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1
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Schroers-Martin JG, Alizadeh AA. Cell-Free DNA in Hematologic Malignancies. JCO Oncol Pract 2024; 20:1491-1499. [PMID: 39531844 DOI: 10.1200/op-24-00648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Accepted: 08/27/2024] [Indexed: 11/16/2024] Open
Abstract
Liquid biopsy techniques using cell-free DNA (cfDNA) play an increasingly important role in the characterization and surveillance of solid tumors. For blood cancers, molecular response assessment techniques using circulating malignant cells or bone marrow aspirates are well established in clinical care. However, cfDNA has an emerging role in hematology as well, with the opportunity for disease assessment and quantification independent of circulating disease burden or invasive biopsies. In this review, we discuss key technologies and clinical data for the utilization of cfDNA in lymphomas, myeloma, and leukemias.
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Affiliation(s)
- Joseph G Schroers-Martin
- Department of Medicine, Divisions of Hematology & Oncology, Stanford University Medical Center, Stanford, CA
| | - Ash A Alizadeh
- Department of Medicine, Divisions of Hematology & Oncology, Stanford University Medical Center, Stanford, CA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA
- Stanford Cancer Institute, Stanford University, Stanford, CA
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2
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Rezazadeh A, Pruett J, Detzner A, Edwin N, Hamadani M, Shah NN, Fenske TS. Immunoglobulin High Throughput Sequencing (Ig-HTS) Minimal Residual Disease (MRD) Analysis is an Effective Surveillance Tool in Patients With Mantle Cell Lymphoma. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2024; 24:254-259. [PMID: 38195321 DOI: 10.1016/j.clml.2023.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 12/03/2023] [Accepted: 12/07/2023] [Indexed: 01/11/2024]
Abstract
INTRODUCTION Mantle cell lymphoma (MCL) accounts for 4% to 6% of B-cell non-Hodgkin lymphoma with historically poor outcomes. With the advent of intensive first-line, targeted, and cellular therapies, outcomes have improved, and initial remission can be 8 to 10 years or longer. As patients experience longer remissions, this raises the question of the optimal surveillance modality. Peripheral blood minimal residual disease (MRD) analysis offers a potential alternative to surveillance imaging that is sensitive, less costly, and eliminates the risk of radiation exposure. MATERIALS AND METHODS The clonoSEQ assay (Adaptive Biotechnologies) is an FDA-cleared commercially available Ig-HTS MRD assay with a sensitivity of 1 cell in 1,000,000. We performed a retrospective analysis of 34 patients from 2015 to 2021, who underwent MRD testing after achieving remission with first-line therapy. RESULTS With a median follow-up of 6.5 years, 10-year progression free survival (PFS) was 60% and 10-year overall survival was 92% of the entire cohort. Among 12 patients who sustained a radiographic relapse, peripheral blood became MRD+ either at or prior to the time of relapse in 11 patients (92%). The first MRD+ test had a lead time of 0 to 24 months (median 34 days) prior to radiographic relapse. Only 1 patient had a MRD- result while being found to have progressive disease on imaging. Among 22 patients who sustained continuous clinical remission, 21 have remained MRD-. Several patients were able to enjoy 2 to 4-year intervals without surveillance imaging. CONCLUSIONS Our data suggest that the clonoSEQ MRD assay is an effective surveillance tool for MCL patients following first-line therapy and is predictive of relapse prior to imaging.
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Affiliation(s)
- Alexandra Rezazadeh
- Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, WI
| | - Julie Pruett
- Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, WI
| | - Amy Detzner
- Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, WI
| | | | - Mehdi Hamadani
- Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, WI; BMT & Cellular Therapy Program, Medical College of Wisconsin, Milwaukee, WI
| | - Nirav N Shah
- Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, WI; BMT & Cellular Therapy Program, Medical College of Wisconsin, Milwaukee, WI
| | - Timothy S Fenske
- Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, WI; BMT & Cellular Therapy Program, Medical College of Wisconsin, Milwaukee, WI.
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3
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Minson A, Hamad N, Cheah CY, Tam C, Blombery P, Westerman D, Ritchie D, Morgan H, Holzwart N, Lade S, Anderson MA, Khot A, Seymour JF, Robertson M, Caldwell I, Ryland G, Saghebi J, Sabahi Z, Xie J, Koldej R, Dickinson M. CAR T cells and time-limited ibrutinib as treatment for relapsed/refractory mantle cell lymphoma: the phase 2 TARMAC study. Blood 2024; 143:673-684. [PMID: 37883795 DOI: 10.1182/blood.2023021306] [Citation(s) in RCA: 28] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 10/10/2023] [Accepted: 10/10/2023] [Indexed: 10/28/2023] Open
Abstract
ABSTRACT CD19-directed chimeric antigen receptor T cells (CAR-T) achieve high response rates in patients with relapsed/refractory mantle cell lymphoma (MCL). However, their use is associated with significant toxicity, relapse concern, and unclear broad tractability. Preclinical and clinical data support a beneficial synergistic effect of ibrutinib on apheresis product fitness, CAR-T expansion, and toxicity. We evaluated the combination of time-limited ibrutinib and CTL019 CAR-T in 20 patients with MCL in the phase 2 TARMAC study. Ibrutinib commenced before leukapheresis and continued through CAR-T manufacture for a minimum of 6 months after CAR-T administration. The median prior lines of therapy was 2; 50% of patients were previously exposed to a Bruton tyrosine kinase inhibitor (BTKi). The primary end point was 4-month postinfusion complete response (CR) rate, and secondary end points included safety and subgroup analysis based on TP53 aberrancy. The primary end point was met; 80% of patients demonstrated CR, with 70% and 40% demonstrating measurable residual disease negativity by flow cytometry and molecular methods, respectively. At 13-month median follow-up, the estimated 12-month progression-free survival was 75% and overall survival 100%. Fifteen patients (75%) developed cytokine release syndrome; 12 (55%) with grade 1 to 2 and 3 (20%) with grade 3. Reversible grade 1 to 2 neurotoxicity was observed in 2 patients (10%). Efficacy was preserved irrespective of prior BTKi exposure or TP53 mutation. Deep responses correlated with robust CAR-T expansion and a less exhausted baseline T-cell phenotype. Overall, the safety and efficacy of the combination of BTKi and T-cell redirecting immunotherapy appears promising and merits further exploration. This trial was registered at www.ClinicalTrials.gov as #NCT04234061.
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Affiliation(s)
- Adrian Minson
- Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
- Clinical Haematology, Royal Melbourne Hospital, Melbourne, Australia
| | - Nada Hamad
- Department of Haematology, St Vincent's Hospital, Sydney, Australia
| | - Chan Y Cheah
- Department of Haematology, Sir Charles Gairdner Hospital, Perth, Australia
- School of Medicine, University of Western Australia, Crawley, Australia
| | | | - Piers Blombery
- Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
- Clinical Haematology, Royal Melbourne Hospital, Melbourne, Australia
| | - David Westerman
- Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
- Clinical Haematology, Royal Melbourne Hospital, Melbourne, Australia
| | - David Ritchie
- Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
- Clinical Haematology, Royal Melbourne Hospital, Melbourne, Australia
| | - Huw Morgan
- Clinical Haematology, Royal Melbourne Hospital, Melbourne, Australia
| | - Nicholas Holzwart
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
- Clinical Haematology, Royal Melbourne Hospital, Melbourne, Australia
| | - Stephen Lade
- Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Mary Ann Anderson
- Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
- Clinical Haematology, Royal Melbourne Hospital, Melbourne, Australia
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
| | - Amit Khot
- Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
- Clinical Haematology, Royal Melbourne Hospital, Melbourne, Australia
| | - John F Seymour
- Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
- Clinical Haematology, Royal Melbourne Hospital, Melbourne, Australia
| | - Molly Robertson
- Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
| | - Imogen Caldwell
- Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Georgina Ryland
- Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
| | - Javad Saghebi
- Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Zahra Sabahi
- Department of Haematology, St Vincent's Hospital, Sydney, Australia
| | - Jing Xie
- Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Rachel Koldej
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
- Clinical Haematology, Royal Melbourne Hospital, Melbourne, Australia
| | - Michael Dickinson
- Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
- Clinical Haematology, Royal Melbourne Hospital, Melbourne, Australia
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Jerkeman M, Kolstad A, Hutchings M, Pasanen A, Meriranta L, Niemann CU, Kragh Jørgensen RR, El-Galaly TC, Riise J, Leppä S, Christensen JH, Sonnevi K, Pedersen LB, Wader KF, Glimelius I. MRD-driven treatment with venetoclax-R2 in mantle cell lymphoma: the Nordic Lymphoma Group MCL7 VALERIA trial. Blood Adv 2024; 8:407-415. [PMID: 38113470 PMCID: PMC10827399 DOI: 10.1182/bloodadvances.2023011920] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 11/30/2023] [Accepted: 12/01/2023] [Indexed: 12/21/2023] Open
Abstract
ABSTRACT Despite improvements in treatment of mantle cell lymphoma (MCL), most patients eventually relapse. In this multicenter phase 1b/2 trial, we evaluated safety and efficacy of minimal residual disease (MRD)-driven venetoclax, lenalidomide, and rituximab (venetoclax-R2) in relapsed/refractory (R/R) MCL and explored the feasibility of stopping treatment in molecular remission. The primary end point was overall response rate (ORR) at 6 months. After dose escalation, the recommended phase 2 dose was lenalidomide 20 mg daily, days 1 to 21; venetoclax 600 mg daily after ramp-up; and rituximab 375 mg/m2 weekly for 4 weeks, then every 8 weeks. MRD monitoring by RQ-PCR was performed every 3 months. When MRD-negativity in the blood was reached, treatment was continued for another 3 months; if MRD-negativity was then confirmed, treatment was stopped. In total, 59 patients were enrolled, with a median age of 73 years. At 6 months, the ORR was 63% (29 complete remission [CR], 8 partial remission [PR]), and 40% (4 CR, 2 PR) for patients previously failing a Bruton tyrosine kinase (BTK) inhibitor. Median progression-free survival (PFS) was 21 months, with median overall survival of 31 months. TP53 mutation was associated with inferior PFS (P < .01). Overall, 28 patients (48%) discontinued treatment in molecular remission, and 25 remain MRD negative after a median of 17.4 months. Hematological toxicity was frequent, with 52 of 59 (88%) patients with G3-4 neutropenia and 21 of 59 (36%) patients with G3-4 thrombocytopenia. To conclude, MRD-driven venetoclax-R2 is feasible and tolerable and shows efficacy in R/R MCL, also after BTK inhibitor failure. This trial was registered at www.ClinicalTrials.gov as #NCT03505944.
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Affiliation(s)
- Mats Jerkeman
- Department of Oncology, Institute of Clinical Sciences, Lund University and Skane University Hospital SE22185, Lund, Sweden
| | - Arne Kolstad
- Department of Oncology, Innlandet Hospital, Brumunddal, Norway
| | | | - Annika Pasanen
- Department of Oncology, Helsinki University Hospital, Helsinki, Finland
| | - Leo Meriranta
- Department of Oncology, Helsinki University Hospital, Helsinki, Finland
| | | | - Rasmus Rask Kragh Jørgensen
- Department of Hematology, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Tarec Christoffer El-Galaly
- Department of Hematology, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Jon Riise
- Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Sirpa Leppä
- Department of Oncology, Helsinki University Hospital, Helsinki, Finland
| | | | - Kristina Sonnevi
- Department of Hematology, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | | | - Karin Fahl Wader
- Department of Oncology, St Olav University Hospital, Trondheim, Norway
| | - Ingrid Glimelius
- Department of Immunology, Genetics and Pathology, Unit of Cancer Precision Medicine, Uppsala University, Uppsala, Sweden
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Lakhotia R, Roschewski M. Clinical applications of circulating tumor DNA in indolent B-cell lymphomas. Semin Hematol 2023; 60:164-172. [PMID: 37419716 PMCID: PMC10527907 DOI: 10.1053/j.seminhematol.2023.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/15/2023] [Accepted: 06/24/2023] [Indexed: 07/09/2023]
Abstract
Indolent B-cell lymphomas are generally incurable with standard therapy and most patients have a prolonged disease course that includes multiple treatments and periods of time in which they do not require therapy. Currently available tools to monitor disease burden and define response to treatment rely heavily on imaging scans that lack tumor specificity are unable to detect disease at the molecular level. Circulating tumor DNA (ctDNA) is a versatile and promising biomarker being developed across multiple lymphoma subtypes. Advantages of ctDNA include high tumor specificity and limits of detection that are significantly lower than imaging scans. Potential clinical applications of ctDNA in indolent B-cell lymphomas include baseline prognostication, early signs of treatment resistance, measurements of minimal residual disease, and a noninvasive method to directly monitor disease burden and clonal evolution after therapy. Clinical applications of ctDNA have not yet proven clinical utility but are increasingly used as translational endpoints in clinical trials testing novel approaches and the analytic techniques used for ctDNA continue to evolve. Advances in therapy for indolent B-cell lymphomas include novel targeted agents and combinations that achieve very high rates complete response which amplifies the need to improve our current methods to monitor disease.
