a provincial cohort of CLL patients. Between 1973 and 2014, 1345 patients received CLL treatment: 48% with rituximab, 52% chemotherapy alone. Median overall survival (OS) and treatment-free survival (TFS) were significantly longer with rituximab: OS 8.9 vs. 6.2 years, p < .0001; TFS 3.6 vs. 2.1 years, p < .0001. Addition of rituximab to chemotherapy was a strong independent predictor of mortality with a 32% mortality reduction after controlling for co-variates (age, sex, stage, and treatment with purine analogs). This large population-based study complements clinical trial and registry data demonstrating the benefit of adding rituximab to first-line CLL therapy and adds further evidence of the efficacy of rituximab-based chemoimmunotherapy in a real-world setting.

Chronic Lymphocytic Leukemia Patients With Deletion 11q Have a Short Time to Requirement of First-Line Therapy, But Long Overall Survival: Results of a Population-Based Cohort in British Columbia, Canada.

BACKGROUND: Chronic lymphocytic leukemia (CLL) patients with 11q22.3 deletion (11q-) have an aggressive clinical course, and thus selection of first-line therapy in this group is important. This study aimed to improve our understanding of real-world practice patterns and outcomes of CLL patients with 11q- in a population-based setting. PATIENTS AND METHODS: The British Columbia CLL Database was used to identify patients with 11q-. Overall survival (OS) and treatment-free survival (TFS) were assessed after adjustment for prognostic factors. RESULTS: Of 1044 patients in the database, 125 had 11q- (12%). Sixty-nine patients had 11q- identified before therapy initiation and had a median OS and TFS of 14.7 (95% confidence interval [CI], 11.3-18.1) and 2.5 (95% CI, 1.5-3.6) years. Patient with copresence of 11q- and deletion 17p had a markedly worse prognosis, with median OS of 4.9 versus 14.7 years (P < .001). Most treated patients (33 of 52) received fludarabine with or without rituximab (FR). Patients treated with FR had a median OS of 12.8 years (standard error, 1.0), which was not statistically different from those treated with alkylator-containing therapy (P = .35). CONCLUSION: Although median TFS of 11q- patients in this cohort was short at 2.5 years, OS remains long at 14.7 years, even when most patients received initial treatment without alkylators.

Characterization of treatment and outcomes in a population-based cohort of patients with chronic lymphocytic leukemia referred for cytogenetic testing in British Columbia, Canada.

This study evaluates outcomes in chronic lymphocytic leukemia (CLL) based on first-line therapy in a large consecutive population-based cohort of 669 patients with fluorescence in-situ hybridization (FISH) data in British Columbia, Canada during the period when chemoimmunotherapy was standard first-line treatment. When analyzed as a time-dependent variable, patients who required treatment (n=336) had a 4.7 times higher hazard of death than patients who did not (95% confidence interval 2.8-7.9, P<0.001). The majority of patients received fludarabine-rituximab (FR) in front-line. On multivariate Cox regression analysis, fludarabine-based first-line therapy predicted longer time-to-next-treatment (TTNT) (HR 0.53, 95% confidence interval 0.33-0.87, P=0.012) but no difference in overall survival (OS) compared to alkylator-based therapy. Deletion 17p was an independent predictor of worse TTNT and OS. The most common second-line treatments were cyclophosphamide-vincristine-prednisone-rituximab and FR. There was no difference in OS between patients retreated in second-line with the same first-line regimen (n=33) versus different regimen (n=113). In conclusion, front-line treatment with fludarabine leads to a longer time until need for next treatment than alkylator-based therapy; however, fludarabine or alkylator therapy produces no difference in OS. This study provides a historical baseline for the comparison of novel agents with standard treatments in CLL on a population-level.

Clonal evolution as detected by interphase fluorescence in situ hybridization is associated with worse overall survival in a population-based analysis of patients with chronic lymphocytic leukemia in British Columbia, Canada.

