Michael Crump

The Princess Margaret Hospital, Toronto, Ontario, Canada

Are you Michael Crump?

Claim your profile

Publications (206)1364.59 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The NCIC CTG LY.12 study showed that gemcitabine, dexamethasone, and cisplatin (GDP) were noninferior to dexamethasone, cytarabine, and cisplatin (DHAP) in patients with relapsed or refractory aggressive histology lymphoma prior to autologous stem cell transplantation. We conducted an economic evaluation from the perspective of the Canadian public healthcare system based on trial data. The primary outcome was an incremental cost utility analysis comparing costs and benefits associated with GDP vs DHAP. Resource utilization data were collected from 519 Canadian patients in the trial. Costs were presented in 2012 Canadian dollars and disaggregated to highlight the major cost drivers of care. Benefit was measured as quality-adjusted life-years (QALYs) based on utilities translated from prospectively collected quality-of-life data. All statistical tests were two-sided. The mean overall costs of treatment per patient in the GDP and DHAP arms were $19 961 (95% confidence interval (CI) = $17 286 to $24 565) and $34 425 (95% CI = $31 901 to $39 520), respectively, with an incremental difference in direct medical costs of $14 464 per patient in favor of GDP (P < .001). The predominant cost driver for both treatment arms was related to hospitalizations. The mean discounted quality-adjusted overall survival with GDP was 0.161 QALYs and 0.152 QALYs for DHAP (difference = 0.01 QALYs, P = .146). In probabilistic sensitivity analysis, GDP was associated with both cost savings and improved quality-adjusted outcomes compared with DHAP in 92.6% of cost-pair simulations. GDP was associated with both lower costs and similar quality-adjusted outcomes compared with DHAP in patients with relapsed or refractory lymphoma. Considering both costs and outcomes, GDP was the dominant therapy. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    CancerSpectrum Knowledge Environment 07/2015; 107(7). DOI:10.1093/jnci/djv106 · 15.16 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The treatment of transformed indolent lymphoma (TRIL) often includes salvage chemotherapy (SC) and autologous stem cell transplant (ASCT). NCIC CTG LY12 is a randomized phase III trial comparing gemcitabine, dexamethasone, cisplatin (GDP) to dexamethasone, cytarabine, cisplatin (DHAP) prior to ASCT. This analysis compares the results of SC and ASCT for TRIL with de novo diffuse large B cell lymphoma (DL). Six hundred nineteen patients with relapsed/refractory aggressive NHL were randomized to GDP or DHAP; 87 patients (14%) had TRIL and 429 (69%) had DLBCL. The response rate to SC was 47% in TRIL and 45% in DL (p=0.81). Transplantation rates were similar: TRIL: 53%; DL: 52% (p=1.0). With a median follow-up of 53 months, 4 year OS was 39% for TRIL and 41% for DL (p=0.78); 4 year EFS was 27% for TRIL and 27% for DL (p=0.83). Post-ASCT, 4 year EFS was 45% for TRIL and 46% for DL. Histology (TRIL or DL) was not a predictor of any outcome in multivariate models. Patients with relapsed or refractory TRIL and DLBCL have similar outcomes with SC and ASCT; this therapy should be considered the standard of care for patients with TRIL who have received prior systemic chemotherapy. NCIC CTG LY12 is registered to www.clinicaltrials.gov as NCT00078949. Copyright © 2015 American Society of Hematology.
    Blood 06/2015; DOI:10.1182/blood-2015-01-622084 · 10.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Follicular lymphoma (FL) in young adults (YA, <40 years old) is uncommon, and the clinical characteristics and outcomes of this group are not well defined. We conducted a retrospective database review of 427 patients with newly diagnosed FL aged 65 years or less registered at Princess Margaret Cancer Centre between 1995 and 2010. YA (n = 61) and those 40-65 (n = 366) were compared with regards to clinical stage at diagnosis, FL International Prognostic Index (FLIPI) score, and the following clinical outcomes: time to second treatment, cause-specific survival (CSS) and overall survival (OS). At diagnosis, stage and FLIPI score were similar, as were the proportion of patients requiring therapy (YA 75% versus older adults 71%). Median follow-up was 8·1 years. Time to second therapy was similar in both age groups (5-year probability 23% YA versus 27% older adults; Gray's P-value = 0·76). Ten-year OS was significantly higher for YA (87% versus older adults 72%; P = 0·029). On multivariate analysis, age <40 years, low FLIPI score and observation as initial management were favourable prognostic factors for OS and CSS. We conclude that YA with FL have a favourable prognosis compared to older patients; whether this reflects competing mortality risks or age-related differences in lymphoma biology warrants further investigation. © 2015 John Wiley & Sons Ltd.
