Publications by authors named "Douglas A Stewart"

59 Publications

Prophylactic high-dose methotrexate in diffuse large B cell lymphoma, authors' response.

Am J Hematol 2021 09 7;96(9):E339-E341. Epub 2021 Jun 7.

University of Calgary and Tom Baker Cancer Centre, Calgary, Alberta, Canada.

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http://dx.doi.org/10.1002/ajh.26256DOI Listing
September 2021

Novel synthetic drugs for the treatment of non-Hodgkin lymphoma.

Expert Opin Pharmacother 2021 Aug 25;22(11):1417-1427. Epub 2021 Mar 25.

Department of Oncology, University of Calgary, Calgary, Alberta, Canada.

: Over the past two decades, deeper understanding of B-cell signaling pathways and other mechanisms of lymphomagenesis have yielded promising targets for novel drugs in the treatment of non-Hodgkin lymphoma.: This article provides a comprehensive review of approved synthetic drugs targeting the BTK, PI3K, immunomodulation, proteasome, HDAC, EZH2, and nuclear export pathways in non-Hodgkin lymphoma. The review includes coverage of the pharmacology, efficacy, toxicity, and active areas of research for each drug. The authors also provide their expert perspectives on the field and their opinions for the future.: Although novel synthetic drugs have generally not impacted clinical practice to the same extent as immune and cellular therapies, there remains an important role for targeted drugs in the treatment of non-Hodgkin lymphoma, particularly in the relapsed setting and for patients ineligible for more intensive therapies. Clinical outcomes and tolerability may improve further with the development of newer generations of synthetic drugs and emerging combination regimens with other targeted and immune therapies.
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http://dx.doi.org/10.1080/14656566.2021.1902988DOI Listing
August 2021

From symptom to cancer diagnosis: Perspectives of patients and family members in Alberta, Canada.

PLoS One 2020 24;15(9):e0239374. Epub 2020 Sep 24.

Cancer Strategic Clinical Network, Alberta Health Services, Calgary, Alberta, Canada.

Background: Significant intervals from the identification of suspicious symptoms to a definitive diagnosis of cancer are common. Streamlining pathways to diagnosis may increase survival, quality of life post-treatment, and patient experience. Discussions of pathways to diagnosis from the perspective of patients and family members are crucial to advancing cancer diagnosis.

Aim: To examine the perspectives of a group of patients with cancer and family members in Alberta, Canada, on factors associated with timelines to diagnosis and overall experience.

Methods: A qualitative approach was used. In-depth, semi-structured interviews with patients with cancer (n = 18) and patient relatives (n = 5) were conducted and subjected to a thematic analysis.

Findings: Participants struggled emotionally in the diagnostic period. Relevant to their experience were: potentially avoidable delays, concerns about health status, and misunderstood investigation process. Participants emphasized the importance of their active involvement in the care process, and had unmet supportive care needs.

Conclusion: Psychosocial supports available to potential cancer patients and their families are minimal, and may be important for improved experiences before diagnosis. Access to other patients' lived experiences with the diagnostic process and with cancer, and an enhanced supportive role of family doctors might help improve experiences for patients and families in the interval before receiving a diagnosis of cancer, which may have a significant impact on wellbeing.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239374PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7514000PMC
November 2020

Impact of Cumulative Chemotherapy Dose on Survival With Adjuvant FEC-D Chemotherapy for Breast Cancer.

J Natl Compr Canc Netw 2019 08;17(8):957-967

Department of Oncology, University of Calgary, Tom Baker Cancer Centre, Calgary, Alberta.

Background: Reductions in adjuvant chemotherapy dose <85% for historical regimens (ie, cyclophosphamide/methotrexate/fluorouracil) are known to affect breast cancer survival. This threshold, in addition to early versus late dose reductions, are poorly defined for third-generation anthracycline/taxane-based chemotherapy. In patients with breast cancer receiving adjuvant 5-fluorouracil/epirubicin/cyclophosphamide followed by docetaxel (FEC-D), we evaluated the impact of chemotherapy total cumulative dose (TCD), and early (FEC) versus late (D only) dose reductions, on survival outcomes.

Patients And Methods: Women with stage I-III, hormone receptor-positive/negative, HER2-negative breast cancer treated with adjuvant FEC-D chemotherapy from 2007 through 2014 in Alberta, Canada, were included. TCD for cycles 1 to 6 of <85% or ≥85% was calculated. Average cumulative dose was also calculated for early (cycles 1-3) and late (cycles 4-6) chemotherapy. Survival outcomes (disease-free survival [DFS] and overall survival [OS]) were estimated using Kaplan-Meier and multivariate analysis. Cohorts were evaluated for uniformity.

Results: Characteristics were reasonably balanced for all cohorts. Overall, 1,302 patients were evaluated for dose reductions, with 16% being reduced <85% (n=202) relative to ≥85% (n=1,100; 84%). Patients who received TCD ≥85% relative to <85% had superior 5-year DFS (P=.025) and OS (P<.001) according to Kaplan-Meier analysis, which remained significant on univariate and multivariate analyses. In stratified late and early dose reduction cohorts, DFS and OS showed a significant inferior survival trend for dose reduction early in treatment administration in 5-year Kaplan-Meier (P=.002 and P<.001, respectively) and multivariate analyses (hazard ratio [HR], 1.46; P=.073, and HR, 1.77; P=.011, respectively). Dose delays of <14 or ≥14 days and granulocyte colony-stimulating factor use did not affect outcomes.

Conclusions: Chemotherapy TCD <85% for adjuvant FEC-D affects breast cancer survival. Late reductions (D only) were not shown to adversely affect DFS or OS. Conversely, early reductions (FEC±D) negatively affected patient outcomes.
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http://dx.doi.org/10.6004/jnccn.2019.7286DOI Listing
August 2019

Outcomes of Consecutively Diagnosed Primary Central Nervous System Lymphoma Patients Using the Alberta Lymphoma Clinical Practice Guideline Incorporating Thiotepa-Busulfan Conditioning for Transplantation-Eligible Patients.

Biol Blood Marrow Transplant 2019 08 6;25(8):1505-1510. Epub 2019 Apr 6.

