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Lolli G, Argnani L, Gini G, Casadei B, Pellegrini C, Tani M, Pavone V, Cimminiello M, Bonifazi F, Zinzani PL. Pixantrone as bridging therapy to allogeneic transplantation or in chimeric antigen receptor T-cell pathway in patients with diffuse large B-cell lymphoma. Hematol Oncol 2023; 41:947-950. [PMID: 37442805 DOI: 10.1002/hon.3211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/15/2023]
Affiliation(s)
- Ginevra Lolli
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy
- Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
| | - Lisa Argnani
- Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
| | - Guido Gini
- Clinica di Ematologia AOU Ospedali Riuniti, Ancona, Italy
| | - Beatrice Casadei
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy
| | - Cinzia Pellegrini
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy
| | - Monica Tani
- U.O.C Ematologia Ospedale Santa Maria delle Croci, Ravenna, Italy
| | - Vincenzo Pavone
- Department of Hematology and Bone Marrow Transplant, Hospital Card. G. Panico, Tricase, Italy
| | - Michele Cimminiello
- Dipartimento Oncologico, U.O.C. di Ematologia-Centro Trapianti di Cellule Staminali, Azienda Ospedaliera Regionale "San Carlo" di Potenza, Potenza, Italy
| | | | - Pier Luigi Zinzani
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy
- Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
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Yakkala PA, Penumallu NR, Shafi S, Kamal A. Prospects of Topoisomerase Inhibitors as Promising Anti-Cancer Agents. Pharmaceuticals (Basel) 2023; 16:1456. [PMID: 37895927 PMCID: PMC10609717 DOI: 10.3390/ph16101456] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 10/08/2023] [Accepted: 10/11/2023] [Indexed: 10/29/2023] Open
Abstract
Topoisomerases are very important enzymes that regulate DNA topology and are vital for biological actions like DNA replication, transcription, and repair. The emergence and spread of cancer has been intimately associated with topoisomerase dysregulation. Topoisomerase inhibitors have consequently become potential anti-cancer medications because of their ability to obstruct the normal function of these enzymes, which leads to DNA damage and subsequently causes cell death. This review emphasizes the importance of topoisomerase inhibitors as marketed, clinical and preclinical anti-cancer medications. In the present review, various types of topoisomerase inhibitors and their mechanisms of action have been discussed. Topoisomerase I inhibitors, which include irinotecan and topotecan, are agents that interact with the DNA-topoisomerase I complex and avert resealing of the DNA. The accretion of DNA breaks leads to the inhibition of DNA replication and cell death. On the other hand, topoisomerase II inhibitors like etoposide and teniposide, function by cleaving the DNA-topoisomerase II complex thereby effectively impeding the release of double-strand DNA breaks. Moreover, the recent advances in exploring the therapeutic efficacy, toxicity, and MDR (multidrug resistance) issues of new topoisomerase inhibitors have been reviewed in the present review.
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Affiliation(s)
- Prasanna Anjaneyulu Yakkala
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India;
| | - Naveen Reddy Penumallu
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India;
| | - Syed Shafi
- Department of Chemistry, School of Chemical and Life Sciences, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, India;
| | - Ahmed Kamal
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India;
- Department of Pharmacy, Birla Institute of Technology and Science (BITS) Pilani, Hyderabad Campus, Dist. Medchal, Hyderabad 500078, India
- Telangana State Council of Science & Technology, Environment, Forests, Science & Technology Department, Hyderabad 500004, India
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Gong IY, Aminilari M, Landego I, Hueniken K, Zhou Q, Kuruvilla J, Hodgson DC. Comparative effectiveness of salvage chemotherapy regimens and chimeric antigen T-cell receptor therapies in relapsed and refractory diffuse large B cell lymphoma: a network meta-analysis of clinical trials. Leuk Lymphoma 2023; 64:1643-1654. [PMID: 37548344 DOI: 10.1080/10428194.2023.2234528] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/05/2023] [Accepted: 06/30/2023] [Indexed: 08/08/2023]
Abstract
The optimal salvage chemotherapy regimen (SC) for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) prior to autologous stem cell transplant remains unclear. Moreover, although chimeric antigen receptor T cell (CAR-T) therapies were recently approved for primary refractory DLBCL, head-to-head comparisons are lacking. We searched MEDLINE, EMBASE and CENTRAL to July 2022, for randomized trials that enrolled adult patients with R/R DLBCL and performed network meta-analyses (NMA) to assess the efficacy of SC and CAR-T therapies. NMA of SC (6 trials, 7 regimens, n = 1831) indicated that rituximab with gemcitabine, dexamethasone, cisplatin (R-GDP) improved OS and PFS over compared regimens. NMA of 3 CAR-T trials (n = 865) indicated that both axi-cel and liso-cel improved PFS over standard of care, with no difference in OS. Our results indicate that R-GDP may be preferred for R/R DLBCL over other SC compared. Longer follow-up is required for ongoing comparative survival analysis as data from CAR-T trials matures.
