Laurie H Sehn

BC Cancer Agency, Vancouver, British Columbia, Canada

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Publications (81)717.66 Total impact

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    ABSTRACT: Follicular lymphoma (FL) is an indolent disease but transforms in 2-3% of patients per year into aggressive, large cell lymphoma - a critical event in the course of the disease associated with increased lymphoma-related mortality. To date, early transformation cannot be accurately predicted at the time of FL diagnosis and the biology of transformed follicular lymphoma is poorly understood. Here, we assembled a cohort of 126 diagnostic FL specimens including 40 patients experiencing transformation (< 5 years) and 86 patients not experiencing transformation for at least 5 years. In addition, we assembled an overlapping cohort of 155 transformed FL (TFL) patients, including 114 cases for which paired samples were available, and assessed temporal changes of routinely available biomarkers, outcome after transformation as well as molecular subtypes of TFL. We report that the expression of IRF4 is an independent predictor of early transformation (hazard ratio 13.3, P < .001). We also show that composite histology at the time of transformation predicts favourable prognosis. Moreover, applying the Lymph2Cx digital gene expression assay for diffuse large B-cell lymphoma (DLBCL) cell-of-origin determination to 110 patients with DLBCL-like TFL, we demonstrate that TFL is of the germinal-centre B-cell-like subtype in the majority of cases (80%) but that a significant proportion of cases is of the activated B-cell-like subtype (16%). These latter cases are commonly negative for BCL2 translocation and arise preferentially from BCL2 translocation-negative and/or IRF4-expressing FLs. Our study demonstrates existence of molecular heterogeneity in TFL as well as its relationship to the antecedent FL. Copyright © 2015 American Society of Hematology.
    Blood 08/2015; DOI:10.1182/blood-2015-06-649905 · 10.43 Impact Factor
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    ABSTRACT: 18F-fluorodeoxyglucose PET/CT (PET/CT) is the current state-of-the-art in the staging of diffuse large B-cell lymphoma (DLBCL) and has a high sensitivity for extranodal involvement. Therefore, reassessment of extranodal involvement and the current prognostic indices in the PET/CT era is warranted. We screened patients with newly diagnosed DLBCL seen at the academic centers of Aalborg, Copenhagen, and British Columbia for eligibility. Patients that had been staged with PET/CT and treated with R-CHOP(-like) 1(st) line treatment were retrospectively included. In total 443 patients met the inclusion criteria. With a median follow-up of 2.4 years, the 3-year overall (OS) and progression-free survival (PFS) were 73% and 69%, respectively. The Ann Arbor classification had no prognostic impact in itself with the exception of stage IV disease (HR 2.14 for PFS, P<0.01). Extranodal involvement was associated with a worse outcome in general, and in particular for patients with involvement of >2 extranodal sites, including HR 7.81 for PFS, p<0.001 for >3 sites. Bone/bone marrow involvement was the most commonly involved extranodal site identified by PET/CT (29%) and were associated with an inferior PFS and OS. The IPI, R-IPI, and NCCN-IPI were predictive of PFS and OS, and the two latter could identify a very good prognostic subgroup with 3-year PFS and OS of 100%. PET/CT-ascertained extranodal involvement in DLBCL is common and involvement of >2 extranodal sites is associated with a dismal outcome. The IPI, R-IPI, and NCCN-IPI predict outcome with high accuracy. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    American Journal of Hematology 08/2015; DOI:10.1002/ajh.24169 · 3.48 Impact Factor
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    ABSTRACT: Primary refractory diffuse large B cell lymphoma (DLBCL) following R-CHOP chemotherapy is a major concern. We identified 1126 patients with DLBCL treated with R-CHOP from 2000 to 2009, of whom 166 (15 %) had primary refractory disease. Of the 75/166 (45 %) who were age <70 years and had been planned for stage-directed curative therapy, 43 (57 %) were primary nonresponders and 32 (43 %) relapsed within 3 months of completing R-CHOP. Thirty of 75 (40 %) patients had serious comorbidity and organ dysfunction precluding intensive treatment and had palliative treatment only. Twelve of 45 (27 %) patients responded to second-line treatment and underwent ASCT. The median overall survival for the 75 patients was 10 months with only seven patients alive without evidence of disease at follow-up ranging from 14 to 106 months. Primary refractory DLBCL after R-CHOP has a very poor outcome with only anecdotal survivors independent of the intended treatment approach.