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Affiliation(s)
- Rahul Lakhotia
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD
| | - Mark Roschewski
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
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6
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Schroers-Martin JG, Alig S, Garofalo A, Tessoulin B, Sugio T, Alizadeh AA. Molecular Monitoring of Lymphomas. ANNUAL REVIEW OF PATHOLOGY 2023; 18:149-180. [PMID: 36130071 DOI: 10.1146/annurev-pathol-050520-044652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Molecular monitoring of tumor-derived alterations has an established role in the surveillance of leukemias, and emerging nucleic acid sequencing technologies are likely to similarly transform the clinical management of lymphomas. Lymphomas are well suited for molecular surveillance due to relatively high cell-free DNA and circulating tumor DNA concentrations, high somatic mutational burden, and the existence of stereotyped variants enabling focused interrogation of recurrently altered regions. Here, we review the clinical scenarios and key technologies applicable for the molecular monitoring of lymphomas, summarizing current evidence in the literature regarding molecular subtyping and classification, evaluation of treatment response, the surveillance of active cellular therapies, and emerging clinical trial strategies.
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Affiliation(s)
- Joseph G Schroers-Martin
- Department of Medicine, Divisions of Hematology and Oncology, Stanford University Medical Center, Stanford, California, USA;
| | - Stefan Alig
- Department of Medicine, Divisions of Hematology and Oncology, Stanford University Medical Center, Stanford, California, USA;
| | - Andrea Garofalo
- Department of Medicine, Divisions of Hematology and Oncology, Stanford University Medical Center, Stanford, California, USA;
| | - Benoit Tessoulin
- Department of Medicine, Divisions of Hematology and Oncology, Stanford University Medical Center, Stanford, California, USA; .,Current affiliation: Clinical Hematology Department, Nantes University Hospital, Nantes, France
| | - Takeshi Sugio
- Department of Medicine, Divisions of Hematology and Oncology, Stanford University Medical Center, Stanford, California, USA;
| | - Ash A Alizadeh
- Department of Medicine, Divisions of Hematology and Oncology, Stanford University Medical Center, Stanford, California, USA; .,Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA.,Stanford Cancer Institute, Stanford University, Stanford, California, USA
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7
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Predicting the future in MCL with MRD. Blood 2022; 140:1332-1333. [PMID: 36136360 DOI: 10.1182/blood.2022017278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 06/08/2022] [Indexed: 11/20/2022] Open
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8
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Treatment of Mantle Cell Lymphoma in the Frontline Setting: Are We Ready for a Risk-Adapted Approach? J Pers Med 2022; 12:jpm12071134. [PMID: 35887631 PMCID: PMC9324979 DOI: 10.3390/jpm12071134] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/23/2022] [Accepted: 06/28/2022] [Indexed: 12/29/2022] Open
Abstract
Mantle cell lymphoma (MCL), a type of B-cell non-Hodgkin lymphoma characterized by the t(11;14)(q13q32) translocation, is a clinically heterogenous disease which can range from indolent to highly aggressive. Numerous prognostic factors have been identified, including blastoid histology, the Mantle Cell Lymphoma International Prognostic Index (MIPI) score, high proliferation index, p53 deletions and/or mutations, complex karyotype, minimal residual disease, and several others. However, using these prognostic factors to guide treatment selection has largely remained elusive. Given the heterogeneous behavior of this disease and varying patient characteristics, we suggest that the time has come for a more risk-adapted approach to this disease. In this article, we review the numerous prognostic factors that have been described for MCL, both at the time of diagnosis and following first-line treatment. We then propose a risk-adapted approach to first-line therapy for MCL, which would reserve intensive therapy for the highest risk patients and spare others excessive toxicity.
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9
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Liu H, Shi X, Fang H, Cao L, Miao Y, Zhao X, Wu W, Xu W, Li J, Fan L. First-Line Autologous Stem Cell Transplantation for Mantle Cell Lymphoma: A Systematic Analysis and Treatment Recommendation. Front Oncol 2022; 12:881346. [PMID: 35646653 PMCID: PMC9130771 DOI: 10.3389/fonc.2022.881346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 04/11/2022] [Indexed: 11/13/2022] Open
Abstract
Background In the era of immunotherapy, autologous stem cell transplantation (ASCT) in first-line therapy in patients with mantle cell lymphoma (MCL) has been a controversial topic. This report aimed to explore the association between ASCT and MCL survival through a systematic review with meta-analysis. Methods We performed a systematic search of original articles published from inception to September 2021 using PubMed, MEDLINE, Embase, and Cochrane Library databases. Results We included studies that compared ASCT with non-ASCT consolidation in newly diagnosed transplant-eligible MCL. The endpoints were progression-free survival (PFS) and overall survival (OS). There were seven eligible studies (one randomized clinical trial, one prospective cohort study, and five observational studies) published between 2012 and 2021, in which the total number of participants was 3,271. In the non-intensive induction subgroup, patients with ASCT experienced a significant PFS but no OS benefit compared with those without ASCT. In the intensive induction subgroup, the PFS benefit from ASCT still existed but largely attenuated; no OS benefit was observed though only one study was suitable for evaluation. When compared to the rituximab maintenance arm, ASCT had a worse PFS and OS. Conclusions In the rituximab plus HiDAC era, the benefit of ASCT as a component of first-line treatment has been weakened. First-line maintenance strategy instead of ASCT seems worth exploring .
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Affiliation(s)
- Hailing Liu
- Department of Hematology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, China.,Nanjing Pukou District Central Hospital, Pukou Branch of Jiangsu Province Hospital, Pukou CLL Center, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Xiao Shi
- Department of Hematology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, China.,Nanjing Pukou District Central Hospital, Pukou Branch of Jiangsu Province Hospital, Pukou CLL Center, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Huizi Fang
- Nanjing Pukou District Central Hospital, Pukou Branch of Jiangsu Province Hospital, Pukou CLL Center, Nanjing, China
| | - Lei Cao
- Department of Hematology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, China.,Nanjing Pukou District Central Hospital, Pukou Branch of Jiangsu Province Hospital, Pukou CLL Center, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Yi Miao
- Department of Hematology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, China.,Nanjing Pukou District Central Hospital, Pukou Branch of Jiangsu Province Hospital, Pukou CLL Center, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Xiaoli Zhao
- Department of Hematology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, China.,Nanjing Pukou District Central Hospital, Pukou Branch of Jiangsu Province Hospital, Pukou CLL Center, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Wei Wu
- Department of Hematology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, China.,Nanjing Pukou District Central Hospital, Pukou Branch of Jiangsu Province Hospital, Pukou CLL Center, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Wei Xu
- Department of Hematology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, China.,Nanjing Pukou District Central Hospital, Pukou Branch of Jiangsu Province Hospital, Pukou CLL Center, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Jianyong Li
- Department of Hematology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, China.,Nanjing Pukou District Central Hospital, Pukou Branch of Jiangsu Province Hospital, Pukou CLL Center, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Lei Fan
- Department of Hematology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, China.,Nanjing Pukou District Central Hospital, Pukou Branch of Jiangsu Province Hospital, Pukou CLL Center, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
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10
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Yanada M, Yamamoto K. Hematopoietic cell transplantation for mantle cell lymphoma. Int J Hematol 2022; 115:301-309. [DOI: 10.1007/s12185-022-03294-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 01/19/2022] [Accepted: 01/19/2022] [Indexed: 11/28/2022]
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11
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Wu X, Lu H, Pang T, Li X, Luo H, Tan H, Liu S. Association of minimal residual disease levels with clinical outcomes in patients with mantle cell lymphoma: A meta-analysis. Leuk Res 2021; 108:106605. [PMID: 34090063 DOI: 10.1016/j.leukres.2021.106605] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 04/12/2021] [Accepted: 04/26/2021] [Indexed: 02/08/2023]
Abstract
Some studies have elucidated that Minimal residual disease (MRD) in patient with Mantle Cell Lymphoma (MCL) was a significant prognostic factor, with potential value in assessing overall survival (OS) and progression-free survival (PFS). However, most studies were widely varied in included population, sample sources and MRD detection time points. Some studies even have conflicting results. In view of this, a meta-analysis was performed to evaluate association of MRD levels with clinical outcomes in patients with MCL. We identified 7 included articles, which were published in recent 20 years. Then, we extracted or calculated hazard ratios (HRs) and their 95 % confidence intervals (CIs). Our results reveal that patients with MRD negativity have improved OS (HR = 0.63; 95 % CI: 0.50-0.79) and PFS (HR = 0.40, 95 % CI: 0.21-0.76), comparing with patients with MRD positivity. There are also consistent results in subgroups based on sample sources and MRD detection time points. Our study also demonstrates that MRD level is a strong prognostic factor of clinical outcomes. Thus, MRD is expected to be an effective clinical indicator for assessing prognosis and guide treatment decisions in MCL patients.
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Affiliation(s)
- Xue Wu
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, Sichuan Province, China
| | - Hongyu Lu
- School of Medical Technology, Chengdu University of TCM, Chengdu, 611137, Sichuan Province, China; Key Laboratory of Transplant Engineering and Immunology, Regenerative Medical Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Tao Pang
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, Sichuan Province, China
| | - Xue Li
- Department of Laboratory Medicine, Hanyuan People's Hospital, Yuan, 25000, Sichuan, China
| | - Hongzhi Luo
- School of Laboratory Medicine, Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Hong Tan
- Department of General Surgery, Chengdu Integrated TCM&Western Medicine Hospital (Chengdu First People's Hospital), No.18 Vientiane North Road, Hi-tech Zone, Chengdu, 610041, China.
| | - Shan Liu
- Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, No.32 West Second Section First Ring Road, Chengdu, 610072, Sichuan, China.
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Marangon M, Visco C, Barbui AM, Chiappella A, Fabbri A, Ferrero S, Galimberti S, Luminari S, Musuraca G, Re A, Zilioli VR, Ladetto M. Allogeneic Stem Cell Transplantation in Mantle Cell Lymphoma in the Era of New Drugs and CAR-T Cell Therapy. Cancers (Basel) 2021; 13:cancers13020291. [PMID: 33466784 PMCID: PMC7830938 DOI: 10.3390/cancers13020291] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/08/2021] [Accepted: 01/11/2021] [Indexed: 12/11/2022] Open
Abstract
MCL is an uncommon lymphoproliferative disorder that has been regarded as incurable since its identification as a distinct entity. Allogeneic transplantation for two decades has represented the only option capable of ensuring prolonged remissions and possibly cure. Despite its efficacy, its application has been limited by feasibility limitations and substantial toxicity, particularly in elderly patients. Nevertheless, the experience accumulated over time has been wide though often scattered among retrospective and small prospective studies. In this review, we aimed at critically revise and discuss available evidence on allogeneic transplantation in MCL, trying to put available evidence into the 2020 perspective, characterized by unprecedented development of novel promising therapeutic agents and regimens.
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Affiliation(s)
- Miriam Marangon
- Department of Hematology, Azienda Sanitaria Universitaria Giuliano Isontina, 34129 Trieste, Italy;
| | - Carlo Visco
- Section of Hematology, Department of Medicine, University of Verona, 37134 Verona, Italy;
| | | | - Annalisa Chiappella
- Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, 20133 Milan, Italy;
| | - Alberto Fabbri
- Hematology Division, Department of Oncology, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy;
| | - Simone Ferrero
- Hematology Division, Department of Molecular Biotechnologies and Health Sciences, Università di Torino, 10126 Torino, Italy;
- Hematology 1, AOU Città della Salute e della Scienza di Torino, 10126 Torino, Italy
| | - Sara Galimberti
- Hematology Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy;
| | - Stefano Luminari
- Hematology Unit, Azienda Unità Sanitaria Locale IRCCS di Reggio Emilia, 42123 Modena, Italy;
- Surgical, Medical and Dental Department of Morphological Sciences Related to Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, 42123 Modena, Italy
| | - Gerardo Musuraca
- Department of Hematology, IRCCS—Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), 47014 Meldola, Italy;
| | - Alessandro Re
- Hematology Unit, ASST Spedali Civili, 25123 Brescia, Italy;
| | | | - Marco Ladetto
- SC Ematologia, Azienda Ospedaliera Santi Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy
- Dipartimento di Medicina Traslazionale, Università del Piemonte Orientale, 15121 Alessandria, Italy
- Correspondence:
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13
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Kumar A, Bantilan KS, Jacob AP, Park A, Schoninger SF, Sauter C, Ulaner GA, Casulo C, Faham M, Kong KA, Grewal RK, Gerecitano J, Hamilton A, Hamlin P, Matasar M, Moskowitz CH, Noy A, Palomba ML, Portlock CS, Younes A, Willis T, Zelenetz AD. Noninvasive Monitoring of Mantle Cell Lymphoma by Immunoglobulin Gene Next-Generation Sequencing in a Phase 2 Study of Sequential Chemoradioimmunotherapy Followed by Autologous Stem-Cell Rescue. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2021; 21:230-237.e12. [PMID: 33558202 PMCID: PMC9476895 DOI: 10.1016/j.clml.2020.09.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 09/20/2020] [Indexed: 11/28/2022]
Abstract
Limited information exists in mantle cell lymphoma (MCL) on the performance of next-generation sequencing–based assay of immunoglobulin gene rearrangements for minimal residual disease (MRD) assessment. Posttreatment peripheral blood samples were collected from 16 MCL patients and analyzed with the Adaptive Biotechnologies MRD assay, which identified early molecular relapse. We observed more sensitivity in the cellular versus acellular compartment.