    British Journal of Haematology 04/2015; 170(3). DOI:10.1111/bjh.13451 · 4.96 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Temsirolimus, a selective inhibitor of the mammalian target of rapamycin, has demonstrated clinical benefit versus investigator's choice (INV) of therapy in patients with relapsed/refractory mantle cell lymphoma (MCL). This post hoc study retrospectively assigned simplified Mantle Cell Lymphoma International Prognostic Index (MIPI) scores (ie, secondary MIPI) based on parameters at the time of randomization in patients with MCL (N = 162) who received temsirolimus 175 mg once weekly for 3 weeks followed by once-weekly 75 mg or 25 mg or the INV of active therapy. Outcomes were analyzed according to the low-, intermediate- or high-risk category. Patient distribution by MIPI risk category was 31%, 39%, and 30% in the low-, intermediate-, and high-risk groups, respectively. Among patients in all categories, objective response rate (complete response + partial response) was higher in patients in the temsirolimus 175/75-mg group versus the INV group, respectively: 42% versus 0% (low-risk); 33% versus 5% (intermediate-risk); 10% versus 0% (high-risk). Median progression-free survival was significantly longer with temsirolimus 175/75 mg versus INV, respectively, in patients with intermediate (4.3 vs 1.9 months; P = 0.035) or high (4.5 vs 1.6 months; P = 0.0025) risk, and a trend toward improvement was observed in patients with low risk (5.3 vs 2.6 months; P = 0.091). Improvement in median overall survival was observed with temsirolimus 175/75 mg versus INV in low-risk patients (18.0 vs 10.5 months, respectively; P = 0.069). This analysis suggests that, compared with INV, temsirolimus demonstrated benefit in all MIPI risk categories in patients with MCL. In all treatment groups, patients with high secondary MIPI scores at baseline faced a dismal prognosis. ClinicalTrials.gov NCT00117598.
    04/2015; 4(1). DOI:10.1186/s40164-015-0006-1
  • [Show abstract] [Hide abstract]
    ABSTRACT: Gene rearrangements and specific translocations define some B-cell non-Hodgkin lymphoma (NHL) subtypes. Genome-wide mutational studies have revealed recurrent point mutations with prognostic implications. The goals of this study were to evaluate the feasibility of applying a multiplex mutation assay to archival cytospin preparations (CPs) and to investigate the rate of EZH2, CD79B, and MYD88 mutations in B-cell NHL samples previously tested for MYC rearrangement and/or IGH/BCL-2 translocation. DNA was extracted from archival CPs of B-cell NHL cases with previous fluorescence in situ hybridization (FISH) assays for MYC rearrangement and/or IGH/BCL-2 translocation. Multiplex sequencing was performed for the detection of EZH2 (Y641), CD79B (Y196), and MYD88 (L265) mutations. Sanger sequencing was applied to samples with positive results and failed assays. Eighty-eight archival CPs were available from 40 patients. Alterations detected by FISH were: MYC rearrangement (10 cases), IGH/BCL-2 translocations (21 cases), dual translocations (6 cases), and other abnormalities for IGH/BCL-2 (23 cases) and for MYC (16 cases). DNA concentration ranged from 1.88 to 62.85 ng/µL (mean, 9.46 ng/µL). Successful results were obtained in 88.0% of the specimens submitted to multiplex sequencing. With Sanger sequencing, 2 additional mutated cases were found, and all cases with mutations were confirmed. Eight specimens showed mutations: 6 for EZH2, 1 for CD79B, and 1 for MYD88. Among them, 5 cases showed concurrent MYC and/or IGH/BCL-2 translocations and 2 revealed abnormal signals of IGH/BCL-2 and MYC. CPs archived for up to 6 years are a reliable source of high-quality genomic material for multiplex sequencing. Almost all B-cell NHL with point mutations showed concurrent chromosomal abnormalities. Cancer (Cancer Cytopathol) 2015. © 2014 American Cancer Society. © 2015 American Cancer Society.