    Annals of Hematology 08/2015; DOI:10.1007/s00277-015-2467-z · 2.40 Impact Factor
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    ABSTRACT: Follicular lymphoma is a clinically and genetically heterogeneous disease, but the prognostic value of somatic mutations has not been systematically assessed. We aimed to improve risk stratification of patients receiving first-line immunochemotherapy by integrating gene mutations into a prognostic model. We did DNA deep sequencing to retrospectively analyse the mutation status of 74 genes in 151 follicular lymphoma biopsy specimens that were obtained from patients within 1 year before beginning immunochemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). These patients were recruited between May 4, 2000, and Oct 20, 2010, as part of a phase 3 trial (GLSG2000). Eligible patients had symptomatic, advanced stage follicular lymphoma and were previously untreated. The primary endpoints were failure-free survival (defined as less than a partial remission at the end of induction, relapse, progression, or death) and overall survival calculated from date of treatment initiation. Median follow-up was 7·7 years (IQR 5·5-9·3). Mutations and clinical factors were incorporated into a risk model for failure-free survival using multivariable L1-penalised Cox regression. We validated the risk model in an independent population-based cohort of 107 patients with symptomatic follicular lymphoma considered ineligible for curative irradiation. Pretreatment biopsies were taken between Feb 24, 2004, and Nov 24, 2009, within 1 year before beginning first-line immunochemotherapy consisting of rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). Median follow-up was 6·7 years (IQR 5·7-7·6). We established a clinicogenetic risk model (termed m7-FLIPI) that included the mutation status of seven genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), the Follicular Lymphoma International Prognostic Index (FLIPI), and Eastern Cooperative Oncology Group (ECOG) performance status. In the training cohort, m7-FLIPI defined a high-risk group (28%, 43/151) with 5-year failure-free survival of 38·29% (95% CI 25·31-57·95) versus 77·21% (95% CI 69·21-86·14) for the low-risk group (hazard ratio [HR] 4·14, 95% CI 2·47-6·93; p<0·0001; bootstrap-corrected HR 2·02), and outperformed a prognostic model of only gene mutations (HR 3·76, 95% CI 2·10-6·74; p<0·0001; bootstrap-corrected HR 1·57). The positive predictive value and negative predictive value for 5-year failure-free survival were 64% and 78%, respectively, with a C-index of 0·80 (95% CI 0·71-0·89). In the validation cohort, m7-FLIPI again defined a high-risk group (22%, 24/107) with 5-year failure-free survival of 25·00% (95% CI 12·50-49·99) versus 68·24% (58·84-79·15) in the low-risk group (HR 3·58, 95% CI 2·00-6·42; p<0.0001). The positive predictive value for 5-year failure-free survival was 72% and 68% for negative predictive value, with a C-index of 0·79 (95% CI 0·69-0·89). In the validation cohort, risk stratification by m7-FLIPI outperformed FLIPI alone (HR 2·18, 95% CI 1·21-3·92), and FLIPI combined with ECOG performance status (HR 2·03, 95% CI 1·12-3·67). Integration of the mutational status of seven genes with clinical risk factors improves prognostication for patients with follicular lymphoma receiving first-line immunochemotherapy and is a promising approach to identify the subset at highest risk of treatment failure. Deutsche Krebshilfe, Terry Fox Research Institute. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet Oncology 08/2015; DOI:10.1016/S1470-2045(15)00169-2 · 24.73 Impact Factor