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Affiliation(s)
- Inna Y Gong
- Department of Radiation Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Mahmood Aminilari
- Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - Ivan Landego
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - Katrina Hueniken
- Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - Qianghua Zhou
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - John Kuruvilla
- Department of Radiation Medicine, University of Toronto, Toronto, Ontario, Canada
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - David C Hodgson
- Department of Radiation Medicine, University of Toronto, Toronto, Ontario, Canada
- Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
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4
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Jolles S, Giralt S, Kerre T, Lazarus HM, Mustafa SS, Ria R, Vinh DC. Agents contributing to secondary immunodeficiency development in patients with multiple myeloma, chronic lymphocytic leukemia and non-Hodgkin lymphoma: A systematic literature review. Front Oncol 2023; 13:1098326. [PMID: 36824125 PMCID: PMC9941665 DOI: 10.3389/fonc.2023.1098326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 01/04/2023] [Indexed: 02/09/2023] Open
Abstract
Introduction Patients with hematological malignancies (HMs), like chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), have a high risk of secondary immunodeficiency (SID), SID-related infections, and mortality. Here, we report the results of a systematic literature review on the potential association of various cancer regimens with infection rates, neutropenia, lymphocytopenia, or hypogammaglobulinemia, indicative of SID. Methods A systematic literature search was performed in 03/2022 using PubMed to search for clinical trials that mentioned in the title and/or abstract selected cancer (CLL, MM, or NHL) treatments covering 12 classes of drugs, including B-lineage monoclonal antibodies, CAR T therapies, proteasome inhibitors, kinase inhibitors, immunomodulators, antimetabolites, anti-tumor antibiotics, alkylating agents, Bcl-2 antagonists, histone deacetylase inhibitors, vinca alkaloids, and selective inhibitors of nuclear export. To be included, a publication had to report at least one of the following: percentages of patients with any grade and/or grade ≥3 infections, any grade and/or grade ≥3 neutropenia, or hypogammaglobulinemia. From the relevant publications, the percentages of patients with lymphocytopenia and specific types of infection (fungal, viral, bacterial, respiratory [upper or lower respiratory tract], bronchitis, pneumonia, urinary tract infection, skin, gastrointestinal, and sepsis) were collected. Results Of 89 relevant studies, 17, 38, and 34 included patients with CLL, MM, and NHL, respectively. In CLL, MM, and NHL, any grade infections were seen in 51.3%, 35.9% and 31.1% of patients, and any grade neutropenia in 36.3%, 36.4%, and 35.4% of patients, respectively. The highest proportion of patients with grade ≥3 infections across classes of drugs were: 41.0% in patients with MM treated with a B-lineage monoclonal antibody combination; and 29.9% and 38.0% of patients with CLL and NHL treated with a kinase inhibitor combination, respectively. In the limited studies, the mean percentage of patients with lymphocytopenia was 1.9%, 11.9%, and 38.6% in CLL, MM, and NHL, respectively. Two studies reported the proportion of patients with hypogammaglobulinemia: 0-15.3% in CLL and 5.9% in NHL (no studies reported hypogammaglobulinemia in MM). Conclusion This review highlights cancer treatments contributing to infections and neutropenia, potentially related to SID, and shows underreporting of hypogammaglobulinemia and lymphocytopenia before and during HM therapies.