Departments of Oncology and Medicine, University of Calgary, Calgary, Alberta, Canada.

While no widely accepted standard treatment regimen exists for primary central nervous system lymphoma (PCNSL), growing evidence supports an approach that incorporates autologous stem cell transplantation (ASCT) as consolidative therapy when feasible. In November 2011, the Alberta Hematology Tumor Team established a new clinical practice guideline (CPG) for PCNSL involving high-dose methotrexate (HDMTX)/cytarabine-based induction followed by ASCT for eligible patients using a thiotepa and busulfan (TBu) conditioning regimen that omitted cyclophosphamide from the regimen that was used before 2011. This retrospective study analyzed all 64 patients with PCNSL diagnosed consecutively in 3 Canadian centers between November 2011 and December 2017 to evaluate adherence to the 2011 CPG and associated outcomes. Of the 64 patients with PCNSL, 38 were initiated on the transplantation-eligible protocol, of whom 30 underwent successful ASCT, and 26 were deemed transplantation-ineligible, of whom only 7 completed the transplantation-ineligible HDMTX-based protocol. For the transplantation-eligible and -ineligible cohorts, the projected 3-year overall survival (OS) rates were 83.8% and 14.3% and progression-free survival (PFS) rates were 78.1% and 0%, respectively. For the 30 patients who underwent TBu/ASCT, the 3-year OS and PFS rates were 92.7% and 88.9%, respectively, with no treatment-related mortality or significant neurotoxicity. These real-world results highlight the efficacy and tolerability of TBu/ASCT consolidation for PCNSL in patients young and fit enough for an intensive treatment program, along with the significant need for improved therapies for older or less fit patients with PCNSL.
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http://dx.doi.org/10.1016/j.bbmt.2019.04.004DOI Listing
August 2019

Autologous transplantation as consolidation for high risk aggressive T-cell non-Hodgkin lymphoma: a SWOG 9704 intergroup trial subgroup analysis.

Leuk Lymphoma 2019 08 10;60(8):1934-1941. Epub 2019 Jan 10.

a Cardinal Bernardin Cancer Center, Loyola University Medical Center , Maywood , IL , USA.

Phase II data suggest a benefit to autotransplantation for aggressive T-cell non-Hodgkin lymphoma (T-NHL) in first remission; randomized trials have yet to validate this. We performed a retrospective analysis of aggressive T-NHL patients in the intergroup randomized consolidative autotransplant trial (SWOG 9704). Of the 370 enrolled, 40 had T-NHL: 12 were not randomized due to ineligibility ( = 1), choice ( = 2), or progression ( = 9), leaving 13 randomized to control and 15 to autologous stem cell transplantation (ASCT). Two ASCT patients refused transplant and one failed mobilization. The 5-year landmark PFS/OS estimates for ASCT vs. control groups were 40% vs. 38% ( = .56), and 40% vs. 45% ( = .98), respectively. No difference was seen based on IPI, or histologic subtype. Only 1/7 receiving BCNU-based therapy survived vs. 4/5 receiving TBI. Aggressive T-NHL autotransplanted in first remission did not appear to benefit from consolidative ASCT. This and the 30% who dropped out pre-randomization mostly to progression, suggests that improved induction regimens be developed.
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http://dx.doi.org/10.1080/10428194.2018.1563691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620162PMC
August 2019

The Adverse Consequences of Initial Watchful Waiting for Patients With Follicular Lymphoma.

Clin Lymphoma Myeloma Leuk 2018 12 29;18(12):829-835. Epub 2018 Aug 29.

Departments of Oncology and Medicine, University of Calgary, Tom Baker Cancer Centre, Calgary, AB, Canada.

Background: Patients with low tumor burden follicular lymphoma (FL) are commonly managed with watchful waiting (WW). The incidence of organ dysfunction and/or transformation at disease progression, and subsequent impact on outcomes is poorly understood.

Patients And Methods: Patients managed with WW during 1994 to 2011 were identified through the Alberta Lymphoma Database. Individuals receiving immediate rituximab (R)-chemotherapy were identified as a comparator group to those on WW who received R-chemotherapy at progression. Endpoints included transformation, organ dysfunction, time to progression, time to next treatment, progression-free survival (PFS) after chemotherapy, and overall survival (OS).

Results: We identified 238 patients managed with WW (28.9% of registry patients) during this 17-year period. The median follow up was 8.2 years. At a median of 29.9 months, 58 (24.4%) of these patients developed organ dysfunction and/or transformation. Of 169 (71%) patients who required therapy, 10-year OS was inferior for those with transformation (hazard ratio, 2.88; P = .002) and organ dysfunction (hazard ratio, 2.10; P = .028). PFS after R-chemotherapy and OS in patients without organ dysfunction and/or transformation was not affected by the initial WW period, compared with immediate R-chemotherapy. WW resulted in increased high risk FL International Prognostic Index scores at initiation of R-chemotherapy (45% vs. 20%), and more frequent transformation at progression (5-year risk, 17.8% vs. 3.5%; P < .001). Baseline characteristics did not predict organ dysfunction.

Conclusion: Patients with FL accepting initial WW should be aware of the 1 in 4 risk of organ dysfunction and/or transformation, and subsequent inferior OS. Physicians should consider surveillance for progression to consider early therapy.
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http://dx.doi.org/10.1016/j.clml.2018.08.015DOI Listing
December 2018

Autologous transplantation improves survival rates for follicular lymphoma patients who relapse within two years of chemoimmunotherapy: a multi-center retrospective analysis of consecutively treated patients in the real world.

Leuk Lymphoma 2019 01 3;60(1):133-141. Epub 2018 Jul 3.

a Department of Oncology and Medicine , University of Calgary and Tom Baker Cancer Centre , Calgary , Alberta , Canada.