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    ABSTRACT: To evaluate the prognostic impact of cell-of-origin (COO) subgroups, assigned using the recently described gene expression-based Lymph2Cx assay in comparison with International Prognostic Index (IPI) score and MYC/BCL2 coexpression status (dual expressers). Reproducibility of COO assignment using the Lymph2Cx assay was tested employing repeated sampling within tumor biopsies and changes in reagent lots. The assay was then applied to pretreatment formalin-fixed paraffin-embedded tissue (FFPET) biopsies from 344 patients with de novo diffuse large B-cell lymphoma (DLBCL) uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the British Columbia Cancer Agency. MYC and BCL2 protein expression was assessed using immunohistochemistry on tissue microarrays. The Lymph2Cx assay provided concordant COO calls in 96% of 49 repeatedly sampled tumor biopsies and in 100% of 83 FFPET biopsies tested across reagent lots. Critically, no frank misclassification (activated B-cell-like DLBCL to germinal center B-cell-like DLBCL or vice versa) was observed. Patients with activated B-cell-like DLBCL had significantly inferior outcomes compared with patients with germinal center B-cell-like DLBCL (log-rank P < .001 for time to progression, progression-free survival, disease-specific survival, and overall survival). In pairwise multivariable analyses, COO was associated with outcomes independent of IPI score and MYC/BCL2 immunohistochemistry. The prognostic significance of COO was particularly evident in patients with intermediate IPI scores and the non-MYC-positive/BCL2-positive subgroup (log-rank P < .001 for time to progression). Assignment of DLBCL COO by the Lymph2Cx assay using FFPET biopsies identifies patient groups with significantly different outcomes after R-CHOP, independent of IPI score and MYC/BCL2 dual expression. © 2015 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 08/2015; DOI:10.1200/JCO.2014.60.2383 · 18.43 Impact Factor
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    ABSTRACT: Bendamustine is a bifunctional alkylating agent with unique properties that distinguish it from other agents in its class. Bendamustine is used as monotherapy or in combination with other agents to treat patients with non-Hodgkin lymphoma (nhl) and chronic lymphocytic leukemia (cll). The prospective interventional open-label bend-act trial evaluated bendamustine in patients with rituximab-refractory indolent nhl (inhl) and previously untreated cll. Study objectives were to assess the safety and tolerability of bendamustine monotherapy and to provide patients with access to bendamustine before Health Canada approval. The study aimed to enrol up to 100 patients. All patients with inhl received an intravenous dose of bendamustine 120 mg/m(2) over 60 minutes on days 1 and 2 for up to eight 21- or 28-day treatment cycles. All patients with cll received an intravenous dose of bendamustine 100 mg/m(2) over 30 minutes on days 1 and 2 for up to six 28-day treatment cycles. Of 90 patients treated on study (16 with cll and 74 with inhl), 35 completed the study (4 with cll and 31 with inhl). The most common treatment-emergent adverse events (teaes) were nausea (70%), fatigue (57%), vomiting (40%), and diarrhea (33%)-mostly grades 1 and 2. Ondansetron was the most common supportive medication used in the patients (63.5% of those with inhl and 68.8% of those with cll). Neutropenia (32%), anemia (23%), and thrombocytopenia (21%) were the most frequent hematologic teaes, with neutropenia being the most common grade 3 or 4 teae leading to dose modification. Dose delays occurred in 28 patients (31.3%) because of grade 3 or 4 teaes, with a higher incidence of dose delays being observed in inhl patients on the 21-day treatment cycle than in those on the 28-day treatment cycle (50.0% vs. 24.1%). During the study, 33 patients (36.7%) experienced at least 1 serious adverse event, and 4 deaths were reported (all in patients with inhl). The type and frequency of the teaes reported accorded with observations in earlier clinical trials and post-marketing experiences, thus confirming the acceptable and manageable safety profile of bendamustine.
