247 results on '"Savage KJ"'
Search Results
2. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.
- Author
-
Johnson NA, Slack GW, Savage KJ, Connors JM, Ben-Neriah S, Rogic S, Scott DW, Tan KL, Steidl C, Sehn LH, Chan WC, Iqbal J, Meyer PN, Lenz G, Wright G, Rimsza LM, Valentino C, Brunhoeber P, Grogan TM, and Braziel RM
- Published
- 2012
- Full Text
- View/download PDF
3. The spectrum of peripheral T-cell lymphomas.
- Author
-
O'leary H and Savage KJ
- Published
- 2009
- Full Text
- View/download PDF
4. Involved-nodal radiation therapy as a component of combination therapy for limited-stage Hodgkin's lymphoma: a question of field size.
- Author
-
Campbell BA, Voss N, Pickles T, Morris J, Gascoyne RD, Savage KJ, and Connors JM
- Published
- 2008
5. Population-based analysis of incidence and outcome of transformed non-Hodgkin's lymphoma.
- Author
-
Al-Tourah AJ, Gill KK, Chhanabhai M, Hoskins PJ, Klasa RJ, Savage KJ, Sehn LH, Shenkier TN, Gascoyne RD, and Connors JM
- Published
- 2008
6. Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma.
- Author
-
Robertson MJ, Kahl BS, Vose JM, de Vos S, Laughlin M, Flynn PJ, Rowland K, Cruz JC, Goldberg SL, Musib L, Darstein C, Enas N, Kutok JL, Aster JC, Neuberg D, Savage KJ, LaCasce A, Thornton D, Slapak CA, and Shipp MA
- Published
- 2007
7. Anaplastic large cell lymphoma, ALK-positive
- Author
-
Silvia Govi, Stefano Pileri, Andrés J.M. Ferreri, Kerry J. Savage, Ferreri AJ, Govi S, Pileri SA, and Savage KJ.
- Subjects
Pathology ,medicine.medical_specialty ,Anaplastic Lymphoma ,CD30 ,Prednisolone ,T-Lymphocytes ,Leucovorin ,CHOP ,Translocation, Genetic ,Bleomycin ,International Prognostic Index ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Animals ,Humans ,Medicine ,Anaplastic lymphoma kinase ,Anaplastic Lymphoma Kinase ,Cyclophosphamide ,Anaplastic large-cell lymphoma ,Etoposide ,business.industry ,Large cell ,Receptor Protein-Tyrosine Kinases ,Hematology ,medicine.disease ,Lymphoma ,Methotrexate ,Oncology ,Doxorubicin ,Vincristine ,Anaplastic lymphoma ,Cancer research ,Lymphoma, Large-Cell, Anaplastic ,Prednisone ,business ,Stem Cell Transplantation - Abstract
Anaplastic large cell lymphoma (ALCL), anaplastic lymphoma kinase (ALK)-positive (ALK+ ALCL) is an aggressive CD30-positive T-cell lymphoma that exhibits a chromosomal translocation involving the ALK gene and the expression of ALK protein. No particular risk factor has been clearly identified for ALCL. ALK+ ALCL shows a broad morphologic spectrum, but all cases contain a variable proportion of cells with eccentric, horseshoe- or kidney-shaped nuclei often with an eosinophilic region near the nucleus (hallmark cells). Five morphologic patterns can be recognized. ALK+ ALCL occurs in young subjects (median age ∼35years), with male predominance, and frequently presents at an advanced stage, with systemic symptoms and extranodal involvement. Near 40% of patients are low risk according to the International Prognostic Index (IPI). Overall, the prognosis of ALK+ ALCL is remarkably better than other T-cell lymphomas. The IPI and the PIT scores in general predict survival in patients with ALK+ ALCL. Standard first-line treatment for ALK+ ALCL consists of doxorubicin-containing polychemotherapy, which is associated with an overall response rate of ∼90%, a 5-year relapse-free survival of ∼60%, and a 5-year overall survival of 70%. Excellent results have been reported with a variety of anthracycline-based chemotherapy regimens including CHOP, CHOEP or MACOP-B. Consolidative high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) has also been evaluated in patients in first remission with favourable results, however, superiority to standard chemotherapy is unproven and this approach remains investigational. Following universally accepted guidelines for the treatment of failed aggressive lymphomas, HDC/ASCT can effectively salvage a proportion of patients with relapsed or refractory ALK+ ALCL. Recently, the development of novel therapies targeting CD30 and ALK appear promising.
- Published
- 2012
8. Peripheral T-cell lymphoma - Not otherwise specified
- Author
-
Stefano Pileri, Pier Luigi Zinzani, Kerry J. Savage, Andrés J.M. Ferreri, Savage KJ, Ferreri AJ, Zinzani PL, and Pileri SA.
- Subjects
Oncology ,medicine.medical_specialty ,Antibodies, Neoplasm ,T-Lymphocytes ,Peripheral T-cell lymphoma not otherwise specified ,CHOP ,Antibodies, Monoclonal, Humanized ,Romidepsin ,chemistry.chemical_compound ,Autologous stem-cell transplantation ,Antigens, CD ,Antigens, Neoplasm ,Risk Factors ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Transplantation, Homologous ,Anthracyclines ,Brentuximab vedotin ,Survival rate ,Alemtuzumab ,Glycoproteins ,Neoplasm Staging ,business.industry ,Pralatrexate ,Lymphoma, T-Cell, Peripheral ,Hematology ,medicine.disease ,Prognosis ,Neoadjuvant Therapy ,Survival Rate ,chemistry ,CD52 Antigen ,Immunology ,Radiotherapy, Adjuvant ,business ,Belinostat ,peripheral T-cell lymphomas ,medicine.drug - Abstract
Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) does correspond to a heterogeneous group of nodal and extranodal mature T-cell lymphomas, with a low prevalence in Western countries. PTCL-NOS accounts for about 25% of all PTCL, which represent over 15% of all lymphomas. In the lymph node, PTCL-NOS shows paracortical or diffuse infiltrates with effacement of the normal architecture, with a broad cytological spectrum and a frequently observed inflammatory background. Some morphological variants include: lymphoepithelioid or Lennert's type, T-zone, and follicular. PTCL-NOS is characterized by an aberrant T-cell phenotype, with frequent loss of CD5 and CD7. A CD4+/CD8- phenotype predominates in nodal cases. CD4/CD8 +/+ or -/- is at times seen, as is CD8, CD56 and cytotoxic granule expression. Ki-67 rate is typically high. TCR β-chain is usually expressed; TCR genes are most often clonally rearranged. PTCL-NOS typically occurs in adults (median age 55-60 years), with a higher prevalence in males. It presents more often as disseminated disease, occasionally with eosinophilia, pruritis or hemophagocytic syndrome. Patients often have B symptoms, generalized lymphadenopathy, bone marrow infiltration, and extranodal involvement, with high or high-intermediate IPI score in 50-70% of cases. Prognosis is poor, with a 5-year OS of 20-30%. Some variables, like ST2(L), CXCR5, CXCR3, EBV infection, cytotoxic granule expression, high proliferative index, NF-κB expression, were proposed as prognostic indicators, but the IPI score, and its variant called PIT, remains the most effective prognostic factor. Patients with PTCL-NOS should be treated with anthracycline-containing chemotherapy, followed by radiotherapy in cases of stage I-II disease. This strategy is associated with an overall response rate higher than 60%, but the 5-year overall survival is only 20-30%. Upfront high-dose chemotherapy supported by autologous or allogeneic SCT is an investigational approach, with a 4-year overall survival of about 40%. Patients with chemosensitive relapse respond favorably to high-dose chemotherapy and ASCT, with long-term survival rates of 35-45%. Graft-versus-lymphoma effect following allogeneic SCT has been observed; and reduced intensity conditioning emerges as an attractive strategy for frail patients. Most patients with PTCL-NOS are enrolled in prospective trials to explore new approaches, and new agents, like gemcitabine, alemtuzumab and pralatrexate, are being investigated.
- Published
- 2011
9. Brentuximab vedotin plus cyclophosphamide, doxorubicin, etoposide, and prednisone followed by brentuximab vedotin consolidation in CD30-positive peripheral T-cell lymphomas: a multicentre, single-arm, phase 2 study.
- Author
-
Herrera AF, Zain J, Savage KJ, Feldman T, Brammer JE, Chen L, Puverel S, Popplewell L, Budde LE, Mei M, Hosing C, Nair R, Leslie L, Daniels S, Peters L, Forman S, Rosen S, Kwak L, and Iyer SP
- Subjects
- Humans, Female, Male, Middle Aged, Adult, Aged, Consolidation Chemotherapy, Brentuximab Vedotin therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cyclophosphamide therapeutic use, Cyclophosphamide administration & dosage, Doxorubicin therapeutic use, Doxorubicin administration & dosage, Lymphoma, T-Cell, Peripheral drug therapy, Etoposide therapeutic use, Etoposide administration & dosage, Ki-1 Antigen metabolism, Prednisone therapeutic use, Prednisone administration & dosage, Prednisone adverse effects
- Abstract
Background: CD30 expression is universal in anaplastic large-cell lymphoma and is expressed in some other peripheral T-cell lymphoma subtypes. Incorporation of brentuximab vedotin into initial therapy for people with CD30-positive peripheral T-cell lymphomas prolonged progression-free survival, but there is room for improvement, especially for people with non-anaplastic large-cell lymphoma subtypes., Methods: We conducted a multicentre, international, single-arm, phase 2 trial to evaluate the safety and activity of CHEP-BV (cyclophosphamide, doxorubicin, prednisone, brentuximab vedotin, and etoposide) followed by brentuximab vedotin consolidation in patients with CD30-expressing peripheral T-cell lymphomas across five academic centres in the USA and Canada. Adults aged 18 years or older with newly diagnosed, untreated CD30-positive peripheral T-cell lymphomas, Eastern Cooperative Oncology Group score of 0-2, and adequate organ function were eligible to receive six planned cycles of CHEP-BV (ie, 1·8 mg/kg brentuximab vedotin intravenously on day 1, cyclophosphamide 750 mg/m
2 intravenously on day 1, doxorubicin 50 mg/m2 intravenously on day 1, etoposide 100 mg/m2 daily intravenously on days 1-3, and prednisone 100 mg daily orally on days 1-5) with prophylactic G-CSF. Patients who responded to the treatment could receive brentuximab vedotin consolidation for up to ten additional cycles either after autologous haematopoietic stem-cell transplantation (HSCT) or directly after CHEP-BV. The primary endpoints were unacceptable toxicity during a 3-plus-3 safety lead-in in participants who received study treatment and completed the safety evaluation period (to confirm the recommended phase 2 dose of brentuximab vedotin in CHEP-BV) and the complete response rate after CHEP-BV induction therapy in participants who received study treatment and had response evaluation. The study was registered at ClinicalTrials.gov (NCT03113500), and this cohort completed the trial. The trial is ongoing with the enrolment of a new cohort., Findings: 54 patients were screened for eligibility and 48 were eligible for the study. The participants (18 [38%] women and 30 [63%] men; 34 [71%] White, four [8%] Black, five [10%] Asian, ten [21%] Hispanic, and 37 [77%] non-Hispanic people) were recruited and enrolled between Dec 4, 2017, and June 14, 2021, and followed up until Aug 25, 2023, when the database was locked for analysis. 48 participants were evaluable for toxicity, and 47 were evaluable for response (one participant died from COVID-19 before response assessment). During the safety lead-in, one of six participants had an unacceptable toxicity (ie, platelet count <10 000 per mm3 in a participant with extensive bone marrow involvement), and the proposed phase 2 dose of 1·8 mg/kg brentuximab vedotin in CHEP-BV was confirmed. At completion of CHEP-BV, 37 of 47 participants had complete response, yielding a complete response rate of 79% (95% CI 64-89). The most common CHEP-BV-related toxicities of grade 3 or higher were neutropenia (14 [29%] of 48), leukopenia (11 [23%]), anaemia (ten [21%]), febrile neutropenia (ten [21%]), lymphopenia (nine [19%]), and thrombocytopenia (nine [19%]). There were no treatment-related deaths., Interpretation: In patients with mostly CD30-expressing peripheral T-cell lymphomas other than non-anaplastic large-cell lymphoma, CHEP-BV (with or without autologous HSCT) followed by brentuximab vedotin consolidation was safe and active., Funding: SeaGen, Leukemia and Lymphoma Society, Lymphoma Research Foundation, and the National Cancer Institute of the National Institutes of Health., Competing Interests: Declaration of interests AFH reports research funding from Bristol Myers Squibb, Merck, Genentech/F Hoffmann-La Roche, Gilead Sciences, Seattle Genetics, AstraZeneca, and ADC Therapeutics and consultancy for Bristol Myers Squibb, Merck, Genentech/F Hoffmann-La Roche, Kite Pharma/Gilead, Seattle Genetics, Karyopharm, Takeda, Tubulis, AstraZeneca, Genmab, Regeneron, Pfizer, AbbVie, Allogene Therapeutics, Adicet Bio, and Caribou Biosciences. MM reports research funding from Bristol Myers Squibb, Incyte, and Morphosys; consultancy for Novartis, Seattle Genetics, CTI Biopharma, Janssen, and EUSA Pharma; and being part of speakers' bureau for Morphosys and Seattle Genetics. CH reports consultancy for BioLineRx. KJS reports honoraria or consulting for Seagen, Bristol Myers Squibb, Janssen, and AbbVie; research funding from Bristol Myers Squibb and Roche (institutional); participation on a data and safety monitoring committee for Regeneron; and participation on a steering committee for Beigene. SP reports research funding from Acrotech, AstraZeneca, CRISPR, Innate, Legend, Merck, Myeloid, Trillium/Pfizer, and Seagen and consultancy for Acrotech, March Bio, Star, Pfizer, Salarius, and Seagen. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)- Published