Although chemoimmunotherapy improves outcomes for patients with follicular lymphoma (FL), approximately 20% of patients experience early disease progression within two years of treatment and subsequently poor median survival. We conducted a retrospective study to evaluate survival rates of patients with early relapse who were treated with or without autologous transplantation. Of 517 patients with FL and who received chemoimmunotherapy, 152 relapsed and survived a minimum of four months after progression, including 84 (55.3%) with early relapse ≤2 years following initial therapy and 68 (44.7%) with later relapse. Five-year survival was superior for patients who received autologous transplantation compared to non-transplanted patients within the early relapse group (85.4% vs 57.9%, p = .001), but not within the late relapse group (p = .64). Given the limitations of a retrospective study, our study may suggest that the use of autologous transplantation for FL patients who relapse within two years of initial chemoimmunotherapy is associated with improved survival.
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http://dx.doi.org/10.1080/10428194.2018.1473576DOI Listing
January 2019

Epstein-barr virus DNAemia monitoring for the management of post-transplant lymphoproliferative disorder.

Cytotherapy 2018 05 23;20(5):706-714. Epub 2018 Mar 23.

University of Calgary, Calgary, Alberta, Canada.

Background: Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication of allogeneic hematopoietic cell transplantation (HCT). Epstein-Barr virus (EBV) reactivation (detectable DNAemia) predisposes to the development of PTLD.

Methods: We retrospectively studied 306 patients monitored for EBV DNAemia after Thymoglobulin-conditioned HCT to determine the utility of the monitoring in the management of PTLD. DNAemia was monitored weekly for ≥12 weeks post-transplantation.

Results: Reactivation was detected in 82% of patients. PTLD occurred in 14% of the total patients (17% of patients with reactivation). PTLD was treated with rituximab only when and if the diagnosis was established. This allowed us to evaluate potential DNAemia thresholds for pre-emptive therapy. We suggest 100,000-500,000 IU per mL whole blood as this would result in unnecessary rituximab administration to only 4-20% of patients and near zero mortality due to PTLD. After starting rituximab (for diagnosed PTLD), sustained regression of PTLD occurred in 25/25 (100%) patients in whom DNAemia became undetectable. PTLD progressed or relapsed in 12/17 (71%) patients in whom DNAemia was persistently detectable.

Discussion: In conclusion, for pre-emptive therapy of PTLD, we suggest threshold DNAemia of 100,000-500,000 IU/mL. Persistently detectable DNAemia after PTLD treatment with rituximab appears to have 71% positive predictive value and 100% negative predictive value for PTLD progression/relapse.
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http://dx.doi.org/10.1016/j.jcyt.2018.02.367DOI Listing
May 2018

Risk factors for post-transplant lymphoproliferative disorder after Thymoglobulin-conditioned hematopoietic cell transplantation.

Clin Transplant 2018 01 1;32(1). Epub 2017 Dec 1.

University of Calgary, Calgary, AB, Canada.

Epstein-Barr virus (EBV)-induced post-transplant lymphoproliferative disorder (PTLD) occurs frequently when rabbit antithymocyte globulin (ATG) is used in hematopoietic cell transplant (HCT) conditioning. We retrospectively studied 554 patients undergoing ATG-conditioned myeloablative HCT. Strategies used to minimize mortality due to PTLD were either therapy of biopsy-diagnosed PTLD in the absence of EBV DNAemia monitoring (n = 266) or prompt therapy of presumed PTLD (based on clinical/radiologic signs and high EBV DNAemia, in the setting of weekly EBV DNAemia monitoring) (n = 199). Both strategies resulted in similar mortality due to PTLD (0.7% vs 1% at 2 years, P = .43) and similar overall survival (63% vs 67% at 2 years, P = .23) even though there was a trend toward higher PTLD incidence with the prompt therapy. Donor positive with recipient negative EBV (D+R-) serostatus was a risk factor for developing PTLD. Older patient age, HLA-mismatched donor, and graft-versus-host disease were not associated with increased risk of PTLD. In summary, in ATG-conditioned HCT, D+R- serostatus, but not older age, mismatched donor or GVHD is a risk factor for developing PTLD. EBV DNAemia monitoring may be a weak risk factor for developing/diagnosing PTLD; the monitoring coupled with prompt therapy does not improve survival.
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http://dx.doi.org/10.1111/ctr.13150DOI Listing
January 2018

A bioclinical prognostic model using MYC and BCL2 predicts outcome in relapsed/refractory diffuse large B-cell lymphoma.

Haematologica 2018 02 2;103(2):288-296. Epub 2017 Nov 2.

University of Calgary, AB, Canada

The objective of this study was to create a bioclinical model, based on clinical and molecular predictors of event-free and overall survival for relapsed/refractory diffuse large B-cell lymphoma patients treated on the Canadian Cancer Trials Group (CCTG) LY12 prospective study. In 91 cases, sufficient histologic material was available to create tissue microarrays and perform immunohistochemistry staining for CD10, BCL6, MUM1/IRF4, FOXP1, LMO2, BCL2, MYC, P53 and phosphoSTAT3 (pySTAT3) expression. Sixty-seven cases had material sufficient for fluorescent hybridization (FISH) for and In addition, 97 formalin-fixed, paraffin-embedded tissue samples underwent digital gene expression profiling (GEP) to evaluate , and expression, and to determine cell-of-origin (COO) using the Lymph2Cx assay. No method of determining COO predicted event-free survival (EFS) or overall survival (OS). Factors independently associated with survival outcomes in multivariate analysis included primary refractory disease, elevated serum lactate dehydrogenase (LDH) at relapse, and MYC or BCL2 protein or gene expression. A bioclinical score using these four factors predicted outcome with 3-year EFS for cases with 0-1 2-4 factors of 55% 16% (<0.0001), respectively, assessing MYC and BCL2 by immunohistochemistry, 46% vs. 5% (<0.0001) assessing and messenger ribonucleic acid (mRNA) by digital gene expression, and 42% 21% (=0.079) assessing and by FISH. This proposed bioclinical model should be further studied and validated in other datasets, but may discriminate relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients who could benefit from conventional salvage therapy from others who require novel approaches. The LY12 study; .
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http://dx.doi.org/10.3324/haematol.2017.179309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792273PMC
February 2018

Targeting non-Hodgkin lymphoma with blinatumomab.