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MESH Headings
- Aged
- Chemoradiotherapy
- DNA, Neoplasm/blood
- Female
- Gene Rearrangement
- High-Throughput Nucleotide Sequencing
- Humans
- Immunoglobulins/genetics
- Immunotherapy
- Induction Chemotherapy
- Lymphoma, Mantle-Cell/blood
- Lymphoma, Mantle-Cell/diagnosis
- Lymphoma, Mantle-Cell/genetics
- Lymphoma, Mantle-Cell/therapy
- Male
- Middle Aged
- Neoplasm Recurrence, Local/blood
- Neoplasm Recurrence, Local/diagnosis
- Neoplasm Recurrence, Local/genetics
- Neoplasm, Residual
- Neoplastic Cells, Circulating
- Prospective Studies
- Remission Induction
- Stem Cell Transplantation
- Transplantation, Autologous
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Affiliation(s)
- Anita Kumar
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
| | - K S Bantilan
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - A P Jacob
- Adaptive Biotechnologies, Seattle, WA
| | - A Park
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - S F Schoninger
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - C Sauter
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - G A Ulaner
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - C Casulo
- Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY
| | - M Faham
- Adaptive Biotechnologies, Seattle, WA
| | - K A Kong
- Adaptive Biotechnologies, Seattle, WA
| | - R K Grewal
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - J Gerecitano
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - A Hamilton
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - P Hamlin
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - M Matasar
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - C H Moskowitz
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - A Noy
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - M L Palomba
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - C S Portlock
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - A Younes
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - T Willis
- Adaptive Biotechnologies, Seattle, WA
| | - A D Zelenetz
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
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14
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Zhou Y, Chen H, Tao Y, Zhong Q, Shi Y. Minimal Residual Disease and Survival Outcomes in Patients with Mantle Cell Lymphoma: a systematic review and meta-analysis. J Cancer 2021; 12:553-561. [PMID: 33391451 PMCID: PMC7738989 DOI: 10.7150/jca.51959] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 10/18/2020] [Indexed: 01/07/2023] Open
Abstract
Background: Minimal residual disease (MRD) has shown the prognostic value in mantle cell lymphoma (MCL). To quantify the relationships between progression free survival (PFS) and overall survival (OS) with MRD status in MCL, we conducted this meta-analysis. Methods: We searched databases including Pubmed, Embase, Web of Science and the Cochrane Library up to July 15th, 2020. Data of patients' characteristics, MRD assessment and survival outcomes were extracted and analyzed. Results: Ten articles were included. For the impact of post-induction MRD status on survival outcomes, MRD positive status was associated with worse PFS (HR=1.44; 95%CI 1.27-1.62; P<0.00001) and OS (HR=1.30; 95%CI 1.03-1.64; P=0.03) compared with MRD negative status. Regarding the impact of post-consolidation MRD status on survival outcomes, MRD positivity predicted shorter PFS (HR=1.84; 95%CI 1.49-2.26; P<0.00001) and OS (HR=2.38; 95%CI 1.85-3.06; P<0.00001) than MRD negativity. Conclusions: This study indicated that MRD positivity after induction and consolidation treatments was associated with worse PFS and OS for MCL. MRD-based treatment strategies should be further explored in clinical trials and real-world practice.
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Affiliation(s)
| | | | | | | | - Yuankai Shi
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, 100021, China
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15
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Minimal Residual Disease in Mantle Cell Lymphoma: Methods and Clinical Significance. Hematol Oncol Clin North Am 2020; 34:887-901. [PMID: 32861285 DOI: 10.1016/j.hoc.2020.06.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Several biological and clinical features have been recognized in mantle cell lymphoma (MCL). In recent years, the minimal residual disease (MRD) has been extensively investigated and is now considered as one of the strongest clinical predictors in this lymphoma. This article reviews methods used for the assessment of MRD in MCL and discusses their strengths and weaknesses. In addition, it examines the MRD contribution to the biology knowledge of MCL and the development of effective strategies for its management, including the possibility of personalized treatment based on MRD response.
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16
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Doorduijn JK, Zijlstra JM, Lugtenburg PJ, Kersten MJ, Böhmer LH, Minnema MC, MacKenzie MA, van Marwijk Kooij R, de Jongh E, Snijders TJ, de Weerdt O, van Gelder M, Hoogendoorn M, Leys RB, Kibbelaar RE, de Jong D, Chitu DA, Van’t Veer MB, Kluin‐Nelemans HC. Bortezomib maintenance after R-CHOP, cytarabine and autologous stem cell transplantation in newly diagnosed patients with mantle cell lymphoma, results of a randomised phase II HOVON trial. Br J Haematol 2020; 190:385-393. [PMID: 32150297 PMCID: PMC7496560 DOI: 10.1111/bjh.16567] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2019] [Revised: 02/11/2020] [Accepted: 02/15/2020] [Indexed: 11/29/2022]
Abstract
Rituximab-containing induction followed by autologous stem cell transplantation (ASCT) is the standard first-line treatment for young mantle cell lymphoma patients. However, most patients relapse after ASCT. We investigated in a randomised phase II study the outcome of a chemo-immuno regimen and ASCT with or without maintenance therapy with bortezomib. Induction consisted of three cycles R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), two cycles high-dose cytarabine, BEAM (carmustine, etoposide, cytarabine, melphalan) and ASCT. Patients responding were randomised between bortezomib maintenance (1·3 mg/m2 intravenously once every 2 weeks, for 2 years) and observation. Of 135 eligible patients, 115 (85%) proceeded to ASCT, 60 (44%) were randomised. With a median follow-up of 77·5 months for patients still alive, 5-year event-free survival (EFS) was 51% (95% CI 42-59%); 5-year overall survival (OS) was 73% (95% CI 65-80%). The median follow-up of randomised patients still alive was 71·5 months. Patients with bortezomib maintenance had a 5-year EFS of 63% (95% CI 44-78%) and 5-year OS of 90% (95% CI 72-97%). The patients randomised to observation had 5-year PFS of 60% (95% CI, 40-75%) and OS of 90% (95% CI 72-97%). In conclusion, in this phase II study we found no indication of a positive effect of bortezomib maintenance after ASCT.
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Affiliation(s)
| | | | | | - Marie Josee Kersten
- HaematologyAmsterdam UMCUniversity of AmsterdamCancer Center Amsterdam and LYMMCARE (lymphoma and myeloma Center)AmsterdamNetherlands
| | | | | | | | | | - Eva de Jongh
- Albert Schweitzer Hospital Location DordwijkDordrechtNetherlands
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17
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Cortelazzo S, Ponzoni M, Ferreri AJM, Dreyling M. Mantle cell lymphoma. Crit Rev Oncol Hematol 2020; 153:103038. [PMID: 32739830 DOI: 10.1016/j.critrevonc.2020.103038] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 06/29/2019] [Accepted: 06/23/2020] [Indexed: 12/11/2022] Open
Abstract
MCL is a well-characterized generally aggressive lymphoma with a poor prognosis. However, patients with a more indolent disease have been reported in whom the initiation of therapy can be delayed without any consequence for the survival. In 2017 the World Health Organization updated the classification of MCL describing two main subtypes with specific molecular characteristics and clinical features, classical and indolent leukaemic nonnodal MCL. Recent research results suggested an improving outcome of this neoplasm. The addition of rituximab to conventional chemotherapy has increased overall response rates, but it did not improve overall survival compared to chemotherapy alone. The use of intensive frontline therapies including rituximab and consolidation with autologous stem cell transplantation ameliorated response rate and prolonged progression-free survival in young fit patients, but any impact on survival remains to be proven. Furthermore, the optimal timing, cytoreductive regimen and conditioning regimen, and the clinical implications of achieving a disease remission even at molecular level remain to be elucidated. The development of targeted therapies as the consequence of better understanding of pathogenetic pathways in MCL might improve the outcome of conventional chemotherapy and spare the toxicity of intense therapy in most patients. Cases not eligible for intensive regimens, may be considered for less demanding therapies, such as the combination of rituximab either with CHOP or with purine analogues, or bendamustine. Allogeneic SCT can be an effective option for relapsed disease in patients who are fit enough and have a compatible donor. Maintenance rituximab may be considered after response to immunochemotherapy as the first-line strategy in a wide range of patients. Finally, since the optimal approach to the management of MCL is still evolving, it is critical that these patients are enrolled in clinical trials to identify the better treatment options.
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Affiliation(s)
| | - Maurilio Ponzoni
- Pathology Unit, San Raffaele Scientific Institute, Milan, Italy; Unit of Lymphoid Malignancies, San Raffaele Scientific Institute, Milan, Italy
| | - Andrés J M Ferreri
- Unit of Lymphoid Malignancies, San Raffaele Scientific Institute, Milan, Italy; Medical Oncology Unit, San Raffaele Scientific Institute, Milan, Italy
| | - Martin Dreyling
- Medizinische Klinik III der Universität München-Grosshadern, München, Germany
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18
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Droplet Digital PCR Quantification of Mantle Cell Lymphoma Follow-up Samples From Four Prospective Trials of the European MCL Network. Hemasphere 2020; 4:e347. [PMID: 32309784 PMCID: PMC7162081 DOI: 10.1097/hs9.0000000000000347] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 01/21/2020] [Accepted: 01/27/2020] [Indexed: 12/25/2022] Open
Abstract
Minimal residual disease (MRD) has been increasingly investigated in mantle cell lymphoma (MCL), including for individual therapeutic stratification and pre-emptive treatment in clinical trials. Although patient/allele specific real-time quantitative polymerase chain reaction (qPCR) of IGH or BCL1-IGH clonal markers is the gold-standard method, its reliance on a standard curve for relative quantification limits quantification of low-level positivity within the 1E-4 to 1E-5 range; over half of positive MRD samples after treatment fall below the quantitative range (BQR) of the standard curve. Droplet digital PCR (ddPCR), in contrast, allows absolute quantification, including for samples with no baseline determination of tumor infiltration by multicolor flow cytometry (MFC), avoiding the need for a reference standard curve. Using updated, optimized, ddPCR criteria we compared it with qPCR in 416 MRD samples (and with MFC in 63), with over-representation (61%) of BQR results by qPCR, from a total of 166 patients from four prospective MCL clinical trials. ddPCR, qPCR and MFC gave comparable results in MRD samples with at least 0.01% (1E-4) positivity. ddPCR was preferable to qPCR since it provided more robust quantification at positivity between 1E-4 and 1E-5. Amongst 240 BQR samples with duplicate or triplicate analysis, 39% were positive by ddPCR, 49% negative and only 12% remained positive below quantifiable ddPCR limits. The prognostic relevance of ddPCR is currently under assessment in the context of prospective trials within the European MCL Network.
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19
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Klener P. Advances in Molecular Biology and Targeted Therapy of Mantle Cell Lymphoma. Int J Mol Sci 2019; 20:ijms20184417. [PMID: 31500350 PMCID: PMC6770169 DOI: 10.3390/ijms20184417] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 09/02/2019] [Accepted: 09/04/2019] [Indexed: 12/21/2022] Open
Abstract
Mantle cell lymphoma (MCL) is a heterogeneous malignancy with a broad spectrum of clinical behavior from indolent to highly aggressive cases. Despite the fact that MCL remains in most cases incurable by currently applied immunochemotherapy, our increasing knowledge on the biology of MCL in the last two decades has led to the design, testing, and approval of several innovative agents that dramatically changed the treatment landscape for MCL patients. Most importantly, the implementation of new drugs and novel treatment algorithms into clinical practice has successfully translated into improved outcomes of MCL patients not only in the clinical trials, but also in real life. This review focuses on recent advances in our understanding of the pathogenesis of MCL, and provides a brief survey of currently used treatment options with special focus on mode of action of selected innovative anti-lymphoma molecules. Finally, it outlines future perspectives of patient management with progressive shift from generally applied immunotherapy toward risk-stratified, patient-tailored protocols that would implement innovative agents and/or procedures with the ultimate goal to eradicate the lymphoma and cure the patient.
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Affiliation(s)
- Pavel Klener
- First Dept. of Medicine-Hematology, General University Hospital in Prague, 128 08 Prague, Czech Republic.
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, 128 53 Prague, Czech Republic.
