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Wahl RL, Kahl B. The Rebirth of Radioimmunotherapy of Non-Hodgkin Lymphoma: The Phoenix of Nuclear Medicine? Semin Nucl Med 2024; 54:513-529. [PMID: 39019652 DOI: 10.1053/j.semnuclmed.2024.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/19/2024]
Abstract
In Greek mythology, The Phoenix is an immortal bird that dies, but then achieves new life by rising from the ashes of its predecessor. Radioimmunotherapy (RIT) of B-cell Non-Hodgkin lymphoma (NHL) is a field which once began to fly high-with FDA approval of the anti-CD20 RITs Zevalin® and Bexxar® in 2002 and 2003 respectively, as safe and effective therapies of NHL. However, despite their therapeutic efficacy, Bexxar® was withdrawn from the market by the manufacturer in 2014 due to limited commercial demand and Zevalin® has had very limited to no availability of late. I-131 rituximab is used to a limited extent in Australia, India and other countries, as well. But has RIT of NHL been (perhaps prematurely) left for dead by many? Given the current great clinical and commercial interest in radiopharmaceutical therapies of cancer, notably PSMA and SSTR targeting agents in prostate and neuroendocrine cancers, can radioimmunotherapy of NHL-like the mythical Phoenix-now rise from its ashes in an even better form to fly higher, faster, farther and longer than before?
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Affiliation(s)
- Richard L Wahl
- Mallinckrodt Institute of Radiology, Department of Radiology and Radiation Oncology, Washington University School of Medicine in St. Louis.
| | - Brad Kahl
- Mallinckrodt Institute of Radiology, Department of Radiology and Radiation Oncology, Washington University School of Medicine in St. Louis; Department of Internal Medicine, Division of Hematology and Oncology, Washington University School of Medicine in St. Louis
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2
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Ghobadi A, Foley NC, Cohen J, Rettig MP, Cashen AF, Gehrs L, Christ S, Street E, Wallace N, Ritchey J, Mehta-Shah N, Westervelt P, Fehniger TA, Kahl B, Bartlett NL, DiPersio JF. Blinatumomab consolidation post-autologous stem cell transplantation in patients with diffuse large B-cell lymphoma. Blood Adv 2024; 8:513-522. [PMID: 37871306 PMCID: PMC10835165 DOI: 10.1182/bloodadvances.2023011130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 09/18/2023] [Accepted: 10/07/2023] [Indexed: 10/25/2023] Open
Abstract
ABSTRACT Outcomes in patients with relapsed diffuse large B-cell lymphoma (DLBCL) who undergo autologous stem cell transplant (auto-SCT) are poor. Blinatumomab is a CD3/CD19 bispecific T-cell engager that directs cytotoxic T cells to CD19+ cells. Here, we performed a pilot study of blinatumomab consolidation after auto-SCT for 14 patients with DLBCL or transformed follicular lymphoma. All patients underwent standard-of-care auto-SCT with carmustine, etoposide, cytarabine, and melphalan (BEAM) conditioning followed by 1 cycle (4 weeks continuous infusion) of blinatumomab consolidation starting at day 42 after auto-SCT. All 14 patients treated on study completed BEAM auto-SCT and 1 cycle of posttransplant blinatumomab. Five patients developed grade 1 cytokine release syndrome (CRS), with no grade 2 or higher CRS. Immune effector cell-associated neurotoxicity syndrome was not observed. Patients were followed up for 3 years after auto-SCT, with median follow-up of 37 (range, 12-65) months. One-hundred days after auto-SCT (1 month after blinatumomab consolidation), 12 patients (86%) had achieved complete remission. At 1 year after auto-SCT, 7 patients (50%) remained in CR, and 1 patient had died of progressive disease. Patients who relapsed had a lower CD8:CD4 T-cell ratio before starting blinatumomab than patients who remained in remission. This pilot study demonstrates blinatumomab consolidation after auto-SCT is safe and well tolerated. Strategies to increase the CD8:CD4 ratio and use additional cycles of consolidation in a larger randomized trial are needed to confirm the efficacy of consolidation with blinatumomab after auto-SCT. This trial was registered at www.clinicaltrials.gov as #NCT03072771.
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Affiliation(s)
- Armin Ghobadi
- Washington University School of Medicine, Department of Medicine, Division of Medical Oncology, St. Louis, MO
| | - Nicole C. Foley
- Washington University School of Medicine, Department of Medicine, Division of Medical Oncology, St. Louis, MO
| | - Jared Cohen
- Washington University School of Medicine, Department of Medicine, Division of Medical Oncology, St. Louis, MO
| | - Michael P. Rettig
- Washington University School of Medicine, Department of Medicine, Division of Medical Oncology, St. Louis, MO
| | - Amanda F. Cashen
- Washington University School of Medicine, Department of Medicine, Division of Medical Oncology, St. Louis, MO
| | - Leah Gehrs
- Washington University School of Medicine, Department of Medicine, Division of Medical Oncology, St. Louis, MO
| | - Stephanie Christ
- Washington University School of Medicine, Department of Medicine, Division of Medical Oncology, St. Louis, MO
| | - Emily Street
- Washington University School of Medicine, Department of Medicine, Division of Medical Oncology, St. Louis, MO
| | - Nicholas Wallace
- Washington University School of Medicine, Department of Medicine, Division of Medical Oncology, St. Louis, MO
| | - Julie Ritchey
- Washington University School of Medicine, Department of Medicine, Division of Medical Oncology, St. Louis, MO
| | - Neha Mehta-Shah
- Washington University School of Medicine, Department of Medicine, Division of Medical Oncology, St. Louis, MO
| | - Peter Westervelt
- Washington University School of Medicine, Department of Medicine, Division of Medical Oncology, St. Louis, MO
| | - Todd A. Fehniger
- Washington University School of Medicine, Department of Medicine, Division of Medical Oncology, St. Louis, MO
| | - Brad Kahl
- Washington University School of Medicine, Department of Medicine, Division of Medical Oncology, St. Louis, MO
| | - Nancy L. Bartlett
- Washington University School of Medicine, Department of Medicine, Division of Medical Oncology, St. Louis, MO
| | - John F. DiPersio
- Washington University School of Medicine, Department of Medicine, Division of Medical Oncology, St. Louis, MO
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3
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Brooks TR, Caimi PF. A paradox of choice: Sequencing therapy in relapsed/refractory diffuse large B-cell lymphoma. Blood Rev 2024; 63:101140. [PMID: 37949705 DOI: 10.1016/j.blre.2023.101140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 10/24/2023] [Accepted: 10/25/2023] [Indexed: 11/12/2023]
Abstract
The available treatments for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have experienced a dramatic change since 2017. Incremental advances in basic and translational science over several decades have led to innovations in immune-oncology. These innovations have culminated in eight separate approvals by the US Food and Drug Administration for the treatment of patients with R/R DLBCL over the last 10 years. High-dose therapy and autologous stem cell transplant (HDT-ASCT) remains the standard of care for transplant-eligible patients who relapse after an initial remission. For transplant-ineligible patients or for those who relapse following HDT-ASCT, multiple options exist. Monoclonal antibodies targeting CD19, antibody-drug conjugates, bispecific antibodies, immune effector cell products, and other agents with novel mechanisms of action are now available for patients with R/R DLBCL. There is increasing use of chimeric antigen receptor (CAR) T-cells as second-line therapy for patients with early relapse of DLBCL or those who are refractory to initial chemoimmunotherapy. The clinical benefits of these strategies vary and are influenced by patient and disease characteristics, as well as the type of prior therapy administered. Therefore, there are multiple clinical scenarios that clinicians might encounter when treating R/R DLBCL. An optimal sequence of drugs has not been established, and there is no evidence-based consensus on how to best order these agents. This abundance of choices introduces a paradox: proliferating treatment options are initially a boon to patients and providers, but as choices grow further they no longer liberate. Rather, more choices make the management of R/R DLBCL more challenging due to lack of direct comparisons among agents and a desire to maximize patient outcomes. Here, we provide a review of recently-approved second- and subsequent-line agents, summarize real-world data detailing the use of these medicines, and provide a framework for sequencing therapy in R/R DLBCL.
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Affiliation(s)
- Taylor R Brooks
- Department of Hematology and Oncology, Cleveland Clinic Taussig Cancer Center, Cleveland, OH, United States of America
| | - Paolo F Caimi
- Department of Hematology and Oncology, Cleveland Clinic Taussig Cancer Center, Cleveland, OH, United States of America; Case Comprehensive Cancer Center, Cleveland, OH, United States of America.
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4
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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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Lin M, Wu X, Zhang L, Li L, Wang X, Fu X, Sun Z, Zhang X, Zhu L, Yu H, Chang Y, Nan F, Yan J, Zhou Z, Shi C, Zhang M, Li X. Fotemustine, etoposide, cytarabine, and cyclophosphamide (FEAC) conditioning regimen for autologous stem cell transplantation in lymphoma. Leuk Lymphoma 2023; 64:605-612. [PMID: 36657436 DOI: 10.1080/10428194.2023.2167492] [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: 01/21/2023]
Abstract
To investigate the efficacy and safety of the FEAC (fotemustine, etoposide, cytarabine, and cyclophosphamide) conditioning regimen for the treatment of lymphoma, we retrospectively analyzed the records of 76 Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients who underwent autologous stem cell transplantation (ASCT) after the FEAC conditioning regimen. Their survival, as well as the clinical efficacy, hematopoietic engraftment time, and toxicity, were analyzed. One patient died of severe pulmonary infection, and the transplant-related mortality (TRM) was 1.3% (1/76). Hematopoietic engraftment was achieved successfully in the remaining 75 patients. The median times of neutrophil and platelet engraftment were 11 d (6-21 d) and 13 d (8-24 d), respectively. The 2-year progression-free survival (PFS) rate was 69.1%, and the 2-year overall survival (OS) rate was 84.2%. FEAC conditioning regimen has acceptable toxicity, and the prognosis of patients is good, making it a feasible alternative to the BEAM regimen for ASCT.
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Affiliation(s)
- Meng Lin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
- Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, P.R. China
| | - Xiaolong Wu
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
- Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, P.R. China
| | - Lei Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
- Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, P.R. China
| | - Ling Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
- Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, P.R. China
| | - Xinhua Wang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
- Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, P.R. China
| | - Xiaorui Fu
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
- Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, P.R. China
| | - Zhenchang Sun
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
- Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, P.R. China
| | - Xudong Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
- Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, P.R. China
| | - Linan Zhu
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
- Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, P.R. China
| | - Hui Yu
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
- Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, P.R. China
| | - Yu Chang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
- Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, P.R. China
| | - Feifei Nan
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
- Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, P.R. China
| | - Jiaqin Yan
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
- Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, P.R. China
| | - Zhiyuan Zhou
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
- Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, P.R. China
| | - Cunzhen Shi
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
- Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, P.R. China
| | - Mingzhi Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
- Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, P.R. China
| | - Xin Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China
- Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, P.R. China
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Tian L, Li C, Sun J, Zhai Y, Wang J, Liu S, Jiang Y, Wu W, Xing D, Lv Y, Guo J, Xu H, Sun H, Li Y, Li L, Zhao Z. Efficacy of chimeric antigen receptor T cell therapy and autologous stem cell transplant in relapsed or refractory diffuse large B-cell lymphoma: A systematic review. Front Immunol 2023; 13:1041177. [PMID: 36733398 PMCID: PMC9886865 DOI: 10.3389/fimmu.2022.1041177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 12/21/2022] [Indexed: 01/18/2023] Open
Abstract
Background We aimed to compare the efficacy of chimeric antigen receptor T (CAR-T) cell therapy with that of autologous stem cell transplantation (auto-HSCT) in relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL). Research design and methods We searched eligible publications up to January 31st, 2022, in PubMed, Cochrane Library, Springer, and Scopus. A total of 16 publications with 3484 patients were independently evaluated and analyzed using STATA SE software. Results Patients who underwent CAR-T cell therapy showed a better overall response rate (ORR) and partial response (PR) than those treated with auto-HSCT (CAR-T vs. auto-HSCT, ORR: 80% vs. 73%, HR:0.90,95%CI:0.76-1.07,P = 0.001; PR: 20% vs. 14%, HR:0.65,95%CI:0.62-0.68,P = 0.034). No significant difference was observed in 6-month overall survival (OS) (CAR-T vs. auto-HSCT, six-month OS: 81% vs. 84%, HR:1.23,95%CI:0.63-2.38, P = 0.299), while auto-HSCT showed a favorable 1 and 2-year OS (CAR-T vs. auto-HSCT, one-year OS: 64% vs. 73%, HR:2.42,95%CI:2.27-2.79, P < 0.001; two-year OS: 54% vs. 68%, HR:1.81,95%CI:1.78-1.97, P < 0.001). Auto-HSCT also had advantages in progression-free survival (PFS) (CAR-T vs. auto-HSCT, six-month PFS: 53% vs. 76%, HR:2.81,95%CI:2.53-3.11,P < 0.001; one-year PFS: 46% vs. 61%, HR:1.84,95%CI:1.72-1.97,P < 0.001; two-year PFS: 42% vs. 54%, HR:1.62,95%CI:1.53-1.71, P < 0.001). Subgroup analysis by age, prior lines of therapy, and ECOG scores was performed to compare the efficacy of both treatment modalities. Conclusion Although CAR-T cell therapy showed a beneficial ORR, auto-HSCT exhibited a better long-term treatment superiority in R/R DLBCL patients. Survival outcomes were consistent across different subgroups.
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Affiliation(s)
- Linyan Tian
- Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Cheng Li
- Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Juan Sun
- Clinical Testing Center, Chinese Academy of Medical Sciences Blood Disease Hospital, Chinese Academy of Medical Sciences Institute of Hematology, State Key Laboratory of Experimental Hematology, National Clinical Medical Center for Blood Disease, Tianjin, China
| | - Yixin Zhai
- Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Jinhuan Wang
- Department of Oncology, Second Hospital of Tianjin Medical University, Institute of Urology, Tianjin, China
| | - Su Liu
- Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Yanan Jiang
- Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Wenqi Wu
- Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Donghui Xing
- Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Yangyang Lv
- Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Jing Guo
- Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Hong Xu
- Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Huimeng Sun
- Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Yuhang Li
- Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Lanfang Li
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, The Sino‐US Center for Lymphoma and Leukemia Research, Tianjin, China,*Correspondence: Lanfang Li, ; Zhigang Zhao,
| | - Zhigang Zhao
- Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China,Department of Medical Oncology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China,*Correspondence: Lanfang Li, ; Zhigang Zhao,
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7
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Steffanoni S, Calimeri T, Marktel S, Nitti R, Foppoli M, Ferreri AJM. Diagnosis and Treatment Using Autologous Stem-Cell Transplantation in Primary Central Nervous System Lymphoma: A Systematic Review. Cancers (Basel) 2023; 15:cancers15020526. [PMID: 36672475 PMCID: PMC9856418 DOI: 10.3390/cancers15020526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/08/2023] [Accepted: 01/10/2023] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Consolidation therapy has improved the outcome of newly diagnosed PCNSL patients. Whole-brain radiotherapy (WBRT) was the first consolidation strategy used and represented the gold standard for many years, but at the expense of a high risk of neurotoxicity. Thus, alternative strategies are being investigated in order to improve disease outcomes and to spare the neurocognitive side effects due to WBRT. METHODS We reviewed published studies on PCNSL patients treated with HDC/ASCT, focusing on the efficacy and safety of the conditioning regimens. Prospective and retrospective studies, published in the English language from 1992 to 2022, in high-quality international journals were identified in PubMed. RESULTS Consolidation with HDC containing highly CNS-penetrating agents (thiotepa, busulfan or BCNU) followed by ASCT provided long-term disease control and survival in PCNSL patients. Two prospective randomized studies, comparing HDC/ASCT versus WBRT, reported similar progression-free survival (PFS) and similar results on the decline in neurocognitive functions in a substantial proportion of patients after WBRT but not after HDC-ASCT. A recent randomized study comparing HDC/ASCT versus non-myeloablative consolidation reported a longer PFS in transplanted patients. CONCLUSION ASCT conditioned with regimens, including highly CNS-penetrating agents, represents, to date, the best choice among the available consolidation strategies for fit newly diagnosed PCNSL patients.