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Affiliation(s)
- Stephen Jolles
- Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, United Kingdom
| | - Sergio Giralt
- Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Tessa Kerre
- Faculty of Medicine and Health Sciences, Ghent University Hospital, Ghent, Belgium
| | - Hillard M. Lazarus
- Department of Medicine, Hematology-Oncology, Case Western Reserve University, Cleveland, OH, United States
| | - S. Shahzad Mustafa
- Rochester Regional Health, Rochester, NY, United States
- Department of Medicine, Allergy/Immunology and Rheumatology, University of Rochester, Rochester, NY, United States
| | - Roberto Ria
- Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro Medical School, Bari, Italy
| | - Donald C. Vinh
- Department of Medicine, McGill University Health Centre, Montreal, QC, Canada
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Miller SD, Lozano-Ortega G, Mutebi A, Briggs O, Sail K, Elliott B, Kalsekar A. Systematic review of outcomes and patient heterogeneity in relapsed or refractory diffuse large B-cell lymphoma. J Comp Eff Res 2023; 12:e220146. [PMID: 36417238 PMCID: PMC10288944 DOI: 10.2217/cer-2022-0146] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 11/04/2022] [Indexed: 11/24/2022] Open
Abstract
Aim: To evaluate trials of systemic therapies in transplant-ineligible or -experienced, relapsed/refractory diffuse large-B cell lymphoma and the impact of patient characteristics on overall response rate (ORR). Patients & methods: Systematically reviewed multiple databases through 22 July 2021. Analyzed variations in patient characteristics and their relationship with ORR across trials. Results: Among 17 included trials, key patient characteristics varied substantially: primary refractory (0-69%), refractory to last line of therapy (LOT) (12-100%), ≥2 prior LOTs (14-100%), ≥3 prior LOTs (0-64%), IPI ≥3 (23-73%), tumor stage III/IV (50-90%) and median age (56-74 years). ORRs varied substantially (25-83%), correlating with these characteristics. Conclusion: Differences in patient characteristics significantly contribute to the variability in ORR across these trials and should be considered when contextualizing efficacy data.
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Affiliation(s)
- Sally D Miller
- Broadstreet HEOR, 201-343 Railway St, Vancouver, BC V6A 1A4, Canada
| | | | - Alex Mutebi
- Genmab, 777 Scudders Mill Road, Plainsboro, NJ 08536, USA
| | - Owanate Briggs
- Genmab, 777 Scudders Mill Road, Plainsboro, NJ 08536, USA
| | - Kavita Sail
- AbbVie, 1 N. Waukegan Road, Chicago, IL 60064, USA
| | - Brian Elliott
- Genmab, 777 Scudders Mill Road, Plainsboro, NJ 08536, USA
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Rösler W, Zenz T. GOALs in relapsed DLBCL. Br J Haematol 2022; 198:419-420. [PMID: 35695285 PMCID: PMC9544586 DOI: 10.1111/bjh.18296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 05/19/2022] [Accepted: 05/20/2022] [Indexed: 11/02/2022]
Affiliation(s)
- Wiebke Rösler
- Department of Medical Oncology and Hematology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Thorsten Zenz
- Department of Medical Oncology and Hematology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
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Cencini E, Mecacci B, Rocco M, Innocenti F, Ghio F, Puccini B, Della Seta R, Simonetti F, Mannelli L, Cuccaro A, Bocchia M, Fabbri A. Pixantrone in patients with relapsed/refractory diffuse large B-cell lymphoma: A real-life, retrospective, multicenter trial on behalf of the "RTL" (Regional Tuscan Lymphoma network). Eur J Haematol 2022; 108:383-390. [PMID: 35051301 DOI: 10.1111/ejh.13745] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/13/2022] [Accepted: 01/17/2022] [Indexed: 11/03/2022]
Abstract