    Current Oncology 08/2015; 22(4):260-71. DOI:10.3747/co.22.2431 · 1.64 Impact Factor
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    ABSTRACT: The routine use of anti-CD20 monoclonal antibodies (mAbs) has improved patient outcomes in CD20-positive non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Despite the clinical success achieved with rituximab, relapses are still common with further improvements in anti-CD20 mAb efficacy required. Many novel anti-CD20 antibodies are in development, but obinutuzumab is currently the only type II glycoengineered anti-CD20 mAb in clinical testing. Obinutuzumab has increased antibody-dependent cell-mediated cytotoxicity, reduced complement-dependent cytotoxicity and enhanced direct non-apoptotic cell death. In preclinical models, obinutuzumab induced superior tumor remission compared with rituximab at the equivalent dose levels, and was active in rituximab-refractory tumors. Obinutuzumab exhibits encouraging efficacy as monotherapy in NHL, and combined with chemotherapy in relapsed/refractory NHL and treatment-naïve symptomatic CLL. In a recent randomized, phase III trial in patients with untreated comorbid CLL, overall response rate was significantly greater (78% vs. 65%, P<0.0001) and median progression-free survival was significantly prolonged (26.7 vs. 15.2months, P<0.0001) for obinutuzumab plus chlorambucil vs. rituximab plus chlorambucil. Obinutuzumab is a type II anti-CD20 antibody that utilizes distinct mechanisms of action relative to type I antibodies like rituximab and has led to significant clinical improvement over rituximab in a phase III trial in CLL. Further trials are ongoing to determine whether such improvements in outcome will be seen in CD20-positive B-cell malignancies. Copyright © 2015. Published by Elsevier Ltd.
    Cancer Treatment Reviews 07/2015; DOI:10.1016/j.ctrv.2015.07.003 · 6.47 Impact Factor
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    ABSTRACT: Gray zone lymphoma (GZL) with features between classical Hodgkin lymphoma and diffuse large B-cell lymphoma (DLBCL) is a recently recognized entity reported to present primarily with mediastinal disease. We examined detailed clinical features, outcomes, and prognostic factors among 112 GZL patients treated across 19 North American centers. Forty-three percent of patients presented with mediastinal disease (MGZL), while 57% did not (NMGZL). NMGZL patients were older ((50 versus 37 years,) (P) (=0.0001); more often had) bone marrow involvement (19% versus 0%, P=0.001); >1 extranodal site (27% versus 8%, P=0.014); and advanced stage disease (81% versus 13%, respectively, P=0.0001); but less bulk (8% versus 44%, respectively, P=0.0001). Common frontline treatments were cyclophosphamide-doxorubicin-vincristine-prednisone +/- rituximab (CHOP+/-R) 46%, doxorubicin-bleomycin-vinblastine-dacarbazine +/- rituximab (ABVD+/-R) 30%, and dose-adjusted etoposide-doxorubicin-cyclophosphamide-vincristine-prednisone-rituximab (DA-EPOCH-R) 10%. Overall and complete response rates for all patients were 71% and 59%, respectively; 33% had primary refractory disease. At 31-month median follow-up, 2-year progression-free survival (PFS) and overall survival rates were 40% and 88%, respectively. Interestingly, MGZL outcomes appeared similar compared with NMGZL patients. On multivariable analyses, performance status and stage were highly prognostic for survival. Additionally, patients treated with ABVD+/-R had markedly inferior 2-year PFS (22% versus 52%, P=0.03) compared with DLBCL-directed therapy (CHOP+/-R and DA-EPOCH-R), which persisted on Cox regression (HR 1.88, 95%CI 1.03-3.83, P=0.04). Furthermore, rituximab was associated with improved PFS on multivariable analyses (HR 0.35, 95%CI 0.18-0.69, P=0.002). Collectively, GZL is a heterogeneous and likely more common entity that includes non-mediastinal presentation, while outcomes appear superior when treated with a rituximab-based, DLBCL-specific regimen. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    American Journal of Hematology 06/2015; DOI:10.1002/ajh.24082 · 3.48 Impact Factor
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    ABSTRACT: Although it is generally regarded appropriate to start chemotherapy promptly after a diagnosis of diffuse large B-cell lymphoma (DLBCL), the optimal time from diagnosis to treatment (TDT) is unknown. A total of 689 patients diagnosed with DLBCL and treated with ≥1 cycle of CHOP-R with curative intent during 2003 - 2008 in British Columbia were identified: 347 (50%) TDT ≤4 weeks, 277 (40%) TDT 5-8 weeks, 65 (10%) TDT >8 weeks. For the respective TDT groups, 5-year OS estimates were 61%, 74%, 63% (p=0.006); 5-year PFS 57%, 70%, 61% (p=0.006); and 5-year DSS 64%, 80%, 77% (p<0.001). In multivariate analysis, TDT >8 weeks was associated with worse OS (HR 1.20 (95% CI 1.03, 1.41), p=0.020), PFS (HR 1.33 (95% CI 1.15, 1.54), p<0.001), and DSS (HR 1.40 (95% CI 1.10, 1.78), p=0.006). Clinicians should endeavor to initiate curative chemotherapy as soon as possible after a diagnosis of DLBCL is established.
