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van der Weyden C, Bressel M, Khot A, Prince HM, Dickinson M. Assessment of the Tolerability and Optimal Dosing of the Combination of Brentuximab Vedotin and Lenalidomide in Patients With Relapsed or Refractory T-cell Lymphoma: Results of a Single-centre Phase 1 Dose-escalation Study. EJHAEM 2025; 6:e70033. [PMID: 40364805 PMCID: PMC12070942 DOI: 10.1002/jha2.70033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 03/02/2025] [Accepted: 03/05/2025] [Indexed: 05/15/2025]
Abstract
Objective We report the results of a pilot study investigating the combination of brentuximab vedotin (BV) and lenalidomide in patients with relapsed/ refractory T-cell lymphoma. Methods A dose escalation study design was utilized. Primary and secondary endpoints included maximum tolerated dose (MTD), adverse events, and response rates. Results Six patients were treated with BV and two dose levels of lenalidomide, in 21-day cycles. The protocol-determined MTD was BV 1.8 mg/kg and lenalidomide 25 mg, however, all patients required subsequent dose reductions with ongoing treatment. The most common adverse event was peripheral neuropathy in four of six patients. Two patients achieved complete responses and three achieved partial responses. Discussion The combination is deliverable with dose attenuation. Further study is needed to define clinical benefit. Clinical Trial Registration This trial was registered on ClinicalTrials.gov (NCT number 03302728).
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Affiliation(s)
- Carrie van der Weyden
- Department of HaematologyPeter MacCallum Cancer CentreMelbourneAustralia
- Sir Peter MacCallum Department of OncologyUniversity of MelbourneParkvilleAustralia
| | - Mathias Bressel
- Sir Peter MacCallum Department of OncologyUniversity of MelbourneParkvilleAustralia
- Department of Biostatistics and Clinical TrialsPeter MacCallum Cancer CentreMelbourneAustralia
| | - Amit Khot
- Department of HaematologyPeter MacCallum Cancer CentreMelbourneAustralia
- Sir Peter MacCallum Department of OncologyUniversity of MelbourneParkvilleAustralia
| | - Henry Miles Prince
- Department of HaematologyPeter MacCallum Cancer CentreMelbourneAustralia
- Sir Peter MacCallum Department of OncologyUniversity of MelbourneParkvilleAustralia
| | - Michael Dickinson
- Department of HaematologyPeter MacCallum Cancer CentreMelbourneAustralia
- Sir Peter MacCallum Department of OncologyUniversity of MelbourneParkvilleAustralia
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2
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Lam HPJ, Amin F, Arulogun SO, Gleeson M. Nodal Peripheral T-Cell Lymphoma: Therapeutic Challenges and Future Perspectives. Cancers (Basel) 2025; 17:1134. [PMID: 40227698 PMCID: PMC11987733 DOI: 10.3390/cancers17071134] [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: 02/17/2025] [Revised: 03/21/2025] [Accepted: 03/26/2025] [Indexed: 04/15/2025] Open
Abstract
Peripheral T-cell lymphomas (PTCLs) present a significant clinical challenge despite recent advances in the development of novel therapeutic agents, guided by a deeper understanding of the pathobiology and the genetic and molecular characteristics underlying this complex and heterogeneous group of aggressive non-Hodgkin lymphomas (NHLs) [...].
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Affiliation(s)
- Ho Pui Jeff Lam
- Department of Clinical Haematology, Guy’s and St Thomas’ NHS Foundation Trust, London SE1 9RT, UK; (F.A.); (S.O.A.); (M.G.)