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Affiliation(s)
- Sara Steffanoni
- Department of Medicine, Division of Hematology, Valduce Hospital, 22100 Como, Italy
- Correspondence:
| | - Teresa Calimeri
- Lymphoma Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Sarah Marktel
- Hematology and BMT Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Rosamaria Nitti
- Hematology and BMT Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Marco Foppoli
- Lymphoma Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
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8
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Kim KH, Lee JH, Lee M, Kim HG, Do YR, Park Y, Oh SY, Shin HJ, Kim WS, Park SK, Kong JH, Park MR, Yang DH, Kwak JY, Kang HJ, Mun YC, Won JH. Busulfan, Melphalan, and Etoposide (BuME) Showed an Equivalent Effect to Busulfan, Cyclophosphamide, and Etoposide (BuCE) as Conditioning Therapy for Autologous Stem Cell Transplantation in Patients with Relapsed or High-Risk Non-Hodgkin's Lymphoma: A Multicenter Randomized Phase II Study bythe Consortium for Improving Survival of Lymphoma (CISL). Cancer Res Treat 2023; 55:304-313. [PMID: 35381164 PMCID: PMC9873313 DOI: 10.4143/crt.2022.004] [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: 01/03/2022] [Accepted: 03/29/2022] [Indexed: 02/04/2023] Open
Abstract
PURPOSE High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard management for relapsed or high-risk non-Hodgkin's lymphoma (NHL). We reported the busulfan, melphalan, and etoposide (BuME) conditioning regimen was effective in patients with relapsed or high-risk NHL. Moreover, the busulfan, cyclophosphamide, and etoposide (BuCE) conditioning regimen has been used widely in ASCT for NHL. Therefore, based on these encouraging results, this randomized phase II multicenter trial compared the outcomes of BuME and BuCE as conditioning therapies for ASCT in patients with NHL. MATERIALS AND METHODS Patients were randomly assigned to receive either BuME (n=36) or BuCE (n=39). The BuME regimen was comprised of busulfan (3.2 mg/kg/day, intravenously) administered on days -7, -6, and -5, etoposide (400 mg/m2 intravenously) on days -5 and -4, and melphalan (50 mg/m2/day intravenously) on days -3 and -2. The BuCE regimen was comprised of busulfan (3.2 mg/kg/day intravenously) on days -7, -6, and -5, etoposide (400 mg/m2/day intravenously) on days -5 and -4, and cyclophosphamide (50 mg/kg/day intravenously) on days -3 and -2. The primary endpoint was 2-year progression-free survival (PFS). RESULTS Seventy-five patients were enrolled. Eleven patients (30.5%) in the BuME group and 13 patients (33.3%) in the BuCE group had disease progression or died. The 2-year PFS rate was 65.4% in the BuME group and 60.6% in the BuCE group (p=0.746). There were no non-relapse mortalities within 100 days after transplantation. CONCLUSION There were no significant differences in PFS between the two groups. Therefore, busulfan-based conditioning regimens, BuME and BuCE, may be important treatment substitutes for the BCNU-containing regimens.
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Affiliation(s)
- Kyoung Ha Kim
- Division of Hematology and Oncology, Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul,
Korea
| | - Jae Hoon Lee
- Deparment of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon,
Korea
| | - Mark Lee
- Department of Internal Medicine, Konkuk University Medical Center and School of Medicine, Seoul,
Korea
| | - Hoon-Gu Kim
- Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju,
Korea
| | - Young Rok Do
- Division of Hematology-Oncology, Department of Medicine, Dongsan Medical Center, Keimyung University, Daegu,
Korea
| | - Yong Park
- Division of Hematology/Oncology, Department of Internal Medicine, Korea University School of Medicine, Seoul,
Korea
| | - Sung Yong Oh
- Department of Internal Medicine, Dong-A University College of Medicine, Busan,
Korea
| | - Ho-Jin Shin
- Division of Hematology-Oncology, Department of Internal Medicine, Pusan National University School of Medicine and Medical Research Institute, Pusan National University Hospital, Busan,
Korea
| | - Won Seog Kim
- Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul,
Korea
| | - Seong Kyu Park
- Division of Hematology and Oncology, Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon,
Korea
| | - Jee Hyun Kong
- Division of Oncology and Hematology, Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju,
Korea
| | - Moo-Rim Park
- Department of Internal Medicine, Wonkwang University School of Medicine, Iksan,
Korea
| | - Deok-Hwan Yang
- Department of Hematology/Oncology, Chonnam National University Hwasun Hospital, Hwasun,
Korea
| | - Jae-Yong Kwak
- Division of Hematology/Oncology, Department of Internal Medicine, Jeonbuk National University Medical School, Jeonju,
Korea
| | - Hye Jin Kang
- Division of Hematology-Oncology, Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Science, Seoul,
Korea
| | - Yeung-Chul Mun
- Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul,
Korea
| | - Jong-Ho Won
- Division of Hematology and Oncology, Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul,
Korea
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9
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Perales MA, Anderson LD, Jain T, Kenderian SS, Oluwole OO, Shah GL, Svoboda J, Hamadani M. Role of CD19 Chimeric Antigen Receptor T Cells in Second-Line Large B Cell Lymphoma: Lessons from Phase 3 Trials. An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy. Transplant Cell Ther 2022; 28:546-559. [PMID: 35768052 PMCID: PMC9427727 DOI: 10.1016/j.jtct.2022.06.019] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 06/20/2022] [Accepted: 06/22/2022] [Indexed: 12/25/2022]
Abstract
Since 2017, 3 CD19-directed chimeric antigen receptor (CAR) T cell therapies-axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel-have been approved for relapsed/refractory aggressive diffuse large B cell lymphoma after 2 lines of therapy. Recently, 3 prospective phase 3 randomized clinical trials were conducted to define the optimal second-line treatment by comparing each of the CAR T cell products to the current standard of care: ZUMA-7 for axicabtagene ciloleucel, BELINDA for tisagenlecleucel, and TRANSFORM for lisocabtagene maraleucel. These 3 studies, although largely addressing the same question, had different outcomes, with ZUMA-7 and TRANSFORM demonstrating significant improvement with CD19 CAR T cells in second-line therapy compared with standard of care but BELINDA not showing any benefit. The US Food and Drug Administration has now approved axicabtagene ciloleucel and lisocabtagene maraleucel for LBCL that is refractory to first-line chemoimmunotherapy or relapse occurring within 12 months of first-line chemoimmunotherapy. Following the reporting of these practice changing studies, here a group of experts convened by the American Society for Transplantation and Cellular Therapy provides a comprehensive review of the 3 studies, emphasizing potential differences, and shares perspectives on what these results mean to clinical practice in this new era of treatment of B cell lymphomas.
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Affiliation(s)
- Miguel-Angel Perales
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.
| | - Larry D Anderson
- Hematologic Malignancies, Transplantation, and Cellular Therapy Program, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas
| | - Tania Jain
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Saad S Kenderian
- T Cell Engineering, Mayo Clinic, Mayo Clinic Graduate School of Biomedical Sciences, Division of Hematology, Department of Immunology and Department of Molecular Medicine, Rochester, Minnesota
| | - Olalekan O Oluwole
- Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee
| | - Gunjan L Shah
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Jakub Svoboda
- Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Mehdi Hamadani
- BMT & Cellular Therapy Program, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
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10
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Parakh S, Lee ST, Gan HK, Scott AM. Radiolabeled Antibodies for Cancer Imaging and Therapy. Cancers (Basel) 2022; 14:1454. [PMID: 35326605 PMCID: PMC8946248 DOI: 10.3390/cancers14061454] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/14/2022] [Accepted: 03/07/2022] [Indexed: 12/04/2022] Open
Abstract
Radioimmunoconjugates consist of a monoclonal antibody (mAb) linked to a radionuclide. Radioimmunoconjugates as theranostics tools have been in development with success, particularly in hematological malignancies, leading to approval by the US Food and Drug Administration (FDA) for the treatment of non-Hodgkin's lymphoma. Radioimmunotherapy (RIT) allows for reduced toxicity compared to conventional radiation therapy and enhances the efficacy of mAbs. In addition, using radiolabeled mAbs with imaging methods provides critical information on the pharmacokinetics and pharmacodynamics of therapeutic agents with direct relevance to the optimization of the dose and dosing schedule, real-time antigen quantitation, antigen heterogeneity, and dynamic antigen changes. All of these parameters are critical in predicting treatment responses and identifying patients who are most likely to benefit from treatment. Historically, RITs have been less effective in solid tumors; however, several strategies are being investigated to improve their therapeutic index, including targeting patients with minimal disease burden; using pre-targeting strategies, newer radionuclides, and improved labeling techniques; and using combined modalities and locoregional application. This review provides an overview of the radiolabeled intact antibodies currently in clinical use and those in development.
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Affiliation(s)
- Sagun Parakh
- Department of Medical Oncology, Heidelberg, VIC 3084, Australia; (S.P.); (H.K.G.)
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia;
- School of Cancer Medicine, La Trobe University, Heidelberg, VIC 3086, Australia
| | - Sze Ting Lee
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia;
- School of Cancer Medicine, La Trobe University, Heidelberg, VIC 3086, Australia
- Department of Molecular Imaging and Therapy, Austin Health, Heidelberg, VIC 3084, Australia
| | - Hui K. Gan
- Department of Medical Oncology, Heidelberg, VIC 3084, Australia; (S.P.); (H.K.G.)
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia;
- School of Cancer Medicine, La Trobe University, Heidelberg, VIC 3086, Australia
- Department of Medicine, University of Melbourne, Heidelberg, VIC 3010, Australia
| | - Andrew M. Scott
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia;
- School of Cancer Medicine, La Trobe University, Heidelberg, VIC 3086, Australia
- Department of Molecular Imaging and Therapy, Austin Health, Heidelberg, VIC 3084, Australia
- Department of Medicine, University of Melbourne, Heidelberg, VIC 3010, Australia
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11
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Cicone F, Sarnelli A, Guidi C, Belli ML, Ferrari ME, Wahl R, Cremonesi M, Paganelli G. Dosimetric Approaches for Radioimmunotherapy of Non-Hodgkin Lymphoma in Myeloablative Setting. Semin Nucl Med 2022; 52:191-214. [PMID: 34996594 DOI: 10.1053/j.semnuclmed.2021.11.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Radioimmunotherapy (RIT) is a safe and active treatment available for non-Hodgkin lymphomas (NHLs). In particular, two monoclonal antibodies raised against CD20, that is Zevalin (90Y-ibritumomab-tiuxetan) and Bexxar (131I-tositumomab) received FDA approval for the treatment of relapsing/refractory indolent or transformed NHLs. RIT is likely the most effective and least toxic anticancer agent in NHLs. However, its use in the clinical setting is still debated and, in case of relapse after optimized rituximab-containing regimens, the efficacy of RIT at standard dosage is suboptimal. Thus, clinical trials were based on the hypothesis that the inclusion of RIT in myeloablative conditioning would allow to obtain improved efficacy and toxicity profiles when compared to myeloablative total-body irradiation and/or high-dose chemotherapy regimens. Standard-activity RIT has a safe toxicity profile, and the utility of pretherapeutic dosimetry in this setting can be disputed. In contrast, dose-escalation clinical protocols require the assessment of radiopharmaceutical biodistribution and dosimetry before the therapeutic injection, as dose constrains for critical organs may be exceeded when RIT is administered at high activities. The aim of the present study was to review and discuss the internal dosimetry protocols that were adopted for non-standard RIT administration in the myeloablative setting before hematopoietic stem cell transplantation in patients with NHLs.
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Affiliation(s)
- Francesco Cicone
- Department of Experimental and Clinical Medicine, and Neuroscience Research Centre, PET/RM Unit, "Magna Graecia" University of Catanzaro, Catanzaro, Italy; Nuclear Medicine Unit, University Hospital "Mater Domini", Catanzaro, Italy
| | - Anna Sarnelli
- Medical Physics Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy.
| | - Claretta Guidi
- Medical Physics Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Maria Luisa Belli
- Medical Physics Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | | | - Richard Wahl
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO
| | - Marta Cremonesi
- Radiation Research Unit, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - Giovanni Paganelli
- Nuclear Medicine Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
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12
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Herrera AF, Palmer J, Adhikarla V, Yamauchi D, Poku EK, Bading J, Yazaki P, Dandapani S, Mei M, Chen R, Cao T, Karras N, McTague P, Nademanee A, Popplewell L, Sahebi F, Shively JE, Simpson J, Smith DL, Song J, Spielberger R, Tsai NC, Thomas SH, Forman SJ, Colcher D, Wu AM, Wong J, Smith E. Anti-CD25 radioimmunotherapy with BEAM autologous hematopoietic cell transplantation conditioning in Hodgkin lymphoma. Blood Adv 2021; 5:5300-5311. [PMID: 34638132 PMCID: PMC9153018 DOI: 10.1182/bloodadvances.2021004981] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 08/31/2021] [Indexed: 11/27/2022] Open
Abstract
High-risk relapsed or refractory (R/R) classical Hodgkin lymphoma (HL) is associated with poor outcomes after conventional salvage therapy and autologous hematopoietic cell transplantation (AHCT). Post-AHCT consolidation with brentuximab vedotin (BV) improves progression-free survival (PFS), but with increasing use of BV early in the treatment course, the utility of consolidation is unclear. CD25 is often expressed on Reed-Sternberg cells and in the tumor microenvironment in HL, and we hypothesized that the addition of 90Y-antiCD25 (aTac) to carmustine, etoposide, cytarabine, melphalan (BEAM) AHCT would be safe and result in a transplantation platform that is agnostic to prior HL-directed therapy. Twenty-five patients with high-risk R/R HL were enrolled in this phase 1 dose-escalation trial of aTac-BEAM. Following an imaging dose of 111In-antiCD25, 2 patients had altered biodistribution, and a third developed an unrelated catheter-associated bacteremia; therefore, 22 patients ultimately received therapeutic 90Y-aTac-BEAM AHCT. No dose-limiting toxicities were observed, and 0.6 mCi/kg was deemed the recommended phase 2 dose, the dose at which the heart wall would not receive >2500 cGy. Toxicities and time to engraftment were similar to those observed with standard AHCT, though 95% of patients developed stomatitis (all grade 1-2 per Bearman toxicity scale). Seven relapses (32%) were observed, most commonly in patients with ≥3 risk factors. The estimated 5-year PFS and overall survival probabilities among 22 evaluable patients were 68% and 95%, respectively, and non-relapse mortality was 0%. aTac-BEAM AHCT was tolerable in patients with high-risk R/R HL, and we are further evaluating the efficacy of this approach in a phase 2 trial. This trial was registered at www.clinicaltrials.gov as #NCT01476839.