INTRODUCTION Pixantrone is a novel aza-anthracenedione with antineoplastic activity, currently approved for multiply relapsed/refractory diffuse large B-cell lymphoma (DLBCL), even if real-life data are limited. METHODS We investigated pixantrone efficacy and safety in clinical practice, as 3rd or 4th line therapy. We retrospectively analyzed a cohort of 37 R/R DLBCL patients managed in 8 Tuscan onco-hematological centers. Pixantrone, 50 mg/m2 , was administered on days 1, 8, 15 of a 28 days cycle for up to 6 cycles. Response to therapy was evaluated according to the Lugano 2014 classification. RESULTS Pixantrone was administered as 3rd or 4th line in 24/37 (64.9%) and 13/37 (35.1%) cases. Overall response rate and CR rate were 43.2% and 32.4%. After a median follow-up of 6 months, 17/37 patients (46%) were alive, the main cause of death was progressive disease (14/37 cases, 37.9%). Median PFS was 3 months, median DOR was 17.9 months, and median OS was 9.7 months. A significant proportion of patients achieved a long-lasting response >12 months (8/37 cases). IPI>2 showed a trend toward inferior PFS. CONCLUSION In this real-life setting, pixantrone demonstrated appreciable efficacy in a population with poor prognosis; in a small proportion of cases, it can be associated with long-term remission.
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Affiliation(s)
- Emanuele Cencini
- Unit of Hematology, Azienda Ospedaliera Universitaria Senese and University of Siena, Siena, Italy
| | - Bianca Mecacci
- Unit of Hematology, Azienda Ospedaliera Universitaria Senese and University of Siena, Siena, Italy
| | - Melania Rocco
- SOC Ematologia Clinica e Oncoematologia, Firenze, Italy
| | | | - Francesco Ghio
- Unit of Hematology, Azienda Ospedaliera Universitaria Pisana and University of Pisa, Pisa, Italy
| | - Benedetta Puccini
- Lymphoma Unit, Hematology Department, Careggi Hospital and University of Florence, Firenze, Italy
| | | | | | - Lara Mannelli
- SOS Oncoematologia, Ospedale S. Stefano, Prato, Italy
| | - Annarosa Cuccaro
- UOC Ematologia Aziendale, Azienda USL Toscana Nordovest, Spedali Riuniti, Livorno, Italy
| | - Monica Bocchia
- Unit of Hematology, Azienda Ospedaliera Universitaria Senese and University of Siena, Siena, Italy
| | - Alberto Fabbri
- Unit of Hematology, Azienda Ospedaliera Universitaria Senese and University of Siena, Siena, Italy
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Paszkiewicz-Kozik E, Michalski W, Taszner M, Mordak-Domagała M, Romejko-Jarosińska J, Knopińska-Posłuszny W, Najda J, Borawska A, Chełstowska M, Świerkowska M, Dąbrowska-Iwanicka A, Malenda A, Druzd-Sitek A, Konecki R, Kumiega B, Osowiecki M, Ostrowska B, Szpila T, Szymański M, Targoński Ł, Domańska-Czyż K, Popławska L, Giebel S, Lange A, Pluta A, Zaucha JM, Rymkiewicz G, Walewski J. Ofatumumab with iphosphamide, etoposide and cytarabine for patients with transplantation-ineligible relapsed and refractory diffuse large B-cell lymphoma. Br J Haematol 2022; 198:73-81. [PMID: 35362096 PMCID: PMC9322457 DOI: 10.1111/bjh.18166] [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: 01/14/2022] [Revised: 03/14/2022] [Accepted: 03/15/2022] [Indexed: 11/29/2022]
Abstract
The efficacy of salvage treatment of diffuse large B-cell lymphoma (DLBCL) patients who relapse or progress (rrDLBCL) after initial therapy is limited. Efficacy and safety of ofatumumab with iphosphamide, etoposide and cytarabine (O-IVAC) was evaluated in a single-arm study. Dosing was modified for elderly patients. Patients received up to six cycles of treatment. The primary end-point was the overall response rate (ORR). Patients were evaluated every two cycles and then six and 12 months after treatment. Other end-points included progression-free survival (PFS), event-free survival (EFS), overall survival (OS) and safety. Seventy-seven patients received salvage treatment with O-IVAC. The average age was 56.8 years; 39% had an Eastern Cooperative Oncology Group (ECOG) performance status of at least 3; 78% had disease of Ann Arbor stage 3 or 4; 58% received one or more prior salvage therapies. The ORR for O-IVAC was 54.5%. The median duration of study follow-up was 70 months. The median PFS and EFS were 16.3 months each. The median OS was 22.7 months. Age, ECOG performance status and the number of prior therapy lines were independent predictors of survival. Treatment-related mortality was 15.5%. O-IVAC showed a high response rate in a difficult-to-treat population and is an attractive treatment to bridge to potentially curative therapies.