- 2024
- Full Text
- View/download PDF
10. Unbalanced MYC break-apart FISH patterns indicate the presence of a MYC rearrangement in HGBCL-DH-BCL2.
- Author
-
Collinge BJ, Ben-Neriah S, Hilton LK, Alduaij W, Tucker T, Slack GW, Farinha P, Craig JW, Boyle M, Meissner B, Villa D, Gerrie AS, Sehn LH, Savage KJ, Morin RD, Mungall AJ, Steidl C, and Scott DW
- Abstract
Fluorescence in situ hybridization (FISH) using break-apart probes is recommended for identifying high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-DH-BCL2). Unbalanced MYC break-apart patterns, where the red or green signal is lost, are commonly reported as an equivocal result by clinical laboratories. In a cohort of 297 HGBCL-DH-BCL2, 13% of tumors had unbalanced MYC break-apart patterns with loss of red (LR: 2%) or green (LG: 11%) signal. To determine the significance of these patterns, MYC rearrangements were characterized by sequencing in 130 HGBCL-DH-BCL2, including 3 LR and 14 LG tumors. A MYC rearrangement was identified for 71% of tumors with LR or LG patterns, with the majority involving immunoglobulin loci or other recurrent MYC rearrangement partners. The architecture of these rearrangements consistently preserved the rearranged MYC allele, with the MYC gene predicted to be on the derivative chromosome containing the signal that is still present in nearly all cases. MYC protein expression, MYC mRNA expression, and the proportion of tumors expressing the dark zone signature was not significantly different between balanced and unbalanced groups. These results support a recommendation that unbalanced MYC break-apart FISH patterns be reported as positive for MYC rearrangement in the context of diagnosing HGBCL-DH-BCL2., (Copyright © 2024 American Society of Hematology.)
- Published
- 2024
- Full Text
- View/download PDF
11. Motive and opportunity: MYC rearrangements in high-grade B-cell lymphoma with MYC and BCL2 rearrangements (an LLMPP study).
- Author
-
Hilton LK, Collinge B, Ben-Neriah S, Alduaij W, Shaalan H, Weng AP, Cruz M, Slack GW, Farinha P, Miyata-Takata T, Boyle M, Meissner B, Cook JR, Ondrejka SL, Ott G, Rosenwald A, Campo E, Amador C, Greiner TC, Raess PW, Song JY, Inghirami G, Jaffe ES, Weisenburger DD, Chan WC, Beiske K, Fu K, Delabie J, Pittaluga S, Iqbal J, Wright G, Sehn LH, Savage KJ, Mungall AJ, Feldman AL, Staudt LM, Steidl C, Rimsza LM, Morin RD, and Scott DW
- Subjects
- Humans, Lymphoma, B-Cell genetics, Lymphoma, B-Cell pathology, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse pathology, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-myc genetics, Gene Rearrangement
- Abstract
Abstract: Rearrangements that place the oncogenes MYC, BCL2, or BCL6 adjacent to superenhancers are common in mature B-cell lymphomas. Lymphomas with diffuse large B-cell lymphoma (DLBCL) or high-grade morphology with both MYC and BCL2 rearrangements are classified as high-grade B-cell lymphoma with MYC and BCL2 rearrangements ("double hit"; HGBCL-DH-BCL2) and are associated with aggressive disease and poor outcomes. Although it is established that MYC rearrangements involving immunoglobulin (IG) loci are associated with inferior outcomes relative to those involving other non-IG superenhancers, the frequency of and mechanisms driving IG vs non-IG MYC rearrangements have not been elucidated. Here, we used custom targeted capture and/or whole-genome sequencing to characterize oncogene rearrangements across 883 mature B-cell lymphomas including Burkitt lymphoma, follicular lymphoma, DLBCL, and HGBCL-DH-BCL2 tumors. We demonstrate that, although BCL2 rearrangement topology is consistent across entities, HGBCL-DH-BCL2 have distinct MYC rearrangement architecture relative to tumors with single MYC rearrangements or with both MYC and BCL6 rearrangements (HGBCL-DH-BCL6), including both a higher frequency of non-IG rearrangements and different architecture of MYC::IGH rearrangements. The distinct MYC rearrangement patterns in HGBCL-DH-BCL2 occur on the background of high levels of somatic hypermutation across MYC partner loci in HGBCL-DH-BCL2, creating more opportunity to form these rearrangements. Furthermore, because 1 IGH allele is already disrupted by the existing BCL2 rearrangement, the MYC rearrangement architecture in HGBCL-DH-BCL2 likely reflects selective pressure to preserve both BCL2 and B-cell receptor expression. These data provide new mechanistic explanations for the distinct patterns of MYC rearrangements observed across different lymphoma entities.
- Published
- 2024
- Full Text
- View/download PDF
12. International Prognostic Score for Nodular Lymphocyte-Predominant Hodgkin Lymphoma.
- Author
-
Binkley MS, Flerlage JE, Savage KJ, Akhtar S, Steiner R, Zhang XY, Dickinson M, Prica A, Major A, Hendrickson PG, Hopkins D, Ng A, Casulo C, Baron J, Roberts KB, Al Kendi J, Balogh A, Ricardi U, Torka P, Specht L, De Silva R, Pickard K, Blazin LJ, Henry M, Smith CM, Halperin D, Brady J, Brennan B, Senchenko MA, Reeves M, Hoppe BS, Terezakis S, Talaulikar D, Picardi M, Kirova Y, Fergusson P, Hawkes EA, Lee D, Doo NW, Barraclough A, Cheah CY, Ku M, Hamad N, Mutsando H, Gilbertson M, Marconi T, Viiala N, Maurer MJ, Eichenauer DA, and Hoppe RT
- Subjects
- Humans, Male, Adult, Female, Middle Aged, Retrospective Studies, Young Adult, Prognosis, Progression-Free Survival, Neoplasm Staging, Hodgkin Disease therapy, Hodgkin Disease pathology, Hodgkin Disease mortality
- Abstract
Purpose: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare cancer, and large international cooperative efforts are needed to evaluate the significance of clinical risk factors and immunoarchitectural patterns (IAPs) for all stages of pediatric and adult patients with NLPHL., Methods: Thirty-eight institutions participated in the Global nLPHL One Working Group retrospective study of NLPHL cases from 1992 to 2021. We measured progression-free survival (PFS), overall survival (OS), transformation rate, and lymphoma-specific death rate. We performed uni- and multivariable (MVA) Cox regression stratified by management to select factors for the lymphocyte-predominant international prognostic score (LP-IPS) validated by five-fold cross-validation., Results: We identified 2,243 patients with a median age of 37 years (IQR, 23-51). The median follow-up was 6.3 years (IQR, 3.4-10.8). Most had stage I to II (72.9%) and few B symptoms (9.9%) or splenic involvement (5.4%). IAP was scored for 916 (40.8%). Frontline management included chemotherapy alone (32.4%), combined modality therapy (30.5%), radiotherapy alone (24.0%), observation after excision (4.6%), rituximab alone (4.0%), active surveillance (3.4%), and rituximab and radiotherapy (1.1%). The PFS, OS, transformation, and lymphoma-specific death rates at 10 years were 70.8%, 91.6%, 4.8%, and 3.3%, respectively. On MVA, IAPs were not associated with PFS or OS, but IAP E had higher risk of transformation (hazard ratio [HR], 1.81; P < .05). We developed the LP-IPS with 1 point each for age ≥45 years, stage III-IV, hemoglobin <10.5 g/dL, and splenic involvement. Increasing LP-IPS was significantly associated with worse PFS (HR, 1.52) and OS (HR, 2.31) and increased risk of lymphoma-specific death (HR, 2.63) and transformation (HR, 1.41)., Conclusion: In this comprehensive study of all ages of patients with NLPHL, we develop the LP-IPS to identify high-risk patients and inform upcoming prospective clinical trials evaluating de-escalation of therapy for patients with low LP-IPS scores (<2).
- Published
- 2024
- Full Text
- View/download PDF
13. TMTV-Net: fully automated total metabolic tumor volume segmentation in lymphoma PET/CT images - a multi-center generalizability analysis.