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20
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Gressin R, Daguindau N, Tempescul A, Moreau A, Carras S, Tchernonog E, Schmitt A, Houot R, Dartigeas C, Pignon JM, Corm S, Banos A, Mounier C, Dupuis J, Macro M, Fleury J, Jardin F, Sarkozy C, Damaj G, Feugier P, Fornecker LM, Chabrot C, Dorvaux V, Bouadallah K, Amorin S, Garidi R, Voillat L, Joly B, Celigny PS, Morineau N, Moles MP, Zerazhi H, Fontan J, Arkam Y, Alexis M, Delwail V, Vilque JP, Ysebaert L, Le Gouill S, Callanan MB. A phase 2 study of rituximab, bendamustine, bortezomib and dexamethasone for first-line treatment of older patients with mantle cell lymphoma. Haematologica 2018; 104:138-146. [PMID: 30171024 PMCID: PMC6312036 DOI: 10.3324/haematol.2018.191429] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 08/23/2018] [Indexed: 01/30/2023] Open
Abstract
We present results of a prospective, multicenter, phase II study evaluating rituximab, bendamustine, bortezomib and dexamethasone as first-line treatment for patients with mantle cell lymphoma aged 65 years or older. A total of 74 patients were enrolled (median age, 73 years). Patients received a maximum of six cycles of treatment at 28-day intervals. The primary objective was to achieve an 18-month progression-free survival rate of 65% or higher. Secondary objectives were to evaluate toxicity and the prognostic impact of mantle cell lymphoma prognostic index, Ki67 expression, [18F]fluorodeoxyglucose-positron emission tomography and molecular minimal residual disease, in peripheral blood or bone marrow. With a median follow-up of 52 months, the 24-month progression-free survival rate was 70%, hence the primary objective was reached. After six cycles of treatment, 91% (54/59) of responding patients were analyzed for peripheral blood residual disease and 87% of these (47/54) were negative. Four-year overall survival rates of the patients who did not have or had detectable molecular residual disease in the blood at completion of treatment were 86.6% and 28.6%, respectively (P<0.0001). Neither the mantle cell lymphoma index, nor fluorodeoxyglucose-positron emission tomography nor Ki67 positivity (cut off of ≥30%) showed a prognostic impact for survival. Hematologic grade 3-4 toxicities were mainly neutropenia (51%), thrombocytopenia (35%) and lymphopenia (65%). Grade 3-4 non-hematologic toxicities were mainly fatigue (18.5%), neuropathy (15%) and infections. In conclusion, the tested treatment regimen is active as frontline therapy in older patients with mantle cell lymphoma, with manageable toxicity. Minimal residual disease status after induction could serve as an early predictor of survival in mantle cell lymphoma. ClinicalTrials.gov: NCT 01457144.
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Affiliation(s)
- Rémy Gressin
- Onco-Hematology Department, Grenoble University Hospital .,INSERM 1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble-Alpes, Institute for Advanced Biosciences, Grenoble
| | | | | | - Anne Moreau
- Pathology Department, Nantes University Hospital
| | - Sylvain Carras
- Onco-Hematology Department, Grenoble University Hospital
| | | | - Anna Schmitt
- Hematology Department, Cancer Institute Bergonie Bordeaux
| | - Roch Houot
- Hematology Department, Rennes University Hospital
| | | | | | - Selim Corm
- Hematology Department, Chambery Hospital
| | | | | | - Jehan Dupuis
- Lymphoid Malignancies Unit, Henri Mondor University Hospital, Assistance Publique-Hôpitaux de Paris, Créteil
| | | | - Joel Fleury
- Hematology Department, Clermont-Ferrand Cancer Institute
| | | | - Clementine Sarkozy
- Hematology Department, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud. INSERM 1052
| | - Ghandi Damaj
- Hematology Department, Amiens University Hospital
| | | | | | - Cecile Chabrot
- Hematology Department, University Clermont-Ferrand Hospital
| | | | | | - Sandy Amorin
- Hematology Department, University Hospital Paris Saint-Louis
| | - Reda Garidi
- Hematology Department, Saint Quentin Hospital
| | | | | | | | | | | | | | - Jean Fontan
- Hematology Department, Besançon University Hospital
| | | | | | - Vincent Delwail
- Onco-Hematology Department, University Hospital Poitiers and INSERM, CIC 1402, Poitiers University
| | | | | | | | - Mary B Callanan
- INSERM 1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble-Alpes, Institute for Advanced Biosciences, Grenoble .,Unit for Innovation in Genetics and Epigenetics in Oncology, Dijon University Hospital, France
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21
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Abstract
Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma with historically poor long-term survival compared with other B-cell malignancies. Treatment strategies for this disease are variable and dependent on symptoms and patient fitness. Despite recent advances, MCL remains incurable and patients with high-risk disease have particularly poor outcomes. This review focuses on recent developments that enhance our understanding of the biology of MCL and new treatment approaches that have led to substantial improvements in clinical outcomes. We will outline induction immuno-chemotherapy and maintenance strategies in transplant-eligible patients. In addition, effective strategies for patients unfit for intensive induction will be discussed, with a particular focus on novel molecular therapies with activity in MCL. Lastly, a number of ongoing clinical trials will be presented; the data from these trials are anticipated to redefine standards of care in the near future.
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Affiliation(s)
- Michael Schieber
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA
| | - Leo I Gordon
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA
| | - Reem Karmali
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA
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22
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Maintenance Therapy in Diffuse Large B Cell Lymphoma and Mantle Cell Lymphoma. Curr Treat Options Oncol 2018; 19:45. [DOI: 10.1007/s11864-018-0561-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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23
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What is the optimal initial management of the younger mantle cell lymphoma patient? Best Pract Res Clin Haematol 2018; 31:90-98. [DOI: 10.1016/j.beha.2017.10.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Accepted: 10/23/2017] [Indexed: 11/19/2022]
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24
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Magne J, Jenvrin A, Chauchet A, Casasnovas O, Donzel A, Jego L, Aral B, Guy J, Nadal N, Vernerey D, Callier P, Garnache-Ottou F, Ferrand C. Potential added value of a RT-qPCR method of SOX 11 expression, in the context of a multidisciplinary diagnostic assessment of B cell malignancies. Exp Hematol Oncol 2018; 7:5. [PMID: 29484276 PMCID: PMC5819690 DOI: 10.1186/s40164-018-0097-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Accepted: 02/02/2018] [Indexed: 01/24/2023] Open
Abstract
Background Expression of SRY [sex-determining region Y]-box11 (SOX11) is specific to mantle cell lymphoma (MCL) and contributes, in conjunction with immunoglobulin variable heavy chain gene mutation status, to the identification of two forms of this disease. Methods The aim of this report was firstly, to design an easy and suitable RT-qPCR method to quantify SOX11 mRNA expression in mantle cell lymphoma and other B cell malignancies with the proper reference gene; secondly, to define the best threshold of relative quantity of SOX11 mRNA in order to reach the best compromise between sensitivity and specificity. Results For best discrimination of MCL and non-MCL groups we determined an area under the curve (AUC) of 0.9750 and a threshold of 1.76 with 100% sensitivity and 88% specificity. AUC and threshold values of respectively 0.91/1.346 [87% sensitivity, 80% specificity] and 0.9525/1.7120 [100% sensitivity, 88% specificity] for GAPDH and RPLP0 respectively denote that the RPLP0 reference gene alone is sufficient for PCR housekeeping gene. Conclusion This work describes an RT-qPCR assay for SOX11 expression in order to better characterize MCL at diagnosis. Further studies on larger cohorts are needed to evaluate this molecular tool, especially for the follow-up of minimal residual disease. Electronic supplementary material The online version of this article (10.1186/s40164-018-0097-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Julien Magne
- 1INSERM, UMR866, Faculté des Sciences de Santé, Univ. Bourgogne Franche-Comté, 21000 Dijon, France
| | - Alizée Jenvrin
- INSERM, EFS BFC, UMR1098, Univ. Bourgogne Franche-Comté, Besançon, 25000 France
| | - Adrien Chauchet
- 3Department of Hematology, University Hospital of Besancon, 25000 Besançon, France
| | - Olivier Casasnovas
- 4Department of Hematology, University Hospital of Dijon, 21000 Dijon, France
| | - Anne Donzel
- 1INSERM, UMR866, Faculté des Sciences de Santé, Univ. Bourgogne Franche-Comté, 21000 Dijon, France
| | - Laurence Jego
- 1INSERM, UMR866, Faculté des Sciences de Santé, Univ. Bourgogne Franche-Comté, 21000 Dijon, France
| | - Bernard Aral
- 1INSERM, UMR866, Faculté des Sciences de Santé, Univ. Bourgogne Franche-Comté, 21000 Dijon, France
| | - Julien Guy
- 1INSERM, UMR866, Faculté des Sciences de Santé, Univ. Bourgogne Franche-Comté, 21000 Dijon, France
| | - Nathalie Nadal
- 1INSERM, UMR866, Faculté des Sciences de Santé, Univ. Bourgogne Franche-Comté, 21000 Dijon, France
| | - Dewi Vernerey
- Univ. Bourgogne Franche-Comté, EA 3181, 25000 Besançon, France
| | - Patrick Callier
- 1INSERM, UMR866, Faculté des Sciences de Santé, Univ. Bourgogne Franche-Comté, 21000 Dijon, France
| | | | - Christophe Ferrand
- INSERM, EFS BFC, UMR1098, Univ. Bourgogne Franche-Comté, Besançon, 25000 France.,Laboratoire de Thérapeutique Immuno-Moléculaire et cellulaire des cancers, INSERM UMR1098, Etablissement Français du Sang Bourgogne/Franche-Comté, 8, rue du Docteur Jean-François-Xavier Girod, 25020 Besançon, France
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Drandi D, Ferrero S, Ladetto M. Droplet Digital PCR for Minimal Residual Disease Detection in Mature Lymphoproliferative Disorders. Methods Mol Biol 2018; 1768:229-256. [PMID: 29717447 DOI: 10.1007/978-1-4939-7778-9_14] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Minimal residual disease (MRD) detection has a powerful prognostic relevance for response evaluation and prediction of relapse in hematological malignancies. Real-time quantitative PCR (qPCR) has become the settled and standardized method for MRD assessment in lymphoid disorders. However, qPCR is a relative quantification approach, since it requires a reference standard curve. Droplet digitalTM PCR (ddPCRTM) allows a reliable absolute tumor burden quantification withdrawing the need for preparing, for each experiment, a tumor-specific standard curve. We have recently shown that ddPCR has a good concordance with qPCR and could be a feasible and reliable tool for MRD monitoring in mature lymphoproliferative disorders. In this chapter we describe the experimental workflow, from the detection of the clonal molecular marker to the MRD monitoring by ddPCR, in patients affected by multiple myeloma, mantle cell lymphoma and follicular lymphoma. However, standardization programs among different laboratories are needed in order to ensure the reliability and reproducibility of ddPCR-based MRD results.
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Affiliation(s)
- Daniela Drandi
- Department of Molecular Biotechnologies and Health Sciences, Hematology Division, University of Torino, Torino, Italy.
| | - Simone Ferrero
- Department of Molecular Biotechnologies and Health Sciences, Hematology Division, University of Torino, Torino, Italy
| | - Marco Ladetto
- Division of Hematology, A.O. SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
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Chase ML, Armand P. Minimal residual disease in non-Hodgkin lymphoma - current applications and future directions. Br J Haematol 2017; 180:177-188. [PMID: 29076131 DOI: 10.1111/bjh.14996] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Revised: 09/21/2017] [Accepted: 09/21/2017] [Indexed: 02/03/2023]
Abstract
Non-Hodgkin Lymphomas (NHLs) are a heterogeneous group of tumours with distinct treatment paradigms, but in all cases the goal of treatment is to maximize quality and duration of remission while minimizing therapy-related toxicity. Identification of persistent disease or relapse is most often the trigger to intensify or re-initiate anti-neoplastic therapy, respectively. In the current era of NHL treatment, this determination is mostly based on imaging and clinical evaluations, tools with imperfect sensitivity and specificity. The availability of minimal residual disease (MRD) monitoring could transform treatment paradigms by allowing intensification of treatment in at-risk patients or early intervention for impending relapse. Novel methods based on polymerase chain reaction and next-generation sequencing are now being studied in NHL with promising results. This review outlines the current status of the field in the use of MRD techniques for diffuse large B-cell lymphoma, mantle cell lymphoma and follicular lymphoma. Specifically, we address their demonstrated and potential clinical utility in risk stratification, monitoring of remission status, and guiding interim and post-treatment escalation. Future applications of these techniques could identify novel markers of MRD, improve initial treatment selection, guide treatment escalation or de-escalation, and allow for real-time monitoring of patterns of clonal evolution, which together could redefine NHL treatment paradigms.
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Affiliation(s)
- Matthew L Chase
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Philippe Armand
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.,Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA
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28
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TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood 2017; 130:1903-1910. [DOI: 10.1182/blood-2017-04-779736] [Citation(s) in RCA: 208] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Accepted: 08/14/2017] [Indexed: 12/12/2022] Open
Abstract
Key Points
The intensified standard-of-care regimens for younger patients with MCL do not overcome the deleterious effects of TP53 mutations. MCLs with TP53 mutations should be considered for alternative frontline treatment.
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Riedell PA, Bishop MR. Post-autologous transplant maintenance therapies in lymphoma: current state and future directions. Bone Marrow Transplant 2017; 53:11-21. [PMID: 28967896 DOI: 10.1038/bmt.2017.196] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Revised: 07/19/2017] [Accepted: 07/20/2017] [Indexed: 01/11/2023]
Abstract
Disease relapse following high-dose chemotherapy and autologous stem cell transplant (ASCT) remains the principal cause of mortality in patients with relapsed or refractory lymphomas. In an effort to prevent post-ASCT relapse, a number of studies have evaluated the role of maintenance therapy with varying success. In diffuse large B-cell lymphoma, studies evaluating maintenance rituximab (MR) following ASCT failed to demonstrate improved outcomes. In follicular lymphoma, MR was associated with an improvement in PFS; however, no overall survival (OS) benefit was noted. Emerging data evaluating MR in mantle cell lymphoma (MCL) have demonstrated improvements in PFS, although a consistent improvement in OS has yet to be demonstrated. Given the aggressive and incurable nature of MCL, it is prudent for practitioners to weigh the risks and benefits of MR in the post-ASCT setting. Similarly, post-ASCT maintenance therapy with brentuximab vedotin in Hodgkin lymphoma, has led to improved PFS and may be considered in those with a high risk of relapse. Ongoing clinical studies evaluating a multitude of novel maintenance therapies are crucial to the efforts of further defining and optimizing the role of post-transplant maintenance therapy in lymphoma.
