Genome-wide profiling of follicular lymphoma by array comparative genomic hybridization reveals prognostically significant DNA copy number imbalances.

The secondary genetic events associated with follicular lymphoma (FL) progression are not well defined. We applied genome-wide BAC array comparative genomic hybridization to 106 diagnostic biopsies of FL to characterize regional genomic imbalances. Using an analytical approach that defined regions of copy number change as intersections between visual annotations and a Hidden Markov model-based algorithm, we identified 71 regional alterations that were recurrent in at least 10% of cases. These ranged in size from approximately 200 kb to 44 Mb, affecting chromosomes 1, 5, 6, 7, 8, 10, 12, 17, 18, 19, and 22. We also demonstrated by cluster analysis that 46.2% of the 106 cases could be sub-grouped based on the presence of +1q, +6p/6q-, +7, or +18. Survival analysis showed that 21 of the 71 regions correlated significantly with inferior overall survival (OS). Of these 21 regions, 16 were independent predictors of OS using a multivariate Cox model that included the international prognostic index (IPI) score. Two of these 16 regions (1p36.22-p36.33 and 6q21-q24.3) were also predictors of transformation risk and independent of IPI. These prognostic features may be useful to identify high-risk patients as candidates for risk-adapted therapies.

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.

Sunitinib in relapsed or refractory diffuse large B-cell lymphoma: a clinical and pharmacodynamic phase II multicenter study of the NCIC Clinical Trials Group.

There are limited effective therapies for most patients with relapsed diffuse large B-cell lymphoma (DLBCL). We conducted a phase II trial of the multi-targeted vascular endothelial growth factor receptor (VEGFR) kinase inhibitor, sunitinib, 37.5 mg given orally once daily in adult patients with relapsed or refractory DLBCL. Of 19 enrolled patients, 17 eligible patients were evaluable for toxicity and 15 for response. No objective responses were seen and nine patients achieved stable disease (median duration 3.4 months). As a result, the study was closed at the end of the first stage. Grades 3-4 neutropenia and thrombocytopenia were observed in 29% and 35%, respectively. There was no relationship between change in circulating endothelial cell numbers (CECs) and bidimensional tumor burden over time. Despite some activity in solid tumors, sunitinib showed no evidence of response in relapsed/refractory DLBCL and had greater than expected hematologic toxicity.

Population-based analysis of incidence and outcome of transformed non-Hodgkin's lymphoma.

PURPOSE: To assess the incidence and predictive factors for development of transformed lymphoma in a population-based series of patients with follicular lymphoma (FL). PATIENTS AND METHODS: The Lymphoid Cancer Database was used to identify patients with FL diagnosed and treated in the province of British Columbia, Canada. Transformed lymphoma was defined as the development of aggressive non-Hodgkin's lymphoma (NHL) in patients with FL. Factors present at the time of initial diagnosis of indolent NHL and at transformation were analyzed for their impact on risk of transformation and subsequent outcome. RESULTS: Between 1986 and 2001, 600 patients with newly diagnosed FL met the inclusion criteria. With a median follow-up of 109 months (range, 10 to 244), 170 (28%) developed transformation, 107 (63%) based on biopsy confirmation. The annual risk of transformation was 3% continuously through 15 years. A multivariate analysis of clinical factors at diagnosis identified advanced stage as the only predictor of future transformation. The median post-transformation survival was 1.7 years. The 5-year survival was superior for patients with limited extent transformation compared with those with advanced cases (66% v 19%, P < .0001). Patients with transformation based on clinical versus histological criteria had an identical median survival of 1.8 years (P = .2). CONCLUSION: The annual risk of transformation of FL is 3% continuing without plateau beyond 15 years. Advanced stage at diagnosis is predictive of future transformation. Clinically diagnosed transformation has an equal impact on outcome as biopsy proven transformation.

Minimizing treatment without compromising cure with primary surveillance for clinical stage I embryonal predominant nonseminomatous testicular cancer: a population based analysis from British Columbia.

PURPOSE: We evaluated the outcome of patients with embryonal carcinoma predominant (ECP) clinical stage (CS) I nonseminomatous testicular germ cell tumors (NSGCT) treated with primary surveillance or primary retroperitoneal lymph node dissection (RPLND). MATERIALS AND METHODS: This study was a retrospective evaluation of the pathology, use of chemotherapy, surgery and outcomes in all patients with CS I NSGCT who were diagnosed within the province of British Columbia between 1990 and 2000. RESULTS: A total of 205 patients were identified, of whom 107 (52%) had ECP disease. Of these patients 72 (67%) underwent primary surveillance, 32 (33%) underwent primary RPLND and 3 refused treatment. Median followup was 4 years (range 1 to 10). In the primary surveillance group 24 patients (33%) had relapse and all were treated initially with chemotherapy with 6 also requiring RPLND. The remaining 48 patients (67%) in the surveillance group were cured of disease with orchiectomy alone. In the primary RPLND group 18 patients (56%) had pathological stage I disease and 14 (44%) had pathological stage II disease. In the primary RPLND group 15 patients (46%) required chemotherapy with 11 (34%) receiving adjuvant chemotherapy and 4 receiving chemotherapy for post-RPLND relapse. No deaths from ECP testicular cancer occurred in either group. The 4-year chemotherapy-free survival rate was 65% in the surveillance group vs 50% in the RPLND group (p = 0.2). CONCLUSIONS: For appropriately selected patients with CS I ECP NSGCT, primary surveillance results in fewer therapeutic interventions compared to RPLND without compromising the probability of cure.