- Author
-
Yousefirizi F, Klyuzhin IS, O JH, Harsini S, Tie X, Shiri I, Shin M, Lee C, Cho SY, Bradshaw TJ, Zaidi H, Bénard F, Sehn LH, Savage KJ, Steidl C, Uribe CF, and Rahmim A
- Subjects
- Humans, Fluorodeoxyglucose F18, Automation, Male, Female, Positron Emission Tomography Computed Tomography methods, Lymphoma diagnostic imaging, Tumor Burden, Image Processing, Computer-Assisted methods
- Abstract
Purpose: Total metabolic tumor volume (TMTV) segmentation has significant value enabling quantitative imaging biomarkers for lymphoma management. In this work, we tackle the challenging task of automated tumor delineation in lymphoma from PET/CT scans using a cascaded approach., Methods: Our study included 1418 2-[
18 F]FDG PET/CT scans from four different centers. The dataset was divided into 900 scans for development/validation/testing phases and 518 for multi-center external testing. The former consisted of 450 lymphoma, lung cancer, and melanoma scans, along with 450 negative scans, while the latter consisted of lymphoma patients from different centers with diffuse large B cell, primary mediastinal large B cell, and classic Hodgkin lymphoma cases. Our approach involves resampling PET/CT images into different voxel sizes in the first step, followed by training multi-resolution 3D U-Nets on each resampled dataset using a fivefold cross-validation scheme. The models trained on different data splits were ensemble. After applying soft voting to the predicted masks, in the second step, we input the probability-averaged predictions, along with the input imaging data, into another 3D U-Net. Models were trained with semi-supervised loss. We additionally considered the effectiveness of using test time augmentation (TTA) to improve the segmentation performance after training. In addition to quantitative analysis including Dice score (DSC) and TMTV comparisons, the qualitative evaluation was also conducted by nuclear medicine physicians., Results: Our cascaded soft-voting guided approach resulted in performance with an average DSC of 0.68 ± 0.12 for the internal test data from developmental dataset, and an average DSC of 0.66 ± 0.18 on the multi-site external data (n = 518), significantly outperforming (p < 0.001) state-of-the-art (SOTA) approaches including nnU-Net and SWIN UNETR. While TTA yielded enhanced performance gains for some of the comparator methods, its impact on our cascaded approach was found to be negligible (DSC: 0.66 ± 0.16). Our approach reliably quantified TMTV, with a correlation of 0.89 with the ground truth (p < 0.001). Furthermore, in terms of visual assessment, concordance between quantitative evaluations and clinician feedback was observed in the majority of cases. The average relative error (ARE) and the absolute error (AE) in TMTV prediction on external multi-centric dataset were ARE = 0.43 ± 0.54 and AE = 157.32 ± 378.12 (mL) for all the external test data (n = 518), and ARE = 0.30 ± 0.22 and AE = 82.05 ± 99.78 (mL) when the 10% outliers (n = 53) were excluded., Conclusion: TMTV-Net demonstrates strong performance and generalizability in TMTV segmentation across multi-site external datasets, encompassing various lymphoma subtypes. A negligible reduction of 2% in overall performance during testing on external data highlights robust model generalizability across different centers and cancer types, likely attributable to its training with resampled inputs. Our model is publicly available, allowing easy multi-site evaluation and generalizability analysis on datasets from different institutions., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)- Published
- 2024
- Full Text
- View/download PDF
14. Nivolumab plus brentuximab vedotin for relapsed/refractory peripheral T-cell lymphoma and cutaneous T-cell lymphoma.
- Author
-
Zinzani PL, Salles G, Moskowitz AJ, Santoro A, Mehta A, Barr PM, Mehta-Shah N, Collins GP, Ansell SM, Brody JD, Domingo-Domenech E, Johnson NA, Cunningham D, Ferrari S, Lisano J, Krajewski J, Wen R, Akyol A, Crowe R, and Savage KJ
- Subjects
- Humans, Male, Middle Aged, Female, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Aged, Neoplasm Recurrence, Local drug therapy, Adult, Skin Neoplasms drug therapy, Skin Neoplasms pathology, Brentuximab Vedotin therapeutic use, Lymphoma, T-Cell, Peripheral drug therapy, Nivolumab therapeutic use, Nivolumab administration & dosage, Lymphoma, T-Cell, Cutaneous drug therapy, Lymphoma, T-Cell, Cutaneous pathology
- Published
- 2024
- Full Text
- View/download PDF
15. Exploration of Germline Correlates and Risk of Immune-Related Adverse Events in Advanced Cancer Patients Treated with Immune Checkpoint Inhibitors.
- Author
-
Titmuss E, Yu IS, Pleasance ED, Williamson LM, Mungall K, Mungall AJ, Renouf DJ, Moore R, Jones SJM, Marra MA, Laskin JJ, and Savage KJ
- Subjects
- Humans, Male, Female, Middle Aged, Aged, Germ-Line Mutation, Adult, Aged, 80 and over, Immune Checkpoint Inhibitors adverse effects, Immune Checkpoint Inhibitors therapeutic use, Neoplasms drug therapy
- Abstract
Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of many tumor types, and durable responses can be observed in select populations. However, patients may exhibit significant immune-related adverse events (irAEs) that may lead to morbidity. There is limited information on whether the presence of specific germline mutations may highlight those at elevated risk of irAEs. We evaluated 117 patients with metastatic solid tumors or hematologic malignancies who underwent genomic analysis through the ongoing Personalized OncoGenomics (POG) program at BC Cancer and received an ICI during their treatment history. Charts were reviewed for irAEs. Whole genome sequencing of a fresh biopsy and matched normal specimens (blood) was performed at the time of POG enrollment. Notably, we found that MHC class I alleles in the HLA-B27 family, which have been previously associated with autoimmune conditions, were associated with grade 3 hepatitis and pneumonitis (q = 0.007) in patients treated with combination PD-1/PD-L1 and CTLA-4 inhibitors, and PD-1 inhibitors in combination with IDO-1 inhibitors. These data highlight that some patients may have a genetic predisposition to developing irAEs.
- Published
- 2024
- Full Text
- View/download PDF
16. Semi-supervised learning towards automated segmentation of PET images with limited annotations: application to lymphoma patients.
- Author
-
Yousefirizi F, Shiri I, O JH, Bloise I, Martineau P, Wilson D, Bénard F, Sehn LH, Savage KJ, Zaidi H, Uribe CF, and Rahmim A
- Abstract
Manual segmentation poses a time-consuming challenge for disease quantification, therapy evaluation, treatment planning, and outcome prediction. Convolutional neural networks (CNNs) hold promise in accurately identifying tumor locations and boundaries in PET scans. However, a major hurdle is the extensive amount of supervised and annotated data necessary for training. To overcome this limitation, this study explores semi-supervised approaches utilizing unlabeled data, specifically focusing on PET images of diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma (PMBCL) obtained from two centers. We considered 2-[
18 F]FDG PET images of 292 patients PMBCL (n = 104) and DLBCL (n = 188) (n = 232 for training and validation, and n = 60 for external testing). We harnessed classical wisdom embedded in traditional segmentation methods, such as the fuzzy clustering loss function (FCM), to tailor the training strategy for a 3D U-Net model, incorporating both supervised and unsupervised learning approaches. Various supervision levels were explored, including fully supervised methods with labeled FCM and unified focal/Dice loss, unsupervised methods with robust FCM (RFCM) and Mumford-Shah (MS) loss, and semi-supervised methods combining FCM with supervised Dice loss (MS + Dice) or labeled FCM (RFCM + FCM). The unified loss function yielded higher Dice scores (0.73 ± 0.11; 95% CI 0.67-0.8) than Dice loss (p value < 0.01). Among the semi-supervised approaches, RFCM + αFCM (α = 0.3) showed the best performance, with Dice score of 0.68 ± 0.10 (95% CI 0.45-0.77), outperforming MS + αDice for any supervision level (any α) (p < 0.01). Another semi-supervised approach with MS + αDice (α = 0.2) achieved Dice score of 0.59 ± 0.09 (95% CI 0.44-0.76) surpassing other supervision levels (p < 0.01). Given the time-consuming nature of manual delineations and the inconsistencies they may introduce, semi-supervised approaches hold promise for automating medical imaging segmentation workflows., (© 2024. Australasian College of Physical Scientists and Engineers in Medicine.)- Published
- 2024
- Full Text
- View/download PDF
17. Spatially Resolved Tumor Microenvironment Predicts Treatment Outcomes in Relapsed/Refractory Hodgkin Lymphoma.
- Author
-
Aoki T, Jiang A, Xu A, Yin Y, Gamboa A, Milne K, Takata K, Miyata-Takata T, Chung S, Rai S, Wu S, Warren M, Strong C, Goodyear T, Morris K, Chong LC, Hav M, Colombo AR, Telenius A, Boyle M, Ben-Neriah S, Power M, Gerrie AS, Weng AP, Karsan A, Roth A, Farinha P, Scott DW, Savage KJ, Nelson BH, Merchant A, and Steidl C
- Subjects
- Humans, Tumor Microenvironment, Ecosystem, Neoplasm Recurrence, Local, Treatment Outcome, Recurrence, Hodgkin Disease drug therapy
- Abstract
Purpose: About a third of patients with relapsed or refractory classic Hodgkin lymphoma (r/r CHL) succumb to their disease after high-dose chemotherapy followed by autologous stem-cell transplantation (HDC/ASCT). Here, we aimed to describe spatially resolved tumor microenvironment (TME) ecosystems to establish novel biomarkers associated with treatment failure in r/r CHL., Patients and Methods: We performed imaging mass cytometry (IMC) on 71 paired primary diagnostic and relapse biopsies using a marker panel specific to CHL biology. For each cell type in the TME, we calculated a spatial score measuring the distance of nearest neighbor cells to the malignant Hodgkin Reed Sternberg cells within the close interaction range. Spatial scores were used as features in prognostic model development for post-ASCT outcomes., Results: Highly multiplexed IMC data revealed shared TME patterns in paired diagnostic and early r/r CHL samples, whereas TME patterns were more divergent in pairs of diagnostic and late relapse samples. Integrated analysis of IMC and single-cell RNA sequencing data identified unique architecture defined by CXCR5
+ Hodgkin and Reed Sternberg (HRS) cells and their strong spatial relationship with CXCL13+ macrophages in the TME. We developed a prognostic assay (RHL4S) using four spatially resolved parameters, CXCR5+ HRS cells, PD1+CD4+ T cells, CD68+ tumor-associated macrophages, and CXCR5+ B cells, which effectively separated patients into high-risk versus low-risk groups with significantly different post-ASCT outcomes. The RHL4S assay was validated in an independent r/r CHL cohort using a multicolor immunofluorescence assay., Conclusion: We identified the interaction of CXCR5+ HRS cells with ligand-expressing CXCL13+ macrophages as a prominent crosstalk axis in relapsed CHL. Harnessing this TME biology, we developed a novel prognostic model applicable to r/r CHL biopsies, RHL4S, opening new avenues for spatial biomarker development.- Published
- 2024
- Full Text
- View/download PDF
18. Evaluating Outcome Prediction via Baseline, End-of-Treatment, and Delta Radiomics on PET-CT Images of Primary Mediastinal Large B-Cell Lymphoma.