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Affiliation(s)
- P A Riedell
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA
| | - M R Bishop
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA
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Autologous hematopoietic cell transplantation of mantle cell lymphoma: emerging trends. Curr Opin Hematol 2017; 24:502-508. [PMID: 28832354 DOI: 10.1097/moh.0000000000000383] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW The management of mantle cell lymphoma has changed significantly with the adoption of immunochemotherapy and dose intensive treatment strategies in specific patient populations. Randomized controlled trials have established the role of rituximab-based treatments and autologous stem cell transplantation as standards of care. Novel therapeutics are also being integrated into these treatment strategies. RECENT FINDINGS Rituximab-based primary treatment has been shown to significantly improve complete remission rates. The addition of autologous stem cell transplantation has also improved progression-free survival (PFS) although data regarding potential overall survival (OS) benefits are not clear. Complete remission and minimal residual disease (MRD) negative disease states are predictive of outcome. Rituximab maintenance post SCT has also been shown to significantly improves PFS and OS. SUMMARY Current therapeutic standards in mantle cell lymphoma have clearly improved patient outcomes with improvements in remission rates, PFS, and OS. Autologous stem cell transplant (ASCT) as a consolidation strategy of primary treatment has improved outcomes, and the incorporation of novel drugs into frontline therapy may further improve the efficacy of the treatment. MRD-driven strategies may ultimately define appropriate patient subsets towards ASCT or alternative approaches.
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Staton AD, Langston AA. Autologous Stem Cell Transplant: Still the Standard for Fit Patients With Mantle Cell Lymphoma. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2017; 17S:S96-S99. [PMID: 28760309 DOI: 10.1016/j.clml.2017.02.021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 02/28/2017] [Indexed: 12/22/2022]
Abstract
Mantle cell lymphoma is a relatively rare malignancy, comprising fewer than 10% of all non-Hodgkin lymphomas. It is a heterogeneous disease, and although most patients experience an aggressive clinical course, some have a more indolent disease and may not require immediate therapy. There are currently few reliable prognostic markers, making it difficult to accurately predict which patients require early intensive treatment. We argue that consolidative autologous stem cell transplantation in first remission remains the standard of care for the young and fit patient population, based on long-term data from phase II and III trials demonstrating that early transplantation extends both progression-free and overall survival. Novel targeted agents are currently being investigated in both the upfront and relapse settings, but to date there are few data to suggest durable treatment responses that compare favorably with results of transplantation.
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Affiliation(s)
- Ashley D Staton
- Department of Hematology and Medical Oncology, Emory University, Atlanta, GA
| | - Amelia A Langston
- Department of Hematology and Medical Oncology, Emory University, Atlanta, GA.
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High-throughput sequencing for noninvasive disease detection in hematologic malignancies. Blood 2017; 130:440-452. [PMID: 28600337 DOI: 10.1182/blood-2017-03-735639] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 05/25/2017] [Indexed: 12/20/2022] Open
Abstract
Noninvasive monitoring of minimal residual disease (MRD) has led to significant advances in personalized management of patients with hematologic malignancies. Improved therapeutic options and prolonged survival have further increased the need for sensitive tumor assessment that can inform treatment decisions and patient outcomes. At diagnosis or relapse of most hematologic neoplasms, malignant cells are often easily accessible in the blood as circulating tumor cells (CTCs), making them ideal targets to noninvasively profile the molecular features of each patient. In other cancer types, CTCs are generally rare and noninvasive molecular detection relies on circulating tumor DNA (ctDNA) shed from tumor deposits into circulation. The ability to precisely detect and quantify CTCs and ctDNA could minimize invasive procedures and improve prediction of clinical outcomes. Technical advances in MRD detection methods in recent years have led to reduced costs and increased sensitivity, specificity, and applicability. Among currently available tests, high-throughput sequencing (HTS)-based approaches are increasingly attractive for noninvasive molecular testing. HTS-based methods can simultaneously identify multiple genetic markers with high sensitivity and specificity without individual optimization. In this review, we present an overview of techniques used for noninvasive molecular disease detection in selected myeloid and lymphoid neoplasms, with a focus on the current and future role of HTS-based assays.
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Yan F, Gopal AK, Graf SA. Targeted Drugs as Maintenance Therapy after Autologous Stem Cell Transplantation in Patients with Mantle Cell Lymphoma. Pharmaceuticals (Basel) 2017; 10:E28. [PMID: 28287430 PMCID: PMC5374432 DOI: 10.3390/ph10010028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Revised: 03/06/2017] [Accepted: 03/08/2017] [Indexed: 11/17/2022] Open
Abstract
The treatment landscape for mantle cell lymphoma (MCL) is rapidly evolving toward the incorporation of novel and biologically targeted pharmaceuticals with improved disease activity and gentler toxicity profiles compared with conventional chemotherapeutics. Upfront intensive treatment of MCL includes autologous stem cell transplantation (SCT) consolidation aimed at deepening and lengthening disease remission, but subsequent relapse occurs. Maintenance therapy after autologous SCT in patients with MCL in remission features lower-intensity treatments given over extended periods to improve disease outcomes. Targeted drugs are a natural fit for this space, and are the focus of considerable clinical investigation. This review summarizes recent advances in the field and their potential impact on treatment practices for MCL.
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Affiliation(s)
- Fengting Yan
- Department of Medicine, University of Washington, Seattle, WA 98195, USA.
- Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
| | - Ajay K Gopal
- Department of Medicine, University of Washington, Seattle, WA 98195, USA.
- Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
| | - Solomon A Graf
- Department of Medicine, University of Washington, Seattle, WA 98195, USA.
- Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
- Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA.
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Spurgeon SE, Till BG, Martin P, Goy AH, Dreyling MP, Gopal AK, LeBlanc M, Leonard JP, Friedberg JW, Baizer L, Little RF, Kahl BS, Smith MR. Recommendations for Clinical Trial Development in Mantle Cell Lymphoma. J Natl Cancer Inst 2016; 109:2758475. [PMID: 28040733 DOI: 10.1093/jnci/djw263] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 06/24/2016] [Accepted: 10/04/2016] [Indexed: 12/16/2022] Open
Abstract
Mantle cell lymphoma (MCL) comprises around 6% of all non-Hodgkin's lymphoma (NHL) diagnoses. In younger patients, age less than 60 to 65 years, aggressive induction often followed by consolidation with autologous stem cell transplant has suggested improved outcomes in this population. Less intensive therapies in older patients often followed by maintenance have been studied or are under active investigation. However, despite recent advances, MCL remains incurable, with a median overall survival of around five years. Patients with high-risk disease have particularly poor outcomes. Treatment varies widely across institutions, and to date no randomized trials comparing intensive vs less intensive approaches have been reported. Although recent data have highlighted the heterogeneity of MCL outcomes, patient assessment for treatment selection has largely been driven by patient age with little regard to fitness, disease biology, or disease risk. One critical advance is the finding that minimal residual disease status (MRD) after induction correlates with long-term outcomes. As such, its use as a potential end point could inform clinical trial design. In order to more rapidly improve the outcomes of MCL patients, clinical trials are needed that prospectively stratify patients on the basis of MCL biology and disease risk, incorporate novel agents, and use MRD to guide the need for additional therapy.
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Affiliation(s)
- Stephen E Spurgeon
- Affiliations of authors: Division of Hematology and Medical Oncology, Oregon Health and Science (OHSU) University Knight Cancer Institute, Portland, OR (SES); Clinical Research Division, Fred Hutchinson Cancer Research Center/ Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA (BGT, AKG); Department of Medicine, Weill Cornell Medicine, New York, NY (PM, JPL); John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ (AHG); Department of Medicine III, Klinikum der Universität München, Campus Grosshadern, Munich, Germany (MPD); Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (ML); Wilmot Cancer Center and Division of Hematology/Oncology, University of Rochester, Rochester, NY (JWF); Coordinating Center for Clinical Trials, National Cancer Institute, National Institutes of Health, Bethesda, MD (LB); HIV and AIDS Malignancy Branch, Center for Cancer Research, and Clinical Investigations Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD (RFL); Department of Medicine, Oncology Division, Washington University, St. Louis, MO (BSK); Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH (MRS)
| | - Brian G Till
- Affiliations of authors: Division of Hematology and Medical Oncology, Oregon Health and Science (OHSU) University Knight Cancer Institute, Portland, OR (SES); Clinical Research Division, Fred Hutchinson Cancer Research Center/ Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA (BGT, AKG); Department of Medicine, Weill Cornell Medicine, New York, NY (PM, JPL); John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ (AHG); Department of Medicine III, Klinikum der Universität München, Campus Grosshadern, Munich, Germany (MPD); Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (ML); Wilmot Cancer Center and Division of Hematology/Oncology, University of Rochester, Rochester, NY (JWF); Coordinating Center for Clinical Trials, National Cancer Institute, National Institutes of Health, Bethesda, MD (LB); HIV and AIDS Malignancy Branch, Center for Cancer Research, and Clinical Investigations Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD (RFL); Department of Medicine, Oncology Division, Washington University, St. Louis, MO (BSK); Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH (MRS)
| | - Peter Martin
- Affiliations of authors: Division of Hematology and Medical Oncology, Oregon Health and Science (OHSU) University Knight Cancer Institute, Portland, OR (SES); Clinical Research Division, Fred Hutchinson Cancer Research Center/ Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA (BGT, AKG); Department of Medicine, Weill Cornell Medicine, New York, NY (PM, JPL); John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ (AHG); Department of Medicine III, Klinikum der Universität München, Campus Grosshadern, Munich, Germany (MPD); Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (ML); Wilmot Cancer Center and Division of Hematology/Oncology, University of Rochester, Rochester, NY (JWF); Coordinating Center for Clinical Trials, National Cancer Institute, National Institutes of Health, Bethesda, MD (LB); HIV and AIDS Malignancy Branch, Center for Cancer Research, and Clinical Investigations Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD (RFL); Department of Medicine, Oncology Division, Washington University, St. Louis, MO (BSK); Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH (MRS)
| | - Andre H Goy
- Affiliations of authors: Division of Hematology and Medical Oncology, Oregon Health and Science (OHSU) University Knight Cancer Institute, Portland, OR (SES); Clinical Research Division, Fred Hutchinson Cancer Research Center/ Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA (BGT, AKG); Department of Medicine, Weill Cornell Medicine, New York, NY (PM, JPL); John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ (AHG); Department of Medicine III, Klinikum der Universität München, Campus Grosshadern, Munich, Germany (MPD); Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (ML); Wilmot Cancer Center and Division of Hematology/Oncology, University of Rochester, Rochester, NY (JWF); Coordinating Center for Clinical Trials, National Cancer Institute, National Institutes of Health, Bethesda, MD (LB); HIV and AIDS Malignancy Branch, Center for Cancer Research, and Clinical Investigations Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD (RFL); Department of Medicine, Oncology Division, Washington University, St. Louis, MO (BSK); Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH (MRS)
| | - Martin P Dreyling
- Affiliations of authors: Division of Hematology and Medical Oncology, Oregon Health and Science (OHSU) University Knight Cancer Institute, Portland, OR (SES); Clinical Research Division, Fred Hutchinson Cancer Research Center/ Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA (BGT, AKG); Department of Medicine, Weill Cornell Medicine, New York, NY (PM, JPL); John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ (AHG); Department of Medicine III, Klinikum der Universität München, Campus Grosshadern, Munich, Germany (MPD); Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (ML); Wilmot Cancer Center and Division of Hematology/Oncology, University of Rochester, Rochester, NY (JWF); Coordinating Center for Clinical Trials, National Cancer Institute, National Institutes of Health, Bethesda, MD (LB); HIV and AIDS Malignancy Branch, Center for Cancer Research, and Clinical Investigations Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD (RFL); Department of Medicine, Oncology Division, Washington University, St. Louis, MO (BSK); Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH (MRS)
| | - Ajay K Gopal
- Affiliations of authors: Division of Hematology and Medical Oncology, Oregon Health and Science (OHSU) University Knight Cancer Institute, Portland, OR (SES); Clinical Research Division, Fred Hutchinson Cancer Research Center/ Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA (BGT, AKG); Department of Medicine, Weill Cornell Medicine, New York, NY (PM, JPL); John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ (AHG); Department of Medicine III, Klinikum der Universität München, Campus Grosshadern, Munich, Germany (MPD); Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (ML); Wilmot Cancer Center and Division of Hematology/Oncology, University of Rochester, Rochester, NY (JWF); Coordinating Center for Clinical Trials, National Cancer Institute, National Institutes of Health, Bethesda, MD (LB); HIV and AIDS Malignancy Branch, Center for Cancer Research, and Clinical Investigations Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD (RFL); Department of Medicine, Oncology Division, Washington University, St. Louis, MO (BSK); Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH (MRS)
| | - Michael LeBlanc