This study evaluates prognostic markers as predictors of clonal evolution (CE) and assesses the impact of CE on overall survival (OS) in a population-based cohort of 159 consecutive eligible patients with chronic lymphocytic leukemia (CLL) obtained from the British Columbia Provincial CLL Database. CE was detected by interphase fluorescence in situ hybridization (FISH) in 34/159 patients (21%) with 65% of CE patients acquiring deletion 17p or 11q. CD38 positive status (≥30%) on flow cytometry predicted 2.7 times increased risk of high-risk CE (acquisition of deletion 17p or 11q) on multivariate analysis. Prior CLL therapy was not a significant predictor of CE. CE was associated with 4.1 times greater risk of death when analyzed as a time-dependent variable for OS after adjusting for age, lymphocyte count, and FISH timing. High-risk CE was associated with worse OS while acquisition of low/intermediate-risk abnormalities (trisomy 12, deletion 13q, and IGH translocation) had no difference in OS. Our study demonstrates the negative impact of CE detected by FISH on OS in this population-based cohort. These data provide support for repeating FISH testing during CLL follow-up as patients with high-risk CE have reduced survival and may require closer observation.

Population-based characterization of the genetic landscape of chronic lymphocytic leukemia patients referred for cytogenetic testing in British Columbia, Canada: the role of provincial laboratory standardization.

Detection of recurrent chromosome abnormalities by fluorescence in situ hybridization (FISH) is an essential component of care in chronic lymphocytic leukemia (CLL) patients. In the province of British Columbia (BC), Canada, population 4.6 million, CLL patients receive uniform evaluation and therapy with FISH testing performed in three jurisdictions. The aims of this study were to (i) validate CLL-FISH testing among the BC cytogenetic laboratories to ensure standardization of results and (ii) characterize population-level CLL-FISH abnormalities by pooling provincial data. From 2004 to 2011, 585 consecutive patients underwent pretreatment CLL-FISH testing at laboratory A (50.1%), laboratory B (32.3%), or laboratory C (17.6%). For validation purposes, 26 CLL-FISH abnormalities were tested by each laboratory's protocol, with 91% result concordance. Discordant results involved percent abnormalities at or near cutoff values; therefore, a 10% universal cutoff was established when pooling results. Applying the universal cutoff to the provincial cohort, CLL-FISH abnormalities were detected in 74.9%: 54.9% 13q-, 18.8% +12, 8.5% 11q-, and 7.7% 17p-. In this large population-based cohort of patients referred for CLL-FISH testing, frequencies of abnormalities detected by FISH analysis were highly consistent with those reported in single-institution and clinical trial populations. Provinces or districts that work together to care for CLL patients can effectively pool data with appropriate laboratory validation to ensure standardization of results.

Immunoglobulin heavy chain (IGH@) translocations negatively impact treatment-free survival for chronic lymphocytic leukemia patients who have an isolated deletion 13q abnormality.

Immunoglobulin heavy chain translocations (t(IGH@)) are suggested to portend a poor prognosis in chronic lymphocytic leukemia (CLL). To determine the clinical significance of a t(IGH@) on CLL-specific cytogenetic abnormalities, we analyzed the outcomes of 142 CLL patients referred for fluorescence in situ hybridization (FISH) analysis with our standard FISH panel, which includes testing for a t(IGH@). Whereas patients with unfavorable (deletion 17p, deletion 11q) and intermediate (trisomy 12, normal FISH) cytogenetics with concomitant t(IGH@) had similar median treatment-free survival (TFS) as those without a t(IGH@), patients with deletion 13q (del13q) and a t(IGH@) had significantly worse TFS than those without a t(IGH@): median TFS 4.7 versus 8.0 years, P = 0.03 (hazard ratio 4.21, 95% confidence interval 1.06-16.69 y, P = 0.04 in multivariate analysis after adjusting for age, sex, Rai stage, and white blood cell count). The presence of a t(IGH@) further stratified patients with del13q into two prognostic entities, whereby outcomes of those with coexistent del13q and a t(IGH@) were similar to outcomes of those with high risk cytogenetics. Knowledge of the t(IGH@) status in CLL is therefore of clinical importance, as del13q patients with concomitant t(IGH@) may not retain the previously expected favorable outcome.