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Affiliation(s)
| | - Wojciech Michalski
- Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | | | - Monika Mordak-Domagała
- Lower Silesian Center for Cellular Transplantation with National Bone Marrow Donor Registry, Wroclaw, Poland
| | | | - Wanda Knopińska-Posłuszny
- Maritime Hospital, Gdynia, Poland.,Warmian-Masurian Cancer Center of the Ministry of the Interior and Administration's Hospital, Olsztyn, Poland
| | - Jacek Najda
- Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland
| | - Anna Borawska
- Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | | | - Monika Świerkowska
- Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | | | - Agata Malenda
- Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | | | - Robert Konecki
- Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Beata Kumiega
- Sniadecki Memorial Specialist Hospital, Nowy Sacz, Poland
| | - Michał Osowiecki
- Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Beata Ostrowska
- Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Tomasz Szpila
- Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Marcin Szymański
- Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Łukasz Targoński
- Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | | | - Lidia Popławska
- Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Sebastian Giebel
- Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland
| | - Andrzej Lange
- Lower Silesian Center for Cellular Transplantation with National Bone Marrow Donor Registry, Wroclaw, Poland
| | - Andrzej Pluta
- Department of Hematology, Brzozow Oncology Center, Brzozow, Poland
| | - Jan Maciej Zaucha
- Medical University of Gdansk, Gdansk, Poland.,Maritime Hospital, Gdynia, Poland
| | - Grzegorz Rymkiewicz
- Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Jan Walewski
- Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
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Hess G, Hüttmann A, Witzens-Harig M, Dreyling MH, Keller U, Marks R, Ernst T, Pott C, Viardot A, Frontzek F, Trautmann M, Ruckes C, Deuster O, Rosenwald A, Theobald M, Lenz G. A phase II trial to evaluate the combination of pixantrone and obinutuzumab for patients with relapsed aggressive lymphoma: Final results of the prospective, multicentre GOAL trial. Br J Haematol 2022; 198:482-491. [PMID: 35362552 DOI: 10.1111/bjh.18161] [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: 11/30/2021] [Revised: 03/08/2022] [Accepted: 03/13/2022] [Indexed: 12/14/2022]
Abstract
The prognosis of patients with relapsed diffuse large B-cell lymphoma (DLBCL) remains poor with current options. Here we prospectively evaluated the combination of pixantrone with obinutuzumab for up to six cycles for patients with relapsed or refractory DLBCL. Overall response rate (ORR) was the primary end-point. Sixty-eight patients were evaluated, median age was 75 years, median number of prior lines was three (range 1-10), 52 patients (76.5%) were diagnosed with DLBCL and 16 (23.5%) patients had transformed indolent lymphoma or follicular lymphoma (FL) IIIB. ORR was 35.3% for all and 40% for evaluable patients (16.6% complete response), median progression-free survival (PFS) and overall survival (OS) were 2.8 months and 8 months, respectively. Analysis of the cell of origin revealed a superior course for patients with non-GCB (germinal centre B-cell-like) phenotype [median OS not reached (n.r.) vs 5.2 months]. Patients with one prior line had an improved outcome over patients treated in later lines (PFS n.r. vs 2.5 months). Disease progression was the main reason for premature termination. Adverse events were mainly haematologic. The combination treatment revealed no unexpected adverse events. Most relevant non-haematologic toxicity was infection in 28% of patients. In summary, pixantrone-obinutuzumab showed clinical activity with sometimes long-term remission; however, the trial failed to meet its primary end-point.