Expert Opin Biol Ther 2017 08 1;17(8):1013-1017. Epub 2017 Jun 1.

b Departments of Medicine and Oncology , University of Calgary and Tom Baker Cancer Centre , Calgary , Canada.

Introduction: Management of patients with relapsed or refractory non-Hodgkin lymphoma (NHL) remains challenging, and novel effective agents are eagerly awaited. Blinatumomab is a bispecific T-cell engager, targeting CD19. While blinatumomab's primary clinical use has been in B-cell acute lymphoblastic leukemia (B-ALL), there are increasing data for its use in B-lineage lymphomas. Areas covered: The aim of this review is to highlight the clinical data for blinatumomab use in NHL. Herein, the authors provide an overview of blinatumomab, its mechanism of action, its proven efficacy against B-ALL, and its phase I-II data assessing its use in NHL Expert opinion: Blinatumomab has modest activity in phase I-II trials in NHL, and may represent a means of bridging patients with relapsed disease to hematopoietic stem cell transplant. More widespread use is currently hampered by lack of phase III data, multiple competing agents, an onerous administration schedule and significant side effect profile. Further studies are eagerly awaited assessing its use in combination with other immunotherapy strategies.
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http://dx.doi.org/10.1080/14712598.2017.1334053DOI Listing
August 2017

Incidence of late onset neutropenia associated with rituximab use in B cell lymphoma patients undergoing autologous stem cell transplantation.

J Oncol Pharm Pract 2018 Jul 30;24(5):323-331. Epub 2017 Mar 30.

4 Department of Oncology, University of Calgary and Tom Baker Cancer Centre, Calgary, Canada.

Reversible late onset neutropenia associated with rituximab has been reported with incidence rates varying from 15 to 70% in B cell lymphoma patients receiving autologous stem cell transplantation. We conducted a retrospective descriptive study at one tertiary care center in adult B cell lymphoma patients treated with rituximab and autologous stem cell transplantation between 1 January 2004 and 30 June 2014. Late onset neutropenia was defined as an absolute neutrophil count <1.0 × 10 cells/L after neutrophil engraftment and less than six months post autologous stem cell transplantation. The primary objective was to determine the incidence of late onset neutropenia. The secondary objectives were to examine whether the use of rituximab with re-induction therapy, mobilization or high dose chemotherapy regimens increased the risk for late onset neutropenia, and to evaluate infectious complications. Of 315 subjects, 92 (29.2%) developed late onset neutropenia. Mobilization regimens containing rituximab (OR 2.90 95% CI: 1.31-6.40), high dose chemotherapy containing rituximab (OR 1.87 95% CI: 1.14-3.05), and exposure to rituximab in either or both regimens (OR 3.05 95% CI: 1.36-6.88) significantly increased the risk of late onset neutropenia. While neutropenic, 17.4% experienced an infection, 7.6% experienced febrile neutropenia, and 5.4% were hospitalized. In conclusion, rituximab with mobilization or high dose chemotherapy may increase the risk of late onset neutropenia post autologous stem cell transplantation.
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http://dx.doi.org/10.1177/1078155217702214DOI Listing
July 2018

Impact of Donor and Recipient Cytomegalovirus Serostatus on Outcomes of Antithymocyte Globulin-Conditioned Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2016 09 28;22(9):1654-1663. Epub 2016 May 28.

Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Alberta Bone Marrow and Blood Cell Transplant Program, Alberta Health Services, Edmonton, Alberta, Canada.

Although previous studies involving allogeneic hematopoietic cell transplantation (HCT) without in vivo T cell depletion by rabbit antithymocyte globulin (ATG) have reported a substantial survival difference between D-R- and D+R- patients, but little to no survival difference between D-R+ and D+R+ patients (D, donor; R, recipient; +, cytomegalovirus [CMV] seropositive; -, CMV seronegative), whether this applies to HCT using ATG is unknown. We studied 928 patients who underwent myeloablative HCT for hematologic malignancies in Alberta between 1999 and 2014 who received graft-versus-host disease (GVHD) prophylaxis using ATG (Thymoglobulin, 4.5 mg/kg) in addition to methotrexate and cyclosporine. D-R- and D+R- patients had similar survival (no significant difference). D-R+ patients had a substantially lower survival than D+R+ patients (41% versus 59% at 5 years; P = .001). This difference was attributed to higher nonrelapse mortality, apparently due to higher GVHD-associated mortality. Survival rates were also lower for D-R+ HLA-matched sibling transplant recipients compared with D+R+ HLA-matched unrelated donor transplant recipients (44% versus 66% at 5 years; P = .009). In conclusion, when using ATG, choosing a seronegative donor for a seronegative patient is relatively unimportant, whereas choosing a seropositive donor for a seropositive patient is important, even if this requires the use of a seropositive matched unrelated donor graft.
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http://dx.doi.org/10.1016/j.bbmt.2016.05.020DOI Listing
September 2016

Quantifying Benefit of Autologous Transplantation for Relapsed Follicular Lymphoma Patients via Instrumental Variable Analysis.

Biol Blood Marrow Transplant 2016 May 16;22(5):941-8. Epub 2016 Jan 16.

Departments of Oncology and Medicine, University of Calgary and Tom Baker Cancer Centre, Calgary, Alberta, Canada. Electronic address:

The role of autologous stem cell transplantation (ASCT) in patients with relapsed follicular lymphoma (FL) remains controversial because of a lack of proven overall survival (OS) benefit versus nontransplant strategies. We conducted a comparative effectiveness research study involving 3 tertiary Canadian cancer centers to determine whether the ASCT-based approach used at 1 center improved OS relative to non-ASCT approaches used at the other centers. Of 1082 consecutive patients aged 18 to 60 years and diagnosed with FL from 2001 to 2010, the study population included 355 patients who experienced relapse from chemotherapy (center A = 96, center B = 84, center C = 175). Data were analyzed according to the instrumental variable of treatment center to control for confounding factors. The frequency of using ASCT at first or second relapse was significantly different between the centers (A = 58%, B = 7%, C = 5%, P < .001). With a median follow-up of 69.1 months, the actuarial 5-year OS rates after first chemotherapy relapse were 89%, 60%, and 60% for centers A, B, and C respectively (log rank P < .0001). Based on instrumental variable analysis, the use of ASCT at relapse 1 or 2 significantly decreased the risk of death from first relapse (HR .127, P = .004) and from initial diagnosis (HR .116, P = .004). In conclusion, for FL patients who relapse after chemotherapy, these results strongly support more frequent use of ASCT at first or second relapse.
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http://dx.doi.org/10.1016/j.bbmt.2016.01.015DOI Listing
May 2016

Low Counts of B Cells, Natural Killer Cells, Monocytes, Dendritic Cells, Basophils, and Eosinophils are Associated with Postengraftment Infections after Allogeneic Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2016 Jan 9;22(1):37-46. Epub 2015 Sep 9.

