Publications by authors named "Stephen M Ansell"

404 Publications

Clinicopathologic Characteristics, Treatment, and Outcomes of Post-transplant Lymphoproliferative Disorders: A Single-institution Experience Using 2017 WHO Diagnostic Criteria.

Hemasphere 2021 Oct 6;5(10):e640. Epub 2021 Sep 6.

Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.

The (WHO 2017) included updated criteria for diagnosis and classification of post-transplant lymphoproliferative disorders (PTLDs). This study evaluated the clinicopathologic spectrum using WHO 2017 criteria and adult PTLD patients' outcomes over 30 years between 1987 and 2017 at Mayo Clinic (Rochester, MN). Patients were retrospectively reviewed for clinical features, outcomes, and diagnostic pathology material and classified based on WHO 2017 criteria. A total of 227 patients were diagnosed with PTLD, with a median time from transplant to PTLD of 45 months. PTLD occurred >1 year after transplant in 149 (66%) patients. Monomorphic PTLD was the most common subtype (173, 76%), with diffuse large B cell lymphoma as the commonest morphology (n = 137). Epstein-Barr virus was positive in 61% of total cases and 90% of PTLD that developed within 1 year from transplant. The median event-free survival (EFS) and overall survival for the entire cohort were 21 months (95% confidence interval [CI]: 9-35) and 82 months (95% CI: 39-115), respectively. The EFS or overall survival was not impacted by Epstein-Barr virus status but differed based on WHO subtypes and year of diagnosis. Management changed over time with increased use of rituximab or chemotherapy + immunosuppression reduction as initial therapy. When compared to the matched general population and de novo diffuse large B cell lymphoma, patients not achieving EFS 24 status (no progression/treatment or death within 24 mo of diagnosis) had a worse standardized mortality ratio 16.75 (95% CI: 13.91-20) versus SMR 1.72 (95% CI: 1.26-2.28) in those who achieved EFS24. Cause of death was mostly attributed to non-lymphoma-related causes in those achieving EFS 24.
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http://dx.doi.org/10.1097/HS9.0000000000000640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423401PMC
October 2021

Outcomes in primary cutaneous diffuse large B-cell lymphoma, leg type.

Hematol Oncol 2021 Aug 28. Epub 2021 Aug 28.

Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT) is a rare, aggressive lymphoma characterized by skin involvement predominantly in the lower extremities. Immunochemotherapy with or without involved-site radiation therapy (ISRT) is considered standard front-line therapy. Over-expression of PD-L1/PD-L2 is seen in a high proportion of PCDLBCL, LT cases, but efficacy of immune checkpoint inhibitors (ICI) in relapsed/refractory, PCDLBCL, LT has not been thoroughly studied. We conducted a retrospective cohort study of patients diagnosed with PCDLBCL, LT seen at Mayo Clinic from 1 January 2000 to 31 December 2020. Using the Kaplan-Meier method, we calculated progression-free survival, duration of response, and overall survival in patients who received front-line rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with and without ISRT, and salvage ICI therapy for relapsed/refractory disease. A total of 28 patients with PCDLBCL, LT were identified. The median PFS in patients treated with R-CHOP plus ISRT was 58 months (95% CI: 18-112) compared to 14 months (95% CI: 5-not reached; p = 0.04) in those treated with R-CHOP without ISRT. The median PFS from salvage ICI therapy was 10 months (95% CI: 4-not reached), and median DOR from salvage ICI therapy was 23 months [95% CI: 4-26]. R-CHOP with ISRT had a significantly longer median PFS compared to R-CHOP without ISRT as front-line therapy for PCDLBCL, LT. ICIs may have a role in treating relapsed/refractory disease as reasonable activity in heavily pre-treated patients was observed in this study.
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http://dx.doi.org/10.1002/hon.2919DOI Listing
August 2021

Role of the Bone Marrow Niche in Supporting the Pathogenesis of Lymphoid Malignancies.

Front Cell Dev Biol 2021 28;9:692320. Epub 2021 Jul 28.

Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, United States.

While the bone marrow (BM) microenvironment is the primary location for nurturing the multipotent hematopoietic stem cells and developing the blood cells of either myeloid or lymphoid origin under normal physiological conditions, it could provide a supportive milieu for the proliferation of blood cancer cells. In fact, the multiple and complex direct cell-to-cell or indirect soluble factors-mediated interactions taking place among the BM cells of different origins are shown to play a significant role in tumorigenesis of hematological cancers. In the current review, we focus on lymphoid malignancies and highlight the novel insights surrounding the role of both cellular as well as non-cellular BM compartments in modulating hematopoiesis and promoting growth and proliferation of cancer cells across a variety of aggressive and indolent lymphoid malignancies, including diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and Waldenstrom Macroglobulinemia. We also discuss the mechanisms of potential intervention and discuss their therapeutic impact in clinical settings.
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http://dx.doi.org/10.3389/fcell.2021.692320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355623PMC
July 2021

Disease outcomes and biomarkers of progression in smouldering Waldenström macroglobulinaemia.

Br J Haematol 2021 Aug 2. Epub 2021 Aug 2.

Division of Hematology, Mayo Clinic, Rochester, MN, USA.