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Affiliation(s)
- Georg Hess
- Department of Internal Medicine III, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Andreas Hüttmann
- Department of Hematology, University Hospital Essen, West German Cancer Center, University of Duisburg-Essen, Essen, Germany
| | - Mathias Witzens-Harig
- Department of Internal Medicine V, University Hospital Heidelberg, Heidelberg, Germany
| | - Martin H Dreyling
- Department of Internal Medicine III, Ludwig-Maximilians University of Munich, Munich, Germany
| | - Ulrich Keller
- Internal Medicine III, Technical University of Munich, Munich, Germany
| | - Reinhard Marks
- Department of Hematology/Oncology and Stem Cell Transplantation, University Medical Center, Freiburg, Germany
| | - Thomas Ernst
- Department of Internal Medicine II, Jena University Hospital, Jena, Germany
| | - Christiane Pott
- Department of Internal Medicine II, University of Schleswig-Holstein, Kiel, Germany
| | - Andreas Viardot
- Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany
| | - Fabian Frontzek
- Department of Medicine A, University Hospital Münster, Münster, Germany
| | - Marcel Trautmann
- Division of Translational Pathology, Gerhard Domagk Institute of Pathology, Münster University Hospital, Münster, Germany
| | - Christian Ruckes
- Interdisciplinary Center for Clinical Trials (IZKS), University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Oliver Deuster
- Interdisciplinary Center for Clinical Trials (IZKS), University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | | | - Matthias Theobald
- Department of Internal Medicine III, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Georg Lenz
- Department of Medicine A, University Hospital Münster, Münster, Germany
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10
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Perrone S, Lopedote P, Levis M, Di Rocco A, Smith SD. Management of relapsed or refractory large B-cell lymphoma in patients ineligible for CAR-T cell therapy. Expert Rev Hematol 2022; 15:215-232. [PMID: 35184664 DOI: 10.1080/17474086.2022.2044778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Chimeric antigen receptor T (CAR-T) therapy has revolutionized the treatment of relapsed/refractory large B-cell lymphoma (LBCL). However, patients who are excluded or have no access to CAR-T represent a challenge for clinicians and have generally a dismal outcome. The landscape for this category of patients is constantly evolving: new agents have been approved in the last 2-3 years, alone or in combination, and novel treatment modalities are under investigations. AREAS COVERED Thereafter, we reviewed the currently available therapeutic strategies: conventional chemotherapy, Antibody-drug conjugate ADC (mainly polatuzumab and loncastuxumab), bispecific antibodies (CD19/CD3 and focus on novel CD20/CD3 Abs), immunomodulatory drugs (covering tafasitamab and lenalidomide, checkpoint inhibitors mainly in PMBL), small molecules (selinexor, BTK and PI3K inhibitors), and the role of radiotherapy. EXPERT OPINION Navigating this scenario, will uncover new challenges, including identifying an ideal sequence for these therapies, the most effective combinations, and search for consistent predictive factors to help selecting the appropriate population of LBCL patients. At present, supporting clinical research for CAR-T ineligible patients, a new and challenging group, must remain a major focus that is complementary to advances in CAR T-cell therapy.