- Affiliations of authors: Division of Hematology and Medical Oncology, Oregon Health and Science (OHSU) University Knight Cancer Institute, Portland, OR (SES); Clinical Research Division, Fred Hutchinson Cancer Research Center/ Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA (BGT, AKG); Department of Medicine, Weill Cornell Medicine, New York, NY (PM, JPL); John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ (AHG); Department of Medicine III, Klinikum der Universität München, Campus Grosshadern, Munich, Germany (MPD); Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (ML); Wilmot Cancer Center and Division of Hematology/Oncology, University of Rochester, Rochester, NY (JWF); Coordinating Center for Clinical Trials, National Cancer Institute, National Institutes of Health, Bethesda, MD (LB); HIV and AIDS Malignancy Branch, Center for Cancer Research, and Clinical Investigations Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD (RFL); Department of Medicine, Oncology Division, Washington University, St. Louis, MO (BSK); Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH (MRS)
| | - John P Leonard
- Affiliations of authors: Division of Hematology and Medical Oncology, Oregon Health and Science (OHSU) University Knight Cancer Institute, Portland, OR (SES); Clinical Research Division, Fred Hutchinson Cancer Research Center/ Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA (BGT, AKG); Department of Medicine, Weill Cornell Medicine, New York, NY (PM, JPL); John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ (AHG); Department of Medicine III, Klinikum der Universität München, Campus Grosshadern, Munich, Germany (MPD); Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (ML); Wilmot Cancer Center and Division of Hematology/Oncology, University of Rochester, Rochester, NY (JWF); Coordinating Center for Clinical Trials, National Cancer Institute, National Institutes of Health, Bethesda, MD (LB); HIV and AIDS Malignancy Branch, Center for Cancer Research, and Clinical Investigations Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD (RFL); Department of Medicine, Oncology Division, Washington University, St. Louis, MO (BSK); Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH (MRS)
| | - Jonathan W Friedberg
- Affiliations of authors: Division of Hematology and Medical Oncology, Oregon Health and Science (OHSU) University Knight Cancer Institute, Portland, OR (SES); Clinical Research Division, Fred Hutchinson Cancer Research Center/ Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA (BGT, AKG); Department of Medicine, Weill Cornell Medicine, New York, NY (PM, JPL); John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ (AHG); Department of Medicine III, Klinikum der Universität München, Campus Grosshadern, Munich, Germany (MPD); Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (ML); Wilmot Cancer Center and Division of Hematology/Oncology, University of Rochester, Rochester, NY (JWF); Coordinating Center for Clinical Trials, National Cancer Institute, National Institutes of Health, Bethesda, MD (LB); HIV and AIDS Malignancy Branch, Center for Cancer Research, and Clinical Investigations Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD (RFL); Department of Medicine, Oncology Division, Washington University, St. Louis, MO (BSK); Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH (MRS)
| | - Lawrence Baizer
- Affiliations of authors: Division of Hematology and Medical Oncology, Oregon Health and Science (OHSU) University Knight Cancer Institute, Portland, OR (SES); Clinical Research Division, Fred Hutchinson Cancer Research Center/ Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA (BGT, AKG); Department of Medicine, Weill Cornell Medicine, New York, NY (PM, JPL); John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ (AHG); Department of Medicine III, Klinikum der Universität München, Campus Grosshadern, Munich, Germany (MPD); Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (ML); Wilmot Cancer Center and Division of Hematology/Oncology, University of Rochester, Rochester, NY (JWF); Coordinating Center for Clinical Trials, National Cancer Institute, National Institutes of Health, Bethesda, MD (LB); HIV and AIDS Malignancy Branch, Center for Cancer Research, and Clinical Investigations Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD (RFL); Department of Medicine, Oncology Division, Washington University, St. Louis, MO (BSK); Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH (MRS)
| | - Richard F Little
- Affiliations of authors: Division of Hematology and Medical Oncology, Oregon Health and Science (OHSU) University Knight Cancer Institute, Portland, OR (SES); Clinical Research Division, Fred Hutchinson Cancer Research Center/ Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA (BGT, AKG); Department of Medicine, Weill Cornell Medicine, New York, NY (PM, JPL); John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ (AHG); Department of Medicine III, Klinikum der Universität München, Campus Grosshadern, Munich, Germany (MPD); Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (ML); Wilmot Cancer Center and Division of Hematology/Oncology, University of Rochester, Rochester, NY (JWF); Coordinating Center for Clinical Trials, National Cancer Institute, National Institutes of Health, Bethesda, MD (LB); HIV and AIDS Malignancy Branch, Center for Cancer Research, and Clinical Investigations Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD (RFL); Department of Medicine, Oncology Division, Washington University, St. Louis, MO (BSK); Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH (MRS)
| | - Brad S Kahl
- Affiliations of authors: Division of Hematology and Medical Oncology, Oregon Health and Science (OHSU) University Knight Cancer Institute, Portland, OR (SES); Clinical Research Division, Fred Hutchinson Cancer Research Center/ Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA (BGT, AKG); Department of Medicine, Weill Cornell Medicine, New York, NY (PM, JPL); John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ (AHG); Department of Medicine III, Klinikum der Universität München, Campus Grosshadern, Munich, Germany (MPD); Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (ML); Wilmot Cancer Center and Division of Hematology/Oncology, University of Rochester, Rochester, NY (JWF); Coordinating Center for Clinical Trials, National Cancer Institute, National Institutes of Health, Bethesda, MD (LB); HIV and AIDS Malignancy Branch, Center for Cancer Research, and Clinical Investigations Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD (RFL); Department of Medicine, Oncology Division, Washington University, St. Louis, MO (BSK); Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH (MRS)
| | - Mitchell R Smith
- Affiliations of authors: Division of Hematology and Medical Oncology, Oregon Health and Science (OHSU) University Knight Cancer Institute, Portland, OR (SES); Clinical Research Division, Fred Hutchinson Cancer Research Center/ Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA (BGT, AKG); Department of Medicine, Weill Cornell Medicine, New York, NY (PM, JPL); John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ (AHG); Department of Medicine III, Klinikum der Universität München, Campus Grosshadern, Munich, Germany (MPD); Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (ML); Wilmot Cancer Center and Division of Hematology/Oncology, University of Rochester, Rochester, NY (JWF); Coordinating Center for Clinical Trials, National Cancer Institute, National Institutes of Health, Bethesda, MD (LB); HIV and AIDS Malignancy Branch, Center for Cancer Research, and Clinical Investigations Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD (RFL); Department of Medicine, Oncology Division, Washington University, St. Louis, MO (BSK); Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH (MRS)
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Kolstad A, Pedersen LB, Eskelund CW, Husby S, Grønbæk K, Jerkeman M, Laurell A, Räty R, Elonen E, Andersen NS, Brown PD, Kimby E, Bentzen H, Sundström C, Ehinger M, Karjalainen-Lindsberg ML, Delabie J, Ralfkiær E, Fagerli UM, Nilsson-Ehle H, Lauritzsen GF, Kuittinen O, Niemann C, Geisler CH. Molecular Monitoring after Autologous Stem Cell Transplantation and Preemptive Rituximab Treatment of Molecular Relapse; Results from the Nordic Mantle Cell Lymphoma Studies (MCL2 and MCL3) with Median Follow-Up of 8.5 Years. Biol Blood Marrow Transplant 2016; 23:428-435. [PMID: 28039078 DOI: 10.1016/j.bbmt.2016.12.634] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Accepted: 12/23/2016] [Indexed: 11/18/2022]
Abstract
The main objectives of the present study were to monitor minimal residual disease (MRD) in the bone marrow of patients with mantle cell lymphoma (MCL) to predict clinical relapse and guide preemptive treatment with rituximab. Among the patients enrolled in 2 prospective trials by the Nordic Lymphoma Group, 183 who had completed autologous stem cell transplantation (ASCT) and in whom an MRD marker had been obtained were included in our analysis. Fresh samples of bone marrow were analyzed for MRD by a combined standard nested and quantitative real-time PCR assay for Bcl-1/immunoglobulin heavy chain gene (IgH) and clonal IgH rearrangements. Significantly shorter progression-free survival (PFS) and overall survival (OS) was demonstrated for patients who were MRD positive pre-ASCT (54 patients) or in the first analysis post-ASCT (23 patients). The median PFS was only 20 months in those who were MRD-positive in the first sample post-ASCT, compared with 142 months in the MRD-negative group (P < .0001). OS was 75% at 10 years and median not reached in the MRD-negative group, compared with only 35 months in the MRD-positive group (P < .0001). Of the 86 patients (47%) who remained in continuous molecular remission, 73% were still in clinical remission after 10 years. For all patients, the median time from ASCT to first molecular relapse was 55 months, with a continuous occurrence of late molecular relapses. Fifty-eight patients who experienced MRD relapse received rituximab as preemptive treatment on 1 or more occasions, and in this group, the median time from first molecular relapse to clinical relapse was 55 months. In most cases, rituximab converted patients to MRD negativity (87%), but many patients became MRD-positive again later during follow-up (69%). By multivariate analysis, high-risk Mantle Cell Lymphoma International Prognostic Index score and positive MRD status pre-ASCT predicted early molecular relapse. In conclusion, preemptive rituximab treatment converts patients to MRD negativity and likely postpones clinical relapse. Molecular monitoring offers an opportunity to select some patients for therapeutic intervention and to avoid unnecessary treatment in others. MRD-positive patients in the first analysis post-ASCT have a dismal prognosis and thus are in need of novel strategies.
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Affiliation(s)
- Arne Kolstad
- Department of Oncology, Oslo University Hospital, Radiumhospitalet, Oslo, Norway.
| | - Lone Bredo Pedersen
- Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Christian W Eskelund
- Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Simon Husby
- Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Kirsten Grønbæk
- Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Mats Jerkeman
- Department of Oncology, Skåne University Hospital, Lund, Sweden
| | - Anna Laurell
- Department of Oncology, Uppsala University Hospital, Uppsala, Sweden
| | - Riikka Räty
- Department of Hematology and Oncology, Helsinki University Central Hospital, Helsinki, Finland
| | - Erkki Elonen
- Department of Hematology and Oncology, Helsinki University Central Hospital, Helsinki, Finland
| | | | - Peter deNully Brown
- Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Eva Kimby
- Department of Hematology, Karolinska Institute, Stockholm, Sweden
| | - Hans Bentzen
- Department of Hematology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Mats Ehinger
- Department of Pathology, Skåne University Hospital, Lund, Sweden
| | | | - Jan Delabie
- Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Elisabeth Ralfkiær
- Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | | | - Herman Nilsson-Ehle
- Department of Hematology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | | | - Outi Kuittinen
- Department of Oncology, Oulu University Hospital, Oulu, Finland
| | - Carsten Niemann
- Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
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Hoster E, Pott C. Minimal residual disease in mantle cell lymphoma: insights into biology and impact on treatment. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2016; 2016:437-445. [PMID: 27913513 PMCID: PMC6142459 DOI: 10.1182/asheducation-2016.1.437] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
Despite the recent substantial improvement of clinical outcome in mantle cell lymphoma (MCL), resistance to immunochemotherapy and common relapses are challenges for long-term tumor control. The assessment of minimal residual disease (MRD) by real-time quantitative polymerase chain reaction has emerged as a widely feasible and standardized tool for direct assessment of therapy-induced reduction of tumor burden and regrowth after cytotoxic treatment in MCL, with much improved sensitivity compared with conventional staging procedures. Several studies have shown that intensification of initial treatment, which has resulted in improved clinical outcome, is immediately reflected in higher molecular remission rates; they have also shown that high-dose consolidation might not be able to compensate for less intensive induction regimens. Persistence or reappearance of MRD in clinical remission proved to be highly predictive for imminent clinical relapse associated with shorter overall survival. Therefore, the investigation of novel MRD-guided treatment strategies aimed at early eradication of MRD and pre-emptive treatment of molecular relapse seems warranted. Furthermore, the integration of MRD assessment into clinical response criteria could result in a more specific and potentially earlier end point for treatment efficacy. New technical developments such as high-throughput sequencing will further enhance the wide applicability of MRD detection in MCL.
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Affiliation(s)
- Eva Hoster
- Department of Internal Medicine III, University Hospital Munich, and Institute of Medical Informatics, Biometry, and Epidemiology, Ludwig-Maximilians-University Munich, Munich, Germany; and
| | - Christiane Pott
- Second Medical Department, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
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Rule S. Frontline therapy and role of high-dose consolidation in mantle cell lymphoma. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2016; 2016:419-424. [PMID: 27913510 PMCID: PMC6142468 DOI: 10.1182/asheducation-2016.1.419] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin lymphoma. It is predominantly a disease of older individuals, with a median age at presentation of ∼70 years. For the majority of patients, the management revolves around immuno-chemotherapy often followed by maintenance rituximab, and at relapse, a range of options are available. For the younger patient, it is possible to be more intensive with therapy, consolidate responses with high-dose procedures, and in a few there might be the prospect of a cure. The incorporation of high-dose cytarabine into the treatment algorithm has had a major impact on outcomes, with approximately half of the patients alive at 10 years whether an autologous stem cell transplant is adopted or not. Allogeneic transplantation produces some very durable responses in the relapsed setting and has a potential role up front in the highest-risk patients. However, with the advent of Bruton tyrosine kinase inhibitor and other highly effective nontraditional chemotherapeutic approaches, there is the potential for the management of this disease to change fundamentally over the next few years.