    Cancer Cytopathology 03/2015; DOI:10.1002/cncy.21535 · 3.81 Impact Factor
  • Blood 01/2015; 125(11). DOI:10.1182/blood-2014-08-545152 · 10.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Increasingly, targeted therapies are being developed to treat malignancies. To define targets, determine mechanisms of response and resistance, and develop biomarkers for the successful investigation of novel therapeutics, high-quality tumor biospecimens are critical. We have developed standard operating procedures (SOPs) to acquire and process serial blood and tumor biopsies from patients with diffuse large B-cell lymphoma enrolled in multicenter clinical trials. These SOPs allow for collection and processing of materials suitable for multiple downstream applications, including immunohistochemistry, cDNA microarrays, exome sequencing, and metabolomics. By standardizing these methods, we control preanalytic variables that ensure high reproducibility of results and facilitate the integration of datasets from such trials. This will facilitate translational research, better treatment selection, and more rapid and efficient development of new drugs. See all the articles in this CEBP Focus section, "Biomarkers, Biospecimens, and New Technologies in Molecular Epidemiology." Cancer Epidemiol Biomarkers Prev; 23(12); 2688-93. ©2014 AACR. ©2014 American Association for Cancer Research.
    Cancer Epidemiology Biomarkers & Prevention 12/2014; 23(12):2688-93. DOI:10.1158/1055-9965.EPI-14-0549 · 4.32 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background The role of allogeneic (ALLO) and autologous (AUTO) stem cell transplantation in the management of patients with transformed indolent non-follicular non-Hodgkin lymphoma is unknown. Methods This is a multicenter, retrospective cohort study of patients with biopsy-proven indolent B-cell non-follicular non-Hodgkin lymphoma, and simultaneous or subsequent biopsy-proven aggressive histology transformation who were treated with ALLO or AUTO between 1996-2013. All patients received myeloablative conditioning regimens. Outcomes were compared to a cohort of 246 patients with transformed follicular lymphoma who also underwent ALLO (n=47) or AUTO (n=199) across the same institutions and timeframe. Results Thirty-four patients were identified with the following underlying indolent histologies: 15 (44%) marginal zone lymphoma, 11 (32%) chronic lymphocytic leukemia, 6 (18%) small lymphocytic lymphoma, and 2 (6%) lymphoplasmacytic lymphoma. Patients received various anthracycline or platinum-containing chemotherapy regimens for transformation, incorporating rituximab in 25 (74%). Twelve (35%) subsequently underwent ALLO, while 33 (65%) underwent AUTO. The 3-year OS after transplantation was 67% (ALLO 54%, AUTO 74%), and 3-year PFS was 49% (ALLO 40%, AUTO 54%). The 3-year non-relapse mortality was 14% (ALLO 15%, AUTO 7%). Transplant-related mortality at 100 days was ALLO 17% and AUTO 0%. Adjusted for type of stem cell transplantation, 3-year OS, PFS, and NRM were similar to those of patients with transformed follicular lymphoma receiving ALLO and AUTO (p=0.38, p=0.69, p=0.54 respectively). Conclusions ALLO and AUTO may be reasonable treatments for selected patients with transformed non-follicular indolent lymphoma, although medium-term outcomes and toxicity appear to be more favorable with AUTO.
    Biology of Blood and Marrow Transplantation 11/2014; 20(11). DOI:10.1016/j.bbmt.2014.07.015 · 3.35 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: ABSTRACT Rituximab is a monoclonal anti-CD20 antibody that is standard of care for the treatment of B-cell non-Hodgkin lymphoma (NHL). The purpose of this study was to quantify the incidence of rituximab-related interstitial pneumonitis (IP) in NHL patients receiving immunochemotherapy. All patients with NHL who received CHOP, CVP, R-CHOP, or R-CVP in Princess Margaret Hospital between June 1998 and August 2009 were retrospectively reviewed. We compared cohorts of patients who did and did not receive rituximab and documented the incidence of IP during and/or post-treatment. 560 patients are included in this analysis. The rate of IP in the entire cohort was 2.9% (16/560) with a trend towards a higher rate in the R group [3.95% vs. 1.3%, (OR 3.1, 0.84-17.27, p=0.074)]. Baseline pulmonary CT abnormalities in lymphoma patients are relatively common. The addition of rituximab to chemotherapy does not significantly increase the risk of symptomatic chemotherapy-related IP.