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Affiliation(s)
- Alex F. Herrera
- Department of Hematology and Hematopoietic Cell Transplantation
| | | | | | | | | | | | | | | | - Matthew Mei
- Department of Hematology and Hematopoietic Cell Transplantation
| | - Robert Chen
- Department of Hematology and Hematopoietic Cell Transplantation
| | - Thai Cao
- Department of Hematology and Hematopoietic Cell Transplantation
| | | | | | | | | | - Firoozeh Sahebi
- Department of Hematology and Hematopoietic Cell Transplantation
| | | | | | | | - Joo Song
- Department of Pathology, City of Hope National Medical Center, Duarte, CA
| | | | - Ni-Chun Tsai
- Department of Computational and Quantitative Biology
| | | | | | | | - Anna M. Wu
- Department of Immunology and Theranostics
| | | | - Eileen Smith
- Department of Hematology and Hematopoietic Cell Transplantation
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13
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Immunotherapy for Diffuse Large B-Cell Lymphoma: Current Landscape and Future Directions. Cancers (Basel) 2021; 13:cancers13225827. [PMID: 34830980 PMCID: PMC8616088 DOI: 10.3390/cancers13225827] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/12/2021] [Accepted: 11/16/2021] [Indexed: 01/05/2023] Open
Abstract
Simple Summary Immunotherapy has played a pivotal role in the management of relapsed DLBCL. Stem cell transplant and CAR T-cell therapy are curative treatment modalities for relapsed disease. Despite this, a subset of patients continues to progress, and their outcomes remain dismal. Newer therapeutic options to optimize outcomes as well as minimize toxicity are warranted. Abstract Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease. B-cell receptor (BCR) pathway is essential for malignant B-cell growth, survival, and proliferation. Various immune cells, including T-cells and macrophages in the tumor microenvironment (TME) contribute to tumor cell survival and pathogenesis of chemo-resistance. The presence of many targets on the malignant B-cells and in the TME has led to emergence of novel therapeutic agents. Stem cell transplant is the oldest treatment modality leveraging immune system in DLBCL. Subsequently, CD20 targeting monoclonal antibody and chimeric antigen receptor (CAR) T-cell therapy changed the treatment landscape of DLBCL. Recently, multiple novel immunotherapeutic agents have been added in the armamentarium for the management of DLBCL, and many are under development. In this review article, we will review latest updates of immunotherapeutic agents in the management of DLBCL.
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14
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The Use of Etoposide, Ara-Cytarabine, and Melphalan (EAM) Conditioning Chemotherapy in Autologous Stem Cell Transplantation (ASCT) for a Patient with Relapsed Hodgkin's Lymphoma. Case Rep Hematol 2021; 2021:9632427. [PMID: 34777885 PMCID: PMC8580659 DOI: 10.1155/2021/9632427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 10/15/2021] [Indexed: 11/24/2022] Open
Abstract
Up to 20–40% of patients with Hodgkin's lymphoma will eventually relapse after treatment, among which early relapse confers a poor outcome. With salvage chemotherapy followed by autologous stem cell transplantation (ASCT), the long-term remission rate is 30%. We report our experience of using a modified-BEAM conditioning regimen without BCNU consisting of etoposide, cytarabine, and melphalan (EAM) in a patient with relapsed Hodgkin's lymphoma. Before transplantation, the patient achieved second complete remission (CR2) using brentuximab vedotin and ESHAP (BR-ESHAP) chemotherapy. The ASCT went well without significant complications. This case demonstrated the considerable efficacy of EAM protocol as a conditioning regimen in terms of sufficient ablative capabilities, and the patient showed a successful hematopoietic engraftment. Although durability of the disease-free survival needs further observation, it had nearly 18 months of complete remission and the patient was in good performance status at the time of writing this manuscript.
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15
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Rondon A, Rouanet J, Degoul F. Radioimmunotherapy in Oncology: Overview of the Last Decade Clinical Trials. Cancers (Basel) 2021; 13:cancers13215570. [PMID: 34771732 PMCID: PMC8583425 DOI: 10.3390/cancers13215570] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 10/26/2021] [Accepted: 11/05/2021] [Indexed: 12/17/2022] Open
Abstract
Simple Summary Monoclonal antibody-bearing radionuclides have been under clinical investigation over the last two decades for their use in theranostic (diagnostic and therapeutic) applications in cancer. However, despite the numerous trials that have been conducted, only two radioimmunotherapies (RIT) have been approved by the FDA for the targeted therapy of hematologic tumors expressing CD20 antigens. Moreover, RIT applications for solid cancers faced major issues—such as radiotoxicity due to low antibodies penetrance requiring substantial curative dose—where new discoveries concerning antibody engineering or radionuclides are trying to overcome. Here, we performed an overview of the last 11-year clinical trials involving RIT for solid and non-solid cancers conducted either with full antibodies or antibody fragments. We discussed the low-to-moderate efficiency of RIT compared to conventional therapies and described the last advances in clinic for antibodies carriers (F(ab′)2, Fab′, ScFv). Finally, we discussed about the complexity of RIT as a therapy and depicted both the issues and the prospects of such a strategy. Abstract The specific irradiation of tumors with selective radiolabeled antibodies constitutes an attractive therapeutic approach. Consequent preclinical research has been conducted by both biologists to identify pertinent targets and to select corresponding antibodies (mAb) and by radiochemists to radiolabel mAbs. These numerous preclinical investigations have ascertained the therapeutic interest of radioimmunotherapy (RIT) protocols in mice models. Here, we summarize the clinical studies that have been performed the last decade, including clinical trials (phases I, II, and III), prospective and retrospective studies, and cases series. We thereby reported 92 clinical studies. Among them, 62 concern the treatment of hematological malignancies, and 30 concern solid tumors. For hematologic diseases, the analysis was complex due to the high discrepancy of therapeutic strategies (first-line therapy, consolidation, stem cell transplantation conditioning) as well as the high variety of malignancies that were treated. The clinical studies from the last decade failed to expand anti-CD20 RIT indications but confirmed that RIT using radiolabeled anti-CD20 remains a pertinent choice for patients with relapse follicular lymphomas. For solid tumors, the positive benefit of RIT is more mitigated, apart for few malignancies that can be treated locally. Clinical trials also demonstrated the potential of some antibody formats, such as F(ab′)2, which has already been approved by the China State FDA under the trend name Licartin®. Despite disparate results, mAb fragments are an interesting prospect for the improvement of RIT efficiency as well as for pretargeted strategies that delay the injection of radioactive treatments from the mAb ones.
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Affiliation(s)
- Aurélie Rondon
- Advanced Drug Delivery and Biomaterials, Louvain Drug Research Institute, UCLouvain, BE-1200 Brussels, Belgium
- Correspondence: (A.R.); (F.D.)
| | - Jacques Rouanet
- Imagerie Moléculaire et Stratégies Théranostiques, Inserm UMR1240, Université Clermont-Auvergne, F-63000 Clermont-Ferrand, France;
- Service de Dermatologie et d’Oncologie Cutanée, CHU Estaing, F-63011 Clermont-Ferrand, France
| | - Françoise Degoul
- CNRS 6293, INSERM U1103, GReD, Centre de Recherche et de Biologie Clinique, Université Clermont-Auvergne, F-63000 Clermont-Ferrand, France
- Correspondence: (A.R.); (F.D.)
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16
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El Fakih R, Lazarus HM, Muffly L, Altareb M, Aljurf M, Hashmi SK. Historical perspective and a glance into the antibody-based conditioning regimens: A new era in the horizon? Blood Rev 2021; 52:100892. [PMID: 34674852 DOI: 10.1016/j.blre.2021.100892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 10/10/2021] [Accepted: 10/11/2021] [Indexed: 11/17/2022]
Abstract
The hematopoietic cell transplantation practice has changed significantly over the years. More than 1500 centers around the globe are offering transplant for different types of diseases. This growth was driven by improving the efficacy and the safety of the procedure and the ability to use alternate donors. These improvements made the procedure feasible in virtually all patients in need for it. With the availability of novel therapies and targeted agents, we may be witnessing a new transplant-era. These agents may help to circumvent some of the remaining limitations of the procedure and open the doors for new indications. Herein, we review historical transplant milestones, the accomplishments that led to the modern transplant practice and we discuss the idea of minimal-intensity conditioning and the possibility to adopt chemotherapy and radiation-free preparative regimens in the near future.
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Affiliation(s)
- Riad El Fakih
- Oncology Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
| | - Hillard M Lazarus
- Division of Hematology-Oncology, Case Western Reserve University, Cleveland, OH, USA
| | - Lori Muffly
- Stanford University, Blood and Marrow Transplant and Cellular therapy, Stanford, CA, USA
| | - Majed Altareb
- Oncology Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Mahmoud Aljurf
- Oncology Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Shahrukh K Hashmi
- Department of Medicine, Sheikh Shakhbout Medical City, Abu Dhabi, UAE; Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
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17
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Doraiswamy A, Shah MR, Bannerji R. Immunotherapies Old and New: Hematopoietic Stem Cell Transplant, Chimeric Antigen Receptor T Cells, and Bispecific Antibodies for the Treatment of Relapsed/Refractory Diffuse Large B Cell Lymphoma. Curr Hematol Malig Rep 2021; 16:72-81. [PMID: 33619641 DOI: 10.1007/s11899-021-00610-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/01/2021] [Indexed: 12/22/2022]
Abstract
PURPOSE OF REVIEW Diffuse large B cell lymphoma (DLBCL) is curable in a majority of patients; however, a significant portion of patients develop relapsed or refractory disease. High-dose chemotherapy followed by autologous stem cell transplant is the standard approach in appropriately selected patients. Many patients are not candidates for transplant and many who do receive autologous transplant relapse. Therapies which harness T cells including chimeric antigen receptor T cells (CAR-T) and bispecific antibodies are active in this chemotherapy-resistant population. We review the role of autologous and allogeneic stem cell transplant, CAR-T therapy, and bispecific antibodies in the treatment of relapsed or refractory DLBCL. RECENT FINDINGS Phase I studies of bispecific antibodies directed against CD20 × CD3 have shown activity in heavily pre-treated DLBCL including in patients who have progressed following autologous transplant and/or CAR-T therapy. Two CAR-T products have received regulatory approval in relapsed or refractory DLBCL, with other products in clinical trials. CAR-T treatment has resulted in durable remissions and trials are ongoing to determine if CAR-T should replace autologous transplant as second-line therapy for DLBCL. The development of multiple T cell-directed therapies for DLBCL offers new treatment options for chemotherapy-resistant disease. We discuss our approach to relapsed or refractory DLBCL patients and the open question of optimal sequencing of autologous transplant (a current standard treatment), CAR-T therapy (FDA approved), and bispecific antibodies (in clinical trials).
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Affiliation(s)
- Anupama Doraiswamy
- Division of Blood Disorders, Section of Hematologic Malignancies, Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ, 08903, USA
| | - Mansi R Shah
- Division of Blood Disorders, Section of Hematologic Malignancies, Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ, 08903, USA
| | - Rajat Bannerji
- Division of Blood Disorders, Section of Hematologic Malignancies, Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ, 08903, USA.
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18
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Alencar AJ, Moskowitz CH. Autologous Stem Cell Transplantation in the Management of Relapsed Non-Hodgkin Lymphoma. J Clin Oncol 2021; 39:467-475. [PMID: 33434059 DOI: 10.1200/jco.20.01751] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- Alvaro J Alencar
- Division of Hematology, Department of Medicine, University of Miami Sylvester Comprehensive Cancer Center, Miami, FL
| | - Craig H Moskowitz
- Division of Hematology, Department of Medicine, University of Miami Sylvester Comprehensive Cancer Center, Miami, FL
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19
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Devine SM, Horowitz MM. Building a Fit for Purpose Clinical Trials Infrastructure to Accelerate the Assessment of Novel Hematopoietic Cell Transplantation Strategies and Cellular Immunotherapies. J Clin Oncol 2021; 39:534-544. [PMID: 33434065 PMCID: PMC8443822 DOI: 10.1200/jco.20.01623] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/09/2020] [Indexed: 01/07/2023] Open
Affiliation(s)
- Steven M. Devine
- National Marrow Donor Program/Be The Match, Minneapolis, MN
- Center for International Blood and Marrow Transplant Research, Minneapolis, MN
| | - Mary M. Horowitz
- Center for International Blood and Marrow Transplant Research, Department of Medicine, Medical College of Wisconsin, WI
- Division of Hematology-Oncology, Department of Medicine, Medical College of Wisconsin, WI
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20
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Luo C, Wu G, Huang X, Ma Y, Zhang Y, Song Q, Xie M, Sun Y, Huang Y, Huang Z, Hou Y, Xu S, Chen J, Li X. Efficacy and safety of new anti-CD20 monoclonal antibodies versus rituximab for induction therapy of CD20 + B-cell non-Hodgkin lymphomas: a systematic review and meta-analysis. Sci Rep 2021; 11:3255. [PMID: 33547368 PMCID: PMC7864901 DOI: 10.1038/s41598-021-82841-w] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 01/20/2021] [Indexed: 12/25/2022] Open
Abstract
Rituximab combined with chemotherapy is the first-line induction therapy of CD20 positive B-cell non-Hodgkin lymphomas (CD20+ B-NHL). Recently new anti-CD20 monoclonal antibodies (mAbs) have been developed, but their efficacy and safety compared with rituximab are still controversial. We searched MEDLINE, Embase, and Cochrane Library for eligible randomized controlled trials (RCTs) that compared new anti-CD20 mAbs with rituximab in induction therapy of B-NHL. The primary outcomes are progression-free survival (PFS) and overall survival (OS), additional outcomes include event-free survival (EFS), disease-free survival (DFS), overall response rate (ORR), complete response rate (CRR) and incidences of adverse events (AEs). Time-to-event data were pooled as hazard ratios (HRs) using the generic inverse-variance method and dichotomous outcomes were pooled as odds ratios (ORs) using the Mantel-Haenszel method with their respective 95% confidence interval (CI). Eleven RCTs comprising 5261 patients with CD20+ B-NHL were included. Compared with rituximab, obinutuzumab significantly prolonged PFS (HR 0.84, 95% CI 0.73-0.96, P = 0.01), had no improvement on OS, ORR, and CRR, but increased the incidences of serious AEs (OR 1.29, 95% CI 1.13-1.48, P < 0.001). Ofatumumab was inferior to rituximab in consideration of ORR (OR 0.73, 95% CI 0.55-0.96, P = 0.02), and had no significant differences with rituximab in regard to PFS, OS and CRR. 131I-tositumomab yielded similar PFS, OS, ORR and CRR with rituximab. 90Y-ibritumomab tiuxetan increased ORR (OR 3.07, 95% CI 1.47-6.43, P = 0.003), but did not improve PFS, DFS, OS and CRR compared with rituximab. In conclusion, compared with rituximab in induction therapy of CD20+ B-NHL, obinutuzumab significantly improves PFS but with higher incidence of AEs, ofatumumab decreases ORR, 90Y-ibritumomab tiuxetan increases ORR.