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Affiliation(s)
- Simon Rule
- Department of Haematology, Derriford Hospital, Plymouth and Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, United Kingdom
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38
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Ladetto M, Buske C, Hutchings M, Dreyling M, Gaidano G, Le Gouill S, Luminari S, Pott C, Zamò A, Zucca E. ESMO consensus conference on malignant lymphoma: general perspectives and recommendations for prognostic tools in mature B-cell lymphomas and chronic lymphocytic leukaemia. Ann Oncol 2016; 27:2149-2160. [PMID: 27701070 DOI: 10.1093/annonc/mdw419] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 08/11/2016] [Accepted: 08/23/2016] [Indexed: 01/02/2023] Open
Abstract
The European Society for Medical Oncology (ESMO) consensus conference on mature B-cell lymphomas and chronic lymphocytic leukaemia (CLL) was held on 20 June 2015 in Lugano, Switzerland, and included a multidisciplinary panel of 25 leading experts. The aim of the conference was to develop recommendations on critical subjects difficult to consider in detail in the ESMO Clinical Practice Guidelines. The following areas were identified: (i) the elderly patient, (ii) prognostic factors suitable for clinical use and (iii) the 'ultra-high-risk' group. Before the conference, the expert panel was divided into three working groups; each group focused on one of these areas in order to address four clinically relevant questions relating to that topic. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, each working group developed recommendations to address each of the four questions assigned to their group. These recommendations were then presented to the entire panel and a consensus was reached. This manuscript presents recommendations dedicated to the second area of interest, i.e. prognostic factors suitable for clinical use. The four topics [i.e. interim positron emission tomography (PET), TP53 mutations, cell of origin (COO) and minimal residual disease (MRD)] were primarily chosen because of the bulk of available data together with the lack of clear guidance regarding their use in clinical practice and within clinical trials. Results, including a summary of evidence supporting each recommendation, are detailed in this manuscript. The panel acknowledged that detection of TP53 inactivation by deletion or mutation in CLL should be implemented in clinical practice (level of evidence I, strength of recommendation A). Due to their potentially high prognostic value, at least in some lymphoma entities, implementation of interim PET, COO and MRD was highly recommended in the context of clinical trials. All expert panel members approved this final article.
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Affiliation(s)
- M Ladetto
- Hematology Division, Azienda Ospedaliera Santi Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
| | - C Buske
- Comprehensive Cancer Center Ulm and Department of Internal Medicine III, Institute of Experimental Cancer Research, University Hospital, Ulm, Germany
| | - M Hutchings
- Department of Hematology, Rigshospitalet, Copenhagen, Denmark
| | - M Dreyling
- Medizinische Klinik III, Klinikum der Universität München/LMU, Munich, Germany
| | - G Gaidano
- Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
| | - S Le Gouill
- Clinical Hematology, Centre Hospitalo-Universitaire de Nantes, UMR892 Team 10, CIC Nantes, France
| | - S Luminari
- Hematology, Arcispedale S. Maria Nuova, IRCCS Reggio Emilia.,Department of Diagnostic, Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - C Pott
- Second Medical Department, University Hospital Schleswig-Holstein, Kiel, Germany
| | - A Zamò
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - E Zucca
- Lymphoma Unit, Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland
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Taverna JA, Yun S, Jonnadula J, Saleh A, Riaz IB, Abraham I, Yeager AM, Persky DO, McBride A, Haldar S, Anwer F. Role of Maintenance Therapy after High-Dose Chemotherapy and Autologous Hematopoietic Cell Transplantation in Aggressive Lymphomas: A Systematic Review. Biol Blood Marrow Transplant 2016; 22:1182-1196. [PMID: 26899562 DOI: 10.1016/j.bbmt.2016.02.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 02/08/2016] [Indexed: 11/29/2022]
Abstract
Significant uncertainty exists in regard to the efficacy of maintenance therapy after high-dose chemotherapy (HDC) as well as autologous stem cell transplantation (ASCT) for the treatment of patients with aggressive lymphoma. A systematic review was performed to evaluate the effectiveness of post-ASCT maintenance therapy in patients with relapsed/refractory lymphoma. A comprehensive literature search yielded 4476 studies and a total of 42 studies (11 randomized controlled trials [RCT], 9 retrospective comparative studies, and 22 single-arm studies) were included in the systematic review. There was significant heterogeneity in study design, chemotherapeutic regimens, post-ASCT maintenance strategies, patient enrollment criteria, and study endpoints. Our findings suggest that post-ASCT maintenance immune-targeting strategies, including PD-1/PD-L1 blocking antibodies, rituximab, and brentuximab, may improve progression-free survival but not overall survival. Collectively, the results indicate a need for testing new strategies with well-designed and adequately powered RCTs to better address the role of post-ASCT maintenance in relapsed/refractory lymphomas.
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Affiliation(s)
- Josephine A Taverna
- Department of Medicine, University of Arizona, Tucson, Arizona; Department of Hematology and Oncology, Blood and Marrow Transplantation Program, University of Arizona, Tucson, Arizona; Department of Hematology and Oncology, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Seongseok Yun
- Department of Medicine, University of Arizona, Tucson, Arizona
| | | | - Ahlam Saleh
- Arizona Health Sciences Library, University of Arizona, Tucson, Arizona
| | - Irbaz Bin Riaz
- Department of Medicine, University of Arizona, Tucson, Arizona
| | - Ivo Abraham
- Center for Health Outcomes and PharmacoEconomic Research, University of Arizona, Tucson, Arizona; Arizona Cancer Center, Tucson, Arizona
| | - Andrew M Yeager
- Department of Medicine, University of Arizona, Tucson, Arizona; Department of Hematology and Oncology, Blood and Marrow Transplantation Program, University of Arizona, Tucson, Arizona; Arizona Cancer Center, Tucson, Arizona
| | - Daniel O Persky
- Department of Medicine, University of Arizona, Tucson, Arizona; Department of Hematology and Oncology, Blood and Marrow Transplantation Program, University of Arizona, Tucson, Arizona; Arizona Cancer Center, Tucson, Arizona
| | - Ali McBride
- Department of Hematology and Oncology, Blood and Marrow Transplantation Program, University of Arizona, Tucson, Arizona; Arizona Cancer Center, Tucson, Arizona
| | - Subrata Haldar
- Department of Hematology and Oncology, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Faiz Anwer
- Department of Medicine, University of Arizona, Tucson, Arizona; Department of Hematology and Oncology, Blood and Marrow Transplantation Program, University of Arizona, Tucson, Arizona; Arizona Cancer Center, Tucson, Arizona.
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Dreyling M, Ferrero S. The role of targeted treatment in mantle cell lymphoma: is transplant dead or alive? Haematologica 2016; 101:104-14. [PMID: 26830211 PMCID: PMC4938333 DOI: 10.3324/haematol.2014.119115] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Accepted: 11/17/2015] [Indexed: 12/16/2022] Open
Abstract
Based on the profound biological insights of the last years into the molecular pathogenesis of mantle cell lymphoma and the clinical introduction of new targeted drugs, with high efficacy and a good safety profile, the therapeutic scenario for this tumor has been shown to be thoroughly favourable. No longer characterized by a uniformly dismal prognosis, mantle cell lymphoma has been revealed as a spectrum of different diseases, ranging from very indolent cases to highly aggressive and refractory ones. Thus, there is an urgent need to adapt therapy to accommodate the diverse presentations of the disease. High-dose chemotherapy, followed by autologous stem cell transplantation is the current standard of care for younger patients, generally providing high responses and long survival rates, but hampered by acute and long-term toxicity. In addition, some patients may be overtreated, while others could benefit from targeted approaches, based on the new, molecular-directed compounds. Such a personalized treatment based on the specific characteristics of individual patients may be guided by validated prognostic tools, such as the Mantle Cell Lymphoma International Prognostic Index and the Ki-67 Proliferative Index, as well as by early predictors of treatment response, like minimal residual disease analysis. Moreover, mutation screening of distinctive genomic alterations may provide new, predictive biomarkers, with an additional impact on clinical practice. Only after tailoring treatment according to the clinical and biological heterogeneity of the disease the role of transplantation and modern therapeutic options will be redefined in mantle cell lymphoma.
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Affiliation(s)
- Martin Dreyling
- Department of Medicine III, Hospital of the University LMU München, Germany
| | - Simone Ferrero
- Division of Hematology, Department of Molecular Biotechnologies and Health Sciences, University of Torino, Italy
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41
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Cheminant M, Derrieux C, Touzart A, Schmit S, Grenier A, Trinquand A, Delfau-Larue MH, Lhermitte L, Thieblemont C, Ribrag V, Cheze S, Sanhes L, Jardin F, Lefrère F, Delarue R, Hoster E, Dreyling M, Asnafi V, Hermine O, Macintyre E. Minimal residual disease monitoring by 8-color flow cytometry in mantle cell lymphoma: an EU-MCL and LYSA study. Haematologica 2015; 101:336-45. [PMID: 26703963 DOI: 10.3324/haematol.2015.134957] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 12/18/2015] [Indexed: 11/09/2022] Open
Abstract
Quantification of minimal residual disease may guide therapeutic strategies in mantle cell lymphoma. While multiparameter flow cytometry is used for diagnosis, the gold standard method for minimal residual disease analysis is real-time quantitative polymerase chain reaction (RQ-PCR). In this European Mantle Cell Lymphoma network (EU-MCL) pilot study, we compared flow cytometry with RQ-PCR for minimal residual disease detection. Of 113 patients with at least one minimal residual disease sample, RQ-PCR was applicable in 97 (86%). A total of 284 minimal residual disease samples from 61 patients were analyzed in parallel by flow cytometry and RQ-PCR. A single, 8-color, 10-antibody flow cytometry tube allowed specific minimal residual disease assessment in all patients, with a robust sensitivity of 0.01%. Using this cut-off level, the true-positive-rate of flow cytometry with respect to RQ-PCR was 80%, whereas the true-negative-rate was 92%. As expected, RQ-PCR frequently detected positivity below this 0.01% threshold, which is insufficiently sensitive for prognostic evaluation and would ideally be replaced with robust quantification down to a 0.001% (10-5) threshold. In 10 relapsing patients, the transition from negative to positive by RQ-PCR (median 22.5 months before relapse) nearly always preceded transition by flow cytometry (4.5 months), but transition to RQ-PCR positivity above 0.01% (5 months) was simultaneous. Pre-emptive rituximab treatment of 2 patients at minimal residual disease relapse allowed re-establishment of molecular and phenotypic complete remission. Flow cytometry minimal residual disease is a complementary approach to RQ-PCR and a promising tool in individual mantle cell lymphoma therapeutic management. (clinicaltrials identifiers: 00209209 and 00209222).