    Leukemia and Lymphoma 10/2014; 56(6):1-19. DOI:10.3109/10428194.2014.963075 · 2.61 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Acute myeloid leukaemia (AML) patients with hyperleucocytosis have higher early mortality, lower complete remission (CR) and overall survival (OS). Whether different pre-induction leucoreduction strategies can improve outcome is unknown. A single centre retrospective cohort study was conducted on AML patients with a white blood cell count (WBC) >100 × 10(9) /l between 1987 and 1997, and on all AML patients between 1998 and 2006, to determine (a) the effect of four different leucoreductive strategies (leukapheresis, hydroxycarbamide, leukapheresis and hydroxycarbamide or no pre-induction leucoreduction) on early (day 28) mortality, CR, and OS; and (b) whether a high presenting WBC remains a negative predictor of OS in patients surviving induction (first 28 d). In the 1998-2006 cohort (n = 702), higher WBC was associated with higher early mortality and lower OS but its effects were greatly diminished in patients who survived the first 28 d (Hazard Ratio 1·094 vs. 1·002). A WBC of 34·1 × 10(9) /l had the highest sensitivity (75·6%) and specificity (67·4%) for early mortality. None of the four leucoreduction strategies differed significantly in early mortality, CR, or OS in patients with WBC>100 × 10(9) /l (n = 166). The number of leucostatic signs was a significant predictor of early mortality (P < 0·0001) and OS (P = 0·0007). The results suggest that AML patients with hyperleucocytosis should be induced, if eligible, without pre-induction leucoreduction.
    British Journal of Haematology 10/2014; 168(3). DOI:10.1111/bjh.13146 · 4.96 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose For patients with relapsed or refractory aggressive lymphoma, we hypothesized that gemcitabine-based therapy before autologous stem-cell transplantation (ASCT) is as effective as and less toxic than standard treatment. Patients and Methods We randomly assigned 619 patients with relapsed/refractory aggressive lymphoma to treatment with gemcitabine, dexamethasone, and cisplatin (GDP) or to dexamethasone, cytarabine, and cisplatin (DHAP). Patients with B-cell lymphoma also received rituximab. Responding patients proceeded to stem-cell collection and ASCT. Coprimary end points were response rate after two treatment cycles and transplantation rate. The noninferiority margin for the response rate to GDP relative to DHAP was set at 10%. Secondary end points included event-free and overall survival, treatment toxicity, and quality of life. Results For the intention-to-treat population, the response rate with GDP was 45.2%; with DHAP the response rate was 44.0% (95% CI for difference, -9.0% to 6.7%), meeting protocol-defined criteria for noninferiority of GDP (P = .005). Similar results were obtained in a per-protocol analysis. The transplantation rates were 52.1% with GDP and 49.3% with DHAP (P = .44). At a median follow-up of 53 months, no differences were detected in event-free survival (HR, 0.99; stratified log-rank P = .95) or overall survival (HR, 1.03; P = .78) between GDP and DHAP. Treatment with GDP was associated with less toxicity (P < .001) and need for hospitalization (P < .001), and preserved quality of life (P = .04). Conclusion For patients with relapsed or refractory aggressive lymphoma, in comparison with DHAP, treatment with GDP is associated with a noninferior response rate, similar transplantation rate, event-free survival, and overall survival, less toxicity and hospitalization, and superior quality of life. (C) 2014 by American Society of Clinical Oncology
    Journal of Clinical Oncology 09/2014; 32(31). DOI:10.1200/JCO.2013.53.9593 · 18.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Current treatment of diffuse-large-B-cell lymphoma (DLBCL) includes rituximab, an expensive drug, combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy. Economic models have predicted rituximab plus CHOP (RCHOP) to be a cost-effective alternative to CHOP alone as first-line treatment of DLBCL, but it remains unclear what its real-world costs and cost-effectiveness are in routine clinical practice.