- Author
-
Yousefirizi F, Gowdy C, Klyuzhin IS, Sabouri M, Tonseth P, Hayden AR, Wilson D, Sehn LH, Scott DW, Steidl C, Savage KJ, Uribe CF, and Rahmim A
- Abstract
Objectives: Accurate outcome prediction is important for making informed clinical decisions in cancer treatment. In this study, we assessed the feasibility of using changes in radiomic features over time (Delta radiomics: absolute and relative) following chemotherapy, to predict relapse/progression and time to progression (TTP) of primary mediastinal large B-cell lymphoma (PMBCL) patients., Material and Methods: Given the lack of standard staging PET scans until 2011, only 31 out of 103 PMBCL patients in our retrospective study had both pre-treatment and end-of-treatment (EoT) scans. Consequently, our radiomics analysis focused on these 31 patients who underwent [
18 F]FDG PET-CT scans before and after R-CHOP chemotherapy. Expert manual lesion segmentation was conducted on their scans for delta radiomics analysis, along with an additional 19 EoT scans, totaling 50 segmented scans for single time point analysis. Radiomics features (on PET and CT), along with maximum and mean standardized uptake values (SUVmax and SUVmean), total metabolic tumor volume (TMTV), tumor dissemination (Dmax), total lesion glycolysis (TLG), and the area under the curve of cumulative standardized uptake value-volume histogram (AUC-CSH) were calculated. We additionally applied longitudinal analysis using radial mean intensity (RIM) changes. For prediction of relapse/progression, we utilized the individual coefficient approximation for risk estimation (ICARE) and machine learning (ML) techniques (K-Nearest Neighbor (KNN), Linear Discriminant Analysis (LDA), and Random Forest (RF)) including sequential feature selection (SFS) following correlation analysis for feature selection. For TTP, ICARE and CoxNet approaches were utilized. In all models, we used nested cross-validation (CV) (with 10 outer folds and 5 repetitions, along with 5 inner folds and 20 repetitions) after balancing the dataset using Synthetic Minority Oversampling TEchnique (SMOTE)., Results: To predict relapse/progression using Delta radiomics between the baseline (staging) and EoT scans, the best performances in terms of accuracy and F1 score (F1 score is the harmonic mean of precision and recall, where precision is the ratio of true positives to the sum of true positives and false positives, and recall is the ratio of true positives to the sum of true positives and false negatives) were achieved with ICARE (accuracy = 0.81 ± 0.15, F1 = 0.77 ± 0.18), RF (accuracy = 0.89 ± 0.04, F1 = 0.87 ± 0.04), and LDA (accuracy = 0.89 ± 0.03, F1 = 0.89 ± 0.03), that are higher compared to the predictive power achieved by using only EoT radiomics features. For the second category of our analysis, TTP prediction, the best performer was CoxNet (LASSO feature selection) with c-index = 0.67 ± 0.06 when using baseline + Delta features (inclusion of both baseline and Delta features). The TTP results via Delta radiomics were comparable to the use of radiomics features extracted from EoT scans for TTP analysis (c-index = 0.68 ± 0.09) using CoxNet (with SFS). The performance of Deauville Score (DS) for TTP was c-index = 0.66 ± 0.09 for n = 50 and 0.67 ± 03 for n = 31 cases when using EoT scans with no significant differences compared to the radiomics signature from either EoT scans or baseline + Delta features ( p -value> 0.05)., Conclusion: This work demonstrates the potential of Delta radiomics and the importance of using EoT scans to predict progression and TTP from PMBCL [18 F]FDG PET-CT scans.- Published
- 2024
- Full Text
- View/download PDF
19. Frontline therapy with bendamustine rituximab (BR) and rituximab cyclophosphamide vincristine prednisone (RCVP) confers similar long-term outcomes in patients with treatment naïve Waldenström macroglobulinemia in a real-world setting: a population-based analysis.
- Author
-
Kim JL, Gerrie AS, Savage KJ, Villa D, Scott D, Craig JW, Farinha P, Skinnider B, Slack G, Connors JM, Sehn LH, Venner C, and Freeman CL
- Subjects
- Humans, Rituximab adverse effects, Bendamustine Hydrochloride adverse effects, Vincristine adverse effects, Prednisone adverse effects, Cyclophosphamide adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Waldenstrom Macroglobulinemia diagnosis, Waldenstrom Macroglobulinemia drug therapy, Waldenstrom Macroglobulinemia etiology
- Abstract
We report on outcomes of 111 patients with treatment naïve Waldenström macroglobulinemia (TN WM) treated with frontline bendamustine-rituximab (BR) ( n = 57) or rituximab-cyclophosphamide-vincristine-prednisone (RCVP) ( n = 54). Median follow-up was 60.7 months (range 1.9-231.6). Median progression-free survival (PFS) was 60.5 months (95% CI 47.6-73.4) for BR and 79.0 months (95% CI 31.3-126.8) for RCVP ( p = .96). Median overall survival (OS) was not reached for BR and 153.4 months (95% CI 114.5-192.4) for RCVP ( p = .37). While overall and major response rates did not differ between treatment groups, BR had numerically higher rate of very good partial response or better response (51% vs. 37%, p = .30) and complete response (26% vs. 13%, p = .13). RCVP confers comparable outcomes to BR in a real-world population of TN WM patients and remains an effective regimen, particularly when tolerance or frailty is an issue, or in resource-limited settings.
- Published
- 2024
- Full Text
- View/download PDF
20. Brentuximab vedotin with chemotherapy in adolescents and young adults with stage III or IV classical Hodgkin lymphoma in ECHELON-1.
- Author
-
Crosswell HE, LaCasce AS, Bartlett NL, Straus DJ, Savage KJ, Zinzani PL, Collins GP, Fanale M, Fenton K, Dong C, Miao H, and Grigg AP
- Subjects
- Adolescent, Young Adult, Humans, Brentuximab Vedotin, Hodgkin Disease drug therapy
- Published
- 2024
- Full Text
- View/download PDF
21. Erratum to : Introduction to the peripheral T-cell lymphoma review series: advances in molecular characterization, classification refinement and treatment optimization.
- Author
-
Savage KJ and De Leval L
- Published
- 2024
- Full Text
- View/download PDF
22. Erratum to: DUSP22 -rearranged ALK-negative anaplastic large cell lymphoma is a pathogenetically distinct disease but can have variable clinical outcome.
- Author
-
Savage KJ and Slack GW
- Published
- 2024
- Full Text
- View/download PDF
23. High-Dose Methotrexate as CNS Prophylaxis in High-Risk Aggressive B-Cell Lymphoma.
- Author
-
Lewis KL, Jakobsen LH, Villa D, Smedby KE, Savage KJ, Eyre TA, Cwynarski K, Bishton MJ, Fox CP, Hawkes EA, Maurer MJ, El-Galaly TC, and Cheah CY
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Humans, Middle Aged, Young Adult, Retrospective Studies, Central Nervous System Neoplasms drug therapy, Central Nervous System Neoplasms pathology, Central Nervous System Neoplasms prevention & control, Lymphoma, B-Cell drug therapy, Methotrexate administration & dosage
- Abstract
Purpose: CNS progression or relapse is an uncommon but devastating complication of aggressive B-cell lymphoma. There is no consensus regarding the optimal approach to CNS prophylaxis. This study was designed to determine whether high-dose methotrexate (HD-MTX) is effective at preventing CNS progression in patients at high risk of this complication., Patients and Methods: Patients age 18-80 years with aggressive B-cell lymphoma and high risk of CNS progression, treated with curative-intent anti-CD20-based chemoimmunotherapy, were included in this international, retrospective, observational study. Cause-specific hazard ratios (HRs) and cumulative risks of CNS progression were calculated according to use of HD-MTX, with time to CNS progression calculated from diagnosis for all patients (all-pts) and from completion of frontline systemic lymphoma induction therapy, for patients in complete response at completion of chemoimmunotherapy (CR-pts)., Results: Two thousand four hundred eighteen all-pts (HD-MTX; n = 425) and 1,616 CR-pts (HD-MTX; n = 356) were included. CNS International Prognostic Index was 4-6 in 83.4% all-pts. Patients treated with HD-MTX had a lower risk of CNS progression (adjusted HR, 0.59 [95% CI, 0.38 to 0.90]; P = .014), but significance was not retained when confined to CR-pts (adjusted HR, 0.74 [95% CI, 0.42 to 1.30]; P = .29), with 5-year adjusted risk difference of 1.6% (95% CI, -1.5 to 4.4; all-pts) and 1.4% (95% CI, -1.5 to 4.1; CR-pts). Subgroups were underpowered to draw definitive conclusions regarding the efficacy of HD-MTX in individual high-risk clinical scenarios; however, there was no clear reduction in CNS progression risk with HD-MTX in any high-risk subgroup., Conclusion: In this large study, high-risk patients receiving HD-MTX had a 7.2% 2-year risk of CNS progression, consistent with the progression risk in previously reported high-risk cohorts. Use of HD-MTX was not associated with a clinically meaningful reduction in risk of CNS progression.
- Published
- 2023
- Full Text
- View/download PDF
24. Past, present and future therapeutic approaches in nodal peripheral T-cell lymphomas.
- Author
-
Ngu HS and Savage KJ
- Subjects
- Humans, Prednisone therapeutic use, Neoplasm Recurrence, Local drug therapy, Brentuximab Vedotin therapeutic use, Doxorubicin therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Lymphoma, T-Cell, Peripheral drug therapy, Lymphoma, T-Cell, Peripheral pathology
- Abstract
Peripheral T-cell lymphomas (PTCL) encompass over 30 different entities and although they share post-thymic T- or NK-cell derivation, the disease biology and genomic landscape are very diverse across subtypes. In Western populations, nodal PTCL are the most frequently encountered entities in clinical practice and although important achievements have been made in deciphering the underlying biology and in therapeutic advances, there are still large gaps in disease understanding and clinical scenarios in which controversy over best practice continues. CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)- based chemotherapy continues to be the 'standard' treatment, with the addition of brentuximab vedotin (BV) in the combination CHP (cyclosphosphamide, doxorubicin, prednisone)-BV representing a new treatment paradigm in CD30+ PTCL although its benefit is less certain in the non-anaplastic large cell lymphoma subtypes. Given the high risk of relapse, consolidative autologous stem cell transplant is considered in nodal PTCL, outside of ALK-positive anaplastic large cell lymphoma; however, in the absence of a randomized controlled trials, practices vary. Beyond CHP-BV, most study activity has focused on adding a novel agent to CHOP (i.e., CHOP + drug X). However, with high complete remission rates observed with some novel therapy combinations, these regimens are being tested in the front-line setting, with a particular rationale in follicular helper T-cell lymphomas which have a clear sensitivity to epigenetic modifying therapies. This is well exemplified in the relapsed/refractory setting in which rational combination therapies are being developed for specific subtypes or guided by underlying biology. Taken together, we have finally moved into an era of a more personalized approach to the management of nodal PTCL.
- Published
- 2023
- Full Text
- View/download PDF
25. Introduction to the peripheral T-cell lymphoma review series: advances in molecular characterization, classification refinement and treatment optimization.
- Author
-
Savage KJ and De Leval L
- Subjects
- Humans, Lymphoma, T-Cell, Peripheral diagnosis, Lymphoma, T-Cell, Peripheral genetics, Lymphoma, T-Cell, Peripheral therapy
- Published
- 2023
- Full Text
- View/download PDF
26. Pathobiology of nodal peripheral T-cell lymphomas: current understanding and future directions.
- Author
-
Bisig B, Savage KJ, and De Leval L
- Subjects
- Humans, Herpesvirus 4, Human, Killer Cells, Natural metabolism, Lymphoma, T-Cell, Peripheral pathology, Epstein-Barr Virus Infections, Lymphoma, Large-Cell, Anaplastic genetics
- Abstract
Predominantly nodal is the most common clinical presentation of peripheral T- (and NK-) cell lymphomas (PTCL), which comprise three main groups of diseases: (i) systemic anaplastic large cell lymphomas (ALCL), whether positive or negative for anaplastic lymphoma kinase (ALK); (ii) follicular helper T-cell lymphomas (TFHL); and (iii) PTCL, not otherwise specified (NOS). Recent advances in the genomic and molecular characterization of PTCL, with enhanced understanding of pathobiology, have translated into significant updates in the latest 2022 classifications of lymphomas. ALK-negative ALCL is now recognized to be genetically heterogeneous, with identification of DUSP22 rearrangements in approximately 20-30% of cases, correlated with distinctive pathological and biological features. The notion of cell-of-origin as an important determinant of the classification of nodal PTCL is best exemplified by TFHL, considered as one disease or a group of related entities, sharing oncogenic pathways with frequent recurrent epigenetic mutations as well as a relationship to clonal hematopoiesis. Data are emerging to support that a similar cell-of-origin concept might be relevant to characterize meaningful subgroups within PTCL, NOS, based on cytotoxic and/or Th1 versus Th2 signatures. The small group of primary nodal Epstein-Barr virus-positive lymphomas of T- or NK-cell derivation, formerly considered PTCL, NOS, is now classified separately, due to distinctive features, and notably an aggressive course. This review summarizes current knowledge of the pathology and biology of nodal-based PTCL entities, with an emphasis on recent findings and underlying oncogenic mechanisms.