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Moskowitz AJ, Stuver RN, Horwitz SM. Current and upcoming treatment approaches to common subtypes of PTCL (PTCL, NOS; ALCL; and TFHs). Blood 2024; 144:1887-1897. [PMID: 38306597 PMCID: PMC11830973 DOI: 10.1182/blood.2023021789] [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: 12/05/2023] [Revised: 01/26/2024] [Accepted: 01/26/2024] [Indexed: 02/04/2024] Open
Abstract
ABSTRACT The treatment of common nodal peripheral T-cell lymphomas (PTCLs), including PTCL, not otherwise specified (PTCL, NOS), anaplastic large-cell lymphomas, and T-follicular helper lymphomas, is evolving. These entities are currently treated similarly with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (CHOEP) for CD30-negative diseases, or brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (CHP) for CD30-positive diseases, followed by consolidation with autologous stem cell transplantation in the first remission. Ongoing improvements in PTCL classification, identification of predictive biomarkers, and development of new targeted agents will lead to more specific therapies that address the unique biologic and clinical properties of each entity. For example, widespread efforts focused on molecular profiling of PTCL, NOS is likely to identify distinct subtypes that warrant different treatment approaches. New agents, such as EZH1/2 and JAK/STAT pathway inhibitors, have broadened treatment options for relapsed or refractory diseases. Furthermore, promising strategies for optimizing immune therapy for PTCL are currently under investigation and have the potential to significantly alter the therapeutic landscape. Ongoing frontline study designs incorporate an understanding of disease biology and drug sensitivities and are poised to evaluate whether newer-targeted agents should be incorporated into frontline settings for various disease entities. Although current treatment strategies lump most disease entities together, future treatments will include distinct strategies for each disease subtype that optimize therapy for individuals. This movement toward individualized therapy will ultimately lead to dramatic improvements in the prognosis of patients with PTCL.
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Affiliation(s)
- Alison J. Moskowitz
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Robert N. Stuver
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Steven M. Horwitz
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
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4
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Chang EWY, Tan YH, Chan JY. Novel clinical risk stratification and treatment strategies in relapsed/refractory peripheral T-cell lymphoma. J Hematol Oncol 2024; 17:38. [PMID: 38824603 PMCID: PMC11144347 DOI: 10.1186/s13045-024-01560-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 05/26/2024] [Indexed: 06/03/2024] Open
Abstract
Peripheral T cell lymphoma (PTCL) represents a group of heterogeneous hematological malignancies, which are notoriously challenging to treat and outcomes are typically poor. Over the past two decades, clinical prognostic indices for patient risk stratification have evolved, while several targeted agents are now available to complement combination chemotherapy in the frontline setting or as a salvage strategy. With further understanding of the molecular pathobiology of PTCL, several innovative approaches incorporating immunomodulatory agents, epigenetic therapies, oncogenic kinase inhibitors and immunotherapeutics have come to the forefront. In this review, we provide a comprehensive overview of the progress in developing clinical prognostic indices for PTCL and describe the broad therapeutic landscape, emphasizing novel targetable pathways that have entered early phase clinical studies.
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Affiliation(s)
- Esther Wei Yin Chang
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
- Duke-NUS Medical School, Singapore, Singapore.
| | - Ya Hwee Tan
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
| | - Jason Yongsheng Chan
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
- Duke-NUS Medical School, Singapore, Singapore.
- Cancer Discovery Hub, National Cancer Centre Singapore, Singapore, Singapore.
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5
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Ong SY, Zain JM. Aggressive T-cell lymphomas: 2024: Updates on diagnosis, risk stratification, and management. Am J Hematol 2024; 99:439-456. [PMID: 38304959 DOI: 10.1002/ajh.27165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 10/18/2023] [Accepted: 11/05/2023] [Indexed: 02/03/2024]
Abstract
INTRODUCTION Aggressive T-cell lymphomas continue to have a poor prognosis. There are over 30 different subtypes of peripheral T-cell lymphoma (PTCL), and we are now beginning to understand the differences between the various subtypes beyond histologic variations. MOLECULAR PATHOGENESIS OF VARIOUS SUBTYPES OF PTCL Gene expression profiling and other molecular techniques have enabled deeper understanding of differences in various subtypes as reflected in the latest 5th WHO classification of PTCL. It is becoming increasingly clear that therapeutic approaches that target specific cellular pathways are needed to improve the clinical outcomes of PTCL. TARGETED THERAPIES There are many targeted agents currently in various stages of clinical trials for PTCL that take advantage of the differential expression of specific proteins or receptors in PTCL tumors. This includes the CD30 directed antibody drug conjugate brentuximab vedotin. Other notable targets are phosphatidylinositol 3-kinase inhibitors, histone deacetylase inhibitors, CD25, and chemokine receptor 4. Anaplastic lymphoma kinase (ALK) inhibitors are promising for ALK expressing tumors. IMMUNOTHERAPIES Allogeneic stem cell transplant continues to be the curative therapy for most aggressive subtypes of PTCL. The use of checkpoint inhibitors in the treatment of PTCL is still controversial, with best results seen in cases of extranodal natural killer cell/T-cell lymphoma. Bispecific antibody-based treatments and chimeric antigen receptor cell-based therapies are in clinical trials.