Patients with asymptomatic/smouldering Waldenström macroglobulinaemia (SWM) have a variable risk of progression to active WM. Our study evaluated 143 patients with SWM consecutively seen between January 1996 and December 2013. With a median [95% confidence interval (CI)] follow-up of 9·5 [8·1-11·5] years, the cumulative rate of progression was 11% at 1 year, 38% at 3 years and 55% at 5 years. On multivariate analysis, haemoglobin (Hb) ≤123 g/l [risk ratio (RR) 2·08; P = 0·009] and β -microglobulin (β M) ≥2·7 µg/ml (RR 2·0; P = 0·01) were independent predictors of a shorter time-to-progression (TTP) to active WM. Patients with myeloid differentiation factor 88 wild type (MYD88 ) genotype (n = 11) demonstrated a trend toward shorter TTP [median (95% CI) 1·7 (0·7-8·7) vs. 4·7 (2·4-7·7) years for the MYD88 cohort, n = 42; P = 0·11]. The presence of C-X-C chemokine receptor type 4 (CXCR4) mutation (n = 29) did not impact the TTP (median: 3 years for CXCR4 vs. 5·6 years for CXCR4 , P = 0·34). The overall survival (OS) for patients with SWM (median: 18·1 years) was comparable to an age-, sex- and calendar year-matched USA population (median: 20·3 years, P = 0·502). In conclusion, Hb and β M at diagnosis represent independent predictors of progression to active WM. Comparable survival of SWM and a matched USA population argues against pre-emptive intervention in this patient population.
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http://dx.doi.org/10.1111/bjh.17691DOI Listing
August 2021

CD5+ diffuse large B-cell lymphoma: a narrative review.

Leuk Lymphoma 2021 Jul 21:1-9. Epub 2021 Jul 21.

Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity, and cell surface cluster of differentiation (CD) 5 expression may represent a distinct subset. Here, we provide a narrative review of CD5+ DLBCL to understand its clinical implications. Between 5-10% of DLBCL express CD5, making it an uncommon subset. Studies have variably shown that CD5+ DLBCL may be associated with increased age, high lactate dehydrogenase, B symptoms, extra-nodal sites, higher International Prognostic Index score, and advanced stage. CD5+ DLBCLs are more likely to express Bcl-2, MYC, and MUM1; a large proportion exhibit an activated B-cell (ABC)-like phenotype. The balance of studies generally supports an independent prognostic value of CD5 in DLBCL While more aggressive first-line regimens have been advocated for CD5+ DLBCL, including dose-adjusted R-EPOCH and autologous stem cell transplant, evidence to support these approaches is lacking; further study is warranted to identify the optimal treatment strategy for this disease entity.
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http://dx.doi.org/10.1080/10428194.2021.1953010DOI Listing
July 2021

CAR T-cell therapy in mature lymphoid malignancies: clinical opportunities and challenges.

Ann Transl Med 2021 Jun;9(12):1036

Division of Hematology-Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.

The advent of chimeric antigen receptor T-cell (CAR T-cell) therapy has revolutionized the treatment paradigm of various hematologic malignancies. Ever since its first approval for treatment of acute lymphoblastic leukemia (ALL) in 2017, CAR T-cell therapy has been found to be efficacious in various other lymphoid malignancies, with recent approvals in diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). Although CAR T-cell therapeutics offer a novel immunotherapeutic approach to treat otherwise refractory malignancies, the plethora of studies/products and complexities in manufacturing and administration have led to several challenges for clinicians and the healthcare system as a whole. Some of the areas of unmet need include manufacturing delays, short persistence of CAR T-cells in circulation, lack of predictive biomarkers for efficacy and toxicity, and high cost of therapy. In this review, we evaluate the existing data on the efficacy and safety of CAR T-cell therapies in mature lymphoid malignancies [lymphomas, chronic lymphocytic leukemia (CLL), and multiple myeloma]. We also provide an in-depth review of the challenges posed by CAR T-cell therapeutics and potential strategies to overcome them. With newer CAR T-cell products and incorporation of measures to mitigate toxicities pertaining to cytokine release and neurological syndromes, there is a potential to overcome several of these challenges in the near future. Finally, as CAR T-cell therapy gains regulatory approval for more indications, there is a need to tackle the financial toxicity posed by this modality to sustain patient access.
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http://dx.doi.org/10.21037/atm-20-5546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267254PMC
June 2021

Patterns of therapy initiation during the first decade for patients with follicular lymphoma who were observed at diagnosis in the rituximab era.

Blood Cancer J 2021 Jul 17;11(7):133. Epub 2021 Jul 17.

Division of Hematology, Mayo Clinic, Rochester, MN, USA.

Immediate treatment for asymptomatic, low-tumor burden follicular lymphoma (FL) has not shown an overall survival benefit over "watch and wait" (W/W) strategy. We estimated incidence of treatment initiation at specific time points and assessed its association with the presence of any criteria such as GELF, BNLI, GITMO at diagnosis. FL patients managed by W/W strategy were identified from the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma SPORE between 2002 and 2015. Cumulative incidence estimates of treatment initiation were calculated using transformation (as the first event) and death as competing risks. 401 FL patients were identified on W/W strategy. At a median follow-up of 8 years, 256 (64%) initiated treatment. For patients on the W/W strategy for 5 years, the likelihood of treatment initiation in the next 5 years was 12% compared to 43% at diagnosis unlike transformation rates which remained steady. Patients with any of popular treatment criteria at diagnosis did not have increased therapy initiation rates (44% vs. 42%) during the first 5 years or lymphoma-related death rates at 10 years (6% vs. 7%). Identifying biological differences in patients with early vs. late or no progression is a critical next step in understanding outcomes in W/W patients.
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http://dx.doi.org/10.1038/s41408-021-00525-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286048PMC
July 2021

Lack of intrafollicular memory CD4 + T cells is predictive of early clinical failure in newly diagnosed follicular lymphoma.