    BMC Cancer 08/2014; 14(1):586. DOI:10.1186/1471-2407-14-586 · 3.32 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Purpose Extranodal natural killer T-cell lymphoma (ENKTL) nasal type is a rare form of non-Hodgkin lymphoma that is more commonly seen in Asia and Latin America than in North America or Europe. The purpose of this study was to determine the treatment outcomes with a combined modality approach and if treatment outcomes varied according to ethnicity in patients with ENKTL, nasal type in Toronto, Canada. Methods Patients presenting with ENKTL, nasal type, between 1994 and 2011 were retrospectively reviewed. Patient characteristics, including the patient's ethnic origin, treatment details, and outcomes were recorded and analyzed for significant differences between Asian and Caucasian patients. Results A total of 34 patients were identified - 16 Asian, 16 Caucasian, one Aboriginal and one Hispanic. All patients had nasal cavity involvement. The majority had localized disease: stage I (n=22), stage II (n=6); and stage IV in 6 patients. Combined radiotherapy and chemotherapy was intended for 32 of the 34 patients, with two receiving radiotherapy alone. Median RT dose was 45 Gy (range: 35-50.4 Gy). Response to initial treatment was observed in 44% of patients. Two-year disease free survival was 17.8% (Asian patients: 18.8%, Caucasians: 20%, p=0.82), and overall survival 39.2% (Asian patients: 30%, Caucasians: 42%, p=0.52). Conclusions There were no significant differences in clinical outcomes in terms of patient ethnicity. A combined modality approach (with CHOP chemotherapy administered initially) is of limited effectiveness. We have now adopted the use of radiation therapy as the initial treatment approach, followed by multiagent chemotherapy.
    Leukemia & lymphoma 03/2014; 56(1). DOI:10.3109/10428194.2014.909039 · 2.61 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The role of body mass index (BMI) in survival outcomes is controversial among lymphoma patients. We evaluated the association between BMI at study entry and failure-free survival (FFS) and overall survival (OS) in three phase III clinical trials, among patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and Hodgkin's lymphoma (HL). A total of 537, 730 and 282 patients with DLBCL, HL and FL were included in the analysis. Baseline patient and clinical characteristics, treatment received and clinical outcomes were compared across BMI categories. Among patients with DLBCL, HL and FL, the median age was 70, 33 and 56; 29%, 29% and 37% were obese and 38%, 27% and 37% were overweight, respectively. Age was significantly different among BMI groups in all three studies. Higher BMI groups tended to have more favorable prognosis factors at study entry among DLBCL and HL patients. BMI was not associated with clinical outcome with P-values of 0.89, 0.30 and 0.40 for FFS, and 0.64, 0.67 and 0.09 for OS, for patients with DLBCL, HL and FL, respectively. The association remains non-significant after adjusting for other clinical factors in the Cox model. A subset analysis of males with DLBCL treated on R-CHOP revealed no differences in FFS (P = 0.48) or OS (P = 0.58). BMI was not significantly associated with clinical outcomes among patients with DLBCL, HD or FL, in three prospective phase III clinical trials. The findings contradict some previous reports of similar investigations. Further work is required to understand the observed discrepancies.
    Annals of Oncology 03/2014; 25(3):669-74. DOI:10.1093/annonc/mdt594 · 6.58 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: ABSTRACT Follicular lymphoma (FL) is characterized by initial response to treatment with inevitable relapse. We evaluated chemoimmunotherapy resistance (CIR resistance) including transformation. We identified patients who received rituximab combination therapy for symptomatic FL. CIR resistance was defined as disease progression during rituximab-based chemoimmunotherapy, rituximab maintenance or within 6 months of treatment completion. Our primary outcome was time to early progression (CIR resistance). Between July 2006 and April 2010, 132 patients met inclusion criteria and 22 (16.7%) demonstrated CIR resistance with median follow-up of 33 months. High-risk FLIPI score was predictive of CIR resistance (HR 2.43; 95% CI, 1.4 to 4.1; P = 0.001). Overall, 8 patients (36.3%) transformed (biopsy-proven) with no transformation in the chemoimmunotherapy responder group. Median overall survival in the CIR resistant group was 47 months. Patients with CIR resistance had high rates of histologic transformation and shorter survival with poor response to next therapy.