- Published
- 2023
- Full Text
- View/download PDF
27. Nivolumab for relapsed/refractory classical Hodgkin lymphoma: 5-year survival from the pivotal phase 2 CheckMate 205 study.
- Author
-
Ansell SM, Bröckelmann PJ, von Keudell G, Lee HJ, Santoro A, Zinzani PL, Collins GP, Cohen JB, de Boer JP, Kuruvilla J, Savage KJ, Trněný M, Provencio M, Jäger U, Willenbacher W, Wen R, Akyol A, Mikita-Geoffroy J, Shipp MA, Engert A, and Armand P
- Subjects
- Humans, Nivolumab therapeutic use, Neoplasm Recurrence, Local drug therapy, Brentuximab Vedotin, Chronic Disease, Hodgkin Disease pathology, Immunoconjugates
- Abstract
Patients with relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) for whom autologous hematopoietic cell transplantation (auto-HCT) had failed experienced frequent and durable responses to nivolumab in the phase 2 CheckMate 205 trial. We present updated results (median follow-up, ∼5 years). Patients with R/R cHL who were brentuximab vedotin (BV)-naive (cohort A), received BV after auto-HCT (cohort B), or received BV before and/or after auto-HCT (cohort C) were administered with nivolumab 3 mg/kg IV every 2 weeks until progression or unacceptable toxicity. Patients in cohort C with complete remission (CR) for 1 year could discontinue nivolumab and resume upon relapse. Among 243 patients (cohort A, n = 63; B, n = 80; and C, n = 100), the objective response rate (ORR) was 71.2% (95% confidence interval [CI], 65.1-76.8); the CR rate was 21.4% (95% CI, 16.4-27.1). Median duration of response, CR, and partial remission were 18.2 (95% CI, 14.7-26.1), 30.3, and 13.5 months, respectively. Median progression-free survival was 15.1 months (95% CI, 11.3-18.5). Median overall survival (OS) was not reached; OS at 5 years was 71.4% (95% CI, 64.8-77.1). In cohort C, all 3 patients who discontinued in CR and were subsequently re-treated achieved objective response. No new or unexpected safety signals were identified. This 5-year follow-up of CheckMate 205 demonstrated favorable OS and confirmed efficacy and safety of nivolumab in R/R cHL after auto-HCT failure. Results suggest patients may discontinue treatment after persistent CR and reinitiate upon progression. This trial was registered at www.clinicaltrials.gov as #NCT02181713., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
28. Relapse Timing Is Associated With Distinct Evolutionary Dynamics in Diffuse Large B-Cell Lymphoma.
- Author
-
Hilton LK, Ngu HS, Collinge B, Dreval K, Ben-Neriah S, Rushton CK, Wong JCH, Cruz M, Roth A, Boyle M, Meissner B, Slack GW, Farinha P, Craig JW, Gerrie AS, Freeman CL, Villa D, Rodrigo JA, Song K, Crump M, Shepherd L, Hay AE, Kuruvilla J, Savage KJ, Kridel R, Karsan A, Marra MA, Sehn LH, Steidl C, Morin RD, and Scott DW
- Subjects
- Humans, Neoplasm Recurrence, Local drug therapy, Chronic Disease, Transplantation, Autologous, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Lymphoma, Large B-Cell, Diffuse therapy, Lymphoma, Large B-Cell, Diffuse drug therapy, Hematopoietic Stem Cell Transplantation
- Abstract
Purpose: Diffuse large B-cell lymphoma (DLBCL) is cured in more than 60% of patients, but outcomes remain poor for patients experiencing disease progression or relapse (refractory or relapsed DLBCL [rrDLBCL]), particularly if these events occur early. Although previous studies examining cohorts of rrDLBCL have identified features that are enriched at relapse, few have directly compared serial biopsies to uncover biological and evolutionary dynamics driving rrDLBCL. Here, we sought to confirm the relationship between relapse timing and outcomes after second-line (immuno)chemotherapy and determine the evolutionary dynamics that underpin that relationship., Patients and Methods: Outcomes were examined in a population-based cohort of 221 patients with DLBCL who experienced progression/relapse after frontline treatment and were treated with second-line (immuno)chemotherapy with an intention-to-treat with autologous stem-cell transplantation (ASCT). Serial DLBCL biopsies from a partially overlapping cohort of 129 patients underwent molecular characterization, including whole-genome or whole-exome sequencing in 73 patients., Results: Outcomes to second-line therapy and ASCT are superior for late relapse (>2 years postdiagnosis) versus primary refractory (<9 months) or early relapse (9-24 months). Diagnostic and relapse biopsies were mostly concordant for cell-of-origin classification and genetics-based subgroup. Despite this concordance, the number of mutations exclusive to each biopsy increased with time since diagnosis, and late relapses shared few mutations with their diagnostic counterpart, demonstrating a branching evolution pattern. In patients with highly divergent tumors, many of the same genes acquired new mutations independently in each tumor, suggesting that the earliest mutations in a shared precursor cell constrain tumor evolution toward the same genetics-based subgroups at both diagnosis and relapse., Conclusion: These results suggest that late relapses commonly represent genetically distinct and chemotherapy-naïve disease and have implications for optimal patient management.
- Published
- 2023
- Full Text
- View/download PDF
29. Critical gaps in understanding treatment outcomes in adolescents and young adults with lymphoma: A review of current data.
- Author
-
Pophali PA, Morton LM, Parsons SK, Hodgson D, Thanarajasingam G, Thompson C, Habermann TM, and Savage KJ
- Abstract
Adolescents and young adults (AYA) with lymphoma experience treatment-related effects in the short and long term that impact their quality of life and survivorship experience. The effort to improve outcomes for AYA lymphoma survivors requires understanding the available literature, identifying current knowledge deficits, designing better clinical trials incorporating the patient perspective, using novel tools to bridge data gaps and building survivorship guidelines that translate research to clinical practice. This review article summarizes the current state of lymphoma treatment-related outcomes in AYAs and provides future direction., Competing Interests: P.A.P. Scientific Advisory Board: SeaGen. G.T. Advisory board: SeaGen (August 2022, all funds to research at Mayo Clinic, no personal remuneration). T.H. Data Monitoring Committee: Seagen, Tess Therapeutics, Eli Lilly & Co.; Scientific Advisory Board: Morpohsys, Incyte, Biegene, Loxo Oncology; Research Support to the LEO grant: Genentech, Sorrento, BMS., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2023
- Full Text
- View/download PDF
30. Treating relapsed/refractory mature T- and NK-cell neoplasms with tislelizumab: a multicenter open-label phase 2 study.
- Author
-
Bachy E, Savage KJ, Huang H, Kwong YL, Gritti G, Zhang Q, Liberati AM, Cao J, Yang H, Hao S, Hu J, Zhou K, Petrini M, Russo F, Zhang H, Sang W, Ji J, Ferreri AJM, Damaj GL, Liu H, Zhang W, Ke X, Ghiggi C, Huang S, Li X, Yao H, Paik J, Novotny W, Zhou W, Zhu H, and Zinzani PL
- Subjects
- Humans, Killer Cells, Natural pathology, Mycosis Fungoides drug therapy, Lymphoma, T-Cell, Cutaneous drug therapy, Skin Neoplasms drug therapy
- Abstract
Patients with relapsed/refractory (R/R) mature T- and natural killer (NK)-cell neoplasms lack effective treatments after failure of standard therapies. This phase 2 study evaluated the efficacy and safety of the programmed cell death protein 1 inhibitor tislelizumab in these patients. Seventy-seven patients were treated with 200 mg tislelizumab every 3 weeks. Twenty-two patients with extranodal NK-/T-cell lymphomas were enrolled in cohort 1; 44 patients with peripheral T-cell lymphoma (PTCL) were enrolled in cohort 2 (21 patients had PTCL not otherwise specified, 11 patients had angioimmunoblastic T-cell lymphoma, and 12 patients had anaplastic large-cell lymphoma). Cohort 3 comprised 11 patients with cutaneous T-cell lymphoma, of which 8 patients had mycosis fungoides (MF) and 3 had Sézary syndrome. Of the 77 patients, 76.6% had advanced-stage disease, 51.9% had refractory disease, and 49.4% received ≥3 prior systemic regimens. Promising efficacy was observed in cohort 3 (median follow-up [FU], 16.6 months; overall response rate [ORR], 45.5%; complete response [CR], 9.1%; median duration of response [DOR], 11.3 months; median progression-free survival, 16.8 months; median overall survival, not reached). Modest efficacy was observed in cohort 1 (median FU, 8.4 months; ORR, 31.8%; CR, 18.2%; median DOR, not reached) and cohort 2 (median FU, 9.3 months; ORR, 20.5%; CR, 9.1%; median DOR, 8.2 months). Most treatment-related adverse events were grade 1 or 2, and the safety profile was consistent with the known safety profile of tislelizumab. In conclusion, tislelizumab was well tolerated, achieving modest efficacy in R/R mature T- and NK-cell neoplasms, with some long-lasting remissions. This trial was registered at www.clinicaltrials.gov as #NCT03493451., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
31. Central nervous system lymphomas-Assessment and treatment and prevention of central nervous system relapse.
- Author
-
Ghione P, Lewis KL, Bobillo S, Nayak L, Schorb E, Nichelli L, Ng A, Savage KJ, McKay P, Nastoupil L, Soussain C, and Cwynarski K
- Abstract
In this review focused on lymphoma and the central nervous system (CNS), we summarize recent developments in the management of primary (PCNSL) and secondary CNS lymphoma (SCNSL), treatment of CNS lymphoma in the older population, the neuroradiological assessment of CNS lymphoma and finally highlight the ongoing debate on optimal CNS prophylaxis. The section on PCNSL focuses on the different approaches available for frontline treatment in Europe and the United States and discusses consolidation strategies. We then highlight available strategies to treat PCNSL in the elderly population, an area of unmet need. New therapies aiming at minimizing toxicity and prioritizing quality of life are emerging for these patients. Secondary CNS lymphoma, especially in the relapsed/refractory setting is another area of unmet need, and the efficacy of CAR-T cell therapy is being explored. We provide an overview of the imaging challenges in the neuroradiological assessment of CNS lymphoma. Finally, the section on CNS prophylaxis summarizes recent findings from large retrospective studies challenging the efficacy of present approaches to prophylaxis in higher-risk patients with lymphoma., (© 2023 John Wiley & Sons Ltd.)
- Published
- 2023
- Full Text
- View/download PDF
32. Hematological Oncology journal women in lymphoma special issue: Latest updates in nodal peripheral T-cell lymphoma.
- Author
-
Poon L, de Leval L, Ng SB, Song Y, Pro B, Savage KJ, Ruan J, Mehta-Shah N, and Vose JM
- Abstract
In the last decade, there has been increased understanding of the pathologic features and biology of peripheral T cell lymphomas (PTCLs) through development of multi omics and molecular profiling techniques. In addition, international collaborations through multi center trials as well as prospective registry studies have improved our knowledge of host and tumor genomic factors and treatment factors affecting disease outcomes. In our review today, we aim to highlight the current epidemiology, latest advances in classification, disease biology and the evolving treatment landscape for nodal PTCLs., (© 2023 John Wiley & Sons Ltd.)
- Published
- 2023
- Full Text
- View/download PDF
33. DUSP22 -rearranged ALK-negative anaplastic large cell lymphoma is a pathogenetically distinct disease but can have variable clinical outcome.