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Affiliation(s)
- Chengxin Luo
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Key Laboratory of Cancer Immunotherapy of Chongqing, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Guixian Wu
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Key Laboratory of Cancer Immunotherapy of Chongqing, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Xiangtao Huang
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Key Laboratory of Cancer Immunotherapy of Chongqing, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Yanni Ma
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Key Laboratory of Cancer Immunotherapy of Chongqing, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Yali Zhang
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Key Laboratory of Cancer Immunotherapy of Chongqing, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Qiuyue Song
- Department of Health Statistics, Third Military Medical University, Chongqing, China
| | - Mingling Xie
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Key Laboratory of Cancer Immunotherapy of Chongqing, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Yanni Sun
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Key Laboratory of Cancer Immunotherapy of Chongqing, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Yarui Huang
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Key Laboratory of Cancer Immunotherapy of Chongqing, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Zhen Huang
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Key Laboratory of Cancer Immunotherapy of Chongqing, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Yu Hou
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Key Laboratory of Cancer Immunotherapy of Chongqing, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Shuangnian Xu
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China.
- Key Laboratory of Cancer Immunotherapy of Chongqing, Southwest Hospital, Third Military Medical University, Chongqing, China.
| | - Jieping Chen
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China.
- Key Laboratory of Cancer Immunotherapy of Chongqing, Southwest Hospital, Third Military Medical University, Chongqing, China.
| | - Xi Li
- Institute of Infectious Disease, Southwest Hospital, Third Military Medical University, Chongqing, China.
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Bazzell BG, Benitez LL, Marini BL, Perissinotti AJ, Phillips TJ, Nachar VR. Evaluating the Role of Novel Oncology Agents: Oncology Stewardship in Relapsed/Refractory Diffuse Large B-Cell Lymphoma. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2021; 21:295-308. [PMID: 33485834 DOI: 10.1016/j.clml.2020.12.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 12/11/2020] [Accepted: 12/19/2020] [Indexed: 10/22/2022]
Abstract
Novel treatment strategies have shifted the treatment landscape for patients with diffuse large B-cell lymphoma, particularly for those with relapsed/refractory disease. However, uncertainty remains regarding the therapeutic value of these novel agents compared to existing salvage chemotherapy regimens. In addition, the high cost associated with these agents puts both patients and health systems at risk of financial toxicity, further complicating their use. The development of clinical pathways incorporating oncology stewardship principles are necessary in order to maximize value-based care. This comprehensive review assesses the efficacy and safety data available for novel treatment options in relapsed/refractory diffuse large B-cell lymphoma and applies stewardship principles to evaluate their optimal place in therapy, with the aim of optimizing safe, effective, and financially responsible patient care.
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Affiliation(s)
- Brian G Bazzell
- Department of Pharmacy Services and Clinical Pharmacy, Michigan Medicine, Ann Arbor, MI; Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI
| | - Lydia L Benitez
- Department of Pharmacy Services and Clinical Pharmacy, Michigan Medicine, Ann Arbor, MI; Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI
| | - Bernard L Marini
- Department of Pharmacy Services and Clinical Pharmacy, Michigan Medicine, Ann Arbor, MI; Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI
| | - Anthony J Perissinotti
- Department of Pharmacy Services and Clinical Pharmacy, Michigan Medicine, Ann Arbor, MI; Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI
| | - Tycel J Phillips
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan Rogel Cancer Center, Michigan Medicine, Ann Arbor, MI
| | - Victoria R Nachar
- Department of Pharmacy Services and Clinical Pharmacy, Michigan Medicine, Ann Arbor, MI; Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI.
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Abramson JS, Ghosh N, Smith SM. ADCs, BiTEs, CARs, and Small Molecules: A New Era of Targeted Therapy in Non-Hodgkin Lymphoma. Am Soc Clin Oncol Educ Book 2021; 40:302-313. [PMID: 32421455 DOI: 10.1200/edbk_279043] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Novel immunotherapies and small molecular inhibitors are transforming our approach to previously treated and newly diagnosed patients across the spectrum of non-Hodgkin lymphomas (NHLs). Anti-CD19 CAR T cells are now indicated for the treatment of relapsed/refractory aggressive B-cell lymphomas after at least two previous lines of therapy in which durable remissions are achieved in approximately 40% of previously incurable patients. Second-line chemoimmunotherapy remains the standard of care at first relapse, but poor outcomes with conventional treatment in this setting creates an appealing rationale for earlier use of CAR T cells, which is currently under investigation, along with even earlier use in selected high-risk patients in the frontline setting. Other emerging immunotherapies include antibody-drug conjugates (ADCs), such as polatuzumab vedotin for multiple-relapsed diffuse large B-cell lymphoma (DLBCL) in combination with bendamustine-rituximab. Multiple bispecific antibodies that bring malignant B cells in contact with effector T cells appear promising in early clinical trials and will likely emerge as off-the-shelf immunotherapy options. Chemotherapy-free small molecule-based regimens are increasingly available for mantle cell (MCLs) and follicular lymphomas (FLs). Bruton tyrosine kinase inhibitors (BTKi) now represent standard second-line therapy for MCL and are being investigated in combination and as initial therapy. Lenalidomide-rituximab is an active regimen in both FL and MCL and may be used in either relapsed/refractory or previously untreated disease. Three PI3K inhibitors are approved for multiple-relapsed FL and can induce durable remissions in patients with chemotherapy- and rituximab-refractory disease. Additional emerging targeted therapies include BCL2 inhibition in MCL and EZH2 inhibition in FL.
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23
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Wang J, Huang J, Zeng Q. Network meta-analysis of targeted therapies for diffuse large B cell lymphoma. BMC Cancer 2020; 20:1218. [PMID: 33308179 PMCID: PMC7733263 DOI: 10.1186/s12885-020-07715-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 02/17/2020] [Indexed: 02/05/2023] Open
Abstract
Background The purpose of this network meta-analysis of randomized controlled trials (RCTs) was to compare rank targeted therapies for patients with diffuse large B-cell lymphoma (DLBCL). Methods The PubMed, EmBase, and Cochrane library electronic databases were systematically searched throughout December 2019. Direct and indirect evidence from relevant RCTs was identified for network meta-analysis. The pooled results for grade 3 or greater adverse events between targeted therapies and chemotherapy were calculated using a random-effects model. Results A total of 18 RCTs enrolling 8207 DLBCL patients were selected for the final meta-analysis. The results of the network analysis indicated that the addition of dacetuzumab (74.8%) to rituximab-based regimens or lenalidomide (77.1%) was associated with better therapeutic effects on overall survival, whereas dacetuzumab (80.4%) or bortezomib (70.8%) added to rituximab was most likely to improve events-free survival. Moreover, lenalidomide (93.8%) and I-tositumomab (77.2%) were associated with higher overall response rates. Finally, patients receiving targeted therapies were associated with an increased risk of diarrhea (RR: 2.63; 95%CI: 1.18–5.86; P = 0.019), and thrombocytopenia (RR: 1.41; 95%CI: 1.05–1.90; P = 0.023). Conclusions This study provides the best treatment strategy for DLBCL patients in terms of overall survival, events-free survival, and overall response rate. The findings of this study require validation with further large-scale RCTs. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-020-07715-2.
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Affiliation(s)
- Jie Wang
- Department of Hematology, West China Hospital of Sichuan University, No. 37 Guoxuexiang Street, Chengdu, 610041, Sichuan, China.
| | - Jun Huang
- West China Medical School, Sichuan University, Chengdu, Sichuan, China
| | - Qing Zeng
- West China Medical School, Sichuan University, Chengdu, Sichuan, China
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Postrelapse survival in diffuse large B-cell lymphoma after therapy failure following autologous transplantation. Blood Adv 2020; 3:1661-1669. [PMID: 31167818 DOI: 10.1182/bloodadvances.2019000102] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 05/08/2019] [Indexed: 01/22/2023] Open
Abstract
Outcomes for diffuse large B-cell lymphoma (DLBCL) patients relapsing after autologous hematopoietic cell transplantation (auto-HCT) have been historically poor. We studied outcomes of such patients using data from 4 transplantation centers. Eligibility criteria included adult patients (age ≥18 years) with DLBCL experiencing disease relapse after auto-HCT performed during 2006 to 2015. The time period was stratified into 2 eras (era 1, 2006-2010; era 2, 2011-2015). The primary end point was postrelapse overall survival (PR-OS). Secondary end points were factors prognostic of PR-OS. Of the 700 patients with DLBCL who underwent auto-HCT, 248 (35%) relapsed after auto-HCT. Median PR-OS of all relapsed DLBCL patients after auto-HCT (n = 228) was 9.8 months (95% confidence interval [CI], 7-15). Median PR-OS was significantly better for patients in complete (17.8 months; 95% CI, 7.9-41.6) vs partial remission at auto-HCT (7.1 months; 95% CI, 5.4-11; P = .01), those undergoing auto-HCT >1 year (12.8 months; 95% CI, 7.6-24.9) vs ≤1 year after DLBCL diagnosis (6.3 months; 95% CI, 4.5-9.2; P = .01), and those with late (56.4 months; 95% CI, 23.7-∞) vs early relapse (5.9 months; 95% CI, 4.5-8.8; P < .0001). On multivariate analysis, although late relapse (hazard ratio [HR], 0.21; 95% CI, 0.13-0.34; P < .0001) was associated with significantly lower mortality, the risk of mortality increased with age (HR, 1.25 per decade; 95% CI, 1.06-1.48; P = .009). This is the largest study to date to evaluate outcomes of DLBCL patients relapsing after auto-HCT. Our study provides benchmarking for future trials of chimeric antigen receptor T cells and other promising agents evaluating PR-OS after auto-HCT.
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Chow VA, Rajendran JG, Fisher DR, Appelbaum FR, Cassaday RD, Martin PS, Holmberg LA, Gooley TA, Stevenson PA, Pagel JM, Green DJ, Press OW, Gopal AK. A phase II trial evaluating the efficacy of high-dose Radioiodinated Tositumomab (Anti-CD20) antibody, etoposide and cyclophosphamide followed by autologous transplantation, for high-risk relapsed or refractory non-hodgkin lymphoma. Am J Hematol 2020; 95:775-783. [PMID: 32243637 DOI: 10.1002/ajh.25818] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 03/18/2020] [Accepted: 03/28/2020] [Indexed: 01/23/2023]
Abstract
Radiation is the most effective treatment for localized lymphoma, but treatment of multifocal disease is limited by toxicity. Radioimmunotherapy (RIT) delivers tumoricidal radiation to multifocal sites, further augmenting response by dose-escalation. This phase II trial evaluated high-dose RIT and chemotherapy prior to autologous stem-cell transplant (ASCT) for high-risk, relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (NHL). The primary endpoint was progression free survival (PFS). Secondary endpoints were overall survival (OS), toxicity, and tolerability. Patients age < 60 years with R/R NHL expressing CD20 were eligible. Mantle cell lymphoma (MCL) patients could proceed to transplant in first remission. Patients received I-131-tositumomab delivered at ≤25Gy to critical normal organs, followed by etoposide, cyclophosphamide and ASCT. A group of 107 patients were treated including aggressive lymphoma (N = 29), indolent lymphoma (N = 45), and MCL (N = 33). After a median follow-up of 10.1 years, the 10-year PFS for the aggressive, indolent, and MCL groups were 62%, 64%, 43% respectively. The 10-year OS for the aggressive, indolent, and MCL groups were 61%, 71%, 48% respectively. Toxicities were similar to standard conditioning regimens and non-relapse mortality at 100 days was 2.8%. Late myeloid malignancies were seen in 6% of patients. High-dose I-131-tositumomab, etoposide and cyclophosphamide followed by ASCT appeared feasible, safe, and effective in treating NHL, with estimated PFS at 10-years of 43%-64%. In light of novel cellular therapies for R/R NHL, high-dose RIT-containing regimens yield comparable efficacy and safety and could be prospectively compared.
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Affiliation(s)
- Victor A Chow
- Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA, USA
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | | | | | - Frederick R Appelbaum
- Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA, USA
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Ryan D Cassaday
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Division of Hematology, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Paul S Martin
- Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Leona A Holmberg
- Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA, USA
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Theodore A Gooley
- Public Health Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Philip A Stevenson
- Public Health Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - John M Pagel
- Center for Blood Disorders and Stem Cell Transplantation, Swedish Cancer Institute, Seattle, WA, USA
| | - Damian J Green
- Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA, USA
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Oliver W Press
- Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA, USA
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Ajay K Gopal
- Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA, USA
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
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Kim KH, Kim WS, Kim SJ, Yoon DH, Suh C, Kang HJ, Choi CW, Lee HS, Bae SH, Park J, Park EK, Kwak JY, Lee MH, Kang BW, Park SK, Won JH. Treatment with intravenous busulfan, melphalan, and etoposide followed by autologous stem cell transplantation in patients with non-Hodgkin's lymphoma: a multicenter study from the consortium for improving survival of lymphoma. Transpl Int 2020; 33:1211-1219. [PMID: 32479690 DOI: 10.1111/tri.13664] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 10/21/2019] [Accepted: 05/26/2020] [Indexed: 11/29/2022]
Abstract
Several high-dose therapy (HDT) conditioning regimens have been used to treat non-Hodgkin's lymphoma (NHL), such as bis-chloroethylnitrosourea (BCNU)/etoposide/cytosine arabinoside/melphalan (BEAM), BCNU/etoposide/cytosine arabinoside/cyclophosphamide (BEAC), and cyclophosphamide/BCNU/etoposide (CBV). BCNU is an active drug in HDT of NHL, but the supply is limited in some countries, including Korea. Busulfan has been used in allogeneic and autologous stem cell transplantation (ASCT). This phase II study evaluated the efficacy of busulfan/melphalan/etoposide (BuME) as a conditioning regimen for HDT in relapsed or high-risk NHL. The regimen consisted of intravenous busulfan (3.2 mg/kg/day) on days -8, -7, and -6, etoposide (400 mg/m2 /day) on days -5 and -4, and melphalan (50 mg/m2 /day) on days -3 and -2. A total of 46 patients were included in the study, with 36 (78.3%) achieving a complete response after ASCT. The 2-year progression-free survival (PFS) and overall survival (OS) rates for all patients were 46.7% (95% CI, 31.8-60.4%) and 63.7% (95% CI, 47.7-76.0%), respectively. There was no development of veno-occlusive disease and no treatment-related deaths within 100 days after ASCT. These results indicate that a BuME regimen is well-tolerated and effective for patients with relapsed or high-risk NHL, and may be comparable to some previously used regimens. This regimen may be useful as a substitute for BCNU-containing regimens.