    Leukemia & lymphoma 01/2014; DOI:10.3109/10428194.2014.885513 · 2.61 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Treatment options for patients with nonbulky stage IA-IIA Hodgkin lymphoma include combined modality therapy (CMT) using doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) plus involved-field radiation therapy (IFRT), and chemotherapy with ABVD alone. There are no mature randomized data comparing ABVD with CMT using modern radiation techniques. Using German Hodgkin Study Group HD10/HD11 and NCIC Clinical Trials Group HD.6 databases, we identified 588 patients who met mutually inclusive eligibility criteria from the preferred arms of HD10 or 11 (n = 406) and HD.6 (n = 182). We evaluated time to progression (TTP), progression-free (PFS) and overall survival, including in three predefined exploratory subset analyses. With median follow-up of 91 (HD10/11) and 134 (HD.6) months, respective 8-year outcomes were for TTP, 93% versus 87% [hazard ratio (HR) 0.44, 95% confidence interval (CI) 0.24-0.78]; for PFS, 89% versus 86% (HR 0.71, 95% CI 0.42-1.18) and for overall survival, 95% versus 95% (HR 1.09, 95% CI 0.49-2.40). In the exploratory subset analysis including HD10 eligible patients who achieved complete response (CR) or unconfirmed complete response (CRu) after two cycles of ABVD, 8-year PFS was 87% (HD10) versus 95% (HD.6) (HR 2.8; 95% CI 0.64-12.5) and overall survival 96% versus 100%. In contrast, among those without CR/CRu after two cycles of ABVD, 8-year PFS was 88% versus 74% (HR 0.35; 95% CI 0.16-0.79) and overall survival 95% versus 91%, respectively (HR 0.42; 95% CI 0.12-1.44). In patients with nonbulky stage IA-IIA Hodgkin lymphoma, CMT provides better disease control than ABVD alone, especially among those not achieving complete response after two cycles of ABVD. Within the follow-up duration evaluated, overall survivals were similar. Longer follow-up is required to understand the implications of radiation and chemotherapy-related late effects. The trials included in this analysis were registered at ClinicalTrials.gov: HD10 - NCT00265018, HD11 - NCT00264953, HD.6 - NCT00002561.
    Annals of Oncology 10/2013; 24(12). DOI:10.1093/annonc/mdt389 · 6.58 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):64-64. DOI:10.1158/1538-7445.AM2013-64 · 9.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: PURPOSEMantle-cell lymphoma (MCL) has a variable natural history but is incurable with current therapies. MicroRNAs (miRs) are useful in prognostic assessment of cancer. We determined an miR signature defining aggressiveness in B-cell non-Hodgkin lymphomas (NHL) and assessed whether this signature aids in MCL prognosis. METHODS We assessed miR expression in a training set of 43 NHL cases. The miR signature was validated in 44 additional cases and examined on a training set of 119 MCL cases from four institutions in Canada. miRs significantly associated with overall survival were examined in an independent cohort of 114 MCL cases to determine association with patient outcome. miR expression was combined with current clinical prognostic factors to develop an enhanced prognostic model in patients with MCL.ResultsFourteen miRs were differentially expressed between aggressive and indolent NHL; 11 of 14 were validated in an independent set of NHL (excluding MCL). miR-127-3p and miR-615-3p were significantly associated with overall survival in the MCL training set. Their expression was validated in an independent MCL patient set. In comparison with Ki-67, expression of these miRs was more significantly associated with overall survival among patients with MCL. miR-127-3p was combined with Ki-67 to create a new prognostic model for MCL. A similar model was created with miR-615-3p and Mantle Cell Lymphoma International Prognostic Index scores. CONCLUSION Eleven miRs are differentially expressed between aggressive and indolent NHL. Two novel miRs were associated with overall survival in MCL and were combined with clinical prognostic models to generate novel prognostic data for patients with MCL.