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Affiliation(s)
- Shin Yeu Ong
- Department of Hematology/Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, California, USA
- Department of Haematology, Singapore General Hospital, Singapore, Singapore
| | - Jasmine M Zain
- Department of Hematology/Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, California, USA
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6
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Ngu HS, Savage KJ. Past, present and future therapeutic approaches in nodal peripheral T-cell lymphomas. Haematologica 2023; 108:3211-3226. [PMID: 38037799 PMCID: PMC10690928 DOI: 10.3324/haematol.2021.280275] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 08/14/2023] [Indexed: 12/02/2023] Open
Abstract
Peripheral T-cell lymphomas (PTCL) encompass over 30 different entities and although they share post-thymic T- or NK-cell derivation, the disease biology and genomic landscape are very diverse across subtypes. In Western populations, nodal PTCL are the most frequently encountered entities in clinical practice and although important achievements have been made in deciphering the underlying biology and in therapeutic advances, there are still large gaps in disease understanding and clinical scenarios in which controversy over best practice continues. CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)- based chemotherapy continues to be the 'standard' treatment, with the addition of brentuximab vedotin (BV) in the combination CHP (cyclosphosphamide, doxorubicin, prednisone)-BV representing a new treatment paradigm in CD30+ PTCL although its benefit is less certain in the non-anaplastic large cell lymphoma subtypes. Given the high risk of relapse, consolidative autologous stem cell transplant is considered in nodal PTCL, outside of ALK-positive anaplastic large cell lymphoma; however, in the absence of a randomized controlled trials, practices vary. Beyond CHP-BV, most study activity has focused on adding a novel agent to CHOP (i.e., CHOP + drug X). However, with high complete remission rates observed with some novel therapy combinations, these regimens are being tested in the front-line setting, with a particular rationale in follicular helper T-cell lymphomas which have a clear sensitivity to epigenetic modifying therapies. This is well exemplified in the relapsed/refractory setting in which rational combination therapies are being developed for specific subtypes or guided by underlying biology. Taken together, we have finally moved into an era of a more personalized approach to the management of nodal PTCL.
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Affiliation(s)
- Henry S Ngu
- Center for Lymphoid Cancer, Division of Medical Oncology BC Cancer and the University of British Columbia, British Columbia, Vancouver
| | - Kerry J Savage
- Center for Lymphoid Cancer, Division of Medical Oncology BC Cancer and the University of British Columbia, British Columbia, Vancouver.
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7
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Taranto EP, Barta SK, Bhansali RS. Central Nervous System Relapse in T and NK cell Lymphomas. Curr Hematol Malig Rep 2023; 18:243-251. [PMID: 37620711 DOI: 10.1007/s11899-023-00710-x] [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] [Accepted: 08/16/2023] [Indexed: 08/26/2023]
Abstract
PURPOSE OF REVIEW T and NK cell lymphomas are relatively rare and heterogeneous forms of non-Hodgkin lymphoma that are associated with high rates of mortality. Central nervous system relapse carries significant morbidity, though management is largely extrapolated from literature in B cell neoplasms. As such, outcomes for central nervous system involvement in T/NK cell lymphomas are dismal with no standard of care. In this review, we discuss the epidemiology of central nervous system relapse in T/NK cell lymphomas and critically analyze available literature regarding prophylaxis and treatment. RECENT FINDINGS Retrospective studies of central nervous system involvement in T/NK cell lymphomas have been limited by small sample sizes and heterogeneity of subtypes, though sites of extranodal involvement and disease subtypes are consistently reported as risk factors. Compelling evidence for the use of central nervous system-directed prophylactic therapy has not yet been established, though recent reports of central nervous system activity with novel agents may suggest promising therapeutic options. The overall rarity of T and NK cell lymphomas has precluded adequate study of prophylaxis and treatment of central nervous system relapse. Collaborative efforts are needed to better define strategies to address CNS disease in T/NK cell lymphomas. These should involve the use of targeted agents, which may hold an advantage over traditional cytotoxic drugs.
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Affiliation(s)
- Eleanor P Taranto
- Division of Hematology and Oncology, Department of Medicine, Hospital of the University of Pennsylvania, South Pavilion, 12th Floor, 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA
| | - Stefan K Barta
- Division of Hematology and Oncology, Department of Medicine, Hospital of the University of Pennsylvania, South Pavilion, 12th Floor, 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA
| | - Rahul S Bhansali
- Division of Hematology and Oncology, Department of Medicine, Hospital of the University of Pennsylvania, South Pavilion, 12th Floor, 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA.