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Affiliation(s)
- Salvatore Perrone
- Hematology, Polo Universitario Pontino, S.M. Goretti Hospital, Latina, Italy
| | - Paolo Lopedote
- Internal Medicine, St Elizabeth's Medical Center, Boston University, Boston, U.S
| | - Mario Levis
- Department of Oncology, University of Torino, Torino, Italy
| | - Alice Di Rocco
- Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
| | - Stephen Douglas Smith
- Division of Medical Oncology, Department of Internal Medicine, University of Washington, Seattle, WA.,Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
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Sawalha Y. Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Look at the Approved and Emerging Therapies. J Pers Med 2021; 11:1345. [PMID: 34945817 PMCID: PMC8708171 DOI: 10.3390/jpm11121345] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/12/2021] [Accepted: 11/28/2021] [Indexed: 12/11/2022] Open
Abstract
Approximately 40% of patients with diffuse large B cell lymphoma (DLBCL) do not respond or develop relapsed disease after first-line chemoimmunotherapy. A minority of these patients can be cured with autologous hematopoietic stem cell transplantation (AHCT). Although chimeric antigen receptor (CAR) T cells have transformed the treatment paradigm of relapsed/refractory DLBCL, only 30-40% of patients achieve durable remissions. In addition, many patients with relapsed/refractory DLBCL are ineligible to receive treatment with CAR T cells due to comorbidities or logistical limitations. Since 2019, the following four non-CAR T-cell treatments have been approved in relapsed/refractory DLBCL: polatuzumab in combination with bendamustine and rituximab, selinexor, tafasitamab plus lenalidomide, and loncastuximab. In this article, I review the data behind these four approvals and discuss important considerations on their use in clinical practice. I also review emerging therapies that have shown promising early results in relapsed/refractory DLBCL including the bispecific antibodies, antibody-drug conjugates, Bruton tyrosine kinase inhibitors, BCL2 inhibitors, immune checkpoint inhibitors, and epigenetic modifiers.
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Affiliation(s)
- Yazeed Sawalha
- Department of Internal Medicine, Division of Hematology, Arthur G. James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
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Nan YY, Zhang WJ, Huang DH, Li QY, Shi Y, Yang T, Liang XP, Xiao CY, Guo BL, Xiang Y. Evaluation of a five-gene signature associated with stromal infiltration for diffuse large B-cell lymphoma. World J Clin Cases 2021; 9:4585-4598. [PMID: 34222425 PMCID: PMC8223837 DOI: 10.12998/wjcc.v9.i18.4585] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 01/26/2021] [Accepted: 02/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Diffuse large B-cell lymphoma (DLBCL) is a common non-Hodgkin lymphoma. The development of immunotherapy greatly improves the patient prognosis but there are some exceptions. Thus, screening for better biomarkers for prognostic evaluation could contribute to the treatment of DLBCL patients.
AIM To screen the novel mediators involved in the development of DLBCL.
METHODS The GSE60 dataset was applied to identify the differentially expressed genes (DEGs) in DLBCL, and the principal components analysis plot was used to determine the quality of the included samples. The protein-protein interactions were analyzed by the STRING tool. The key hub genes were entered into to the GEPIA database to determine their expressions in DLBCL. Furthermore, these hub gene alterations were analyzed in cBioportal. The UALCAN portal was employed to analyze the expression of the hub genes in different stages of DLBCL. The Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data Score was conducted to evaluate the correlation between the gene expression and tumor purity. The gene-gene correlation analysis was conducted in the GEPIA. The stromal score analysis was conducted in TIMER to confirm the correlation between the gene expression and infiltrated stromal cells. The correlation between the indicated genes and infiltration level of cancer-associated fibroblasts (CAFs) was also completed in TIMER with two methods, MCP-Counter and Tumor immune dysfunction and exclusion. The correlation between fibronectin (FN1) protein level and secreted protein acidic and cysteine-rich (SPARC) messenger ribonucleic acid expression was confirmed in the cBioportal.