Department of Medicine, University of Calgary, Calgary, Alberta, Canada.

Hematopoietic cell transplant (HCT) recipients are immunocompromised and thus predisposed to infections. We set out to determine the deficiency of which immune cell subset(s) may predispose to postengraftment infections. We determined day 28, 56, 84, and 180 blood counts of multiple immune cell subsets in 219 allogeneic transplant recipients conditioned with busulfan, fludarabine, and Thymoglobulin. Deficiency of a subset was considered to be associated with infections if the low subset count was significantly associated with subsequent high infection rate per multivariate analysis in both discovery and validation cohorts. Low counts of monocytes (total and inflammatory) and basophils, and low IgA levels were associated with viral infections. Low plasmacytoid dendritic cell (PDC) counts were associated with bacterial infections. Low inflammatory monocyte counts were associated with fungal infections. Low counts of total and naive B cells, total and CD56(high) natural killer (NK) cells, total and inflammatory monocytes, myeloid dendritic cells (MDCs), PDCs, basophils and eosinophils, and low levels of IgA were associated with any infections (due to any pathogen or presumed). In conclusion, deficiencies of B cells, NK cells, monocytes, MDCs, PDCs, basophils, eosinophils, and/or IgA plasma cells appear to predispose to postengraftment infections.
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http://dx.doi.org/10.1016/j.bbmt.2015.09.003DOI Listing
January 2016

Concomitant high expression of Toll-like receptor (TLR) and B-cell receptor (BCR) signalling molecules has clinical implications in mantle cell lymphoma.

Hematol Oncol 2017 Mar 10;35(1):79-86. Epub 2015 Sep 10.

Division of Hematology and Transfusion Medicine, Department of Pathology and Laboratory Medicine, University of Calgary/Calgary Laboratory Services (CLS), Calgary, Alberta, Canada.

Mantle cell lymphoma (MCL) is an aggressive disease with frequent relapse. Targeted therapies against B-cell receptor (BCR) molecules have demonstrated improved outcomes in relapsed cases. However, clinical responses are slow and selective, with failure to attain complete remission in a significant subset of patients. Complex interaction of BCR signal transduction with toll-like receptor (TLR) and other pathways in MCL remains unknown, thus averting progress in development of targeted therapies. We have performed detailed digital quantification of BCR/TLR signalling molecules and their effector pathways in a cohort (n = 81) of MCL patients and correlated these data with overall survival. Hierarchical clustering model based on BCR/TLR genes revealed two distinct (BCR and BCR ) subsets of patients (n = 32; 40%) with significant differences in expression (>1.5-fold change; p < 0.05). Higher levels of BTK/SYK/BLNK/CARD11/PLCG signalosome and lower expression of MALT1/BCL10 genes suggested tonic pattern of BCR activation. Amplified expression of TLR6/TLR7/TLR9 was noted in concert with hyper-responsiveness of BCR machinery. MYD88, a key TLR adaptor molecule, was not upregulated in any of these clusters, which may suggest a 'cross-talk' between BCR and TLR pathways. In sync with BCR/TLR signalling, we recorded significantly enhanced expression of genes associated with NF-kB pathway in BCR subset of MCL patients. On univariate analysis, the BCR patients showed a trend towards inferior clinical response to a standardized treatment protocol, compared with the BCR group (log rank, p = 0.043). In conclusion, we have identified hyperactive BCR/TLR signalling pathways and their effector downstream targets in a subset of MCL patients and associated it with poor clinical outcomes. Our study provides quantitative evidence at RNA expression level of possible concomitant collaboration between TLR and BCR signalling molecules in MCL. These data will provide further insights for future functional studies and, hence, development of targeted therapies for MCL patients. Copyright © 2015 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/hon.2251DOI Listing
March 2017

Evaluation of the International Prognostic Score (IPS-7) and a Simpler Prognostic Score (IPS-3) for advanced Hodgkin lymphoma in the modern era.

Br J Haematol 2015 Nov 7;171(4):530-8. Epub 2015 Sep 7.

Stanford University, Stanford, CA, USA.

The International Prognostic Score (IPS-7) is the most commonly used risk stratification tool for advanced Hodgkin lymphoma (HL), however recent studies suggest the IPS-7 is less discriminating due to improved outcomes with contemporary therapy. We evaluated the seven variables for IPS-7 recorded at study entry for 854 patients enrolled on Eastern Cooperative Oncology Group 2496 trial. Univariate and multivariate Cox models were used to assess their prognostic ability for freedom from progression (FFP) and overall survival (OS). The IPS-7 remained prognostic however its prognostic range has narrowed. On multivariate analysis, two factors (age, stage) remained significant for FFP and three factors (age, stage, haemoglobin level) for OS. An alternative prognostic index, the IPS-3, was constructed using age, stage and haemoglobin level, which provided four distinct risk groups [FFP (P = 0·0001) and OS (P < 0·0001)]. IPS-3 outperformed the IPS-7 on risk prediction for both FFP and OS by model fit and discrimination criteria. Using reclassification calibration, 18% of IPS-7 low risk patients were re-classified as intermediate risk and 13% of IPS-7 intermediate risk patients as low risk. For patients with advanced HL, the IPS-3 may provide a simpler and more accurate framework for risk assessment in the modern era. Validation of these findings in other large data sets is planned.
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http://dx.doi.org/10.1111/bjh.13634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881845PMC
November 2015

Obinutuzumab for the treatment of patients with previously untreated chronic lymphocytic leukemia: overview and perspective.