    Journal of Clinical Oncology 07/2013; 31(23). DOI:10.1200/JCO.2012.45.3050 · 18.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Numerous genomic abnormalities in B-cell non-Hodgkin lymphomas (NHLs) have been revealed by novel high-throughput technologies, including recurrent mutations in EZH2 (enhancer of zeste homolog 2) and CD79B (B cell antigen receptor complex-associated protein beta chain) genes. This study sought to determine the evolution of the mutational status of EZH2 and CD79B over time in different samples from the same patient in a cohort of B-cell NHLs, through use of a customized multiplex mutation assay. METHODS: DNA that was extracted from cytological material stored on FTA cards as well as from additional specimens, including archived frozen and formalin-fixed histological specimens, archived stained smears, and cytospin preparations, were submitted to a multiplex mutation assay specifically designed for the detection of point mutations involving EZH2 and CD79B, using MassARRAY spectrometry followed by Sanger sequencing. RESULTS: All 121 samples from 80 B-cell NHL cases were successfully analyzed. Mutations in EZH2 (Y646) and CD79B (Y196) were detected in 13.2% and 8% of the samples, respectively, almost exclusively in follicular lymphomas and diffuse large B-cell lymphomas. In one-third of the positive cases, a wild type was detected in a different sample from the same patient during follow-up. CONCLUSIONS: Testing multiple minimal tissue samples using a high-throughput multiplex platform exponentially increases tissue availability for molecular analysis and might facilitate future studies of tumor progression and the related molecular events. Mutational status of EZH2 and CD79B may vary in B-cell NHL samples over time and support the concept that individualized therapy should be based on molecular findings at the time of treatment, rather than on results obtained from previous specimens. Cancer (Cancer Cytopathol) 2013;121:377–386. © 2013 American Cancer Society.
    Cancer Cytopathology 07/2013; 121(7). DOI:10.1002/cncy.21262 · 3.81 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: PURPOSE: Identify subgroups of relapsed/refractory follicular lymphoma patients deriving substantial progression-free survival (PFS) benefit with bortezomib-rituximab versus rituximab in the phase 3 LYM-3001 study. EXPERIMENTAL DESIGN: 676 patients were randomized to five 5-week cycles of bortezomib-rituximab or rituximab. The primary endpoint was PFS; this pre-specified analysis of candidate protein biomarkers and genes was an exploratory objective. Archived tumor tissue and whole blood samples were collected at baseline. Immunohistochemistry and genetic analyses were completed for four proteins and eight genes. RESULTS: In initial pair-wise analyses, using individual SNP genotypes, one biomarker pair (PSMB1 P11A C/G heterozygote, low CD68 expression) was associated with a significant PFS benefit with bortezomib-rituximab versus rituximab, controlling for multiple comparison corrections. The pair was analyzed under dominant, recessive, and additive genetic models, with significant association with PFS seen under the dominant model (G/G+C/G). In patients carrying this biomarker pair (PSMB1 P11A G allele, low CD68 expression [≤50 CD68-positive cells], population frequency: 43.6%), median PFS was 14.2 months with bortezomib-rituximab versus 9.1 months with rituximab (HR 0.47, P < 0.0001), and there was a significant overall survival benefit (HR 0.49, P = 0.0461). Response rates were higher and time to next anti-lymphoma therapy longer in the bortezomib-rituximab group. In biomarker-negative patients, no significant efficacy differences were seen between treatment groups. Similar proportions of patients had high-risk features in the biomarker-positive and biomarker-negative subsets. CONCLUSIONS: Patients with PSMB1 P11A (G allele) and low CD68 expression appeared to have significantly longer PFS and greater clinical benefit with bortezomib-rituximab versus rituximab.
    Clinical Cancer Research 04/2013; DOI:10.1158/1078-0432.CCR-12-3069 · 8.19 Impact Factor

Publication Stats

5k Citations
1,364.59 Total Impact Points

Institutions

  • 2000–2014
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada
  • 1991–2014
    • University of Toronto
      • • Department of Radiation Oncology
      • • Department of Medicine
      • • Faculty of Medicine
      Toronto, Ontario, Canada
  • 2006–2013
    • University Health Network
      • • Department of Medical Oncology
      • • Princess Margaret Hospital
      Toronto, Ontario, Canada
  • 2012
    • University of British Columbia - Vancouver
      Vancouver, British Columbia, Canada
  • 2011
    • James A. Haley Veterans Hospital
      Tampa, Florida, United States
  • 2010
    • Chittaranjan National Cancer Institute
      Kolkata, West Bengal, India
  • 2004–2008
    • National Cancer Institute (USA)
      베서스다, Maryland, United States
    • Ontario Institute for Cancer Research
      Toronto, Ontario, Canada
  • 1992–2000
    • Toronto Western Hospital
      Toronto, Ontario, Canada
  • 1997
    • Duke University
      Durham, North Carolina, United States
  • 1990
    • UHN: Toronto General Hospital
      Toronto, Ontario, Canada