    Leukemia & lymphoma 05/2015; DOI:10.3109/10428194.2015.1055480 · 2.89 Impact Factor
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    ABSTRACT: Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody-drug conjugate containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL). In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3 + 3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0·1-2·4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m(2). Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov, number NCT01290549. Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2·4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1·0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1·8 mg/kg. Grade 3-4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3-4 adverse events were neutropenia (18 [40%] of 45), anaemia (five [11%]), and peripheral sensory neuropathy (four [9%]). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3-4 adverse event, with neutropenia (five [56%]), anaemia (two [22%]), and febrile neutropenia (two [22%]) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B-cell lymphoma (due to progressive disease in four patients, infections in three patients [two treatment related], and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity-evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle-cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL. Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL. Genentech. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet Oncology 04/2015; 16(6). DOI:10.1016/S1470-2045(15)70128-2 · 24.73 Impact Factor
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    ABSTRACT: We aimed to assess the prognostic significance of follicular lymphoma (FL)-associated macrophages in the era of rituximab treatment and maintenance. We applied IHC for CD68 and CD163 to two large tissue microarrays (TMAs). The first TMA included samples from 186 patients from the BC Cancer Agency (BCCA) who had been treated with first line systemic treatment including rituximab, cyclophosphamide, vincristine and prednisone. The second contained 395 samples from PRIMA trial patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, and randomized to rituximab maintenance or observation. Macrophage infiltration was assessed using Aperio image analysis. Each of the two cohorts was randomly split into training/validation sets. An increased CD163 positive pixel count was predictive of adverse outcome in the BCCA dataset (5-year progression-free survival (PFS) 38% v 72%, respectively, P=0.004 in the training cohort and 5-year PFS 29% v 61%, respectively, P=0.004 in the validation cohort). In the PRIMA trial, an increased CD163 pixel count was associated with favourable outcome (5-year PFS 60% v 44%, respectively, P=0.011 in the training cohort and 5-year PFS 55% v 37%, respectively, P=0.030 in the validation cohort). CD163-positive macrophages predict outcome in FL but their prognostic impact is highly dependent on treatment received. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 04/2015; DOI:10.1158/1078-0432.CCR-14-3253 · 8.19 Impact Factor
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    ABSTRACT: Splenic marginal zone lymphoma (SMZL) accounts for less than 2% of all non-Hodgkin lymphomas. We identified 107 cases diagnosed with SMZL between 1985 and 2012 from the British Columbia Cancer Agency Centre for Lymphoid Cancer and Lymphoma Pathology Databases. Patient characteristics were: median age 67 years (range 30-88), male 40%, stage IV 98%, splenomegaly 93%, bone marrow involvement 96%, peripheral blood involvement 87%. As initial treatment, 52 underwent splenectomy (10 with chemotherapy), 38 chemotherapy alone (21 chemoimmunotherapy containing rituximab, 1 rituximab alone), two antivirals for hepatitis C, and 15 were only observed. The 10-year overall survival for first-line splenectomy versus chemotherapy was 61% and 42%, respectively [Hazard Ratio (HR) 0·48, 95% confidence interval (CI) 0·26-0·88, P = 0·017]. The 10-year failure-free survival (FFS) after first-line splenectomy vs chemotherapy was 39% and 14%, respectively (HR 0·48, 95% CI 0·28-0·80, P = 0·004). Among the 38 patients who received first-line chemotherapy, FFS was similar between those receiving rituximab (n = 22) and those who did not (n = 16) (HR 0·64, 95% CI 0·31-1·34, P = 0·238). Fifteen patients transformed to aggressive lymphoma with median time to transformation of 3·5 years (range 6 months to 12 years) and the 10-year transformation rate was 18%. In conclusion, splenectomy remains a reasonable treatment for patients with SMZL. © 2015 John Wiley & Sons Ltd.