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8
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Stuver R, Epstein-Peterson ZD, Horwitz SM. Few and far between: clinical management of rare extranodal subtypes of mature T-cell and NK-cell lymphomas. Haematologica 2023; 108:3244-3260. [PMID: 38037801 PMCID: PMC10690914 DOI: 10.3324/haematol.2023.282717] [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: 11/21/2023] [Accepted: 07/03/2023] [Indexed: 12/02/2023] Open
Abstract
While all peripheral T-cell lymphomas are uncommon, certain subtypes are truly rare, with less than a few hundred cases per year in the USA. There are often no dedicated clinical trials in these rare subtypes, and data are generally limited to case reports and retrospective case series. Therefore, clinical management is often based on this limited literature and extrapolation of data from the more common, nodal T-cell lymphomas in conjunction with personal experience. Nevertheless, thanks to tremendous pre-clinical efforts to understand these rare diseases, an increasing appreciation of the biological changes that underlie these entities is forming. In this review, we attempt to summarize the relevant literature regarding the initial management of certain rare subtypes, specifically subcutaneous panniculitis-like T-cell lymphoma, hepatosplenic T-cell lymphoma, intestinal T-cell lymphomas, and extranodal NK/T-cell lymphoma. While unequivocally established approaches in these diseases do not exist, we make cautious efforts to provide our approaches to clinical management when possible.
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Affiliation(s)
- Robert Stuver
- Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center.
| | - Zachary D Epstein-Peterson
- Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center; Department of Medicine, Weill Cornell Medical College
| | - Steven M Horwitz
- Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center; Department of Medicine, Weill Cornell Medical College; Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
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9
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Stuver R, Horwitz SM, Advani RH, Vose JM, Lee HJ, Mehta-Shah N, Zain JM, Haverkos B, Lechowicz MJ, Moskowitz AJ, Pham LQ, Leyden E, Ansell SM, Lunning MA. Final results of a phase II study of CHOEP plus lenalidomide as initial therapy for patients with stage II-IV peripheral T-cell lymphoma. Br J Haematol 2023; 202:525-529. [PMID: 37217196 PMCID: PMC11220724 DOI: 10.1111/bjh.18885] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 05/13/2023] [Accepted: 05/15/2023] [Indexed: 05/24/2023]
Abstract
There remains no one standard induction for nodal-based peripheral T-cell lymphoma (PTCL). We conducted a phase II study of lenalidomide plus CHOEP as a novel induction strategy. Patients received CHOEP at standard doses in combination with 10 mg of lenalidomide on days 1-10 of a 21-day cycle for six cycles of therapy followed by observation, high-dose therapy with autologous stem cell rescue, or maintenance lenalidomide per provider preference. Among 39 patients evaluable for efficacy, the objective response rate after six cycles was 69%, with complete response in 49%, partial response in 21%, stable disease in 0% and progressive disease in 13%. Thirty-two patients (82%) completed full induction, and seven patients (18%) discontinued for toxicity, primarily hematologic. Any grade hematologic toxicity occurred in over 50% of patients, with grade 3 or 4 febrile neutropenia occurring in 35% of patients despite mandated growth factors. With a median followup of surviving patients of 21.3 months, the estimated 2-year progression-free and overall survival were 55% (95% CI 37%-70%) and 78% (95% CI 59%-89%), respectively. In sum, six cycles of lenalidomide plus CHOEP resulted in a modest response rate primarily due to hematologic toxicity, which prevented all patients from completing planned induction.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Luu Q. Pham
- Oakland University William Beaumont School of Medicine
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10
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Zain J, Kallam A. Challenges in nodal peripheral T-cell lymphomas: from biological advances to clinical applicability. Front Oncol 2023; 13:1150715. [PMID: 37188189 PMCID: PMC10175673 DOI: 10.3389/fonc.2023.1150715] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 03/06/2023] [Indexed: 05/17/2023] Open
Abstract
T cell lymphomas are a heterogenous group with varying biological and clinical features that tend to have poor outcomes with a few exceptions. They account for 10-15% of all non-Hodgkin lymphomas (NHL), and 20% of aggressive NHL. There has been little change in the overall prognosis of T cell lymphomas over the last 2 decades. Most subtypes carry an inferior prognosis when compared to the B cell lymphomas, with a 5-year OS of 30%. Gene expression profiling and other molecular techniques has enabled a deeper understanding of these differences in the various subtypes as reflected in the latest 5th WHO and ICC classification of T cell lymphomas. It is becoming increasingly clear that therapeutic approaches that target specific cellular pathways are needed to improve the clinical outcomes of T cell lymphomas. This review will focus on nodal T cell lymphomas and describe novel treatments and their applicability to the various subtypes.