RESULTS The top 20 DEGs in DLBCL were identified, and the principal components analysis plot confirmed the quality of the significant DEGs. The pairwise correlation coefficient analysis among all samples showed that these DEGs have a certain co-expression pattern. The DEGs were subjected to STRING to identify the hub genes, alpha-2-macroglobulin (A2M), cathepsin B (CTSB), FN1, matrix metallopeptidase 9 (MMP9), and SPARC. The five hub genes were confirmed to be overexpressed in DLBCL. The cBioportal portal detected these five hub genes that had gene alteration, including messenger ribonucleic acid high amplification and missense mutation, and the gene alteration percentages of A2M, FN1, CTSB, MMP9, and SPARC were 5%, 8%, 5%, 2.7%, and 5%, respectively. Furthermore, the five hub genes had a potential positive correlation with tumor stage. The correlation analysis between the five genes and tumor purity confirmed that the five genes were overexpressed in DLBCL and had a positive correlation with the development of DLBCL. More interestingly, the five genes had a significant correlation with the stromal infiltration scores. The correlation analysis between the fives genes and CAFs also showed a significant value, among which the top two genes, FN1 and SPARC, had a remarkable co-expression pattern.
CONCLUSION The top DEGs were identified, and the five hub genes were overexpressed in DLBCL. Furthermore, the gene alterations were confirmed and the positive correlation with tumor purity revealed the overexpression of the five genes and close association with the development of DLBCL. More interestingly, the five genes were positively correlated with stromal infiltration, especially in CAFs. The top two genes, FN1 and SPARC, showed a co-expression pattern, which indicates their potential as novel therapeutic targets for DLBCL.
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Affiliation(s)
- Ying-Yu Nan
- Department of Hematology, Chongqing University Cancer Hospital, Chongqing 400030, China
| | - Wen-Jun Zhang
- Department of Hematology, Chongqing University Cancer Hospital, Chongqing 400030, China
| | - De-Hong Huang
- Department of Hematology, Chongqing University Cancer Hospital, Chongqing 400030, China
| | - Qi-Ying Li
- Department of Hematology, Chongqing University Cancer Hospital, Chongqing 400030, China
| | - Yang Shi
- Department of Hematology, Chongqing University Cancer Hospital, Chongqing 400030, China
| | - Tao Yang
- Department of Hematology, Chongqing University Cancer Hospital, Chongqing 400030, China
| | - Xi-Ping Liang
- Department of Hematology, Chongqing University Cancer Hospital, Chongqing 400030, China
| | - Chun-Yan Xiao
- Department of Hematology, Chongqing University Cancer Hospital, Chongqing 400030, China
| | - Bing-Ling Guo
- Department of Hematology, Chongqing University Cancer Hospital, Chongqing 400030, China
| | - Ying Xiang
- Department of Hematology, Chongqing University Cancer Hospital, Chongqing 400030, China
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13
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Jezeršek Novaković B, Boltežar L, Novaković A. Current Opinion on Pixantrone in the Treatment of Non-Hodgkin B-Cell Lymphoma. Ther Clin Risk Manag 2021; 17:183-192. [PMID: 33688197 PMCID: PMC7936695 DOI: 10.2147/tcrm.s269324] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 02/16/2021] [Indexed: 11/26/2022] Open
Abstract
Not many treatment options exist for patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) in whom first- and second-line therapies were unsuccessful. This is especially true for patients with aggressive lymphomas. The innovative agent pixantrone has shown some promising results in terms of disease-free and overall survival, both in monotherapy as well as in combinations. However, recent trials (Phase III and real-world studies) reported unsatisfactory results, thereby raising the question about the role of pixantrone in the current treatment of R/R aggressive lymphomas. Nonetheless, there might still be a potential position for this drug in combinations, for use as first-line treatment of patients with cardiac dysfunction. This article summarizes the definition, structure, mechanism of action and reduced cardiotoxicity of pixantrone as well as efficacy and toxicity both in monotherapy and in combinations, as treatment for aggressive and indolent non-Hodgkin lymphomas.
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Affiliation(s)
| | - Lučka Boltežar
- Division of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, 1000, Slovenia
| | - Aleksander Novaković
- Division of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, 1000, Slovenia
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Eyre TA. Another disappointment in treating relapsed, refractory high-risk aggressive B-cell lymphomas. Br J Haematol 2019; 188:202-204. [PMID: 31680237 DOI: 10.1111/bjh.16259] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Toby A Eyre
- Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
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