- Author
-
Savage KJ and Slack GW
- Subjects
- Humans, Receptor Protein-Tyrosine Kinases, Anaplastic Lymphoma Kinase genetics, Dual-Specificity Phosphatases genetics, Mitogen-Activated Protein Kinase Phosphatases genetics, Lymphoma, Large-Cell, Anaplastic genetics, Lymphoma, Large-Cell, Anaplastic pathology
- Published
- 2023
- Full Text
- View/download PDF
34. Population-level impact of ibrutinib for chronic lymphocytic leukemia in British Columbia, Canada.
- Author
-
Khelifi RS, Huang SJ, Savage KJ, Villa D, Scott DW, Ramadan K, Connors JM, Sehn LH, Toze CL, and Gerrie AS
- Subjects
- Humans, British Columbia epidemiology, Piperidines therapeutic use, Adenine, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell epidemiology
- Abstract
Ibrutinib has dramatically changed the treatment landscape for chronic lymphocytic leukemia (CLL) since its availability in British Columbia (BC), Canada in 2014. We analyzed patterns of use and real-world survival outcomes in 370 patients who received ibrutinib for first-line (1 L, n = 35) and relapsed/refractory (R/R, n = 335) CLL between 2014-2018 in BC. Dose reductions and interruptions were frequent in 32% and 27%, respectively. With a median follow-up of 27.6 months, 35% of patients discontinued ibrutinib, primarily for adverse events (AEs) rather than progressive disease. Over the course of treatment, 87% of patients experienced at least one adverse event. The 2-year overall survival (OS) and event-free survival (EFS) were excellent at 83.9% and 76.1%, respectively, with medians not reached. However, patients who discontinued ibrutinib had a median OS of 32.5 months and median EFS of only 3.8 months from time of discontinuation, highlighting the need to minimize toxicity in the real-world.
- Published
- 2023
- Full Text
- View/download PDF
35. Nivolumab combined with brentuximab vedotin for relapsed/refractory mediastinal gray zone lymphoma.
- Author
-
Santoro A, Moskowitz AJ, Ferrari S, Carlo-Stella C, Lisano J, Francis S, Wen R, Akyol A, and Savage KJ
- Subjects
- Humans, Brentuximab Vedotin, Nivolumab therapeutic use, Hodgkin Disease drug therapy, Hodgkin Disease pathology, Immunoconjugates therapeutic use, Mediastinal Neoplasms drug therapy
- Published
- 2023
- Full Text
- View/download PDF
36. Molecular determinants of clinical outcomes in a real-world diffuse large B-cell lymphoma population.
- Author
-
Alduaij W, Collinge B, Ben-Neriah S, Jiang A, Hilton LK, Boyle M, Meissner B, Chong L, Miyata-Takata T, Slack GW, Farinha P, Craig JW, Lytle A, Savage KJ, Villa D, Gerrie AS, Freeman CL, Gascoyne RD, Connors JM, Morin RD, Sehn LH, Mungall AJ, Steidl C, and Scott DW
- Subjects
- Humans, In Situ Hybridization, Fluorescence, Prospective Studies, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-bcl-2 metabolism, Prognosis, Proto-Oncogene Proteins c-myc genetics, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse epidemiology, Lymphoma, Large B-Cell, Diffuse genetics
- Abstract
Molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) underlies the variable outcomes achieved with immunochemotherapy. However, outcomes of gene expression profiling (GEP)-defined molecular subgroups in a real-world DLBCL population remain unknown. Here we examined the prevalence and outcomes of molecular subgroups in an unselected population of 1149 patients with de novo DLBCL in British Columbia, Canada. Evaluable biopsies were profiled by fluorescence in situ hybridization (FISH), immunohistochemistry, and digital GEP to assign cell-of-origin and the so-called "double-hit signature" (DHITsig)-a signature originally described as being characteristic for high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-DH-BCL2). DHITsig was expressed in 21% of 431 germinal center B-cell-like (GCB)-DLBCL and all 55 Burkitt lymphomas examined. Reflecting this latter finding, DHITsig has been renamed the "dark zone signature" (DZsig). DZsigpos-DLBCL, non-DZsigpos GCB-DLBCL and activated B-cell-like (ABC)-DLBCL were associated with a 2 year overall survival of 57%, 89%, and 71%, respectively. 62% of DZsigpos tumors were negative for HGBCL-DH-BCL2 by FISH, but were associated with outcomes similar to HGBCL-DH-BCL2. A small group of HGBCL-DH-BCL2 that lacked DZsig expression had different molecular features compared with DZsig-expressing HGBCL-DH-BCL2 and were associated with favorable outcomes comparable to DLBCL, not otherwise specified. DZsigpos and ABC-DLBCL had a shorter diagnosis-to-treatment interval (DTI) than GCB-DLBCL, with this metric being associated with outcome. In conclusion, DZsig expression extends beyond HGBCL-DH-BCL2 and captures a poor-prognosis DLBCL subgroup with short DTI, including patients unidentifiable by routine FISH testing, that should be considered for treatment intensification or novel therapies in prospective trials., (© 2023 by The American Society of Hematology.)
- Published
- 2023
- Full Text
- View/download PDF
37. Frontline Management of Nodal Peripheral T-Cell Lymphomas.
- Author
-
Ngu HS and Savage KJ
- Subjects
- Humans, Prednisone therapeutic use, Brentuximab Vedotin therapeutic use, Cyclophosphamide therapeutic use, Doxorubicin therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Lymphoma, T-Cell, Peripheral diagnosis, Lymphoma, T-Cell, Peripheral drug therapy, Lymphoma, T-Cell, Peripheral genetics
- Abstract
Peripheral T-cell lymphomas (PTCLs) represent only 10%-15% of all non-Hodgkin lymphoma but encompass a diverse group of diseases with over 30 different subtypes. As a result of both disease heterogeneity and rarity, therapeutic progress of PTCLs has lagged behind B-cell lymphomas with very few randomized controlled studies to guide management. The most common subtypes are the so-called nodal PTCLs: PTCL-not otherwise specified (NOS), anaplastic large cell lymphoma (ALCL), and nodal T follicular helper cell lymphoma (TFHL) lymphoma, the latter of which includes angioimmunoblastic T-cell lymphoma. Anthracycline-based primary chemotherapy is still the mainstay of treatment for these common PTCL subtypes, but in recent years, we have moved into an era where more personalized therapy can be applied in some settings. Cyclophosphamide, doxorubicin, prednisone, and brentuximab vedotin CHP-BV is the first therapy in PTCL to show an overall survival benefit and represents a new standard for ALCL; however, there is less therapeutic certainty in other CD30-positive PTCLs. Recurrent mutations of epigenetic modifier genes typify TFHLs lymphomas, and collective studies demonstrate a heightened sensitivity to epigenetic therapies, leading to trials integrating these agents in the frontline setting. Molecular studies of PTCL-NOS have defined at least two subtypes, GATA3 and TBX21, the former having a poorer prognosis, but how this guides therapeutics remains unknown. Outside of ALCL, there is a growing debate as to whether trials should focus on adding a novel agent to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or whether combination novel therapies should be explored in the frontline therapy setting. Finally, the role of consolidative autologous stem-cell transplant in first remission remains an area of active debate.
- Published
- 2023
- Full Text
- View/download PDF
38. Cost-Effectiveness of Brentuximab Vedotin Versus Physician's Choice of Methotrexate or Bexarotene for the Treatment of Cutaneous T-cell Lymphoma in Canada.
- Author
-
Elsea D, Savage KJ, Lilley C, Lisano J, Liu J, and Yu KS
- Subjects
- Humans, Brentuximab Vedotin therapeutic use, Bexarotene therapeutic use, Methotrexate therapeutic use, Cost-Benefit Analysis, Neoplasm Recurrence, Local drug therapy, Canada, Immunoconjugates therapeutic use, Lymphoma, T-Cell, Cutaneous drug therapy, Lymphoma, T-Cell, Cutaneous pathology, Skin Neoplasms drug therapy, Skin Neoplasms pathology, Physicians
- Abstract
Introduction: Brentuximab vedotin versus physician's choice of methotrexate (MTX) or bexarotene (BEX) significantly improved progression-free survival (PFS) (median PFS, 16.7 vs. 3.5 months) and delayed time to subsequent treatment (8.4 vs. 3.7 months), with similar overall survival in patients with CD30-expressing mycosis fungoides (MF) or primary cutaneous anaplastic large cell lymphoma (pcALCL), two types of cutaneous T-cell lymphomas. We assessed the cost-effectiveness of brentuximab vedotin versus MTX or BEX from a Canadian healthcare payer perspective in the indicated population., Methods: A 5-state partitioned survival model [pre-progression, non-stem cell transplant (SCT) post-progression, SCT, SCT relapse, death] with a weekly cycle length and 45-year lifetime horizon has been developed. Health-state occupancies, utility estimates, and treatment duration were informed by ALCANZA. Other inputs and costs came from the literature or clinician experts. Scenario analyses varied key parameters and tested assumptions., Results: Brentuximab vedotin versus MTX or BEX was cost-effective; the incremental cost-effectiveness ratio was CAN$43,790 per quality-adjusted life year (QALY) gained. Brentuximab vedotin was more effective (incremental life years: 0.15; QALYs: 0.25) and total treatment costs were slightly higher (incremental costs: $11,105) than MTX or BEX. Key model drivers included end-stage care duration, SCT eligibility, and brentuximab vedotin retreatment rates., Conclusion: Brentuximab vedotin compared with MTX or BEX was cost-effective for CD30-expressing MF and pcALCL. Brentuximab vedotin's higher drug costs versus MTX or BEX were offset by decreased post-progression and end-stage management costs, and showed a 0.25 QALY gain versus MTX or BEX, and increased the proportion of patients eligible for potentially curative SCT., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
39. The Advanced-Stage Hodgkin Lymphoma International Prognostic Index: Development and Validation of a Clinical Prediction Model From the HoLISTIC Consortium.
- Author
-
Rodday AM, Parsons SK, Upshaw JN, Friedberg JW, Gallamini A, Hawkes E, Hodgson D, Johnson P, Link BK, Mou E, Savage KJ, Zinzani PL, Maurer M, and Evens AM
- Subjects
- Adult, Humans, Middle Aged, Aged, Prognosis, Models, Statistical, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Survival Analysis, Retrospective Studies, Hodgkin Disease drug therapy
- Abstract
Purpose: The International Prognostic Score (IPS) has been used in classic Hodgkin lymphoma (cHL) for 25 years. However, analyses have documented suboptimal performance of the IPS among contemporarily treated patients. Harnessing multisource individual patient data from the Hodgkin Lymphoma International Study for Individual Care consortium, we developed and validated a modern clinical prediction model., Methods: Model development via Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis guidelines was performed on 4,022 patients with newly diagnosed advanced-stage adult cHL from eight international phase III clinical trials, conducted from 1996 to 2014. External validation was performed on 1,431 contemporaneously treated patients from four real-world cHL registries. To consider association over a full range of continuous variables, we evaluated piecewise linear splines for potential nonlinear relationships. Five-year progression-free survival (PFS) and overall survival (OS) were estimated using Cox proportional hazard models., Results: The median age in the development cohort was 33 (18-65) years; nodular sclerosis was the most common histology. Kaplan-Meier estimators were 0.77 for 5-year PFS and 0.92 for 5-year OS. Significant predictor variables included age, sex, stage, bulk, absolute lymphocyte count, hemoglobin, and albumin, with slight variation for PFS versus OS. Moreover, age and absolute lymphocyte count yielded nonlinear relationships with outcomes. Optimism-corrected c-statistics in the development model for 5-year PFS and OS were 0.590 and 0.720, respectively. There was good discrimination and calibration in external validation and consistent performance in internal-external validation. Compared with the IPS, there was superior discrimination for OS and enhanced calibration for PFS and OS., Conclusion: We rigorously developed and externally validated a clinical prediction model in > 5,000 patients with advanced-stage cHL. Furthermore, we identified several novel nonlinear relationships and improved the prediction of patient outcomes. An online calculator was created for individualized point-of-care use.