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Affiliation(s)
- Jasmine Zain
- Department of Hematology/Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA, United States
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11
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Bhansali RS, Barta SK. Central Nervous System Progression/Relapse in Mature T- and NK-Cell Lymphomas. Cancers (Basel) 2023; 15:925. [PMID: 36765882 PMCID: PMC9913807 DOI: 10.3390/cancers15030925] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/27/2023] [Accepted: 01/30/2023] [Indexed: 02/04/2023] Open
Abstract
Non-Hodgkin lymphomas (NHL) are cancers of mature B-, T-, and NK-cells which display marked biological heterogeneity between different subtypes. Mature T- and NK-cell neoplasms are an often-aggressive subgroup of NHL and make up approximately 15% of all NHL. Long-term follow up studies have demonstrated that patients with relapsed/refractory disease have dismal outcomes; in particular, secondary central nervous system (CNS) involvement is associated with higher mortality, though it remains controversial whether this independently confers worse outcomes or if it simply reflects more aggressive systemic disease. Possible risk factors predictive of CNS involvement, such as an elevated lactate dehydrogenase and more than two sites of extranodal involvement, may suggest the latter, though several studies have suggested that discrete sites of anatomic involvement or tumor histology may be independent risk factors as well. Ultimately, small retrospective case series form the basis of our understanding of this rare but devastating event but have not yet demonstrated a consistent benefit of CNS-directed prophylaxis in preventing this outcome. Nonetheless, ongoing efforts are working to establish the epidemiology of CNS progression/relapse in mature T- and NK-cell lymphomas with the goal of identifying clinicopathologic risk factors, which may potentially help discern which patients may benefit from CNS-directed prophylactic therapy or more aggressive systemic therapy.
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Affiliation(s)
| | - Stefan K. Barta
- Department of Medicine, Division of Hematology and Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA
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12
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Yap DRY, Lim JQ, Huang D, Ong CK, Chan JY. Emerging predictive biomarkers for novel therapeutics in peripheral T-cell and natural killer/T-cell lymphoma. Front Immunol 2023; 14:1068662. [PMID: 36776886 PMCID: PMC9909478 DOI: 10.3389/fimmu.2023.1068662] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 01/09/2023] [Indexed: 01/27/2023] Open
Abstract
Peripheral T-cell lymphoma (PTCL) and natural killer/T-cell lymphoma (NKTCL) are rare subtypes of non-Hodgkin's lymphoma that are typically associated with poor treatment outcomes. Contemporary first-line treatment strategies generally involve the use of combination chemoimmunotherapy, radiation and/or stem cell transplant. Salvage options incorporate a number of novel agents including epigenetic therapies (e.g. HDAC inhibitors, DNMT inhibitors) as well as immune checkpoint inhibitors. However, validated biomarkers to select patients for individualized precision therapy are presently lacking, resulting in high treatment failure rates, unnecessary exposure to drug toxicities, and missed treatment opportunities. Recent advances in research on the tumor and microenvironmental factors of PTCL and NKTCL, including alterations in specific molecular features and immune signatures, have improved our understanding of these diseases, though several issues continue to impede progress in clinical translation. In this Review, we summarize the progress and development of the current predictive biomarker landscape, highlight potential knowledge gaps, and discuss the implications on novel therapeutics development in PTCL and NKTCL.