    British Journal of Haematology 04/2015; 169(4). DOI:10.1111/bjh.13320 · 4.96 Impact Factor
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    ABSTRACT: Double-hit lymphoma is characterized by the presence of concurrent MYC (myelocytomatosis oncogene) and BCL2 (B-cell lymphoma 2) gene rearrangements. Prognosis is poor with standard chemoimmunotherapy. Since 2003, the British Columbia Cancer Agency has used CODOX-M/IVAC+R (cyclophosphamide, vincristine, doxorubicin, methotrexate, cytarabine, ifosfamide, and etoposide, combined with rituximab) followed by consolidative hematopoietic cell transplantation as definitive treatment for double-hit lymphoma. A retrospective review of the survival outcomes of patients with double-hit lymphoma treated at our institution was conducted. Thirty-two patients diagnosed with non-Hodgkin lymphoma with concurrent MYC and BCL2 translocations from 2003 to 2013 were identified. Cases with MYC or BCL2 amplification and those with overexpression in immunohistochemistry analysis were excluded. Median age at diagnosis was 53.0 years (range, 35.5-70.9 years), 23 (72%) were male, and 30 (94%) had stage III to IV disease. CODOX-M/IVAC+R was administered in 25 (78%) patients and 20 (80%) achieved a partial remission or better, of which 9 (36%) had a complete remission. Nineteen of the 32 (59%) patients underwent upfront hematopoietic cell transplantation. At a median follow-up of living patients of 26.4 months, 14 (44%) were alive in remission, 15 (47%) died, and 3 (9%) were alive in relapse. The 2-year progression-free survival (PFS) and overall survival (OS) of all patients were 41% and 53%, respectively. The sixteen patients treated with CODOX-M/IVAC+R followed by hematopoietic cell transplantation had a 2-year PFS of 60% and 2-year OS of 82%. Patients with double-hit lymphoma treated with CODOX-M/IVAC+R followed by hematopoietic cell transplantation can achieve durable remissions, although disease progression before transplantation remains a significant problem. Copyright © 2015 Elsevier Inc. All rights reserved.
    Clinical Lymphoma, Myeloma and Leukemia 01/2015; 15(6). DOI:10.1016/j.clml.2014.12.015 · 2.02 Impact Factor
  • Laurie H. Sehn
    Blood 12/2014; 125(1). DOI:10.1182/blood-2014-09-594580 · 10.43 Impact Factor
  • Laurie H Sehn · Randy D Gascoyne
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    ABSTRACT: While the majority of patients with diffuse large B-cell lymphoma (DLBCL) can be cured with standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone), patients who fail R-CHOP have a dismal outcome. Thus, optimization of front-line therapy, as well as the development of more effective salvage strategies remains an important objective. Advances in molecular genetics have vastly improved our understanding of the biological diversity of DLBCL and have lead to the discovery of key oncogenic pathways. In addition to the major molecular designations of germinal center B-cell (GCB) and activated B-cell (ABC) subtypes, next generation sequencing technologies have unveiled the remarkable complexity of DLBCL and identified unique molecular targets that may be differentially exploited for therapeutic benefit. These findings have translated into a growing list of promising novel agents. Moving forward, it is of paramount importance to recognize the heterogeneity of DLBCL and to investigate these targeted agents within patient populations who are most likely to benefit. It will be necessary to prioritize drugs that affect key driver pathways and to combine them rationally to optimize their benefit. Improved prognostication and the availability of predictive biomarkers will be crucial to allow for the possibility of individualized risk-adapted therapy. Copyright © 2014 American Society of Hematology.