Ther Adv Hematol 2015 Aug;6(4):161-70

Departments of Medicine and Oncology, University of Calgary, Alberta, Canada.

Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder in the Western world and predominantly affects older people. Until recently, most studies in CLL focused on younger patients in whom intensive therapy with the addition of rituximab to fludarabine and cyclophosphamide was shown to improve survival. Obinutuzumab is a novel type II anti-CD20 monoclonal antibody (mAb) that recently demonstrated an overall survival advantage when combined with chemotherapy in previously untreated older patients with CLL and comorbidities. Obinutuzumab was superior to rituximab in this same study in terms of response rates and progression-free survival. Several preclinical and early phase clinical studies also support the efficacy of obinutuzumab. The most frequent adverse event noted with obinutuzumab is infusion-related reactions, which occur more frequently than with rituximab and are typically restricted to the first cycle of therapy. Based on these results, obinutuzumab should be considered the gold standard mAb for combination with chemotherapy in previously untreated patients with CLL and comorbidities. The marked efficacy of obinutuzumab with a weak chemotherapy backbone implies significant potency of this mAb, making it the ideal partner for combination studies with other agents in CLL.
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http://dx.doi.org/10.1177/2040620715586528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530370PMC
August 2015

CD10-positive mantle cell lymphoma: biologically distinct entity or an aberrant immunophenotype? Insight, through gene expression profile in a unique case series.

J Clin Pathol 2015 Oct 29;68(10):844-8. Epub 2015 Jun 29.

Division of Hematology and Transfusion Medicine, Department of Pathology and Laboratory Medicine, University of Calgary/Calgary Laboratory Services (CLS), Calgary, Alberta, Canada.

Background: Mantle cell lymphoma (MCL) is an aggressive disease with genetic heterogeneity and discrete clinical subtypes. MCL is rarely CD10 positive. These cases raise the question whether a subset of MCL may be germinal centre (GC) derived, and have distinct clinicopathological characteristics.

Aims And Methods: A series of nine CD10-positive MCL cases is described herein. The clinicopathological and immunophenotypic features, immunoglobulin somatic hypermutation (SHM) status and gene expression profile (GEP) data are detailed. These features were compared with two independent sets (n=20, each) of CD10-negative MCL cases (controls), which were randomly selected from our institutional registry.

Results: GEP showed distinct expression of a GC signature in CD10-positive MCL cases with minimal impact on downstream signalling pathways. There were no significant differences in the clinicopathological features or clinical outcome between our CD10-positive and CD10-negative MCL cases. The frequency of SHM was comparable with established data.

Conclusions: This study provides convincing evidence that CD10 expression is related to a distinct GC signature in MCL cases, but without clinical or biological implications.
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http://dx.doi.org/10.1136/jclinpath-2015-202955DOI Listing
October 2015

Randomized Phase III Trial Comparing ABVD Plus Radiotherapy With the Stanford V Regimen in Patients With Stages I or II Locally Extensive, Bulky Mediastinal Hodgkin Lymphoma: A Subset Analysis of the North American Intergroup E2496 Trial.

J Clin Oncol 2015 Jun 20;33(17):1936-42. Epub 2015 Apr 20.

Ranjana H. Advani, Richard T. Hoppe, and Sandra J. Horning, Stanford University, Stanford; Joseph M. Tuscano, University of California, Davis Cancer Center, Sacramento, CA; Fangxin Hong, Dana-Farber Cancer Institute, Boston, MA; Richard I. Fisher and Jonathan W. Friedberg, University of Rochester, Rochester, NY; Nancy L. Bartlett, Washington University School of Medicine, St Louis, MO; K. Sue Robinson, Queen Elizabeth II Health Science Center, Halifax, Nova Scotia; Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia; Douglas A. Stewart, Tim Baker Cancer Institute, Calgary, Alberta, Canada; Henry Wagner Jr, Penn State Cancer Institute, Hershey, PA; Patrick J. Stiff, Loyola University Medical Center, Maywood; Leo I. Gordon, Northwestern University, Chicago, IL; Bruce D. Cheson, Georgetown University Hospital, Washington, DC; Brad S. Kahl, University of Wisconsin, Madison, WI; Kristie A. Blum, Ohio State University, Columbus, OH; and Thomas M. Habermann, Mayo Clinic, Rochester, MN.

Purpose: The phase III North American Intergroup E2496 Trial (Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With Hodgkin's Lymphoma) compared doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with mechlorethamine, doxorubicin, vincristine, bleomycin, vinblastine, etoposide, and prednisone (Stanford V). We report results of a planned subgroup analysis in patients with stage I or II bulky mediastinal Hodgkin lymphoma (HL).

Patients And Methods: Patients were randomly assigned to six to eight cycles of ABVD every 28 days or Stanford V once per week for 12 weeks. Two to 3 weeks after completion of chemotherapy, all patients received 36 Gy of modified involved field radiotherapy (IFRT) to the mediastinum, hila, and supraclavicular regions. Patients on the Stanford V arm received IFRT to additional sites ≥ 5 cm at diagnosis. Primary end points were failure-free survival (FFS) and overall survival (OS).

Results: Of 794 eligible patients, 264 had stage I or II bulky disease, 135 received ABVD, and 129 received Stanford V. Patient characteristics were matched. The overall response rate was 83% with ABVD and 88% with Stanford V. At a median follow-up of 6.5 years, the study excluded a difference of more than 21% in 5-year FFS and more than 16% in 5-year OS between ABVD and Stanford V (5-year FFS: 85% v 79%; HR, 0.68; 95% CI, 0.37 to 1.25; P = .22; 5-year OS: 96% v 92%; HR, 0.49; 95% CI, 0.16 to 1.47; P = .19). In-field relapses occurred in < 10% of the patients in each arm.