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Affiliation(s)
- Daniel Ren Yi Yap
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Jing Quan Lim
- Lymphoma Genomic Translational Research Laboratory, Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore, Singapore
| | - Dachuan Huang
- Lymphoma Genomic Translational Research Laboratory, Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore, Singapore
| | - Choon Kiat Ong
- Lymphoma Genomic Translational Research Laboratory, Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore, Singapore
| | - Jason Yongsheng Chan
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
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13
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Stuver R, Moskowitz AJ. Therapeutic Advances in Relapsed and Refractory Peripheral T-Cell Lymphoma. Cancers (Basel) 2023; 15:cancers15030589. [PMID: 36765544 PMCID: PMC9913081 DOI: 10.3390/cancers15030589] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/06/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
Historic outcomes for patients with relapsed or refractory nodal-based T-cell lymphomas are poor, with survival generally measured in months in multiple reports from the late 20th and early 21st century. Until recently, salvage strategies have mostly been borrowed from other aggressive lymphomas. However, dedicated investigations into the pathogenesis of T-cell lymphomas have resulted in an outpouring of therapies that target these diseases in biologically rational strategies. In particular, an evolving appreciation of the multiple complex oncogenic pathways and epigenetic changes that underlie these diseases has led to numerous agents targeting these aberrancies. Moreover, large reports of salvage allogeneic stem cell transplants in T-cell lymphoma have now been published, showing that adaptive immunotherapy is a potentially curative strategy for patients with relapsed or refractory disease. This review highlights therapeutic advances for relapsed or refractory T-cell lymphomas, including cellular therapy and allogeneic stem cell transplant, and provides a framework for management.
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14
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Sorigue M, Kuittinen O. Controversies in the Front-Line Treatment of Systemic Peripheral T Cell Lymphomas. Cancers (Basel) 2022; 15:220. [PMID: 36612216 PMCID: PMC9818471 DOI: 10.3390/cancers15010220] [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: 10/25/2022] [Revised: 12/13/2022] [Accepted: 12/27/2022] [Indexed: 12/31/2022] Open
Abstract
Systemic peripheral T cell lymphomas (PTCL) are a rare and clinically and biologically heterogeneous group of disorders with scarce and generally low-quality evidence guiding their management. In this manuscript, we tackle the current controversies in the front-line treatment of systemic PTCL including (1) whether CNS prophylaxis should be administered; (2) whether CHOEP should be preferred over CHOP; (3) what role brentuximab vedotin should have; (4) whether stem cell transplant (SCT) consolidation should be used and whether autologous or allogeneic; (5) how should molecular subtypes (including DUSP22 or TP63-rearranged ALCL or GATA3 or TBX21 PTCL, NOS) impact therapeutic decisions; and (6) whether there is a role for targeted agents beyond brentuximab vedotin.
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Affiliation(s)
- Marc Sorigue
- Department of Hematology, ICO-IJC-Hospital Germans Trias i Pujol, LUMN, UAB, 08916 Badalona, Spain
| | - Outi Kuittinen
- Institute of Clinical Medicine, Faculty of Health Medicine, University of Eastern Finland, 70211 Kuopio, Finland
- Medical Research Centre and Cancer and Translational Research Unit, Oulu University Hospital and University of Oulu, 90220 Oulu, Finland
- Department of Oncology, Kuopio University Hospital, 70210 Kuopio, Finland
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15
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Atallah-Yunes SA, Robertson MJ, Davé UP. Epigenetic Aberrations and Targets in Peripheral T-Cell Lymphoma. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2022; 22:659-665. [PMID: 35577752 DOI: 10.1016/j.clml.2022.04.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 04/07/2022] [Accepted: 04/14/2022] [Indexed: 06/02/2023]
Abstract
Peripheral T cell lymphomas (PTCL) comprise a diverse group of aggressive T-cell and NK-cell lymphomas with many subtypes sharing same treatment algorithms despite having different pathobiology and responses to treatment. The molecular advances made in discovery of genetic mutations that disrupt epigenetic modulation in some subtypes of PTCL such as angioimmunoblastic T cell lymphoma and PTCL-not otherwise specified (NOS) may explain the poor outcomes and unsatisfactory responses to frontline line CHOP and CHOP-like therapy seen in this group of lymphomas. In this article, we address the main genetic mutations such as IDH2, TET2 and DNMT3A seen in PTCL and that disrupt the epigenetic modulation pathways, focusing on acetylation, deacetylation and methylation. Since therapeutic agents that target the disrupted epigenetic modulation pathways in PTCL may change treatment landscape in the near future, we will highlight the ones approved for treatment of refractory and/or relapsed PTCL and also the pivotal regimens being evaluated in clinical trials for treatment of frontline and refractory relapsed disease. We stress the importance of determining whether there is an association between the discussed genetic mutations and responses to the highlighted therapeutic agents such that treatments could be better tailored in patients with this kind of lymphoma with unmet needs.