Blood Cancer J 2021 Jul 15;11(7):130. Epub 2021 Jul 15.

Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA.

Despite a characteristic indolent course, a substantial subset of follicular lymphoma (FL) patients has an early relapse with a poor outcome. Cells in the microenvironment may be a key contributor to treatment failure. We used a discovery and validation study design to identify microenvironmental determinants of early failure and then integrated these results into the FLIPI. In total, 496 newly diagnosed FL grade 1-3 A patients who were prospectively enrolled into the MER cohort from 2002 to 2012 were evaluated. Tissue microarrays were stained for CD4, CD8, FOXP3, CD32b, CD14, CD68, CD70, SIRP-α, TIM3, PD-1, and PD-L1. Early failure was defined as failing to achieve event-free survival at 24 months (EFS24) in immunochemotherapy-treated patients and EFS12 in all others. CyTOF and CODEX analysis were performed to characterize intratumoral immunophenotypes. Lack of intrafollicular CD4 expression was the only predictor of early failure that replicated with a pooled OR 2.37 (95%CI 1.48-3.79). We next developed a bio-clinical risk model (BioFLIPI), where lack of CD4 intrafollicular expression moved patients up one FLIPI risk group, adding a new fourth high-risk group. Compared with BioFLIPI score of 1, patients with a score of 2 (OR 2.17; 95% CI 1.08-4.69), 3 (OR 3.53; 95% CI 1.78-7.54), and 4 (OR 8.92; 95% CI 4.00-21.1) had increasing risk of early failure. The favorable intrafollicular CD4 T cells were identified as activated central memory T cells, whose prognostic value was independent from genetic features. In conclusion, lack of intrafollicular CD4 expression predicts early failure in FL and combined with FLIPI improves identification of high-risk patients; however, independent validation is warranted.
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http://dx.doi.org/10.1038/s41408-021-00521-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282842PMC
July 2021

High-dimensional and single-cell transcriptome analysis of the tumor microenvironment in angioimmunoblastic T cell lymphoma (AITL).

Leukemia 2021 Jul 6. Epub 2021 Jul 6.

Department of Hematology, Mayo Clinic, Rochester, MN, USA.

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive lymphoid malignancy associated with a poor clinical prognosis. The AITL tumor microenvironment (TME) is unique, featuring a minority population of malignant CD4+ T follicular helper (TFH) cells inter-mixed with a diverse infiltrate of multi-lineage immune cells. While much of the understanding of AITL biology to date has focused on characteristics of the malignant clone, less is known about the many non-malignant populations that comprise the TME. Recently, mutational consistencies have been identified between malignant cells and non-malignant B cells within the AITL TME. As a result, a significant role for non-malignant populations in AITL biology has been increasingly hypothesized. In this study, we have utilized mass cytometry and single-cell transcriptome analysis to identify several expanded populations within the AITL TME. Notably, we find that B cells within the AITL TME feature decreased expression of key markers including CD73 and CXCR5. Furthermore, we describe the expansion of distinct CD8+ T cell populations that feature an exhausted phenotype and an underlying expression profile indicative of dysfunction, impaired cytotoxicity, and upregulation of the chemokines XCL2 and XCL1.
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http://dx.doi.org/10.1038/s41375-021-01321-2DOI Listing
July 2021

Expression of KLRG1 and CD127 defines distinct CD8 subsets that differentially impact patient outcome in follicular lymphoma.

J Immunother Cancer 2021 Jul;9(7)

Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA

Background: CD8 T-lymphocyte subsets defined by killer lectin-like receptor G1 (KLRG1) and CD127 expression have been reported to have an important role in infection, but their role in the setting of lymphoid malignancies, specifically follicular lymphoma (FL), has not been studied.

Methods: To characterize the phenotype of KLRG1/CD127-defined CD8 subsets, surface and intracellular markers were measured by flow cytometry and Cytometry by time of flight (CyTOF), and the transcriptional profile of these cells was determined by CITE-Seq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing). The functional capacity of each subset was determined, as was their impact on overall survival (OS) and event-free survival (EFS) of patients with FL.

Results: We found that intratumoral CD8 cells in FL are skewed toward effector cell subsets, particularly KLRGCD127 and KLRG1CD127 cells over memory cell subsets, such as KLRG1CD127 and KLRG1CD127 cells. While effector subsets exhibited increased capacity to produce cytokines/granules when compared with memory subsets, their proliferative capacity and viability were found to be substantially inferior. Clinically, a skewed distribution of intratumoral CD8 T cells favoring effector subtypes was associated with an inferior outcome in patients with FL. Increased numbers of CD127KLRG1 and CD127KLRG1 were significantly associated with a favorable OS and EFS, while CD127KLRG1 correlated with a poor EFS and OS in patients with FL. Furthermore, we demonstrated that interleukin (IL)-15 promotes CD127KLRG1 cell development in the presence of dendritic cells via a phosphoinositide 3-kinase (PI3K)-dependent mechanism, and treatment of CD8 T cells with a PI3K inhibitor downregulated the transcription factors responsible for CD127KLRG1 differentiation.