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Affiliation(s)
- Kyoung Ha Kim
- Division of Hematology & Oncology, Department of Internal Medicine, Soonchunhyang University College of Medicine, Soonchunhyang University Hospital, Seoul, Korea
| | - Won Seog Kim
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seok Jin Kim
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Dok Hyun Yoon
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Cheolwon Suh
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hye Jin Kang
- Division of Hematology-Oncology, Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Science, Seoul, Korea
| | - Chul Won Choi
- Division of Oncology-Hematology, Department of Internal Medicine, Korea University Guro Hospital, Seoul, Korea
| | - Ho Sup Lee
- Division of Hematology/Oncology, Department of Internal Medicine, Kosin University College of Medicine, Kosin University Gospel Hospital, Busan, Korea
| | - Sung Hwa Bae
- Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu, Korea
| | - Jinny Park
- Division of Hematology, Deparment of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Eun Kyung Park
- Division of Hematology/Oncology, Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Jae-Yong Kwak
- Division of Hematology/Oncology, Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Korea
| | - Mark Hong Lee
- Division of Hematology-Oncology, Department of Internal Medicine, Konkuk University School of Medicine, Konkuk University, Seoul, Korea
| | - Byung Woog Kang
- Department Hematology/Oncology, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, Daegu, Korea
| | - Sung-Kyu Park
- Division of Hematology and Oncology, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon-Si, Gyeonggi-Do, Korea
| | - Jong-Ho Won
- Division of Hematology & Oncology, Department of Internal Medicine, Soonchunhyang University College of Medicine, Soonchunhyang University Hospital, Seoul, Korea
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Conlon KC, Sportes C, Brechbiel MW, Fowler DH, Gress R, Miljkovic MD, Chen CC, Whatley MA, Bryant BR, Corcoran EM, Kurdziel KA, Pittaluga S, Paik CH, Lee JH, Fleisher TA, Carrasquillo JA, Waldmann TA. 90Y-Daclizumab (Anti-CD25), High-Dose Carmustine, Etoposide, Cytarabine, and Melphalan Chemotherapy and Autologous Hematopoietic Stem Cell Transplant Yielded Sustained Complete Remissions in 4 Patients with Recurrent Hodgkin's Lymphoma. Cancer Biother Radiopharm 2020; 35:249-261. [PMID: 32275165 DOI: 10.1089/cbr.2019.3298] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Background: Despite advances in therapy of Hodgkin's lymphoma (HL), a proportion of patients will not respond or relapse. The authors had previously identified CD25, IL-2Rα, as a target for systemic radioimmunotherapy of HL since most normal cells do not express CD25, but it is expressed by a minority of Hodgkin/Reed-Sternberg (HRS) cells and most Tregs rosetting around HRS cells. Study Design and Treatment: This was a single institution, nonrandomized, open-label phase I/II trial of radiolabeled 90Y-daclizumab, an anti-CD25 monoclonal antibody, BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning treatment followed by autologous hematopoietic stem cell transplant (ASCT). Four patients with refractory and relapsed HL were treated in this trial with 3 patients receiving a single dose of 564.6-574.6 MBq 90Y-daclizumab and the fourth patient receiving two doses of 580.9-566.1 MBq 90Y-daclizumab followed by high-dose chemotherapy and ASCT. Results: All 4 evaluable patients treated with 90Y-daclizumab obtained complete responses (CRs) that are ongoing 4.5-7 years following their stem cell transplant. The spectrum and severity of adverse events were mild and more importantly none of the patients, including several with multiple therapies before this treatment, developed the myelodysplastic syndrome. Discussion: Targeting by daclizumab was not directed primarily at tumor cells, but rather the nonmalignant CD25-expressing T cells adjacent to the HRS cells and 90Y-daclizumab provided strong enough β emissions to kill CD25-negative tumor cells at a distance by a crossfire effect. Furthermore, the strong β irradiation killed normal cells in the tumor microenvironment. Conclusions: 90Y-daclizumab (anti-CD25), high-dose BEAM chemotherapy and ASCT was well tolerated and yielded sustained complete remissions in all 4 patients with recurrent HL patients who completed their treatment. Significance: Despite advances, a proportion of patients with HL will not have a CR to their initial treatment, and some with CRs will relapse. They demonstrated that the addition of 90Y-daclizumab into the preconditioning regimen for refractory and relapsed HL patients with high-dose BEAM chemotherapy and ASCT provided sustained CRs in the 4 patients studied. Two of these patients were highly refractory to multiple prior treatments with bulky disease at entry into this study, including 1 patient who never entered a remission and had failed 6 different therapeutic regimens. Despite the small number of patients treated in this study, the sustained clinical benefit in these patients indicates a highly effective treatment. The daclizumab was directed primarily not at HRS cells themselves but toward nonmalignant T cells rosetting around malignant cells. 90Y provided strong β emissions that killed antigen nonexpressing tumor cells at a distance by a crossfire effect. Furthermore, the strong β radiation killed normal cells in the tumor microenvironment that nurtured the malignant cells in the lymphomatous mass. The present study supports expanded analysis of 90Y-daclizumab as part of the regimen of ASCT in patients with refractory and relapsed HL.
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Affiliation(s)
- Kevin C Conlon
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Claude Sportes
- Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Martin W Brechbiel
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Daniel H Fowler
- Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Ronald Gress
- Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Milos D Miljkovic
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Clara C Chen
- Nuclear Medicine Department, Radiation and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Millie A Whatley
- Nuclear Medicine Department, Radiation and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Bonita R Bryant
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Erin M Corcoran
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Karen A Kurdziel
- Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Stefania Pittaluga
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Chang H Paik
- Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Jae Ho Lee
- Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Thomas A Fleisher
- Department of Laboratory Medicine, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Jorge A Carrasquillo
- Nuclear Medicine Department, Radiation and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Thomas A Waldmann
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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Bair SM, Brandstadter JD, Ayers EC, Stadtmauer EA. Hematopoietic stem cell transplantation for blood cancers in the era of precision medicine and immunotherapy. Cancer 2020; 126:1837-1855. [PMID: 32073653 DOI: 10.1002/cncr.32659] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 09/08/2019] [Accepted: 09/19/2019] [Indexed: 01/12/2023]
Abstract
Hematopoietic stem cell transplantation (HCT) has been an integral component in the treatment of many hematologic malignancies. Since the development of HCT nearly 50 years ago, the role of this modality has evolved as newer treatment approaches have been developed and integrated into the standard of care. In the last decade, novel and highly active targeted therapies and immunotherapies have been approved for many hematologic malignancies, raising the question of whether HCT continues to retain its prominent role in the treatment paradigms of various hematologic malignancies. In this review, the authors have described the current role of autologous and allogeneic HCT in the treatment of patients with acute leukemias, aggressive B-cell lymphomas, and multiple myeloma and discussed how novel targeted therapies and immunotherapies have changed the potential need, timing, and goal of HCT in patients with these diseases.
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Affiliation(s)
- Steven M Bair
- Division of Hematology-Oncology, Perelman Center for Advanced Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Joshua D Brandstadter
- Division of Hematology-Oncology, Perelman Center for Advanced Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Emily C Ayers
- Division of Hematology-Oncology, Perelman Center for Advanced Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Edward A Stadtmauer
- Division of Hematology-Oncology, Perelman Center for Advanced Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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Jagadeesh D, Majhail NS, He Y, Ahn KW, Litovich C, Ahmed S, Aljurf M, Bacher U, Badawy SM, Bejanyan N, Cairo M, Cerny J, Epperla N, Farhadfar N, Freytes CO, Gale RP, Haverkos B, Hossain N, Inwards D, Kamble RT, Kenkre VP, Lazarus HM, Lazaryan A, Lekakis L, Mei M, Murthy HS, Mussetti A, Nathan S, Nishihori T, Olsson RF, Ramakrishnan Geethakumari P, Savani BN, Yared JA, Fenske TS, Kharfan-Dabaja MA, Sureda A, Hamadani M. Outcomes of rituximab-BEAM versus BEAM conditioning regimen in patients with diffuse large B cell lymphoma undergoing autologous transplantation. Cancer 2020; 126:2279-2287. [PMID: 32049359 DOI: 10.1002/cncr.32752] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 12/31/2019] [Accepted: 01/08/2020] [Indexed: 11/07/2022]
Abstract
BACKGROUND Although rituximab-based high-dose therapy is frequently used in diffuse large B cell lymphoma (DLBCL) patients undergoing autologous hematopoietic cell transplantation (auto-HCT), data supporting the benefits are not available. Herein, we report the impact of rituximab-based conditioning on auto-HCT outcomes in patients who have DLBCL. METHODS Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, 862 adult DLBCL patients undergoing auto-HCT between 2003 and 2017 using BEAM (BCNU, etoposide, cytarabine, melphalan) conditioning regimen were included. All patients received frontline rituximab-containing chemoimmunotherapy and had chemosensitive disease pre-HCT. Early chemoimmunotherapy failure was defined as not achieving complete remission (CR) after frontline chemoimmunotherapy or relapse within 1 year of initial diagnosis. The primary outcome was overall survival (OS). RESULTS The study cohort was divided into 2 groups: BEAM (n = 667) and R-BEAM (n = 195). On multivariate analysis, no significant difference was seen in OS (P = .83) or progression-free survival (PFS) (P = .61) across the 2 cohorts. No significant association between the use of rituximab and risk of relapse (P = .15) or nonrelapse mortality (P = .12) was observed. Variables independently associated with lower OS included older age at auto-HCT (P < .001), absence of CR at auto-HCT (P < .001) and early chemoimmunotherapy failure (P < .001). Older age (P < .0002) and non-CR pre-HCT (P < .0001) were also associated with inferior PFS. There was no significant difference in early infectious complications between the 2 cohorts. CONCLUSION In this large registry analysis of DLBCL patients undergoing auto-HCT, the addition of rituximab to the BEAM conditioning regimen had no impact on transplantation outcomes. Older age, absence of CR pre auto-HCT, and early chemoimmunotherapy failure were associated with inferior survival.
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Affiliation(s)
| | - Navneet S Majhail
- Blood & Marrow Transplant Program, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
| | - Yizeng He
- Division of Biostatistics, Institute of Health and Equity, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Kwang W Ahn
- Division of Biostatistics, Institute of Health and Equity, Medical College of Wisconsin, Milwaukee, Wisconsin.,CIBMTR, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Carlos Litovich
- CIBMTR, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Sairah Ahmed
- University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mahmoud Aljurf
- Department of Oncology, King Faisal Specialist Hospital Center & Research, Riyadh, Saudi Arabia
| | - Ulrike Bacher
- Department of Hematology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Sherif M Badawy
- Division of Hematology, Oncology and Stem Cell Transplant, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.,Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Nelli Bejanyan
- Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida
| | - Mitchell Cairo
- Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Department of Pediatrics, New York Medical College, Valhalla, New York
| | - Jan Cerny
- Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical Center, Worcester, Massachusetts
| | - Narendranath Epperla
- Division of Hematology, Department of Medicine, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio
| | - Nosha Farhadfar
- Division of Hematology/Oncology, University of Florida College of Medicine, Gainesville, Florida
| | | | - Robert Peter Gale
- Hematology Research Centre, Division of Experimental Medicine, Department of Medicine, Imperial College London, London, United Kingdom
| | | | - Nasheed Hossain
- Division of Hematology/Oncology, Department of Medicine, Stem Cell Transplant Program, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois
| | - David Inwards
- Division of Hematology, Mayo Clinic, Rochester, Minnesota
| | - Rammurti T Kamble
- Division of Hematology and Oncology, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas
| | - Vaishalee P Kenkre
- Division of Hematology/Oncology, University of Wisconsin, Madison, Wisconsin
| | - Hillard M Lazarus
- Divsion of Hematology/Oncology, Case Western Reserve University, Cleveland, Ohio
| | - Aleksandr Lazaryan
- Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida
| | - Lazaros Lekakis
- Department of Hematology/Oncology, University of Miami, Miami, Florida
| | - Matthew Mei
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, Duarte, California
| | - Hemant S Murthy
- Division of Hematology Oncology, Blood and Marrow Transplantation Program, Mayo Clinic Florida, Jacksonville, Florida
| | - Alberto Mussetti
- Hematology Department, Institut Catalá d'Oncologia-Hospitalet, Barcelona, Spain.,IDIBELL-Institut Català d'Oncologia, l'Hospitalet de Llobregat, El Prat de Llobregat, Spain
| | - Sunita Nathan
- Division of Hematology, Oncology and Cell Therapy, Rush University Medical Center, Chicago, Illinois
| | - Taiga Nishihori
- Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida
| | - Richard F Olsson
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.,Centre for Clinical Research Sormland, Uppsala University, Uppsala, Sweden
| | | | - Bipin N Savani
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jean A Yared
- Blood & Marrow Transplantation Program, Division of Hematology/Oncology, Department of Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, Maryland
| | - Timothy S Fenske
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Mohamed A Kharfan-Dabaja
- Division of Hematology Oncology, Blood and Marrow Transplantation Program, Mayo Clinic Florida, Jacksonville, Florida
| | - Anna Sureda
- Hematology Department, Institut Catalá d'Oncologia-Hospitalet, Barcelona, Spain.,IDIBELL-Institut Català d'Oncologia, l'Hospitalet de Llobregat, El Prat de Llobregat, Spain
| | - Mehdi Hamadani
- CIBMTR, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
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Lekakis LJ, Moskowitz CH. The Role of Autologous Stem Cell Transplantation in the Treatment of Diffuse Large B-cell Lymphoma in the Era of CAR-T Cell Therapy. Hemasphere 2019; 3:e295. [PMID: 31976472 PMCID: PMC6924546 DOI: 10.1097/hs9.0000000000000295] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 08/21/2019] [Accepted: 08/27/2019] [Indexed: 12/29/2022] Open
Abstract
For many years now and based on the results of the PARMA trial, relapsed Diffuse Large B-cell Lymphoma (DLBCL) is treated with salvage combination cytotoxic chemotherapy (most often platinum-based) followed by high dose myeloablative chemotherapy and autologous stem cell transplantation (auto-HCT). This approach has resulted in long-term disease free survival in about half of the patients. With the incorporation of rituximab in the upfront treatment (RCHOP), more patients with DLBCL are cured but there has been a signal of inferior outcomes with auto-HCT if DLBCL relapses. Nevertheless, a careful review of the literature still shows very good outcomes with auto-HCT for DLBCL with complete remission to salvage chemotherapy. For those who do not respond well to classic salvage other approaches are reviewed here including chimeric antigen receptor (CAR) T-cell therapy and treatment with antibody-drug conjugates (ADCs) as well as bispecific T-cell engagers (BiTEs). The outcome of auto-HCT after successful treatment with ADCs or BITEs is unknown. It is also unknown if CAR-T cell therapy should be reserved for those who have failed 2 lines of chemotherapy or it should be moved earlier. Finally, we review here the effects of Myc and bcl2 amplifications or translocations to the outcome of the auto-HCT. Some attempts to improve the salvage or conditioning regimens are mentioned. We also discuss the role of allogeneic stem cell transplantation (allo-HCT) in the paradigm of treatment for relapsed DLBCL.