Conclusion: For patients with stage I or II bulky mediastinal HL, no substantial statistically significant differences were detected between the two regimens, although power was limited. To the best of our knowledge, this is the first prospective trial reporting outcomes specific to this subgroup, and it sets a benchmark for comparison of ongoing and future studies.
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http://dx.doi.org/10.1200/JCO.2014.57.8138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451176PMC
June 2015

Treatment of patients with secondary central nervous system lymphoma with high-dose busulfan/thiotepa-based conditioning and autologous stem cell transplant.

Leuk Lymphoma 2016 27;57(1):28-33. Epub 2015 Mar 27.

a Department of Oncology and Medicine , University of Calgary, Tom Baker Cancer Centre , Calgary , AB , Canada.

Although the survival rates are extremely low for patients with secondary central nervous system lymphoma (SCNSL) treated with conventional chemotherapy and radiotherapy, more encouraging outcomes have recently been reported in small series with high-dose (HD) therapy and autologous stem cell transplant (ASCT). The optimal HD regimen for SCNSL is unknown. Despite reports of thiotepa/busulfan-based conditioning for primary CNS lymphoma, very little data exist regarding the use of this regimen for SCNSL. We analyzed 23 patients with SCNSL (median age 62 years) who underwent ASCT at two Alberta centers using thiotepa, busulfan, cyclophosphamide (TBC) in six patients prior to 2011 and rituximab-busulfan, melphalan, thiotepa (R-BuMelTt) in 17 patients after 2011. At a median follow-up of 27.8 months (4.2-113.6), the 2-year actuarial rate of progression-free survival was 76.1%. In conclusion, our results demonstrate encouraging survival outcomes for patients with SCNSL treated with R-BuMelTt and ASCT.
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http://dx.doi.org/10.3109/10428194.2015.1026901DOI Listing
October 2016

Comparative effectiveness analysis of different salvage therapy intensities used for diffuse large B-cell lymphoma in Northern or Southern Alberta: an instrumental variable analysis.

Leuk Lymphoma 2015 Jun 3;56(6):1756-62. Epub 2014 Nov 3.

Department of Oncology and Medicine, University of Calgary, Tom Baker Cancer Centre , Calgary, AB , Canada.

To date, no clinical trial has addressed salvage therapy intensity for relapsed/refractory diffuse large B-cell lymphoma (DLBCL). We sought to determine whether the more intensive salvage chemotherapy approach used in Southern Alberta (SAB) compared to the conventional dose salvage approach used in Northern Alberta (NAB) affects the rates of autologous stem cell transplant (ASCT) and survival in patients with relapsed DLBCL. Using instrumental variable analysis, we examined 147 consecutive patients with relapsed/refractory DLBCL from 2004 to 2010 who received salvage therapy in SAB (n = 70) or NAB (n = 77). Patients treated in SAB had higher rates of: salvage chemotherapy response (85.0% vs. 54.0%, p = 0.001), ASCT (61.4% vs. 41.6%, p = 0.016) and 4-year overall survival (41% vs. 20%, p = 0.002) than those in NAB, respectively. This study supports the hypothesis that selective use of intensive salvage chemotherapy leads to higher rates of ASCT and survival in this population.
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http://dx.doi.org/10.3109/10428194.2014.971409DOI Listing
June 2015

Favorable outcomes from allogeneic and autologous stem cell transplantation for patients with transformed nonfollicular indolent lymphoma.

Biol Blood Marrow Transplant 2014 Nov 18;20(11):1813-8. Epub 2014 Jul 18.

Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

The role of allogeneic (allo-) and autologous stem cell transplantation (auto-SCT) in the management of patients with transformed indolent nonfollicular non-Hodgkin lymphoma is unknown. This is a multicenter, retrospective cohort study of patients with biopsy-proven indolent B cell nonfollicular non-Hodgkin lymphoma and simultaneous or subsequent biopsy-proven aggressive histology transformation who were treated with allo-SCT or auto-SCT between 1996 and 2013. All patients received myeloablative conditioning regimens. Outcomes were compared with a cohort of 246 patients with transformed follicular lymphoma who also underwent allo-SCT (n = 47) or auto-SCT (n = 199) across the same institutions and time frame. 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-SCT, whereas 33 (65%) underwent auto-SCT. The 3-year overall survival rate after transplantation was 67% (allo-SCT 54%, auto-SCT 74%), and 3-year progression-free survival rate was 49% (allo-SCT 40%, auto-SCT 54%). The 3-year nonrelapse mortality rate was 14% (allo-SCT 15%, auto-SCT 7%). Transplant-related mortality at 100 days was 17% for allo-SCT and 0% for auto-SCT. Adjusted for type of stem cell transplantation, 3-year overall survival, progression-free survival, and nonrelapse mortality rates were similar to those of patients with transformed follicular lymphoma receiving allo-SCT and auto-SCT (P = .38, P = .69, and P = .54, respectively). Allo-SCT and auto-SCT may be reasonable treatments for selected patients with transformed nonfollicular indolent lymphoma, although medium-term outcomes and toxicity appear to be more favorable with auto-SCT.
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http://dx.doi.org/10.1016/j.bbmt.2014.07.015DOI Listing
November 2014

Obinutuzumab for B-cell malignancies.

Expert Opin Biol Ther 2014 Aug 23;14(8):1197-205. Epub 2014 May 23.

University of Calgary, Tom Baker Cancer Centre, Division of Hematology and Hematological Malignancies , 603 South Tower, Foothills Medical Centre, 1403-29th St NW, Calgary, Alberta, T2N 2T9 , Canada

Introduction: We analyse data for the use of obinutuzumab in the treatment of CD20(+) lymphoproliferative disorders with a focus on chronic lymphocytic leukaemia (CLL). Targeted therapy against CD20 with the mAb rituximab led to significant improvements in survival for patients with B-cell non-Hodgkin lymphoma (NHL) and is the current mainstay of treatment for CD20(+) malignancies. Despite this, many patients relapse or become refractory after rituximab-containing therapies, so efforts have been made to develop better anti-CD20 mAbs. Obinutuzumab recently demonstrated superiority over rituximab in the only published Phase III study comparing the two antibodies.

Areas Covered: Obinutuzumab is a humanised, anti-CD20 mAb being compared to rituximab in several Phase III studies. An overview of obinutuzumab, its mechanisms of action and results of Phase I-III studies are presented.