- Published
- 2023
- Full Text
- View/download PDF
40. Relapse timing is associated with distinct evolutionary dynamics in DLBCL.
- Author
-
Hilton LK, Ngu HS, Collinge B, Dreval K, Ben-Neriah S, Rushton CK, Wong JCH, Cruz M, Roth A, Boyle M, Meissner B, Slack GW, Farinha P, Craig JW, Gerrie AS, Freeman CL, Villa D, Crump M, Shepherd L, Hay AE, Kuruvilla J, Savage KJ, Kridel R, Karsan A, Marra MA, Sehn LH, Steidl C, Morin RD, and Scott DW
- Abstract
Diffuse large B-cell lymphoma (DLBCL) is cured in over 60% of patients, but outcomes are poor for patients with relapsed or refractory disease (rrDLBCL). Here, we performed whole genome/exome sequencing (WGS/WES) on tumors from 73 serially-biopsied patients with rrDLBCL. Based on the observation that outcomes to salvage therapy/autologous stem cell transplantation are related to time-to-relapse, we stratified patients into groups according to relapse timing to explore the relationship to genetic divergence and sensitivity to salvage immunochemotherapy. The degree of mutational divergence increased with time between biopsies, yet tumor pairs were mostly concordant for cell-of-origin, oncogene rearrangement status and genetics-based subgroup. In patients with highly divergent tumors, several genes acquired exclusive mutations independently in each tumor, which, along with concordance of genetics-based subgroups, suggests that the earliest mutations in a shared precursor cell constrain tumor evolution. These results suggest that late relapses commonly represent genetically distinct and chemotherapy-naïve disease.
- Published
- 2023
- Full Text
- View/download PDF
41. Gene Expression Signatures for the Accurate Diagnosis of Peripheral T-Cell Lymphoma Entities in the Routine Clinical Practice.
- Author
-
Amador C, Bouska A, Wright G, Weisenburger DD, Feldman AL, Greiner TC, Lone W, Heavican T, Smith L, Pileri S, Tabanelli V, Ott G, Rosenwald A, Savage KJ, Slack G, Kim WS, Hyeh Y, Li Y, Dong G, Song J, Ondrejka S, Cook JR, Barrionuevo C, Lim ST, Ong CK, Chapman J, Inghirami G, Raess PW, Bhagavathi S, Gould C, Blombery P, Jaffe E, Morris SW, Rimsza LM, Vose JM, Staudt L, Chan WC, and Iqbal J
- Subjects
- Humans, Transcriptome, Reproducibility of Results, Gene Expression Profiling, Prognosis, Lymphoma, T-Cell, Peripheral diagnosis, Lymphoma, T-Cell, Peripheral genetics
- Abstract
Purpose: Peripheral T-cell lymphoma (PTCL) includes heterogeneous clinicopathologic entities with numerous diagnostic and treatment challenges. We previously defined robust transcriptomic signatures that distinguish common PTCL entities and identified two novel biologic and prognostic PTCL-not otherwise specified subtypes (PTCL-TBX21 and PTCL-GATA3). We aimed to consolidate a gene expression-based subclassification using formalin-fixed, paraffin-embedded (FFPE) tissues to improve the accuracy and precision in PTCL diagnosis., Materials and Methods: We assembled a well-characterized PTCL training cohort (n = 105) with gene expression profiling data to derive a diagnostic signature using fresh-frozen tissue on the HG-U133plus2.0 platform (Affymetrix, Inc, Santa Clara, CA) subsequently validated using matched FFPE tissues in a digital gene expression profiling platform (nCounter, NanoString Technologies, Inc, Seattle, WA). Statistical filtering approaches were applied to refine the transcriptomic signatures and then validated in another PTCL cohort (n = 140) with rigorous pathology review and ancillary assays., Results: In the training cohort, the refined transcriptomic classifier in FFPE tissues showed high sensitivity (> 80%), specificity (> 95%), and accuracy (> 94%) for PTCL subclassification compared with the fresh-frozen-derived diagnostic model and showed high reproducibility between three independent laboratories. In the validation cohort, the transcriptional classifier matched the pathology diagnosis rendered by three expert hematopathologists in 85% (n = 119) of the cases, showed borderline association with the molecular signatures in 6% (n = 8), and disagreed in 8% (n = 11). The classifier improved the pathology diagnosis in two cases, validated by clinical findings. Of the 11 cases with disagreements, four had a molecular classification that may provide an improvement over pathology diagnosis on the basis of overall transcriptomic and morphological features. The molecular subclassification provided a comprehensive molecular characterization of PTCL subtypes, including viral etiologic factors and translocation partners., Conclusion: We developed a novel transcriptomic approach for PTCL subclassification that facilitates translation into clinical practice with higher precision and uniformity than conventional pathology diagnosis.
- Published
- 2022
- Full Text
- View/download PDF
42. Genomic profiling for clinical decision making in lymphoid neoplasms.
- Author
-
de Leval L, Alizadeh AA, Bergsagel PL, Campo E, Davies A, Dogan A, Fitzgibbon J, Horwitz SM, Melnick AM, Morice WG, Morin RD, Nadel B, Pileri SA, Rosenquist R, Rossi D, Salaverria I, Steidl C, Treon SP, Zelenetz AD, Advani RH, Allen CE, Ansell SM, Chan WC, Cook JR, Cook LB, d'Amore F, Dirnhofer S, Dreyling M, Dunleavy K, Feldman AL, Fend F, Gaulard P, Ghia P, Gribben JG, Hermine O, Hodson DJ, Hsi ED, Inghirami G, Jaffe ES, Karube K, Kataoka K, Klapper W, Kim WS, King RL, Ko YH, LaCasce AS, Lenz G, Martin-Subero JI, Piris MA, Pittaluga S, Pasqualucci L, Quintanilla-Martinez L, Rodig SJ, Rosenwald A, Salles GA, San-Miguel J, Savage KJ, Sehn LH, Semenzato G, Staudt LM, Swerdlow SH, Tam CS, Trotman J, Vose JM, Weigert O, Wilson WH, Winter JN, Wu CJ, Zinzani PL, Zucca E, Bagg A, and Scott DW
- Subjects
- Humans, Genomics methods, Precision Medicine, High-Throughput Nucleotide Sequencing, Clinical Decision-Making, Lymphoma diagnosis, Lymphoma genetics, Lymphoma therapy, Neoplasms
- Abstract
With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. Although the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet, the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification, and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses, and epigenetic profiling will be discussed because these will likely become important future tools for implementing precision medicine approaches in clinical decision making for patients with lymphoid malignancies., (© 2022 by The American Society of Hematology.)
- Published
- 2022
- Full Text
- View/download PDF
43. The outcome of older adults with classic Hodgkin lymphoma in British Columbia.
- Author
-
Cheng PTM, Villa D, Gerrie AS, Freeman CL, Slack GW, Gascoyne RD, Farinha P, Craig JW, Skinnider B, Wilson D, Scott DW, Connors JM, Sehn LH, and Savage KJ
- Subjects
- Humans, Aged, Middle Aged, Aged, 80 and over, British Columbia epidemiology, Bleomycin adverse effects, Hodgkin Disease drug therapy, Hodgkin Disease epidemiology
- Abstract
Outcomes in older adults with classic Hodgkin lymphoma (cHL) have traditionally been poor, in part, related to poor tolerance to standard chemotherapy. Herein, we evaluated the survival of patients with cHL aged ≥60 years in British Columbia in a population-based analysis. From 1961 to 2019, 744 patients with newly diagnosed cHL were identified. With a median follow-up of 9 years, 5-year disease-specific survival (DSS) and overall survival (OS) have improved by decade comparison (both P < .001), remaining stable in the past 20 years (DSS, P = .35; OS, P = .26). In the modern management era (2000-present), 361 of 401 patients (90%) received active therapy for cHL and had a 5-year OS of 60%. For those who received curative-intent therapy (n = 327), the 5-year progression-free survival (PFS), OS, and DSS were 60%, 65%, and 76%, respectively, and estimates were superior in those who were 60 to 69 years of age (72%, 77%, and 83%, respectively) compared with those who were 70 to 79 years of age (54%, 57%, and 70%, respectively) and ≥80 years of age (28%, 39%, and 63%, respectively) (P < .05 for all). Overall, pulmonary toxicity occurred in 58 of 279 patients (21%) treated with bleomycin, with 22 of 58 (38%) occurring after cycles 1 or 2, accounting for 8 of 20 (40%) treatment-related deaths. Outcomes in older adults with cHL have improved in recent decades; however, they remain poor for those aged ≥70 years, even in the modern treatment era. Furthermore, treatment-related toxicity remains a significant concern and use of bleomycin should be avoided in most patients., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
44. Single-cell profiling reveals a memory B cell-like subtype of follicular lymphoma with increased transformation risk.
- Author
-
Wang X, Nissen M, Gracias D, Kusakabe M, Simkin G, Jiang A, Duns G, Sarkozy C, Hilton L, Chavez EA, Segat GC, Wong R, Kim J, Aoki T, Islam R, May C, Hung S, Tyshchenko K, Brinkman RR, Hirst M, Karsan A, Freeman C, Sehn LH, Morin RD, Roth AJ, Savage KJ, Craig JW, Shah SP, Steidl C, Scott DW, and Weng AP
- Subjects
- Humans, Memory B Cells, Germinal Center, B-Lymphocytes, Mutation, Lymphoma, Follicular genetics
- Abstract
Follicular lymphoma (FL) is an indolent cancer of mature B-cells but with ongoing risk of transformation to more aggressive histology over time. Recurrent mutations associated with transformation have been identified; however, prognostic features that can be discerned at diagnosis could be clinically useful. We present here comprehensive profiling of both tumor and immune compartments in 155 diagnostic FL biopsies at single-cell resolution by mass cytometry. This revealed a diversity of phenotypes but included two recurrent patterns, one which closely resembles germinal center B-cells (GCB) and another which appears more related to memory B-cells (MB). GCB-type tumors are enriched for EZH2, TNFRSF14, and MEF2B mutations, while MB-type tumors contain increased follicular helper T-cells. MB-type and intratumoral phenotypic diversity are independently associated with increased risk of transformation, supporting biological relevance of these features. Notably, a reduced 26-marker panel retains sufficient information to allow phenotypic profiling of future cohorts by conventional flow cytometry., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
45. Outcomes after initial refusal of curative treatment in patients with classic Hodgkin lymphoma.
- Author
-
Chahal M, Hayden A, Savage KJ, Villa D, Scott DW, Gerrie AS, Lo A, Chan M, Pickles T, Connors JM, Sehn LH, and Freeman CL
- Subjects
- Humans, Hodgkin Disease diagnosis, Hodgkin Disease therapy, Hodgkin Disease pathology