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31
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Rødland GE, Melhus K, Generalov R, Gilani S, Bertoni F, Dahle J, Syljuåsen RG, Patzke S. The Dual Cell Cycle Kinase Inhibitor JNJ-7706621 Reverses Resistance to CD37-Targeted Radioimmunotherapy in Activated B Cell Like Diffuse Large B Cell Lymphoma Cell Lines. Front Oncol 2019; 9:1301. [PMID: 31850205 PMCID: PMC6897291 DOI: 10.3389/fonc.2019.01301] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 11/11/2019] [Indexed: 12/22/2022] Open
Abstract
The CD37 targeting radioimmunoconjugate 177Lu-lilotomab satetraxetan (Betalutin) is currently being evaluated in a clinical phase 2b trial for patients with follicular lymphoma (FL) and in a phase 1 trial for patients with diffuse large B-cell lymphoma (DLBCL). Herein we have investigated the effect of 177Lu-lilotomab satetraxetan in seven activated B-cell like (ABC) DLBCL cell lines. Although the radioimmunoconjugate showed anti-tumor activity, primary resistance was observed in a subset of cell lines. Thus, we set out to identify drugs able to overcome the resistance to 177Lu-lilotomab satetraxetan in two resistant ABC-DLBCL cell lines. We performed a viability-based screen combining 177Lu-lilotomab satetraxetan with the 384-compound Cambridge Cancer Compound Library. Drug combinations were scored using Bliss and Chou-Talalay algorithms. We identified and characterized the dual-specific CDK1/2 and AURA/B kinase inhibitor JNJ-7706621 as compound able to revert the resistance to RIT, alongside topoisomerase and histone deacetylases (HDAC) inhibitors.
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Affiliation(s)
- Gro Elise Rødland
- Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Katrine Melhus
- Research and Development, Nordic Nanovector ASA, Oslo, Norway
| | - Roman Generalov
- Research and Development, Nordic Nanovector ASA, Oslo, Norway
| | - Sania Gilani
- Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Francesco Bertoni
- Lymphoma and Genomics Research Program, Institute of Oncology Research, Università Della Svizzera Italiana, Lugano, Switzerland
| | - Jostein Dahle
- Research and Development, Nordic Nanovector ASA, Oslo, Norway
| | - Randi G Syljuåsen
- Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Sebastian Patzke
- Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,Research and Development, Nordic Nanovector ASA, Oslo, Norway
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Results of the First Clinical Study in Humans That Combines Hyperbaric Oxygen Pretreatment with Autologous Peripheral Blood Stem Cell Transplantation. Biol Blood Marrow Transplant 2019; 25:1713-1719. [PMID: 31170519 DOI: 10.1016/j.bbmt.2019.05.028] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 05/22/2019] [Accepted: 05/28/2019] [Indexed: 12/26/2022]
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Sauter CS, Senechal B, Rivière I, Ni A, Bernal Y, Wang X, Purdon T, Hall M, Singh AN, Szenes VZ, Yoo S, Dogan A, Wang Y, Moskowitz CH, Giralt S, Matasar MJ, Perales MA, Curran KJ, Park J, Sadelain M, Brentjens RJ. CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma. Blood 2019; 134:626-635. [PMID: 31262783 PMCID: PMC6695562 DOI: 10.1182/blood.2018883421] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Accepted: 06/12/2019] [Indexed: 02/06/2023] Open
Abstract
High-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT) is the standard of care for relapsed or primary refractory (rel/ref) chemorefractory diffuse large B-cell lymphoma. Only 50% of patients are cured with this approach. We investigated safety and efficacy of CD19-specific chimeric antigen receptor (CAR) T cells administered following HDT-ASCT. Eligibility for this study includes poor-risk rel/ref aggressive B-cell non-Hodgkin lymphoma chemosensitive to salvage therapy with: (1) positron emission tomography-positive disease or (2) bone marrow involvement. Patients underwent standard HDT-ASCT followed by 19-28z CAR T cells on days +2 and +3. Of 15 subjects treated on study, dose-limiting toxicity was observed at both dose levels (5 × 106 and 1 × 107 19-28z CAR T per kilogram). Ten of 15 subjects experienced CAR T-cell-induced neurotoxicity and/or cytokine release syndrome (CRS), which were associated with greater CAR T-cell persistence (P = .05) but not peak CAR T-cell expansion. Serum interferon-γ elevation (P < .001) and possibly interleukin-10 (P = .07) were associated with toxicity. The 2-year progression-free survival (PFS) is 30% (95% confidence interval, 20% to 70%). Subjects given decreased naive-like (CD45RA+CCR7+) CD4+ and CD8+ CAR T cells experienced superior PFS (P = .02 and .04, respectively). There was no association between CAR T-cell peak expansion, persistence, or cytokine changes and PFS. 19-28z CAR T cells following HDT-ASCT were associated with a high incidence of reversible neurotoxicity and CRS. Following HDT-ASCT, effector CD4+ and CD8+ immunophenotypes may improve disease control. This trial was registered at www.clinicaltrials.gov as #NCT01840566.
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Affiliation(s)
- Craig S Sauter
- Department of Medicine and
- Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medical College, New York, NY; and
| | - Brigitte Senechal
- Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY
- Michael G. Harris Cell Therapy and Cell Engineering Facility
| | - Isabelle Rivière
- Department of Medicine and
- Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY
- Michael G. Harris Cell Therapy and Cell Engineering Facility
| | - Ai Ni
- Department of Epidemiology and Biostatistics
| | | | - Xiuyan Wang
- Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY
- Michael G. Harris Cell Therapy and Cell Engineering Facility
| | - Terence Purdon
- Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY
| | | | | | | | | | - Ahmet Dogan
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Yongzeng Wang
- Michael G. Harris Cell Therapy and Cell Engineering Facility
| | - Craig H Moskowitz
- Department of Medicine and
- Department of Medicine, Weill Cornell Medical College, New York, NY; and
| | - Sergio Giralt
- Department of Medicine and
- Department of Medicine, Weill Cornell Medical College, New York, NY; and
| | - Matthew J Matasar
- Department of Medicine and
- Department of Medicine, Weill Cornell Medical College, New York, NY; and
| | - Miguel-Angel Perales
- Department of Medicine and
- Department of Medicine, Weill Cornell Medical College, New York, NY; and
| | - Kevin J Curran
- Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Pediatrics, and
| | - Jae Park
- Department of Medicine and
- Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medical College, New York, NY; and
| | - Michel Sadelain
- Department of Medicine and
- Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Renier J Brentjens
- Department of Medicine and
- Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medical College, New York, NY; and
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Scordo M, Lin RJ, Sauter CS. Hematopoietic-cell transplantation for lymphoma in the era of genetically engineered cellular therapy: it's not quite time to scrap the old vehicle for the new car. Curr Opin Hematol 2019; 26:288-293. [PMID: 31170111 PMCID: PMC7428153 DOI: 10.1097/moh.0000000000000515] [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] [Indexed: 10/26/2022]
Abstract
PURPOSE OF REVIEW Second-line platinum-based salvage chemotherapy followed by high-dose chemotherapy and autologous hematopoietic-cell transplantation (AHCT) has remained the standard of care (SOC) for relapsed and primary refractory (r/r) diffuse large B-cell lymphoma (DLBCL) for greater than 2 decades. In the postrituximab era, this strategy has yielded disappointing outcomes for r/r patients with curability in less one-quarter of the patients by intention-to-treat. RECENT FINDINGS Given the Food and Drug Administration (FDA) approval of chimeric antigen receptor (CAR) modified T cells directed against CD19 (CD19 CAR T) for DLBCL following two lines of therapy and/or failed AHCT, encouragement with this therapy in the second line for r/r patients has naturally prompted randomized phase III studies against the aforementioned SOC. The predominant hurdle to procession to AHCT is chemotherapy sensitivity after platinum-based salvage therapy. SUMMARY In this review, we will discuss recent investigations to improve response rates in r/r DLBCL with the intent of proceeding to potentially curative AHCT, as well as investigations to decrease progression post-AHCT. In addition, data regarding currently FDA approved CD19 CAR T cells will be reviewed. Within 2-3 years, we will know if the multicenter/multinational studies of CD19 CAR T will replace SOC salvage therapy and AHCT in the second-line. The role of allogeneic HCT will also be briefly reviewed in the context of these therapies.
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Affiliation(s)
- Michael Scordo
- Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medical College, New York, NY
| | - Richard J. Lin
- Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Craig S. Sauter
- Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medical College, New York, NY
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Dahi PB, Lazarus HM, Sauter CS, Giralt SA. Strategies to improve outcomes of autologous hematopoietic cell transplant in lymphoma. Bone Marrow Transplant 2019; 54:943-960. [PMID: 30390059 PMCID: PMC9062884 DOI: 10.1038/s41409-018-0378-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 09/05/2018] [Accepted: 09/30/2018] [Indexed: 11/08/2022]
Abstract
High-dose chemotherapy and autologous hematopoietic cell transplantation (HDT-AHCT) remains an effective therapy in lymphoma. Over the past several decades, HDT with BEAM (carmustine, etoposide, cytarabine, and melphalan) and CBV (cyclophosphamide, carmustine, and etoposide) have been the most frequently used preparatory regimens for AHCT in Hodgkin (HL) and non-Hodgkin lymphoma (NHL). This article reviews alternative combination conditioning regimens, as well as novel transplant strategies that have been developed, to reduce transplant-related toxicity while maintaining or improving efficacy. These data demonstrate that incorporation of maintenance therapy posttransplant might be the best way to improve outcomes.
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Affiliation(s)
- Parastoo B Dahi
- Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Weill Cornell Medical College, New York, NY, USA.
| | - Hillard M Lazarus
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA
| | - Craig S Sauter
- Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | - Sergio A Giralt
- Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
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36
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BAM conditioning before autologous transplantation for lymphoma: a study on behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC). Ann Hematol 2019; 98:1973-1980. [DOI: 10.1007/s00277-019-03704-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 04/21/2019] [Indexed: 10/26/2022]
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37
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Zhang Y, Zhu TN, Sun J, Zhong DR, Zhang W, Zhou DB. [Clinical characteristics of intravascular large B cell lymphoma: a single-center retrospective study]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2019; 39:1004-1009. [PMID: 30612402 PMCID: PMC7348217 DOI: 10.3760/cma.j.issn.0253-2727.2018.12.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
目的 提高对血管内大B细胞淋巴瘤（IVLBCL）的认识。 方法 回顾性分析北京协和医院自2010年1月至2016年6月收治的12例IVLBCL患者的临床资料。 结果 ①12例患者中，男6例，女6例，中位年龄为58.5（32~76）岁。临床表现：发热最为常见（10/12），其次为呼吸系统症状（咳嗽、呼吸困难、胸腔积液等，6/12）、噬血细胞综合征（6/12）、神经系统症状（1/12）；所有患者均有LDH升高（367~1 700 U/L）、铁蛋白升高（805~1 527 µg/L）、结外器官受累（肺6例，骨髓3例，脑2例，软脑膜、肾上腺、副鼻窦、胆囊、甲状腺各1例）。②组织病理特征：光镜下可见分布于小血管内的单个或小簇状淋巴瘤细胞，毛细血管或血窦结构得以保留，免疫组化显示CD20、CD79a等B淋巴细胞标志阳性。③疗效及预后：11例患者接受CHOP或R-CHOP方案化疗，其总反应率为90.1%，完全缓解率为66.7%。患者平均随访20（1~40）个月，中位生存期及中位无进展生存期尚未达到。单因素Cox回归分析未能发现年龄、分期、IPI等临床参数与预后相关。 结论 IVLBCL临床罕见，出现肺部受累比例高，肺活检有较高阳性率；R-CHOP方案目前仍是最主要的治疗方案。
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Affiliation(s)
- Y Zhang
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
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Redondo AM, Valcárcel D, González‐Rodríguez AP, Suárez‐Lledó M, Bello JL, Canales M, Gayoso J, Colorado M, Jarque I, Campo R, Arranz R, Terol MJ, Rifón JJ, Rodríguez MJ, Ramírez MJ, Castro N, Sánchez A, López‐Jiménez J, Montes‐Moreno S, Briones J, López A, Palomera L, López‐Guillermo A, Caballero D, Martín A. Bendamustine as part of conditioning of autologous stem cell transplantation in patients with aggressive lymphoma: a phase 2 study from the GELTAMO group. Br J Haematol 2018; 184:797-807. [DOI: 10.1111/bjh.15713] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Accepted: 11/05/2018] [Indexed: 01/09/2023]
Affiliation(s)
- Alba M. Redondo
- Department of Haematology Hospital Universitario de Salamanca ‐ IBSAL CIBERONC Salamanca Spain
| | - David Valcárcel
- Department of Haematology Hospital Vall d'Hebron University Autònoma of Barcelona (UAB) Barcelona Spain
- Experimental Haematology Unit Vall d’ Hebron Institute of Oncology (VHIO) Barcelona Spain
| | | | | | - José L. Bello
- Department of Haematology Complejo Hospitalario Universitario de Santiago (CHUS) Santiago de Compostela Spain
| | | | - Jorge Gayoso
- Department of Haematology Hospital Gregorio Marañón Madrid Spain
| | - Mercedes Colorado
- Department of Haematology Hospital Marqués de Valdecilla Santander Spain
| | - Isidro Jarque
- Department of Haematology Hospital Universitario La Fe CIBERONC Valencia Spain
| | - Raquel Campo
- Department of Haematology Hospital Son Llítzer Palma de Mallorca Spain
| | - Reyes Arranz
- Department of Haematology Hospital de La Princesa Madrid Spain
| | - María J. Terol
- Department of Haematology Hospital Clínico de Valencia Valencia Spain
| | - José J. Rifón
- Department of Haematology Clínica Universitaria de Navarra Pamplona Spain
| | - María J. Rodríguez
- Department of Haematology Hospital Universitario de Canarias Las Palmas de Gran Canaria Spain
| | - María J Ramírez
- Department of Haematology Hospital de Jerez Jerez de la Frontera Spain
| | - Nerea Castro
- Department of Haematology Hospital 12 de Octubre Madrid Spain
| | - Andrés Sánchez
- Department of Haematology Hospital Virgen de la Arrixaca Murcia Spain
| | | | - Santiago Montes‐Moreno
- Department of Pathology Hospital Universitario Marqués de Valdecilla IFIMAV Santander Spain
| | - Javier Briones
- Department of Haematology Hospital Santa Creu i Sant Pau Barcelona Spain
| | - Aurelio López
- Department of Haematology Hospital Arnau de Villanova Valencia Spain
| | - Luis Palomera
- Department of Haematology Hospital Clínico de Zaragoza Zaragoza Spain
| | | | - Dolores Caballero
- Department of Haematology Hospital Universitario de Salamanca ‐ IBSAL CIBERONC Salamanca Spain
| | - Alejandro Martín
- Department of Haematology Hospital Universitario de Salamanca ‐ IBSAL CIBERONC Salamanca Spain
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Lopez T, Ramirez A, Benitez C, Mustafa Z, Pham H, Sanchez R, Ge X. Selectivity Conversion of Protease Inhibitory Antibodies. Antib Ther 2018. [PMID: 30406213 PMCID: PMC7990135 DOI: 10.1093/abt/tby010] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Solid tumors are inherently difficult to treat because of large regions of hypoxia and are often chemotherapy- or radiotherapy-resistant. It seems that cancer stem cells reside in hypoxic and adjacent necrotic tumor areas. Therefore, new treatments that are highly selective for tumors and can eradicate cells in both hypoxic and necrotic tumor regions are desirable. Antibody α-radioconjugates couple an α-emitting radionuclide with the specificity of a tumor-targeting monoclonal antibody. The large mass and energy of α-particles result in radiation dose delivery within a smaller area independent of oxygen concentration, thus matching key criteria for killing hypoxic tumor cells. With advances in radionuclide production and chelation chemistry, α-radioconjugate therapy is regaining interest as a cancer therapy. Here, we will review current literature examining radioconjugate therapy specifically targeting necrotic and hypoxic tumor cells and outline how α-radioconjugate therapy could be used to treat tumor regions harboring more resistant cancer cell types.