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Affiliation(s)
- Morgane Cheminant
- Biological Hematology, Paris Descartes - Sorbonne Paris Cité University, Institut Necker-Enfants Malades, AP-HP, France Clinical Hematology, Paris Descartes - Sorbonne Paris Cité University, IMAGINE Institut, Necker Hospital, AP-HP, France
| | - Coralie Derrieux
- Biological Hematology, Paris Descartes - Sorbonne Paris Cité University, Institut Necker-Enfants Malades, AP-HP, France
| | - Aurore Touzart
- Biological Hematology, Paris Descartes - Sorbonne Paris Cité University, Institut Necker-Enfants Malades, AP-HP, France
| | - Stéphanie Schmit
- Biological Hematology, Paris Descartes - Sorbonne Paris Cité University, Institut Necker-Enfants Malades, AP-HP, France
| | - Adrien Grenier
- Biological Hematology, Paris Descartes - Sorbonne Paris Cité University, Institut Necker-Enfants Malades, AP-HP, France
| | - Amélie Trinquand
- Biological Hematology, Paris Descartes - Sorbonne Paris Cité University, Institut Necker-Enfants Malades, AP-HP, France
| | | | - Ludovic Lhermitte
- Biological Hematology, Paris Descartes - Sorbonne Paris Cité University, Institut Necker-Enfants Malades, AP-HP, France
| | - Catherine Thieblemont
- Hemato-Oncology, Saint-Louis Hospital, APHP - Paris Diderot - Sorbonne Paris Cité University - INSERM U728 - Institut Universitaire d'Hematologie, France
| | - Vincent Ribrag
- Département de Médecine, Institut Gustave Roussy, Villejuif, France
| | - Stéphane Cheze
- Clinical Hematology, University Hospital of Caen, France
| | | | - Fabrice Jardin
- Clinical Hematology, INSERM U918, IRIB, Centre Henri Becquerel, Rouen, France
| | - François Lefrère
- Clinical Hematology, Paris Descartes - Sorbonne Paris Cité University, IMAGINE Institut, Necker Hospital, AP-HP, France
| | - Richard Delarue
- Clinical Hematology, Paris Descartes - Sorbonne Paris Cité University, IMAGINE Institut, Necker Hospital, AP-HP, France
| | - Eva Hoster
- Institute of Medical Informatics, Biometry, and Epidemiology, University of Munich, Germany Department of Internal Medicine III, University Hospital Munich, Germany
| | - Martin Dreyling
- Department of Internal Medicine III, University Hospital Munich, Germany
| | - Vahid Asnafi
- Biological Hematology, Paris Descartes - Sorbonne Paris Cité University, Institut Necker-Enfants Malades, AP-HP, France
| | - Olivier Hermine
- Clinical Hematology, Paris Descartes - Sorbonne Paris Cité University, IMAGINE Institut, Necker Hospital, AP-HP, France
| | - Elizabeth Macintyre
- Biological Hematology, Paris Descartes - Sorbonne Paris Cité University, Institut Necker-Enfants Malades, AP-HP, France
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Graf SA, Stevenson PA, Holmberg LA, Till BG, Press OW, Chauncey TR, Smith SD, Philip M, Orozco JJ, Shustov AR, Green DJ, Libby EN, Bensinger WI, Pagel JM, Maloney DG, Zhou Y, Cassaday RD, Gopal AK. Maintenance rituximab after autologous stem cell transplantation in patients with mantle cell lymphoma. Ann Oncol 2015; 26:2323-8. [PMID: 26347113 PMCID: PMC4621031 DOI: 10.1093/annonc/mdv364] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Revised: 07/28/2015] [Accepted: 08/25/2015] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND High-dose therapy and autologous stem cell transplantation (ASCT) improves outcomes for patients with mantle cell lymphoma (MCL), but relapse ultimately occurs in most patients. Recently presented interim results from a phase III prospective trial suggest maintenance rituximab (MR) after ASCT for MCL improves progression-free survival (PFS). The maturation of these data and any benefit of MR on overall survival (OS) remain to be defined. PATIENTS AND METHODS In this retrospective study, we examined a cohort of consecutive patients with MCL that underwent ASCT for MCL at our center and evaluated their outcomes according to whether they received MR after ASCT (n = 50) or did not (n = 107). MR was treated as a time-dependent covariate to account for variation in timing of its initiation. RESULTS MR was associated with an improved PFS [hazard ratio (HR) 0.44; confidence interval (CI) (0.24-0.80), P = 0.007] and overall survival (OS; HR 0.46; CI 0.23-0.93, P = 0.03) following a multivariate adjustment for confounding factors with a median follow-up of ∼5 years. Grade 4 neutropenia was increased (34% versus 18%, P = 0.04) in the MR group, but no effect on the rate of mortality unrelated to relapse was observed. CONCLUSIONS These data support that MR after ASCT for MCL confers a benefit in PFS and additionally suggest it may improve OS. General application of this strategy will require confirmation of benefit in prospective randomized trials.
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Affiliation(s)
- S A Graf
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington Veterans Affairs Puget Sound Health Care System, Seattle, Washington Department of Medicine, University of Washington, Seattle, Washington, USA
| | - P A Stevenson
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington Department of Biostatistics, University of Washington, Seattle, Washington, USA
| | - L A Holmberg
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington Department of Medicine, University of Washington, Seattle, Washington, USA
| | - B G Till
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington Department of Medicine, University of Washington, Seattle, Washington, USA
| | - O W Press
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington Department of Medicine, University of Washington, Seattle, Washington, USA
| | - T R Chauncey
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington Veterans Affairs Puget Sound Health Care System, Seattle, Washington Department of Medicine, University of Washington, Seattle, Washington, USA
| | - S D Smith
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington Department of Medicine, University of Washington, Seattle, Washington, USA
| | - M Philip
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington Department of Medicine, University of Washington, Seattle, Washington, USA
| | - J J Orozco
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington Department of Medicine, University of Washington, Seattle, Washington, USA
| | - A R Shustov
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington Department of Medicine, University of Washington, Seattle, Washington, USA
| | - D J Green
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington Department of Medicine, University of Washington, Seattle, Washington, USA
| | - E N Libby
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington Department of Medicine, University of Washington, Seattle, Washington, USA
| | - W I Bensinger
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington Department of Medicine, University of Washington, Seattle, Washington, USA
| | - J M Pagel
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington Department of Medicine, University of Washington, Seattle, Washington, USA
| | - D G Maloney
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Y Zhou
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA
| | - R D Cassaday
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington Department of Medicine, University of Washington, Seattle, Washington, USA
| | - A K Gopal
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington Department of Medicine, University of Washington, Seattle, Washington, USA
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Minimal Residual Disease Detection by Droplet Digital PCR in Multiple Myeloma, Mantle Cell Lymphoma, and Follicular Lymphoma. J Mol Diagn 2015; 17:652-60. [DOI: 10.1016/j.jmoldx.2015.05.007] [Citation(s) in RCA: 94] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Revised: 03/26/2015] [Accepted: 05/22/2015] [Indexed: 01/27/2023] Open
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Epperla N, Fenske TS, Hari PN, Hamadani M. Recent advances in post autologous transplantation maintenance therapies in B-cell non-Hodgkin lymphomas. World J Transplant 2015; 5:81-88. [PMID: 26421260 PMCID: PMC4580930 DOI: 10.5500/wjt.v5.i3.81] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Revised: 05/27/2015] [Accepted: 06/19/2015] [Indexed: 02/05/2023] Open
Abstract
Lymphomas constitute the second most common indication for high dose therapy (HDT) followed by autologous hematopoietic cell transplantation (auto-HCT). The intent of administering HDT in these heterogeneous disorders varies from cure (e.g., in relapsed aggressive lymphomas) to disease control (e.g., most indolent lymphomas). Regardless of the underlying histology or remission status at transplantation, disease relapse remains the number one cause of post auto-HCT therapy failure and mortality. The last decade has seen a proliferation of clinical studies looking at prevention of post auto-HCT therapy failure with various maintenance strategies. The benefit of such therapies is in turn dependent on disease histology and timing of transplantation. In relapsed, chemosensitive diffuse large B-cell lymphoma (DLBCL), although post auto-HCT maintenance rituximab seems to be safe and feasible, it does not provide improved survival outcomes and is not recommended. The preliminary results with anti- programmed death -1 (PD-1) antibody therapy as post auto-HCT maintenance in DLBCL is promising but requires randomized validation. Similarly in follicular lymphoma, maintenance therapies including rituximab following auto-HCT should be considered investigational and offered only on a clinical trial. Rituximab maintenance results in improved progression-free survival but has not yet shown to improve overall survival in mantle cell lymphoma (MCL), but given the poor prognosis with post auto-HCT failure in MCL, maintenance rituximab can be considered on a case-by-case basis. Ongoing trials evaluating the efficacy of post auto-HCT maintenance with novel compounds (e.g., immunomodulators, PD-1 inhibitors, proteasome inhibitors and bruton’s tyrosine kinase inhibitors) will likely change the practice landscape in the near future for B cell non-Hodgkin lymphomas patients following HDT and auto-HCT.
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Post-autologous transplant maintenance therapies in lymphoid malignancies: are we there yet? Bone Marrow Transplant 2015; 50:1393-404. [DOI: 10.1038/bmt.2015.184] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Revised: 06/30/2015] [Accepted: 07/06/2015] [Indexed: 12/16/2022]
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Dreyling M, Ferrero S, Vogt N, Klapper W. New paradigms in mantle cell lymphoma: is it time to risk-stratify treatment based on the proliferative signature? Clin Cancer Res 2015; 20:5194-206. [PMID: 25320369 DOI: 10.1158/1078-0432.ccr-14-0836] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The elucidation of crucial biologic pathways of cell survival and proliferation has led to the development of highly effective drugs, some of which have markedly improved mantle cell lymphoma (MCL) therapeutic opportunities in the past 10 years. Moreover, an undeniable clinical heterogeneity in treatment response and disease behavior has become apparent in this neoplasm. Thus, the need for biologic markers stratifying patients with MCL in risk classes deserving different treatment approaches has recently been fervently expressed. Among several newly discovered biomarkers, the dismal predictive value of a high proliferative signature has been broadly recognized in large studies of patients with MCL. Different techniques have been used to assess tumor cell proliferation, including mitotic index, immunostaining with Ki-67 antibody, and gene expression profiling. Ki-67 proliferative index, in particular, has been extensively investigated, and its negative impact on relapse incidence and overall survival has been validated in large prospective clinical trials. However, one important pitfall limiting its widespread use in clinical practice is the reported interobserver variability, due to the previous lack of a standardized approach for quantification among different laboratories. In the present review, we describe some of the major techniques to assess cell proliferation in MCL, focusing in particular on the Ki-67 index and its need for a standardized approach to be used in multicenter clinical trials. The value of MCL biologic prognostic scores (as MIPI-b) is discussed, along with our proposal on how to integrate these scores in the planning of future trials investigating a tailored therapeutic approach for patients with MCL. See all articles in this CCR Focus section, "Paradigm Shifts in Lymphoma."
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Affiliation(s)
- Martin Dreyling
- Medizinische Klinik und Poliklinik III, Klinikum der Universität München, München, Germany.
| | - Simone Ferrero
- Division of Hematology, Department of Molecular Biotechnologies and Health Sciences, University of Torino, Italy
| | - Niklas Vogt
- Department of Pathology, Hematopathology Section and Lymph Node Registry Kiel. University Hospital Schleswig-Holstein, Campus Kiel, Germany
| | - Wolfram Klapper
- Department of Pathology, Hematopathology Section and Lymph Node Registry Kiel. University Hospital Schleswig-Holstein, Campus Kiel, Germany
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Cheminant M, Robinson S, Ribrag V, Le Gouill S, Suarez F, Delarue R, Hermine O. Prognosis and outcome of stem cell transplantation for mantle cell lymphoma. Expert Rev Hematol 2015; 8:493-504. [DOI: 10.1586/17474086.2015.1047759] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Rioufol C, Salles G. Biosimilar monoclonal antibodies in lymphoma: a critical appraisal. Expert Rev Anticancer Ther 2015; 15:569-78. [DOI: 10.1586/14737140.2015.1028919] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Shrestha R, Bhatt VR, Guru Murthy GS, Armitage JO. Clinicopathologic features and management of blastoid variant of mantle cell lymphoma. Leuk Lymphoma 2015; 56:2759-67. [PMID: 25747972 DOI: 10.3109/10428194.2015.1026902] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The blastoid variant of mantle cell lymphoma (MCL), which accounts for less than one-third of MCL, may arise de novo or as a transformation from the classical form of MCL. Blastoid variant, which predominantly involves men in their sixth decade, has frequent extranodal involvement (40-60%), stage IV disease (up to 85%) and central nervous system (CNS) involvement. Diagnosis relies on morphological features and is challenging. Immunophenotyping may display CD23 and CD10 positivity and CD5 negativity in a subset. Genetic analysis demonstrates an increased number of complex genetic alterations. Blastoid variant responds poorly to conventional chemotherapy and has a short duration of response. Although the optimal therapy remains to be established, CNS prophylaxis and the use of aggressive immunochemotherapy followed by autologous stem cell transplant may prolong the remission rate and survival. Further studies are crucial to expand our understanding of this disease entity and improve the clinical outcome.
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Affiliation(s)
- Rajesh Shrestha
- a Department of Internal Medicine , Memorial Hospital of Rhode Island , Pawtucket , RI , USA
| | - Vijaya Raj Bhatt
- b Department of Internal Medicine , Division of Hematology-Oncology, University of Nebraska Medical Center , Omaha , NE , USA
| | | | - James O Armitage
- b Department of Internal Medicine , Division of Hematology-Oncology, University of Nebraska Medical Center , Omaha , NE , USA
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miR-18b overexpression identifies mantle cell lymphoma patients with poor outcome and improves the MIPI-B prognosticator. Blood 2015; 125:2669-77. [PMID: 25736311 DOI: 10.1182/blood-2014-06-584193] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Accepted: 02/12/2015] [Indexed: 01/15/2023] Open
Abstract
Recent studies show that mantle cell lymphoma (MCL) express aberrant microRNA (miRNA) profiles; however, the clinical effect of miRNA expression has not previously been examined and validated in large prospective homogenously treated cohorts. We performed genome-wide miRNA microarray profiling of 74 diagnostic MCL samples from the Nordic MCL2 trial (screening cohort). Prognostic miRNAs were validated in diagnostic MCL samples from 94 patients of the independent Nordic MCL3 trial (validation cohort). Three miRNAs (miR-18b, miR-92a, and miR-378d) were significantly differentially expressed in patients who died of MCL in both cohorts. MiR-18b was superior to miR-92a and miR-378d in predicting high risk. Thus, we generated a new biological MCL International Prognostic Index (MIPI-B)-miR prognosticator, combining expression levels of miR-18b with MIPI-B data. Compared to the MIPI-B, this prognosticator improved identification of high-risk patients with regard to cause-specific, overall, and progression-free survival. Transfection of 2 MCL cell lines with miR-18b decreased their proliferation rate without inducing apoptosis, suggesting that miR-18b may render MCL cells resistant to chemotherapy by decelerating cell proliferation. We conclude that overexpression of miR-18b identifies patients with poor prognosis in 2 large prospective MCL cohorts and adds prognostic information to the MIPI-B. MiR-18b may reduce the proliferation rate of MCL cells as a mechanism of chemoresistance.
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