Conclusions: Taken together, these results reveal not only a biological and prognostic role for KLRG1/CD127-defined CD8 subsets in FL but also a potential role for PI3K inhibitors to manipulate the differentiation of CD8 T cells, thereby promoting a more effective antitumor immune response.
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http://dx.doi.org/10.1136/jitc-2021-002662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258669PMC
July 2021

Older patients (aged ≥60 years) with previously untreated advanced-stage classical Hodgkin lymphoma: a detailed analysis from the phase III ECHELON-1 study.

Haematologica 2021 06 24. Epub 2021 Jun 24.

Research and Innovation Department, A Lacassagne Cancer Centre, Nice.

Effective and tolerable treatments are needed for older patients with classical Hodgkin lymphoma (cHL). We report results for older patients with cHL treated in the large phase III ECHELON-1 study of frontline brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Modified progression-free survival (PFS) per independent review facility (IRF) for older versus younger patients (aged ≥60 versus.
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http://dx.doi.org/10.3324/haematol.2021.278438DOI Listing
June 2021

Infused Autograft Absolute Lymphocyte Count Predicts Superior Survival in Diffuse Large B Cell Lymphoma Patients Post-Autologous Peripheral Blood Hematopoietic Stem Cell Transplantation: A Matched Case-Control Study.

Transplant Cell Ther 2021 Sep 6;27(9):769.e1-769.e8. Epub 2021 Jun 6.

Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota.

Our group published a double phase III trial showing that patients infused with an autograft absolute lymphocyte count (A-ALC) ≥0.5 × 10 cells/kg experienced superior survival post-autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT). Based on the results from our phase III study, as well as published retrospective studies, on April 1, 2017, our Bone Marrow Transplant Program changed our standard practice to collect an A-ALC ≥0.5 × 10 cells/kg in addition to stem cells for lymphoma patients undergoing APBHSCT. The primary objective of the present study was to continue to assess the prognostic ability of A-ALC by evaluating overall survival (OS) and progression-free survival (PFS) of diffuse large B cell lymphoma (DLBCL) patients who underwent APBHSCT after April 1, 2017, compared with matched control groups at a 1:1:1 ratio with DLBCL patients infused with an A-ALC <0.5 × 10 cells/kg and A-ALC ≥0.5 × 10 cells/kg before April 1, 2017. Using the GREEDY algorithm, 85 DLBCL patients (cases) infused with an A-ALC ≥0.5 × 10 cells/kg after April 1, 2017, were matched at a 1:1:1 ratio with control groups of DLBCL patients who underwent transplantation before April 1, 2017: patients infused with an A-ALC <0.5 × 10 cells/kg (control 1) and patients infused with an A-ALC ≥0.5 × 10 cells/kg (control 2) before April 1, 2017. Groups were matched in terms of sex, age, stage, lactate dehydrogenase (LDH) level, performance status, extranodal disease, International Prognostic Index (IPI), and disease status before APBHSCT (complete or partial response). Survival follow-up was truncated at 3 years from the date of transplantation. Cases, control 1, and control 2 were balanced as to age (P = .8), sex (P = .9), LDH (P = .6), performance status (P = .5), extranodal disease (P = .2), IPI (P = .6), and disease status before APBHSCT (P = .2). Cases and control 2 showed superior OS and PFS compared with control 1. Multivariate analysis including all patients continued to show A-ALC ≥0.5 × 10 cells/kg as an independent predictor for OS (hazard ratio [HR], 0.382; 95% confidence interval [CI], 0.241 to 0.605; P < .0001) and PFS (HR, 0.437; 95% CI, 0.279 to 0.629; P < .0001). Our matched case-control study supports the results of previously published retrospective studies and our phase III study showing that the infusion of A-ALC is a prognostic factor for survival in DLBCL patients undergoing APBHSCT. Our findings support the practice of collecting not only enough stem cells for hematologic engraftment, but also enough immune effector cells (ie, A-ALC) to improve clinical outcomes in DLBCL patients post-APBHSCT.
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http://dx.doi.org/10.1016/j.jtct.2021.05.026DOI Listing
September 2021

Brentuximab vedotin with chemotherapy for stage III or IV classical Hodgkin lymphoma (ECHELON-1): 5-year update of an international, open-label, randomised, phase 3 trial.

Lancet Haematol 2021 Jun;8(6):e410-e421

University of Manchester and the Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.

Background: Despite advances in the treatment of Hodgkin lymphoma with the introduction of PET-adapted regimens, practical challenges prevent more widespread use of these approaches. The ECHELON-1 study assessed the safety and efficacy of front-line A+AVD (brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine) versus ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) in patients with stage III or IV classical Hodgkin lymphoma. The primary analysis showed improved modified progression-free survival with A+AVD. We present an updated analysis of ECHELON-1 at 5 years, an important landmark for this patient population.