Statement of Significance Tumor-targeting antibodies are excellent vehicles for the delivery of toxic payloads directly to the tumor site. Tumor hypoxia and necrosis promote treatment recurrence, resistance, and metastasis. Targeting these areas with antibody α-radioconjugates would aid in overcoming treatment resistance.
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Affiliation(s)
- Tyler Lopez
- Department of Chemical and Environmental Engineering, Bourns College of Engineering, University of California Riverside, Riverside, CA, USA
| | - Aaron Ramirez
- Department of Chemical and Environmental Engineering, Bourns College of Engineering, University of California Riverside, Riverside, CA, USA
| | - Chris Benitez
- Department of Chemical and Environmental Engineering, Bourns College of Engineering, University of California Riverside, Riverside, CA, USA
| | - Zahid Mustafa
- Department of Chemical and Environmental Engineering, Bourns College of Engineering, University of California Riverside, Riverside, CA, USA
| | - Henry Pham
- Department of Chemical and Environmental Engineering, Bourns College of Engineering, University of California Riverside, Riverside, CA, USA
| | - Ramon Sanchez
- Department of Chemical and Environmental Engineering, Bourns College of Engineering, University of California Riverside, Riverside, CA, USA
| | - Xin Ge
- Department of Chemical and Environmental Engineering, Bourns College of Engineering, University of California Riverside, Riverside, CA, USA
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40
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Staudacher AH, Liapis V, Brown MP. Selectivity Conversion of Protease Inhibitory Antibodies. Antib Ther 2018; 1:55-63. [PMID: 30406213 PMCID: PMC7990135 DOI: 10.1093/abt/tby008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 09/19/2018] [Accepted: 09/25/2018] [Indexed: 11/14/2022] Open
Abstract
Background: Proteases are one of the largest pharmaceutical targets for drug developments. Their dysregulations result in a wide variety of diseases. Because proteolytic networks usually consist of protease family members that share high structural and catalytic homology, distinguishing them using small molecule inhibitors is often challenging. To achieve specific inhibition, this study described a novel approach for the generation of protease inhibitory antibodies. As a proof of concept, we aimed to convert a matrix metalloproteinase (MMP)-14 specific inhibitor to MMP-9 specific inhibitory antibodies with high selectivity. Methods: An error-prone single-chain Fv (scFv) library of an MMP-14 inhibitor 3A2 was generated for yeast surface display. A dual-color competitive FACS was developed for selection on MMP-9 catalytic domain (cdMMP-9) and counter-selection on cdMMP-14 simultaneously, which were fused/conjugated with different fluorophores. Isolated MMP-9 inhibitory scFvs were biochemically characterized by inhibition assays on MMP-2/-9/-12/-14, proteolytic stability tests, inhibition mode determination, competitive ELISA with TIMP-2 (a native inhibitor of MMPs), and paratope mutagenesis assays. Results: We converted an MMP-14 specific inhibitor 3A2 into a panel of MMP-9 specific inhibitory antibodies with dramatic selectivity shifts of 690-4,500 folds. Isolated scFvs inhibited cdMMP-9 at nM potency with high selectivity over MMP-2/-12/-14 and exhibited decent proteolytic stability. Biochemical characterizations revealed that these scFvs were competitive inhibitors binding to cdMMP-9 near its reaction cleft via their CDR-H3s. Conclusions: This study developed a novel approach able to convert the selectivity of inhibitory antibodies among closely related protease family members. This methodology can be directly applied for mAbs inhibiting many proteases of biomedical importance.
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Affiliation(s)
- Alexander H Staudacher
- Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, Australia
- School of Medicine, University of Adelaide, Adelaide, Australia
| | - Vasilios Liapis
- Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, Australia
| | - Michael P Brown
- Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, Australia
- School of Medicine, University of Adelaide, Adelaide, Australia
- Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, Australia
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41
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Management of relapsed/refractory DLBCL. Best Pract Res Clin Haematol 2018; 31:209-216. [DOI: 10.1016/j.beha.2018.07.014] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 07/20/2018] [Indexed: 01/01/2023]
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Olivieri J, Mosna F, Pelosini M, Fama A, Rattotti S, Giannoccaro M, Carli G, Tisi MC, Ferrero S, Sgherza N, Mazzone AM, Marino D, Calimeri T, Loseto G, Saraceni F, Tomei G, Sica S, Perali G, Codeluppi K, Billio A, Olivieri A, Orciuolo E, Matera R, Stefani PM, Borghero C, Ghione P, Cascavilla N, Lanza F, Chiusolo P, Finotto S, Federici I, Gherlinzoni F, Centurioni R, Fanin R, Zaja F. A Comparison of the Conditioning Regimens BEAM and FEAM for Autologous Hematopoietic Stem Cell Transplantation in Lymphoma: An Observational Study on 1038 Patients From Fondazione Italiana Linfomi. Biol Blood Marrow Transplant 2018; 24:1814-1822. [PMID: 29857196 DOI: 10.1016/j.bbmt.2018.05.018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 05/14/2018] [Indexed: 01/17/2023]
Abstract
BEAM (carmustine [bis-chloroethylnitrosourea (BCNU)]-etoposide-cytarabine-melphalan) chemotherapy is the standard conditioning regimen for autologous stem cell transplantation (ASCT) in lymphomas. Owing to BCNU shortages, many centers switched to fotemustine-substituted BEAM (FEAM), lacking proof of equivalence. We conducted a retrospective cohort study in 18 Italian centers to compare the safety and efficacy of BEAM and FEAM regimens for ASCT in lymphomas performed from 2008 to 2015. We enrolled 1038 patients (BEAM = 607, FEAM = 431), of which 27% had Hodgkin lymphoma (HL), 14% indolent non-Hodgkin lymphoma (NHL), and 59% aggressive NHL. Baseline characteristics including age, sex, stage, B-symptoms, extranodal involvement, previous treatments, response before ASCT, and overall conditioning intensity were well balanced between BEAM and FEAM; notable exceptions were median ASCT year (BEAM = 2011 versus FEAM = 2013, P < .001), Sorror score ≥3 (BEAM = 15% versus FEAM = 10%, P = .017), and radiotherapy use (BEAM = 18% versus FEAM = 10%, P < .001). FEAM conditioning resulted in higher rates of gastrointestinal and infectious toxicities, including severe oral mucositis grade ≥3 (BEAM = 31% versus FEAM = 44%, P < .001), and sepsis from Gram-negative bacteria (mean isolates/patient: BEAM = .1 versus FEAM = .19, P < .001). Response status at day 100 post-ASCT (overall response: BEAM = 91% versus FEAM = 88%, P = .42), 2-year overall survival (83.9%; 95% confidence interval [CI], 81.5% to 86.1%) and progression-free survival (70.3%; 95% CI, 67.4% to 73.1%) were not different in the two groups. Mortality from infection was higher in the FEAM group (subhazard ratio, 1.99; 95% CI, 1.02 to 3.88; P = .04). BEAM and FEAM do not appear different in terms of survival and disease control. However, due to concerns of higher toxicity, fotemustine substitution in BEAM does not seem justified, if not for easier supply.
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Affiliation(s)
- Jacopo Olivieri
- Clinica Ematologica, Centro Trapianti e Terapie Cellulari "C. Melzi," Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy; UOC Medicina Interna ed Ematologia, Azienda Sanitaria Unica Regionale Marche AV3, Civitanova Marche, Italy.
| | - Federico Mosna
- UOC di Ematologia e Centro Trapianto di Midollo Osseo, Ospedale Centrale "San Maurizio," Azienda Sanitaria dell'Alto Adige, Bolzano, Italy
| | - Matteo Pelosini
- Clinical and Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy
| | - Angelo Fama
- Ematologia, Arcispedale S. Maria Nuova, IRCCS Azienda Ospedaliera di Reggio Emilia, Reggio Emilia, Italy
| | - Sara Rattotti
- Department of Haematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Margherita Giannoccaro
- Unità Operativa di Ematologia e Trapianto di cellule staminali, Presidio Ospedaliero "Vito Fazzi", Lecce, Italy
| | - Giuseppe Carli
- Cell Therapy and Hematology, San Bortolo Hospital, Vicenza, Italy
| | | | - Simone Ferrero
- Ematologia 1, Dipartimento di Biotecnologie Molecolari e Scienze per la Salute, Università di Torino-AOU Città della Salute e della Scienza di Torino, Turin, Italy
| | - Nicola Sgherza
- Ematologia, IRCCS Ospedale Casa Sollievo Sofferenza, San Giovanni Rotondo, Italy
| | | | - Dario Marino
- Oncologia Medica 1, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy
| | - Teresa Calimeri
- Divisione di Ematologia, IRCCS Ospedale San Raffaele, Milano, Italy
| | - Giacomo Loseto
- Ematologia, IRCCS Ospedale Oncologico di Bari, Bari, Italy
| | | | | | - Simona Sica
- Istituto di Ematologia, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Giulia Perali
- Clinica Ematologica, Centro Trapianti e Terapie Cellulari "C. Melzi," Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy
| | - Katia Codeluppi
- Ematologia, Arcispedale S. Maria Nuova, IRCCS Azienda Ospedaliera di Reggio Emilia, Reggio Emilia, Italy
| | - Atto Billio
- UOC di Ematologia e Centro Trapianto di Midollo Osseo, Ospedale Centrale "San Maurizio," Azienda Sanitaria dell'Alto Adige, Bolzano, Italy
| | - Attilio Olivieri
- Clinica di Ematologia, Azienda Ospedaliera "Ospedali Riuniti," Ancona, Italy
| | - Enrico Orciuolo
- Clinical and Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy
| | - Rossella Matera
- Unità Operativa di Ematologia e Trapianto di cellule staminali, Presidio Ospedaliero "Vito Fazzi", Lecce, Italy
| | - Piero Maria Stefani
- U.O.C. di Ematologia, Dipartimento di Medicina Specialistica, Unità Locale Socio-Sanitaria della Marca Trevigiana, Treviso, Italy
| | - Carlo Borghero
- Cell Therapy and Hematology, San Bortolo Hospital, Vicenza, Italy
| | - Paola Ghione
- Ematologia 1, Dipartimento di Biotecnologie Molecolari e Scienze per la Salute, Università di Torino-AOU Città della Salute e della Scienza di Torino, Turin, Italy
| | - Nicola Cascavilla
- Ematologia, IRCCS Ospedale Casa Sollievo Sofferenza, San Giovanni Rotondo, Italy
| | - Francesco Lanza
- Hematology and Stem Cell Transplant, Ravenna Hospital, Ravenna, Italy
| | - Patrizia Chiusolo
- Istituto di Ematologia, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Silvia Finotto
- Oncologia Medica 1, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy
| | - Irene Federici
- Clinica di Ematologia, Azienda Ospedaliera "Ospedali Riuniti," Ancona, Italy
| | - Filippo Gherlinzoni
- U.O.C. di Ematologia, Dipartimento di Medicina Specialistica, Unità Locale Socio-Sanitaria della Marca Trevigiana, Treviso, Italy
| | - Riccardo Centurioni
- UOC Medicina Interna ed Ematologia, Azienda Sanitaria Unica Regionale Marche AV3, Civitanova Marche, Italy
| | - Renato Fanin
- Clinica Ematologica, Centro Trapianti e Terapie Cellulari "C. Melzi," Dipartimento di Area Medica, Università degli Studi di Udine, Udine, Italy
| | - Francesco Zaja
- Clinica Ematologica, Centro Trapianti e Terapie Cellulari "C. Melzi," Dipartimento di Area Medica, Università degli Studi di Udine, Udine, Italy
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González-Barca E, Coronado M, Martín A, Montalbán C, Montes-Moreno S, Panizo C, Rodríguez G, Sancho JM, López-Hernández A. Spanish Lymphoma Group (GELTAMO) guidelines for the diagnosis, staging, treatment, and follow-up of diffuse large B-cell lymphoma. Oncotarget 2018; 9:32383-32399. [PMID: 30190794 PMCID: PMC6122355 DOI: 10.18632/oncotarget.25892] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 07/23/2018] [Indexed: 01/23/2023] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) accounts for approximately 30% of non-Hodgkin lymphoma (NHL) cases in adult series. DLBCL is characterized by marked clinical and biological heterogeneity, encompassing up to 16 distinct clinicopathological entities. While current treatments are effective in 60% to 70% of patients, those who are resistant to treatment continue to die from this disease. An expert panel performed a systematic review of all data on the diagnosis, prognosis, and treatment of DLBCL published in PubMed, EMBASE and MEDLINE up to December 2017. Recommendations were classified in accordance with the Grading of Recommendations Assessment Development and Evaluation (GRADE) framework, and the proposed recommendations incorporated into practical algorithms. Initial discussions between experts began in March 2016, and a final consensus was reached in November 2017. The final document was reviewed by all authors in February 2018 and by the Scientific Committee of the Spanish Lymphoma Group GELTAMO.