- Published
- 2022
- Full Text
- View/download PDF
46. Role of stem cell transplant in CD30+ PTCL following frontline brentuximab vedotin plus CHP or CHOP in ECHELON-2.
- Author
-
Savage KJ, Horwitz SM, Advani R, Christensen JH, Domingo-Domenech E, Rossi G, Morschhauser F, Alpdogan O, Suh C, Tobinai K, Shustov A, Trneny M, Yuen S, Zinzani PL, Trümper L, Ilidge T, O'Connor OA, Pro B, Miao H, Bunn V, Fenton K, Fanale M, Puhlmann M, and Iyer S
- Subjects
- Brentuximab Vedotin, Cyclophosphamide adverse effects, Doxorubicin adverse effects, Humans, Ki-1 Antigen, Neoplasm Recurrence, Local, Prednisone adverse effects, Vincristine adverse effects, Hematopoietic Stem Cell Transplantation, Lymphoma, Large-Cell, Anaplastic chemically induced, Lymphoma, Large-Cell, Anaplastic therapy
- Abstract
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of aggressive non-Hodgkin lymphomas, the majority of which have high relapse rates following standard therapy. Despite use of consolidative stem cell transplant (SCT) following frontline therapy, there remains no consensus on its utility. The double-blind randomized phase 3 ECHELON-2 study (#NCT01777152; clinicaltrials.gov) demonstrated improved progression-free survival (PFS) and overall survival with frontline brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (A+CHP). Herein, we conducted an exploratory subgroups analysis of the impact of consolidative SCT on PFS in patients with previously untreated CD30+ PTCL (ALK- anaplastic large cell lymphoma [ALCL] and non-ALCL) who were in complete response (CR) after frontline treatment with A+CHP or cyclophosphamide, doxorubicin, vincristine, and prednisone. Median PFS follow-up was 47.57 months. The PFS hazard ratio was 0.36, equating to a 64% reduction in the risk of a PFS event in patients who underwent SCT. The median PFS in patients who underwent SCT was not reached, vs 55.66 months in patients who did not undergo SCT. PFS results favored the use of SCT in both ALK- ALCL and non-ALCL subgroups. These data support the consideration of consolidative SCT in patients with CD30+PTCL who achieve CR following treatment with A+CHP., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
47. Clinicopathological characteristics and long-term outcomes of plasmablastic lymphoma in British Columbia.
- Author
-
Jessa R, Chien N, Villa D, Freeman CL, Slack GW, Savage KJ, Scott DW, Sehn LH, Song KW, and Gerrie AS
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, British Columbia epidemiology, Cyclophosphamide therapeutic use, Doxorubicin therapeutic use, Humans, Neoplasm Recurrence, Local, Prednisone therapeutic use, Retrospective Studies, Treatment Outcome, Vincristine therapeutic use, Plasmablastic Lymphoma diagnosis, Plasmablastic Lymphoma drug therapy
- Abstract
Plasmablastic lymphoma (PBL) is an aggressive and rare subtype of non-Hodgkin lymphoma with no standard-of-care therapy. We reviewed all patients diagnosed with histologically confirmed PBL in British Columbia, Canada between 1997 and 2019. Overall, 42 patients were identified, including 15 (36%) positive for HIV and nine (21%) on chronic immunosuppression. Curative-intent treatment consisting primarily of cyclophosphamide, doxorubicin, vincristine and prednisone was administered to 31 patients, of which 74% achieved response, however 61% relapsed after a median of 7.5 months. At a median follow-up of eight years for the whole cohort, five-year progression-free survival (PFS) and overall survival (OS) were 18% [95% confidence interval (CI): 6%, 30%] and 22% (95% CI: 8%, 36%) with median eight and 15 months respectively. There were no differences in relapse rate (p = 0.962), PFS (p = 0.228) or OS (p = 0.340) according to immune status. For those treated with curative intent, five-year PFS and OS were 24% (95% CI: 8%, 40%) and 31% (95% CI: 13%, 49%) with median 18 and 27 months respectively. In this population-based cohort of PBL patients spanning 20 years, survival outcomes were poor. Ultimately, further research is needed to develop more effective treatment strategies and to improve survival for patients., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2022
- Full Text
- View/download PDF
48. Bendamustine or high-dose cytarabine-based induction with rituximab in transplant-eligible mantle cell lymphoma.
- Author
-
Villa D, Hoster E, Hermine O, Klapper W, Szymczyk M, Bosly A, Unterhalt M, Rimsza LM, Ramsower CA, Freeman CL, Scott DW, Gerrie AS, Savage KJ, Sehn LH, and Dreyling M
- Subjects
- Adolescent, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bendamustine Hydrochloride therapeutic use, Cisplatin therapeutic use, Cyclophosphamide therapeutic use, Cytarabine therapeutic use, Dexamethasone therapeutic use, Doxorubicin therapeutic use, Humans, Ki-67 Antigen, Lactate Dehydrogenases, Middle Aged, Prednisone therapeutic use, Retrospective Studies, Rituximab therapeutic use, Transplantation, Autologous, Vincristine therapeutic use, Young Adult, Hematopoietic Stem Cell Transplantation, Lymphoma, Mantle-Cell pathology
- Abstract
The objective of this study was to explore differences in outcomes between first-line rituximab plus bendamustine (R-B) and R-CHOP/R-DHAP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, dexamethasone, cytarabine, cisplatin) in transplant-eligible patients with mantle cell lymphoma (MCL). A population-based cohort of 97 patients aged 18 to 65 years with stage II-IV MCL, consecutively treated with R-B was retrospectively identified at BC Cancer. Baseline characteristics, response rates, and outcomes were compared with the cohort of 232 patients with MCL randomized to the R-CHOP/R-DHAP arm of the MCL Younger trial. The primary endpoint was the hazard ratio (HR) of the progression-free survival (PFS) comparison between both groups, adjusted for MCL International Prognostic Index (MIPI), Ki67 index, and blastoid/ pleomorphic morphology. Ann Arbor stage, lactate dehydrogenase, MIPI, blastoid morphology, and MCL35 assignments were similar between both groups. The overall response rate (ORR) to R-B was 90% (54% complete response [CR]); 77% of patients proceeded to autologous stem cell transplantation (ASCT) and 78% received maintenance rituximab (MR). The ORR to R-CHOP/R-DHAP was 94% (54% CR); 78% proceeded to ASCT and 2% received MR. There were no differences in PFS in unadjusted (HR, 0.87; 95% confidence interval [CI], 0.53-1.41; P = .56) or adjusted (HR, 0.79; 95% CI, 0.45-1.37; P = .40) comparisons. There were no clear differences in secondary endpoints in unadjusted or adjusted analyses. This retrospective adjusted comparison of 2 independent cohorts of younger patients with MCL suggests that R-B with ASCT and maintenance rituximab is a feasible and effective first-line treatment, with outcomes comparable to R-CHOP/R-DHAP with ASCT., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
49. Primary mediastinal large B-cell lymphoma.
- Author
-
Savage KJ
- Subjects
- Humans, Mediastinum pathology, Rituximab therapeutic use, Hodgkin Disease pathology, Lymphoma, Large B-Cell, Diffuse diagnosis, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse therapy, Mediastinal Neoplasms diagnosis, Mediastinal Neoplasms genetics, Mediastinal Neoplasms therapy
- Abstract
Primary mediastinal large B-cell lymphoma (PMBCL) is a separate entity in the World Health Organization's classification, based on clinicopathologic features and a distinct molecular signature that overlaps with nodular sclerosis classic Hodgkin lymphoma (cHL). Molecular classifiers can distinguish PMBCL from diffuse large B-cell lymphoma (DLBCL) using ribonucleic acid derived from paraffin-embedded tissue and are integral to future studies. However, given that ∼5% of DLBCL can have a molecular PMBCL phenotype in the absence of mediastinal involvement, clinical information remains critical for diagnosis. Studies during the past 10 to 20 years have elucidated the biologic hallmarks of PMBCL that are reminiscent of cHL, including the importance of the JAK-STAT and NF-κB signaling pathways, as well as an immune evasion phenotype through multiple converging genetic aberrations. The outcome of PMBCL has improved in the modern rituximab era; however, whether there is a single standard treatment for all patients and when to integrate radiotherapy remains controversial. Regardless of the frontline therapy, refractory disease can occur in up to 10% of patients and correlates with poor outcome. With emerging data supporting the high efficacy of PD1 inhibitors in PMBCL, studies are underway that integrate them into the up-front setting., (© 2022 by The American Society of Hematology.)
- Published
- 2022
- Full Text
- View/download PDF
50. CNS prophylaxis for diffuse large B-cell lymphoma.
- Author
-
Eyre TA, Savage KJ, Cheah CY, El-Galaly TC, Lewis KL, McKay P, Wilson MR, Evens AM, Bobillo S, Villa D, Maurer MJ, Cwynarski K, and Ferreri AJM
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Humans, Methotrexate therapeutic use, Neoplasm Recurrence, Local pathology, Central Nervous System Neoplasms drug therapy, Central Nervous System Neoplasms pathology, Central Nervous System Neoplasms prevention & control, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse pathology
- Abstract
CNS relapse in the brain parenchyma, eyes, or leptomeninges is an uncommon but devastating complication of diffuse large B-cell lymphoma. CNS prophylaxis strategies, typically involving intrathecal or high-dose antimetabolites, have been developed in the front-line treatment setting with the aim to reduce this subsequent risk. Clinical and biological features associated with elevated risk are increasingly well defined and are discussed in this Review. This Review summarises both the historical and current developments in this challenging field, provides a nuanced discussion regarding current reasons for and against standard prophylactic measures, outlines evidence for the timing of prophylactic measures when delivered, and reflects on possible future developments., Competing Interests: Declaration of interests TCE-G is partly funded from a grant from the Danish Cancer Society. AJMF declares research funding from ADC Therapeutics, Bayer HealthCare Pharmaceuticals, Beigene, Bristol Myers Squibb (BMS), Genmab, Gilead, Hutchison Medipharma, Incyte, Janssen Research & Development, MEI Pharma, Novartis, PletixaPharm, Pharmacyclics, Protherics, Roche, and Takeda; consulting fees from Gilead, Juno, Novartis, PletixaPharm, and Roche; speaker fees from Gilead and Roche; and advisory work for Gilead, Juno, Novartis, PletixaPharm, and Roche. PM declares speaker fees from Janssen. TAE declares advisory work from Janssen, Kite Pharma, Roche, AbbVie, AstraZeneca, Loxo Oncology, Beigene, Incyte, and Secura Bio; speaker bureau fees from Janssen, Kite Pharma, Roche, AbbVie, AstraZeneca, Loxo Oncology, Beigene, and Incyte; and travel support from Roche and AbbVie. MJM recognises the National Cancer Institute: University of Iowa Mayo Clinic Lymphoma SPORE (P50-CA097274) grant; declares advisory work from Adaptive Biotechnologies, Pfizer, Kite Pharma, and Genmab; and research support from BMS, Genentech, Genmab, and Morphosys to his institution. KLL declares speaker bureau from Janssen, AstraZeneca, and Roche; travel support from Novartis and Janssen; and advisory work from IQVIA and Loxo at Lilly. KC declares consulting fees from Roche, BMS, KITE Pharma, and Janssen; speaker bureau from Roche, KITE Pharma, and BMS; and travel support from Roche, KITE Pharma, and BMS. CYC declares speaker bureau from Beigene, Janssen, and Gilead; and advisory work from TG Therapeutics, Roche, Novartis, Janssen, Beigene, AstraZeneca, Eli Lilly, BMS, Gilead, and BMS. KJS declares advisory work from BMS, Seattle Genetics, Merck, Janssen, Novartis, and Kyowa; and DSMC Regeneron, Steering Committee Beigene, research funding from BMS. TCE-G declares previous employment with Roche (March, 2019 until February, 2021) and an honorarium from AbbVie. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.