Methods: ECHELON-1 was an international, open-label, randomised, phase 3 trial done at 218 clinical sites, including hospitals, cancer centres, and community clinics, in 21 countries. Previously untreated patients (≥18 years with an Eastern Cooperative Oncology Group performance status of ≤2) with stage III or IV classical Hodgkin lymphoma were randomly assigned (1:1) to receive A+AVD (brentuximab vedotin, 1·2 mg/kg of bodyweight, doxorubicin 25 mg/m of body surface area, vinblastine 6 mg/m, and dacarbazine 375 mg/m) or ABVD (doxorubicin 25 mg/m, bleomycin 10 U/m, vinblastine 6 mg/m, and dacarbazine 375 mg/m) intravenously on days 1 and 15 of each 28-day cycle for up to six cycles. Stratification factors included region (Americas vs Europe vs Asia) and International Prognostic Score risk group (low, intermediate, or high risk). The primary endpoint was modified progression-free survival; this 5-year update includes analysis of progression-free survival as per investigator assessment in the intention-to-treat population, which was an exploratory endpoint, although the 5-year analysis was not prespecified in the protocol. This trial is registered with ClinicalTrials.gov (NCT01712490) and EudraCT (2011-005450-60), and is ongoing.

Findings: Between Nov 19, 2012, and Jan 13, 2016, 1334 patients were randomly assigned to receive A+AVD (n=664) or ABVD (n=670). At a median follow-up of 60·9 months (IQR 52·2-67·3), 5-year progression-free survival was 82·2% (95% CI 79·0-85·0) with A+AVD and 75·3% (71·7-78·5) with ABVD (hazard ratio [HR] 0·68 [95% CI 0·53-0·87]; p=0·0017). Among PET-2-negative patients, 5-year progression-free survival was higher with A+AVD than with ABVD (84·9% [95% CI 81·7-87·6] vs 78·9% [75·2-82·1]; HR 0·66 [95% CI 0·50-0·88]; p=0·0035). 5-year progression-free survival for PET-2-positive patients was 60·6% (95% CI 45·0-73·1) with A+AVD versus 45·9% (32·7-58·2) with ABVD (HR 0·70 [95% CI 0·39-1·26]; p=0·23). Peripheral neuropathy continued to improve or resolve over time with both A+AVD (375 [85%] of 443 patients) and ABVD (245 [86%] of 286 patients); more patients had ongoing peripheral neuropathy in the A+AVD group (127 [19%] of 662) than in the ABVD group (59 [9%] of 659). Fewer secondary malignancies were reported with A+AVD (19 [3%] of 662) than with ABVD (29 [4%] of 659). More livebirths were reported in the A+AVD group (n=75) than in the ABVD group (n=50).

Interpretation: With 5 years of follow-up, A+AVD showed robust and durable improvement in progression-free survival versus ABVD, regardless of PET-2 status, and a consistent safety profile. On the basis of these findings, A+AVD should be preferred over ABVD for patients with previously untreated stage III or IV classical Hodgkin lymphoma.

Funding: Millennium Pharmaceuticals (a wholly owned subsidiary of Takeda Pharmaceutical Company), and Seagen.
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http://dx.doi.org/10.1016/S2352-3026(21)00102-2DOI Listing
June 2021

Assessment of fixed-duration therapies for treatment-naïve Waldenström macroglobulinemia.

Am J Hematol 2021 08 22;96(8):945-953. Epub 2021 May 22.

Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.

Comparative data guiding initial therapy for Waldenström macroglobulinemia (WM), an infrequently encountered non-Hodgkin lymphoma, are sparse. We evaluated three commonly used rituximab-based frontline regimens: rituximab-bendamustine (R-Benda); dexamethasone, rituximab, cyclophosphamide (DRC); and bortezomib, dexamethasone, rituximab (BDR) in 220 treatment-naïve patients with WM, seen at Mayo Clinic between November 1, 2000 and October 31, 2019. The median follow-up was 4.5 (95%CI: 4-5) years. The R-Benda cohort (n = 83) demonstrated superior overall response rate (ORR: 98%), in comparison to DRC (n = 92, ORR: 78%) or BDR (n = 45, ORR: 84%) cohorts, p = 0.003. Similarly, longer progression-free survival (PFS) was evident with R-Benda use [median 5.2 vs. 4.3 (DRC) and 1.8 years (BDR), p < 0.001]. The time-to-next therapy (TTNT) favored R-Benda [median, not-reached, 4.4 (DRC) and 2.6 years (BDR), p < 0.001). These endpoints were comparable between the DRC and BDR cohorts. Overall survival (OS) was similar across the three cohorts, p = 0.77. In a subset analysis of 142 patients genotyped for MYD88 mutation, the ORR, PFS and TTNT were unaffected by the patients' MYD88 signature within each cohort. In conclusion, ORR, PFS and TTNT with R-Benda are superior compared to DRC or BDR in treatment-naïve patients with active WM. The patient outcomes with any one of these three regimens are unaffected by the MYD88 mutation status.
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http://dx.doi.org/10.1002/ajh.26210DOI Listing
August 2021

Brentuximab vedotin in combination with nivolumab in relapsed or refractory Hodgkin lymphoma: 3-year study results.

Blood 2021 Aug;138(6):427-438

City of Hope National Medical Center, Duarte, CA.