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Affiliation(s)
- Suheil Albert Atallah-Yunes
- Division of Hematology and Medical Oncology, Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN.
| | - Michael J Robertson
- Lymphoma Program, Division of Hematology and Medical Oncology, Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN
| | - Utpal P Davé
- Departments of Medicine and Microbiology and Immunology, Division of Hematology/Oncology, R.L. Roudebush VA Medical Center, IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN
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16
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Peng Z, Xiong J, Dong H. Valproic Acid Inhibits Peripheral T Cell Lymphoma Cells Behaviors via Restraining PI3K/AKT Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:7350489. [PMID: 35966721 PMCID: PMC9374556 DOI: 10.1155/2022/7350489] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 06/30/2022] [Accepted: 07/05/2022] [Indexed: 11/18/2022]
Abstract
Objective Alproic acid (VPA) is a clinic antiepileptic drug. Antitumor role of VPA has been studied. The aim of this study was to clarify the treatment effect and potential mechanism of VPA on peripheral T cell lymphomas (PTCLs). Materials and Methods Hut 78 cells were obtained from the Shanghai Cell Bank, Chinese Academy of Sciences, and randomly divided into six groups: control, VPA (8 mM), empty vector (NC), miR-3196 mimics, miR-3196 inhibitor, and VPA + miR-3196 mimics groups. CCK-8 assay was performed to clarify the regulative role of VPA on cell proliferation. Flow cytometry was applied to determine the apoptotic rate and ROS levels. miR-3196 was tested by RT-qPCR. Western blot was used to test the level of p-PI3K and p-AKT. Biochemical experiments were used to detect changes in the content of ATP, lactate level, and glucose content. Electron microscopy was used to show the structure of mitochondria in Hut 78 cells. Results VPA greatly promoted the expression of miR-3196 and inhibited cell proliferation in a dose-dependent manner. Compared with the NC group, the cell apoptosis rate, Bax and cleaved-caspase-3 expression, lactate level, ROS expression, and glucose content in the VPA group were significantly increased (P < 0.05), and cell proliferation, ATP production, and the expression of Bcl-2, p-PI3K and p-AKT was decreased significantly (P < 0.05). The role of mir-3196 mimics is similar to VPA. While, the miR-3196 inhibitor had the opposite effect to VPA and mimics. The combination of VPA and miR-3196 mimics has the most obvious effect. Conclusion VPA can inhibit the proliferation of Hut 78 cells and promote cell apoptosis and the structure and dysfunction of mitochondria by regulating the activity of the PI3K/AKT pathway.
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Affiliation(s)
- Zhiqiang Peng
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
- Department of Lymphatic Hematology and Oncology, Jiangxi Cancer Hospital, Nanchang 330029, Jiangxi, China
| | - Jianping Xiong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Hanzhi Dong
- General Department of Oncology, Jiangxi Cancer Hospital, Nanchang 330029, Jiangxi, China
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17
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Major A, Kline J, Karrison TG, Fishkin PAS, Kimball AS, Petrich AM, Nattam S, Rao K, Sleckman BG, Cohen K, Besien KV, Rapoport AP, Smith SM. Phase I/II clinical trial of temsirolimus and lenalidomide in patients with relapsed and refractory lymphomas. Haematologica 2022; 107:1608-1618. [PMID: 34320785 PMCID: PMC9244831 DOI: 10.3324/haematol.2021.278853] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Accepted: 07/22/2021] [Indexed: 12/01/2022] Open
Abstract
The PI3K/Akt/mTOR (PAM) axis is constitutively activated in multiple lymphoma subtypes and is a promising therapeutic target. The mTOR inhibitor temsirolimus (TEM) and the immunomodulatory agent lenalidomide (LEN) have overlapping effects within the PAM axis with synergistic potential. This multicenter phase I/II study evaluated combination therapy with TEM/LEN in patients with relapsed and refractory lymphomas. Primary endpoints of the phase II study were rates of complete (CR) and overall response (ORR). There were 18 patients in the phase I dose-finding study, and TEM 25 mg weekly and LEN 20 mg on day 1 through day 21 every 28 days was established as the recommended phase II dose. An additional 93 patients were enrolled in the phase II component with three cohorts: diffuse large B-cell lymphoma (DLBCL, n=39), follicular lymphoma (FL, n=15), and an exploratory cohort of other lymphoma histologies with classical Hodgkin lymphoma (cHL) comprising the majority (n=39 total, n=20 with cHL). Patients were heavily pretreated with a median of four (range, 1-14) prior therapies and one-third with relapse following autologous stem cell transplantation (ASCT); patients with cHL had a median of six prior therapies. The FL cohort was closed prematurely due to slow accrual. ORR were 26% (13% CR) and 64% (18% CR) for the DLBCL and exploratory cohorts, respectively. ORR for cHL patients in the exploratory cohort, most of whom had relapsed after both brentuximab vedotin and ASCT, was 80% (35% CR). Eight cHL patients (40%) proceeded to allogeneic transplantation after TEM/LEN therapy. Grade ≥3 hematologic adverse events (AE) were common. Three grade 5 AE occurred. Combination therapy with TEM/LEN was feasible and demonstrated encouraging activity in heavily-pretreated lymphomas, particularly in relapsed/refractory cHL (clinicaltrials gov. Identifier: NCT01076543).