Expert Opinion: The demonstration of superiority of obinutuzumab over rituximab in the CLL11 Phase III study is potentially practice-changing. Obinutuzumab has also proven safe and efficacious in CD20(+) NHL in Phase I/II studies and results of Phase III studies in NHL are eagerly awaited. The potential implications of improved outcomes for CLL and NHL with the introduction of this more potent anti-CD20 antibody are tremendous given the impressive results obtained after the introduction of rituximab over a decade ago.
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http://dx.doi.org/10.1517/14712598.2014.922535DOI Listing
August 2014

High serum level of antithymocyte globulin immediately before graft infusion is associated with a low likelihood of chronic, but not acute, graft-versus-host disease.

Biol Blood Marrow Transplant 2014 Aug 13;20(8):1156-62. Epub 2014 Apr 13.

University of Calgary, Alberta, Canada.

Rabbit antithymocyte globulin (ATG) is administered during transplant conditioning to decrease the risk of both acute graft-versus-host disease (aGVHD) and chronic graft-versus-host disease (cGVHD). Here we evaluated the relationship between the serum concentration of ATG (capable of binding to lymphocytes) immediately before graft infusion (day 0) or on day +7 or +28 post-transplantation and the development of aGVHD or cGVHD. We studied 180 patients whose conditioning included 4.5 mg/kg antithymocyte globulin (ATG; Thymoglobulin). For aGVHD, we found no association with ATG levels on day 0. Nevertheless, high day +7 and +28 ATG levels were associated with a low likelihood of aGVHD. For cGVHD, high ATG levels at all 3 time points (days 0, +7, and +28) were associated with a low likelihood of cGVHD. In conclusion, high-dose ATG administration at the time of graft infusion appears to inhibit the development of cGVHD, but not aGVHD; however, higher ATG levels on days +7 and +28 are associated with lower rates of both aGVHD and cGVHD.
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http://dx.doi.org/10.1016/j.bbmt.2014.04.007DOI Listing
August 2014

Prolonged progression-free survival and preserved quality of life in the Canadian prospective study of tositumomab and iodine(131)-tositumomab for previously treated, rituximab-exposed, indolent non-Hodgkin lymphoma.

Leuk Lymphoma 2014 Dec 3;55(12):2754-60. Epub 2014 Apr 3.

Centre Hospitalier de l'Université de Montréal , Montreal , Canada.

Radioimmunotherapy offers a unique treatment modality for indolent non-Hodgkin lymphoma (iNHL). We report 5-year outcomes and quality of life (QoL) in tositumomab and iodine(131)-tositumomab (TST/I(131)-TST) treated patients with iNHL previously treated with rituximab. Ninety-three patients with ≥ 2 lines of therapy, responding to last treatment, were enrolled at 12 Canadian centers. Median age, disease duration and number of prior therapies (#PTx) were 59 years, 4.9 years and 5, respectively. Outcomes were response rate (43.0%), median progression-free survival (mPFS) (12.0 months), 5-year PFS (27%) and median overall survival (OS) (59.8 months). In responders, median response duration and mPFS were not reached. Improvements in QoL were seen by week 7. In univariate and multivariate analyses, hemoglobin, disease bulk and body surface area (BSA) predicted OS, whereas lactate dehydrogenase (LDH), bulk, BSA and #PTx predicted PFS. Most common adverse events (AEs) were fatigue and nausea. Two cases of myelodysplastic syndrome (MDS) were reported. TST/I(131)-TST was associated with durable responses, and prolonged OS and PFS in heavily pretreated iNHL.
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http://dx.doi.org/10.3109/10428194.2014.894190DOI Listing
December 2014

Immune cell subset counts associated with graft-versus-host disease.

Biol Blood Marrow Transplant 2014 Apr 6;20(4):450-62. Epub 2014 Jan 6.

Department of Medicine, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.

Graft-versus-host disease (GVHD) is a major transplantation complication. The purpose of this study was to measure immune cell subsets by flow cytometry early after transplantation (before median day of GVHD onset) to identify subsets that may play a role in GVHD pathogenesis. We also measured the subsets later after transplantation to determine which subsets may be influenced by GVHD or its treatment. We studied 219 patients. We found that acute GVHD (aGVHD) was preceded by high counts of CD4 T cells and CD8 T cells. It was followed by low counts of total and naive B cells, total and cytolytic NK cells, and myeloid and plasmacytoid dendritic cells. Chronic GVHD (cGVHD) was preceded by low counts of memory B cells. In conclusion, both CD4 and CD8 T cells appear to play a role in the pathogenesis of aGVHD. Generation of B cells, NK cells, and dendritic cells may be hampered by aGVHD and/or its treatment. Memory B cells may inhibit the development of cGVHD.
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http://dx.doi.org/10.1016/j.bbmt.2014.01.002DOI Listing
April 2014

Results of a prospective phase II trial evaluating interim positron emission tomography-guided high dose therapy for poor prognosis diffuse large B-cell lymphoma.

Leuk Lymphoma 2014 Sep 17;55(9):2064-70. Epub 2014 Feb 17.

Medicine and Oncology, University of Calgary , Calgary , Canada.

Patients with diffuse large B-cell lymphoma (DLBCL) with a poor prognosis based upon advanced stage and elevated serum lactate dehydrogenase achieve a 3-4-year progression-free survival (PFS) of only 55%. The role of interim fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET) to guide use of upfront high dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT) for patients with poor prognosis DLBCL is unproven. A prospective phase II clinical trial was designed to evaluate the outcomes of HDCT/ASCT for patients with poor prognosis DLBCL aged 18-65 years who had unfavorable interim restaging PET scans. Of the 70 eligible patients, 36 had unfavorable and 34 favorable interim PET responses, with 3-year PFS rates of 65.2% and 52.7%, respectively. In conclusion, favorable interim PET response as defined in this study is not associated with improved PFS rates for patients with poor prognosis DLBCL treated with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). A phase III trial evaluating this PET-guided approach is not warranted.
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http://dx.doi.org/10.3109/10428194.2013.862242DOI Listing
September 2014
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