This phase 1-2 study evaluated brentuximab vedotin (BV) combined with nivolumab (Nivo) as first salvage therapy in patients with relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). In parts 1 and 2, patients received staggered dosing of BV and Nivo in cycle 1, followed by same-day dosing in cycles 2 to 4. In part 3, both study drugs were dosed, same day, for all 4 cycles. At end of study treatment, patients could undergo autologous stem cell transplantation (ASCT) per investigator discretion. The objective response rate (ORR; N = 91) was 85%, with 67% achieving a complete response (CR). At a median follow-up of 34.3 months, the estimated progression-free survival (PFS) rate at 3 years was 77% (95% confidence interval [CI], 65% to 86%) and 91% (95% CI, 79% to 96%) for patients undergoing ASCT directly after study treatment. Overall survival at 3 years was 93% (95% CI, 85% to 97%). The most common adverse events (AEs) prior to ASCT were nausea (52%) and infusion-related reactions (43%), all grade 1 or 2. A total of 16 patients (18%) had immune-related AEs that required systemic corticosteroid treatment. Peripheral blood immune signatures were consistent with an activated T-cell response. Median gene expression of CD30 in tumors was higher in patients who responded compared with those who did not. Longer-term follow-up of BV and Nivo as a first salvage regimen shows durable efficacy and impressive PFS, especially in patients who proceeded directly to transplant, without additional toxicity concerns. This trial was registered at www.clinicaltrials.gov as #NCT02572167.
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http://dx.doi.org/10.1182/blood.2020009178DOI Listing
August 2021

Engaging the Innate and Adaptive Antitumor Immune Response in Lymphoma.

Int J Mol Sci 2021 Mar 24;22(7). Epub 2021 Mar 24.

Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.

Immunotherapy has emerged as a powerful therapeutic strategy for many malignancies, including lymphoma. As in solid tumors, early clinical trials have revealed that immunotherapy is not equally efficacious across all lymphoma subtypes. For example, immune checkpoint inhibition has a higher overall response rate and leads to more durable outcomes in Hodgkin lymphomas compared to non-Hodgkin lymphomas. These observations, combined with a growing understanding of tumor biology, have implicated the tumor microenvironment as a major determinant of treatment response and prognosis. Interactions between lymphoma cells and their microenvironment facilitate several mechanisms that impair the antitumor immune response, including loss of major histocompatibility complexes, expression of immunosuppressive ligands, secretion of immunosuppressive cytokines, and the recruitment, expansion, and skewing of suppressive cell populations. Accordingly, treatments to overcome these barriers are being rapidly developed and translated into clinical trials. This review will discuss the mechanisms of immune evasion, current avenues for optimizing the antitumor immune response, clinical successes and failures of lymphoma immunotherapy, and outstanding hurdles that remain to be addressed.
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http://dx.doi.org/10.3390/ijms22073302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038124PMC
March 2021

Hypomagnesemia at the time of autologous stem cell transplantation for patients with diffuse large B-cell lymphoma is associated with an increased risk of failure.

Blood Cancer J 2021 Mar 26;11(3):65. Epub 2021 Mar 26.

Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, MN, 55905, USA.

Magnesium is an essential element that is involved in critical metabolic pathways. A diet deficient in magnesium is associated with an increased risk of developing cancer. Few studies have reported whether a serum magnesium level below the reference range (RR) is associated with prognosis in patients with diffuse large B cell lymphoma (DLBCL). Using a retrospective approach in DLBCL patients undergoing autologous stem cell transplant (AHSCT), we evaluated the association of hypomagnesemia with survival. Totally, 581 patients eligible for AHSCT with a serum magnesium level during the immediate pre-transplant period were identified and 14.1% (82/581) had hypomagnesemia. Hypomagnesemia was associated with an inferior event-free (EFS) and overall survival (OS) compared to patients with a serum magnesium level within RR; median EFS: 3.9 years (95% CI: 1.63-8.98 years) versus 6.29 years (95% CI: 4.73-8.95 years) with HR 1.63 (95% CI: 1.09-2.43, p = 0.017) for EFS, and median OS: 7.3 years (95% CI: 2.91-upper limit not estimable) versus 9.7 years (95% CI: 6.92-12.3 years) with HR 1.90 (95% CI: 1.22-2.96, p = 0.005) for OS months 0-12, respectively. These findings suggest a potentially actionable prognostic factor for patients with DLBCL undergoing AHSCT.
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http://dx.doi.org/10.1038/s41408-021-00452-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998023PMC
March 2021

Novel Therapies in the Treatment of Hodgkin Lymphoma.

Curr Treat Options Oncol 2021 03 23;22(5):42. Epub 2021 Mar 23.

Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.

Opinion Statement: Patients with Hodgkin lymphoma (HL) can achieve excellent response and survival rates following frontline combination chemo- and radiation therapy. However, about 10-15% of patients will experience disease relapse which is associated with poor outcomes. Recent breakthroughs in understanding the mechanisms of oncogenicity and interactions within the tumor microenvironment have resulted in development of novel drugs for treatment of patients with HL. Utilizing this information, treatment of newly diagnosed and relapsed HL has become a rapidly evolving field with multiple clinical trials evaluating novel treatment approaches incorporating targeted immunotherapy. In the frontline setting, the use of novel drugs may allow for de-escalation of therapy to avoid long-term complications associated with bleomycin and consolidation radiation therapy. Patients with early-stage, non-bulky disease are candidates for omitting radiation therapy using treatment combinations that include upfront use of brentuximab vedotin or nivolumab. In patients with advanced disease, the addition of brentuximab vedotin to a chemotherapy backbone is currently the standard of care in our practice, particularly in patients with a contraindication for receiving bleomycin. Future investigations in patients with advanced-stage HL will focus on establishing a new standard of care by comparing brentuximab vedotin and nivolumab in combination with chemotherapy (BV-AVD vs. N-AVD) and decreasing the risk of relapse by exploring consolidation therapy in patients with high-risk disease. In patients who have relapsed or are refractory to first-line therapy, salvage treatment has incorporated brentuximab vedotin or PD-1 checkpoint inhibitors to improve response rates of cytotoxic chemotherapy thereby improving the probability of a successful stem cell transplant. Post-transplant consolidation with brentuximab is currently standard of care in patients with high-risk disease. Patients who relapse following autologous stem cell transplant now have an expanded armamentarium of chemo- and immunotherapy options. However, the challenge is to determine the sequence of therapy after prior brentuximab or checkpoint inhibitor exposure.
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http://dx.doi.org/10.1007/s11864-021-00840-5DOI Listing
March 2021