    Blood 12/2014; 125(1). DOI:10.1182/blood-2014-05-577189 · 10.43 Impact Factor
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    ABSTRACT: Effective treatment of diffuse large B cell lymphoma (DLBCL) is plagued by heterogeneous responses to standard therapy, and molecular mechanisms underlying unfavorable outcomes in lymphoma patients remain elusive. Here, we profiled 148 genomes with 91 matching transcriptomes in an R-CHOP-treated DLBCL cohort to uncover molecular subgroups linked to treatment failure. Systematic integration of high-resolution genotyping arrays and RNA-seq data revealed novel deletions in RCOR1 to be associated with unfavorable progression free survival (P = 0.001). Integration of expression data from the clinical samples with data from RCOR1 knockdowns in the lymphoma cell lines KM-H2 and Raji yielded an RCOR1 loss-associated gene signature comprising of 233 genes. This signature identified a subgroup of patients with unfavorable overall survival (OS) (P = 0.023). The prognostic significance of the 233-gene signature for OS was reproduced in an independent cohort comprising 195 R-CHOP treated patients (P = 0.039). Additionally, we discovered that within the IPI low risk group, the gene signature provides additional prognostic value that was independent of the cell-of-origin phenotype. Taken together, we present a novel and reproducible molecular subgroup of DLBCL, impacting risk-stratification of R-CHOP treated DLBCL patients and revealing a possible new avenue for therapeutic intervention strategies.
    Blood 11/2014; 125(6). DOI:10.1182/blood-2013-06-507152 · 10.43 Impact Factor
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    ABSTRACT: Background High-dose therapy and autologous stem-cell transplant (HDT/ASCT) is the preferred treatment of chemosensitive relapsed/refractory Hodgkin lymphoma (HL). The role for HDT/ASCT in chemoresistant HL is less well defined. We evaluated long-term outcomes of relapsed/refractory HL patients whose disease was refractory to secondary chemotherapy preceding HDT/ASCT.
    Annals of Oncology 08/2014; 25(11). DOI:10.1093/annonc/mdu387 · 6.58 Impact Factor
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    ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with variable therapeutic responses and alternative therapies are needed for patients with unfavourable treatment outcomes after standard treatment with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). One promising candidate is brentuximab vedotin, an antibody-drug conjugate targeting CD30-expressing cells. However, CD30 (TNFRSF8) expression patterns in DLBCL are not well described thus far. Here, we examined CD30 expression in a population-based cohort of immunocompetent patients from British Columbia with de novo DLBCL using immunohistochemistry. 385 cases of formalin-fixed paraffin-embedded DLBCL in tissue microarrays were evaluated. 95 cases (25%) harboured CD30+ tumour cells. Using a > 0% cut-off, CD30 expression was predictive of superior 5-year progression-free survival within R-CHOP treated germinal centre B-cell-like (GCB) DLBCL (86% vs. 64%, P = 0·020), which was independent of the International Prognostic Index. Epstein-Barr virus (EBV) was identified in 11 (3%) cases, all of which were non-GCB (P = 0·001) and almost exclusively positive for CD30 expression (10/11) (P < 0·001). We conclude CD30 is expressed in a substantial proportion of DLBCL and CD30 immunohistochemistry may be a useful prognostic marker in R-CHOP treated GCB-DLBCL. The significant association of CD30 with EBV-positive non-GCB DLBCL suggests a distinct pathobiology for these cases.