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Affiliation(s)
- Eva González-Barca
- Department of Hematology, Institut Català d' Oncologia and IDIBELL, L' Hospitalet de Llobregat, Barcelona, Spain
| | - Mónica Coronado
- Department of Nuclear Medicine, Hospital Universitario La Paz, Madrid, Spain
| | - Alejandro Martín
- Department of Hematology, Hospital Universitario de Salamanca, IBSAL, CIBERONC, Salamanca, Spain
| | - Carlos Montalbán
- Department of Hematology, MD Anderson Cancer Center, Madrid, Spain
| | - Santiago Montes-Moreno
- Department of Pathology and Translational Hematopathology Lab, Hospital Universitario Marqués de Valdecilla/IDIVAL, Santander, Spain
| | - Carlos Panizo
- Department of Hematology, Clínica Universidad de Navarra and Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Guillermo Rodríguez
- Department of Hematology, Hospital Universitario Virgen de la Macarena, Sevilla, Spain
| | - Juan Manuel Sancho
- Department of Hematology, ICO-IJC-Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain
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Eskian M, Khorasanizadeh M, Isidori A, Rezaei N. Radioimmunotherapy-based conditioning regimen prior to autologous stem cell transplantation in non-Hodgkin lymphoma. Int J Hematol Oncol 2018; 7:IJH01. [PMID: 30302233 PMCID: PMC6176953 DOI: 10.2217/ijh-2017-0025] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 02/22/2018] [Indexed: 01/05/2023] Open
Abstract
Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy and the sixth cause of death from cancer in the USA. Autologous stem cell transplantation (ASCT) is a potentially curative therapeutic option for many NHL patients. Choosing the most effective conditioning regimen prior to ASCT can lead to longer survival in these patients, and, as in many cases of high risk NHL, the only potentially curative option is stem cell transplantation. Radioimmunotherapy (RIT) is based on using radiolabeled monoclonal antibodies against tumoral antigens. Since lymphoma cells are sensitive to radiation, RIT has become a potential approach in treating NHL. In this review, we have discussed the efficacy and safety of RIT as an alternative conditioning regimen prior to ASCT.
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Affiliation(s)
- Mahsa Eskian
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, 14194, Iran.,Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, 14194, Iran.,Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - MirHojjat Khorasanizadeh
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, 14194, Iran.,Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, 14194, Iran.,Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Alessandro Isidori
- Haematology & Haematopoietic Stem Cell Transplant Center, AORMN Marche Nord Hospital, Via Lombroso 1, 61122 Pesaro, Italy.,Haematology & Haematopoietic Stem Cell Transplant Center, AORMN Marche Nord Hospital, Via Lombroso 1, 61122 Pesaro, Italy
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, 14194, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Cancer Immunology Project (CIP), Universal Scientific Education & Research Network (USERN), Tehran, Iran.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, 14194, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Cancer Immunology Project (CIP), Universal Scientific Education & Research Network (USERN), Tehran, Iran
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45
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Gisselbrecht C, Van Den Neste E. How I manage patients with relapsed/refractory diffuse large B cell lymphoma. Br J Haematol 2018; 182:633-643. [PMID: 29808921 PMCID: PMC6175435 DOI: 10.1111/bjh.15412] [Citation(s) in RCA: 130] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Despite progress in the upfront treatment of diffuse large B cell lymphoma (DLBCL), patients still experience relapses. Salvage chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard second‐line treatment for relapsed and refractory (R/R) DLBCL. However, half of the patients will not be eligible for transplantation due to ineffective salvage treatment, and the other half will relapse after ASCT. In randomized studies, no salvage chemotherapy regimen is superior to another. The outcomes are affected by the secondary International Prognostic Index at relapse and various biological factors. The strategy is less clear in patients who require third‐line treatment. A multicohort retrospective non‐Hodgkin lymphoma research (SCHOLAR‐1) study conducted in 636 patients with refractory DLBCL showed an objective response rate of 26% (complete response 7%) to the next line of therapy with a median overall survival of 6·3 months. In the case of a response followed by transplantation, long‐term survival can be achieved in DLBCL patients. There is clearly a need for new drugs that improve salvage efficacy. Encouraging results have been reported with chimeric antigen receptor ‐T cell engineering, warranting further studies in a well‐defined control group of refractory patients. The Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) was used as a handy framework to build the discussion.
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46
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Sureda A, Dreger P, Bishop MR, Kroger N, Porter DL. Prevention and treatment of relapse after stem cell transplantation in lymphoid malignancies. Bone Marrow Transplant 2018; 54:17-25. [PMID: 29795433 DOI: 10.1038/s41409-018-0214-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 04/05/2018] [Accepted: 04/16/2018] [Indexed: 12/11/2022]
Abstract
Relapse is now the major cause of treatment failure after allogeneic HSCT (alloHSCT). Many novel strategies to address this critical issue are now being developed and tested. At the 3rd International Workshop on Biology, Prevention, and Treatment of Relapse held in Hamburg, Germany in November 2016, international experts presented and discussed recent developments in the field. Some approaches may be applicable to a wide range of patients after transplant, whereas some may be very disease-specific. We present a report from the session dedicated to issues related to prevention and treatment of relapse of lymphoid malignancies after alloHSCT. This session included detailed reviews as well as forward-looking commentaries that focused on Hodgkin lymphoma, chronic lymphocytic leukemia and mantle cell lymphoma, diffuse large cell and follicular lymphoma, and multiple myeloma.
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Affiliation(s)
- Anna Sureda
- Hematology Department Institut Català d'Oncologia - Hospitale Barcelona, Barcelona, Spain
| | - Peter Dreger
- Department Medicine V, University of Heidelberg, Heidelberg, Germany.,European Society for Blood and Marrow Transplantation (EBMT), Leiden, The Netherlands
| | - Michael R Bishop
- Hematopoietic Cellular Therapy Program Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA
| | - Nicolaus Kroger
- Department of Stem Cell Transplantation, University Medical Center, Hamburg, Germany
| | - David L Porter
- Division of Hematology Oncology, Blood and Marrow Transplant Program, University of Pennsylvania and Perelman School of Medicine, Philadelphia, PA, 19104, USA.
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Chahoud J, Sui D, Erwin WD, Gulbis AM, Korbling M, Zhang M, Ahmed S, Alatrash G, Anderlini P, Ciurea SO, Oran B, Fayad LE, Bassett RL, Jabbour EJ, Medeiros LJ, Macapinlac HA, Young KH, Khouri IF. Updated Results of Rituximab Pre- and Post-BEAM with or without 90Yttrium Ibritumomab Tiuxetan during Autologous Transplant for Diffuse Large B-cell Lymphoma. Clin Cancer Res 2018; 24:2304-2311. [PMID: 29476021 PMCID: PMC5955837 DOI: 10.1158/1078-0432.ccr-17-3561] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 01/21/2018] [Accepted: 02/21/2018] [Indexed: 12/27/2022]
Abstract
Purpose: We evaluated the effect on long-term survival of adding rituximab (R) to BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning with or without yttrium-90 ibritumomab tiuxetan (90YIT) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) undergoing autologous stem cell transplant (ASCT).Experimental design: Patients were enrolled on three consecutive phase II clinical trials. Patients received two doses of rituximab (375 and 1,000 mg/m2) during mobilization of stem cells, followed by 1,000 mg/m2 on days +1 and +8 after ASCT with R-BEAM or 90YIT-R-BEAM (90YIT dose of 0.4 mCi/kg) conditioning.Results: One hundred thirteen patients were enrolled, with 73 receiving R-BEAM and 40 receiving 90YIT-R-BEAM. All patients had a prior exposure to rituximab. The median follow-up intervals for survivors were 11.8, 8.1, and 4.2 years in the three trials, respectively. The 5-year disease-free survival (DFS) rates were 62% for R-BEAM and 65% for 90YIT-R-BEAM (P = 0.82). The 5-year overall survival rates were 73% and 77%, respectively (P = 0.65). In patients with de novo DLBCL, survival outcomes of the germinal center/activated b-cell histologic subtypes were similar with 5-year OS rates (P = 0.52) and DFS rates (P = 0.64), irrespective of their time of relapse (<1 vs. >1 year) after initial induction chemotherapy (P = 0.97).Conclusions: Administering ASCT with rituximab during stem cell collection and immediately after transplantation induces long-term disease remission and abolishes the negative prognostic impact of cell-of-origin in patients with relapsed DLBCL. The addition of 90YIT does not confer a further survival benefit. Clin Cancer Res; 24(10); 2304-11. ©2018 AACR.
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Affiliation(s)
- Jad Chahoud
- Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Dawen Sui
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - William D Erwin
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Alison M Gulbis
- Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Martin Korbling
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mingzhi Zhang
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sairah Ahmed
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Gheath Alatrash
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Paolo Anderlini
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Stefan O Ciurea
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Betul Oran
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Luis E Fayad
- Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Roland L Bassett
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Elias J Jabbour
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - L Jeffrey Medeiros
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Homer A Macapinlac
- Department of Nuclear Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ken H Young
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Issa F Khouri
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Ciochetto C, Botto B, Passera R, Bellò M, Benevolo G, Boccomini C, Castellino A, Chiappella A, Freilone R, Nicolosi M, Orsucci L, Pecoraro C, Pregno P, Bisi G, Vitolo U. Yttrium-90 ibritumomab tiuxetan (Zevalin) followed by BEAM (Z-BEAM) conditioning regimen and autologous stem cell transplantation (ASCT) in relapsed or refractory high-risk B-cell non-Hodgkin lymphoma (NHL): a single institution Italian experience. Ann Hematol 2018; 97:1619-1626. [PMID: 29663029 DOI: 10.1007/s00277-018-3328-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 04/04/2018] [Indexed: 10/17/2022]
Abstract
Chemo-refractory NHL has a very poor outcome; the addiction of RIT to salvage regiment pre ASCT had recently demonstrated promising results.We performed a retrospective sequential study to determine the feasibility of standard Zevalin with BEAM in high-risk relapse/refractory NHL. A matched cohort analysis with a group treated with standard BEAM without Zevalin was performed as secondary endpoint. Between October 2006 and January 2013, 37 NHL patients at high risk for progression or early (< 1 year) or multiple relapses were treated with Z-BEAM and ASCT after R-DHAP or R-ICE as salvage therapy. Clinical characteristics were 19 refractory and 18 early or multiple relapse; 16 patients received 1, and 21 had 2 or more previous rituximab-containing chemotherapy. At the end of treatment, response was CR 22 (59%), PR 10 (27%), PD 4 (11%), and toxic death (TD) 1 (3%). With a median follow up of 61 months, 3-year PFS was 61% and OS 61%. Fifteen patients died, 12 of lymphoma. Comparison with 21 treated with BEAM alone showed a numerical higher 3-yr PFS rate in favor of Z-BEAM but not statistically significant (57 vs 48%). With the limitation of the small sample subgroup analysis, a significant benefit was observed in relapsed patients for PFS (78% Z-BEAM vs 22% BEAM p = 0.016) and OS (83% Z-BEAM vs 22% BEAM p = 0.001). In relapsed/refractory high-risk NHL, Z-BEAM+ASCT is able to achieve a good ORR. Three-year PFS is promising for early relapsed patients but is not satisfactory for those with refractory disease.
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Affiliation(s)
- Chiara Ciochetto
- Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy.
| | - Barbara Botto
- Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy
| | - Roberto Passera
- Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy
| | - Marilena Bellò
- Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy
| | - Giulia Benevolo
- Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy
| | - Carola Boccomini
- Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy
| | - Alessia Castellino
- Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy
| | - Annalisa Chiappella
- Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy
| | - Roberto Freilone
- Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy
| | - Maura Nicolosi
- Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy
| | - Lorella Orsucci
- Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy
| | - Clara Pecoraro
- Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy
| | - Patrizia Pregno
- Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy
| | - Gianni Bisi
- Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy
| | - Umberto Vitolo
- Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy
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49
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Nagai S, Ozawa K. Drug approval based on randomized phase 3 trials for relapsed malignancy: analysis of oncologic drugs granted accelerated approval, publications and clinical trial databases. Invest New Drugs 2018; 36:487-495. [PMID: 29453626 DOI: 10.1007/s10637-018-0572-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 02/07/2018] [Indexed: 10/18/2022]
Abstract
Background As relapsed disease is frequently the first target of newly developed therapies, it is vital to address the difficulty in demonstrating the efficacy of new drugs for relapsed malignancy in randomized phase 3 trials. Methods We analyzed the approved indications, target populations, and development status of post-marketing confirmatory trials of all oncology-related drugs that were granted accelerated approval for both hematological and solid malignancies. Furthermore, we searched for randomized phase 3 trials for adult patients with relapsed lymphoid malignancy, other than chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). Results Thirty-one (81.6%) of the 38 hematological indications and 23 (53.5%) of the 43 solid malignancy indications were in the relapsed settings. The target population of post-marketing studies was different from the approved indication in 18 (47.4%) of 38 hematological indications and 11 (25.6%) of 43 solid malignancy indications; all 18 hematological indications involved relapsed settings. Improved time-to-event outcome for relapsed patients was the primary endpoint in 6 (19.3%) of the 31 relapsed hematological indications. In 4 published studies of relapsed lymphoid malignancy, the medication significantly improved outcomes. From 33 trials listed at Clinicaltrials.gov , 2 were positive and 13 were negative. Five out of the 13 negative trials were terminated due to poor accrual. Conclusion Our analysis indicates that drug approval based on phase 3 trials is more challenging for relapsed hematological malignancies than for solid malignancies. Therefore, determining proper evaluation methods for the efficacy and safety of drugs for relapsed malignancy, without randomized trials, is important.
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Affiliation(s)
- Sumimasa Nagai
- Division of Genetic Therapeutics, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 1088639, Japan.
| | - Keiya Ozawa
- Division of Genetic Therapeutics, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 1088639, Japan
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50
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Abstract
PURPOSE OF REVIEW Chemotherapy remains the first-line therapy for aggressive lymphomas. However, 20-30% of patients with non-Hodgkin lymphoma (NHL) and 15% with Hodgkin lymphoma (HL) recur after initial therapy. We want to explore the role of high-dose chemotherapy (HDT) and autologous stem cell transplant (ASCT) for these patients. RECENT FINDINGS There is some utility of upfront consolidation for-high risk/high-grade B-cell lymphoma, mantle cell lymphoma, and T-cell lymphoma, but there is no role of similar intervention for HL. New conditioning regimens are being investigated which have demonstrated an improved safety profile without compromising the myeloablative efficiency for relapsed or refractory HL. Salvage chemotherapy followed by HDT and rescue autologous stem cell transplant remains the standard of care for relapsed/refractory lymphoma. The role of novel agents to improve disease-related parameters remains to be elucidated in frontline induction, disease salvage, and high-dose consolidation or in the maintenance setting.
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