Allogeneic transplantation after PD-1 blockade for classic Hodgkin lymphoma.

Leukemia 2021 09 3;35(9):2672-2683. Epub 2021 Mar 3.

Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.

Anti-PD-1 monoclonal antibodies yield high response rates in patients with relapsed/refractory classic Hodgkin lymphoma (cHL), but most patients will eventually progress. Allogeneic hematopoietic cell transplantation (alloHCT) after PD-1 blockade may be associated with increased toxicity, raising challenging questions about the role, timing, and optimal method of transplantation in this setting. To address these questions, we assembled a retrospective cohort of 209 cHL patients who underwent alloHCT after PD-1 blockade. With a median follow-up among survivors of 24 months, the 2-year cumulative incidences (CIs) of non-relapse mortality and relapse were 14 and 18%, respectively; the 2-year graft-versus-host disease (GVHD) and relapse-free survival (GRFS), progression-free survival (PFS), and overall survival were 47%, 69%, and 82%, respectively. The 180-day CI of grade 3-4 acute GVHD was 15%, while the 2-year CI of chronic GVHD was 34%. In multivariable analyses, a longer interval from PD-1 to alloHCT was associated with less frequent severe acute GVHD, while additional treatment between PD-1 and alloHCT was associated with a higher risk of relapse. Notably, post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis was associated with significant improvements in PFS and GRFS. While awaiting prospective clinical trials, PTCy-based GVHD prophylaxis may be considered the optimal transplantation strategy for this patient population.
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http://dx.doi.org/10.1038/s41375-021-01193-6DOI Listing
September 2021

Future directions in Hodgkin lymphoma: checkpoint inhibitors and beyond.

Leuk Lymphoma 2021 08 18;62(8):1795-1804. Epub 2021 Feb 18.

Division of Hematology, Mayo Clinic, Rochester, MN, USA.

Classic Hodgkin lymphoma (cHL) is curable with chemotherapy but relapses occur in approximately 30% of cases. Novel agents, including brentuximb vedotin (BV) and programmed cell death-1 (PD-1) inhibitors, alone or in combination with chemotherapy, have encouraging activity in newly diagnosed and relapsed/refractory cHL, confirming that the use of agents that target tumor cells or the tumor microenvironment are promising strategies to improve patient outcomes. The field of immunotherapy in cHL is now moving toward combinations of PD-1 inhibitors with other immunological agents such as cytotoxic T- lymphocyte associated protein-4 (CTLA-4) inhibitors, newer PD-1 inhibitors such as sintilimab, tislelizumab, avelumab and camrelizumab, bispecific antibodies such as AFM-13, cellular therapies using CD30 chimeric antigen T-cells (CD30.CART) and anti-CD25 antibody-drug conjugates such as camidanlumab tesirine (cami-T). Here we review early phase studies evaluating these approaches in the treatment of cHL.
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http://dx.doi.org/10.1080/10428194.2021.1885667DOI Listing
August 2021

Impact of Organ Function-Based Clinical Trial Eligibility Criteria in Patients With Diffuse Large B-Cell Lymphoma: Who Gets Left Behind?

J Clin Oncol 2021 May 2;39(15):1641-1649. Epub 2021 Feb 2.

Division of Hematology, Mayo Clinic, Rochester, MN.

Purpose: Exclusion of patients needing urgent treatment or requiring novel biomarkers before enrollment has impacted the ability to enroll real-world patients in frontline trials of diffuse large B-cell lymphoma (DLBCL). The impact of baseline organ function-based eligibility criteria on this effect and clinical trial exclusion is less well-understood.

Methods: Consecutive patients with newly diagnosed lymphoma were enrolled from 2002 to 2015 into the Molecular Epidemiology Resource (MER) of the University of Iowa and Mayo Clinic Lymphoma Specialized Program of Research Excellence. The current analysis includes 1,265 patients with DLBCL receiving standard immunochemotherapy. Organ function parameters were identified from criteria for hemoglobin, absolute neutrophil count, platelet count, creatinine clearance, and bilirubin, as reported in frontline DLBCL trials. Abstracted laboratory values from MER were used to determine the percent (%) of patients excluded. Outcomes and cause-of-death analyses comparing ineligible and eligible groups in MER were conducted. An interactive online tool was developed to estimate exclusions based on organ function for future trial design.