    British Journal of Haematology 08/2014; 167(5). DOI:10.1111/bjh.13085 · 4.96 Impact Factor
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    ABSTRACT: Vascular endothelial growth factor is involved in lymphoma growth, suggesting a potential role for anti vascular endothelial growth factor therapies in hematological malignancies. In this phase III study, patients with CD20-positive diffuse large B-cell lymphoma were randomized to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone plus either placebo (R-CHOP) or bevacizumab (RA-CHOP). Treatment was administered every 21 (8 cycles) or 14 days (6 cycles plus 2 rituximab cycles) per institutional practice. An early analysis of risk/benefit by the Data and Safety Monitoring Board showed that RA-CHOP increased cardiotoxicity without prolonging progression-free survival compared with R-CHOP, and the trial was stopped early. The study protocol was amended to allow for 12 additional months of follow-up to evaluate safety. With 787 patients enrolled, median follow up was 23.7 and 23.6 months for R-CHOP and RA-CHOP, respectively. Median progression-free survival for R-CHOP and RA CHOP was 42.9 and 40.2 months, respectively (hazard ratio=1.09; P=0.49). The proportion of deaths was identical for R-CHOP (21%, 83/387) and RA-CHOP (21%, 82/390). Relative to R-CHOP, RA-CHOP had a higher rate of left ventricular ejection fraction perturbation (18% versus 8%; odds ratio=2.51; 95% confidence interval: 1.60-3.93) and congestive heart failure (16% versus 7%; odds ratio=2.79; 95% confidence interval: 1.72-4.54). Bevacizumab added to R-CHOP increased cardiac events, without increasing efficacy, arguing against further evaluation of RA-CHOP in patients with diffuse large B-cell lymphoma. The MAIN study is registered at clinicaltrials.gov, NCT00486759.
    Haematologica 06/2014; 99(8). DOI:10.3324/haematol.2013.100818 · 5.87 Impact Factor
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    ABSTRACT: Due to disease rarity, there is limited information regarding the optimal therapy and outcome of patients with advanced stage nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). 42 patients with NLPHL by the REAL/WHO classification with advanced stage disease were identified and paired 1:2 with a matched control with classical Hodgkin lymphoma (CHL) with matching by age, gender, stage, decade of diagnosis, and treatment received. The median follow-up was 11.3 years (range 1.9-35.5) for NLPHL patients and 10.7 years (1.6-26.3) for CHL patients. The majority received ABVD-like chemotherapy. Although the 10 year overall survival (OS) (P=0.579) and Hodgkin lymphoma-freedom from treatment failure (HL-FFTF) were similar between NLPHL and CHL (75% vs 73%, P=0.610), the time to progression (TTP), which also includes the development of secondary aggressive lymphoma, was inferior in NLPHL (10 y 63% vs 73%, P=0.040). Splenic involvement was associated with an inferior 10 y TTP in patients treated with ABVD (48 vs 71%, P=0.049) and an increased cumulative incidence of transformed aggressive lymphoma (P=0.014) providing a rationale for further evaluation of CHOP +/- rituximab in NLPHL.
    Blood 04/2014; 123(23). DOI:10.1182/blood-2013-12-541078 · 10.43 Impact Factor

Publication Stats

3k Citations
717.66 Total Impact Points

Institutions

  • 2006–2015
    • BC Cancer Agency
      • • Centre for Lymphoid Cancer
      • • Radiation Therapy Program
      Vancouver, British Columbia, Canada
  • 2003–2015
    • University of British Columbia - Vancouver
      • Division of Medical Oncology
      Vancouver, British Columbia, Canada
  • 2008
    • Stanford University
      • Department of Medicine
      Palo Alto, California, United States
    • Vancouver Prostate Centre
      Vancouver, British Columbia, Canada