Results: Between 9% and 24% of MER patients with DLBCL receiving standard immunochemotherapy were excluded on the basis of baseline organ function alone. Ineligible patients based on organ function had significantly inferior event-free survival (hazard ratios, 1.67-2.16), overall survival (hazard ratios, 1.87-2.56), and event-free survival at 24 months (odds ratio, 1.71-2.16). Ineligible patients were more likely to die from lymphoma progression than increased therapy-related complications.

Conclusion: Current national and international trials exclude up to 24% of patients from participation on the basis of organ function alone. A significant difference in the outcomes, notably lymphoma-related death, suggests issues with generalization and potential exclusion of high-risk patients. These data will help future clinical trial development and meet US Food and Drug Administration and ASCO recommendations to increase trial accrual.
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http://dx.doi.org/10.1200/JCO.20.01935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274741PMC
May 2021

Brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine in patients with advanced-stage, classical Hodgkin lymphoma: A prespecified subgroup analysis of high-risk patients from the ECHELON-1 study.

Hematol Oncol 2021 Apr 16;39(2):185-195. Epub 2021 Feb 16.

Research and Innovation Department, Centre Antoine Lacassagne, Nice, France.

Approximately one-third of patients diagnosed with Hodgkin lymphoma presenting with Stage IV disease do not survive past 5 years. We present updated efficacy and safety analyses in high-risk patient subgroups, defined by Stage IV disease or International Prognostic Score (IPS) of 4-7, enrolled in the ECHELON-1 study that compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as first-line therapy after a median follow-up of 37.1 months. Among patients treated with A + AVD (n = 664) or ABVD (n = 670), 64% had Stage IV disease and 26% had an IPS of 4-7. Patients with Stage IV disease treated with A + AVD showed consistent improvements in PFS at 3 years as assessed by investigator (hazard ratio [HR], 0.723; 95% confidence interval [CI], 0.537-0.973; p = 0.032). Similar improvements were seen in the subgroup of patients with IPS of 4-7 (HR, 0.588; 95% CI, 0.386-0.894; p = 0.012). The most common adverse events (AEs) in A + AVD-treated versus ABVD-treated patients with Stage IV disease were peripheral neuropathy (67% vs. 40%) and neutropenia (71% vs. 55%); in patients with IPS of 4-7, the most common AEs were peripheral neuropathy (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%), respectively. Patients in high-risk subgroups did not experience greater AE incidence or severity than patients in the total population. This updated analysis of ECHELON-1 shows a favorable benefit-risk balance in high-risk patients.
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http://dx.doi.org/10.1002/hon.2838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247884PMC
April 2021

Phase I Study of the CD47 Blocker TTI-621 in Patients with Relapsed or Refractory Hematologic Malignancies.

Clin Cancer Res 2021 Apr 15;27(8):2190-2199. Epub 2021 Jan 15.

University of Virginia Cancer Center, Charlottesville, Virginia.

Purpose: TTI-621 (SIRPα-IgG1 Fc) is a novel checkpoint inhibitor that activates antitumor activity by blocking the CD47 "don't eat me" signal. This first-in-human phase I study (NCT02663518) evaluated the safety and activity of TTI-621 in relapsed/refractory (R/R) hematologic malignancies.

Patients And Methods: Patients with R/R lymphoma received escalating weekly intravenous TTI-621 to determine the maximum tolerated dose (MTD). During expansion, patients with various malignancies received weekly single-agent TTI-621 at the MTD; TTI-621 was combined with rituximab in patients with B-cell non-Hodgkin lymphoma (B-NHL) or with nivolumab in patients with Hodgkin lymphoma. The primary endpoint was the incidence/severity of adverse events (AEs). Secondary endpoint included overall response rate (ORR).

Results: Overall, 164 patients received TTI-621: 18 in escalation and 146 in expansion (rituximab combination, = 35 and nivolumab combination, = 4). On the basis of transient grade 4 thrombocytopenia, the MTD was determined as 0.2 mg/kg; 0.1 mg/kg was evaluated in combination cohorts. AEs included infusion-related reactions, thrombocytopenia, chills, and fatigue. Thrombocytopenia (20%, grade ≥3) was reversible between doses and not associated with bleeding. Transient thrombocytopenia that determined the initial MTD may not have been dose limiting. The ORR for all patients was 13%. The ORR was 29% (2/7) for diffuse large B-cell lymphoma (DLBCL) and 25% (8/32) for T-cell NHL (T-NHL) with TTI-621 monotherapy and was 21% (5/24) for DLBCL with TTI-621 plus rituximab. Further dose optimization is ongoing.

Conclusions: TTI-621 was well-tolerated and demonstrated activity as monotherapy in patients with R/R B-NHL and T-NHL and combined with rituximab in patients with R/R B-NHL.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3706DOI Listing
April 2021

PD-1 Blockade in Classic Hodgkin Lymphoma.

Authors:
Stephen M Ansell

JCO Oncol Pract 2021 02 13;17(2):72-73. Epub 2021 Jan 13.

Division of Hematology, Mayo Clinic, Rochester, MN.

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http://dx.doi.org/10.1200/OP.20.01020DOI Listing
February 2021

Checkpoint Blockade in Lymphoma.

Authors:
Stephen M Ansell

J Clin Oncol 2021 02 12;39(5):525-533. Epub 2021 Jan 12.

Division of Hematology, Mayo Clinic, Rochester, MN.

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http://dx.doi.org/10.1200/JCO.20.01522DOI Listing
February 2021
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