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Affiliation(s)
| | | | | | | | - Amy S Kimball
- University of Maryland School of Medicine and Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA; Amgen Inc., Thousand Oaks, CA
| | - Adam M Petrich
- Northwestern University, Chicago, IL, USA; Daiichi-Sankyo, Basking Ridge, NJ
| | | | - Krishna Rao
- Southern Illinois University, Springfield, IL
| | | | | | | | - Aaron P Rapoport
- University of Maryland School of Medicine and Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD
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18
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Hue SSS, Ng SB, Wang S, Tan SY. Cellular Origins and Pathogenesis of Gastrointestinal NK- and T-Cell Lymphoproliferative Disorders. Cancers (Basel) 2022; 14:2483. [PMID: 35626087 PMCID: PMC9139583 DOI: 10.3390/cancers14102483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 05/08/2022] [Accepted: 05/13/2022] [Indexed: 11/25/2022] Open
Abstract
The intestinal immune system, which must ensure appropriate immune responses to both pathogens and commensal microflora, comprises innate lymphoid cells and various T-cell subsets, including intra-epithelial lymphocytes (IELs). An example of innate lymphoid cells is natural killer cells, which may be classified into tissue-resident, CD56bright NK-cells that serve a regulatory function and more mature, circulating CD56dim NK-cells with effector cytolytic properties. CD56bright NK-cells in the gastrointestinal tract give rise to indolent NK-cell enteropathy and lymphomatoid gastropathy, as well as the aggressive extranodal NK/T cell lymphoma, the latter following activation by EBV infection and neoplastic transformation. Conventional CD4+ TCRαβ+ and CD8αβ+ TCRαβ+ T-cells are located in the lamina propria and the intraepithelial compartment of intestinal mucosa as type 'a' IELs. They are the putative cells of origin for CD4+ and CD8+ indolent T-cell lymphoproliferative disorders of the gastrointestinal tract and intestinal T-cell lymphoma, NOS. In addition to such conventional T-cells, there are non-conventional T-cells in the intra-epithelial compartment that express CD8αα and innate lymphoid cells that lack TCRs. The central feature of type 'b' IELs is the expression of CD8αα homodimers, seen in monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), which primarily arises from both CD8αα+ TCRαβ+ and CD8αα+ TCRγδ+ IELs. EATL is the other epitheliotropic T-cell lymphoma in the GI tract, a subset of which arises from the expansion and reprograming of intracytoplasmic CD3+ innate lymphoid cells, driven by IL15 and mutations of the JAK-STAT pathway.
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Affiliation(s)
- Susan Swee-Shan Hue
- Department of Pathology, National University Hospital, Singapore 119074, Singapore; (S.S.-S.H.); (S.W.)
| | - Siok-Bian Ng
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore;
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
| | - Shi Wang
- Department of Pathology, National University Hospital, Singapore 119074, Singapore; (S.S.-S.H.); (S.W.)
| | - Soo-Yong Tan
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore;
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19
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Sibon D. Peripheral T-Cell Lymphomas: Therapeutic Approaches. Cancers (Basel) 2022; 14:cancers14092332. [PMID: 35565460 PMCID: PMC9104854 DOI: 10.3390/cancers14092332] [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: 04/12/2022] [Accepted: 05/04/2022] [Indexed: 11/21/2022] Open
Abstract
Simple Summary Peripheral T-cell lymphomas are a group of rare cancers of T cells or natural killer cells, most often with a poor prognosis. In recent years, significant progress has been made through the development of more specific therapies. This review aims to provide an up-to-date overview of current treatments in nodal PTCL. Abstract Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of rare neoplasms of mature T cells or natural killer (NK) cell. PTCLs usually have an aggressive course and a poor outcome. In recent years, significant progress has been made in the knowledge of the molecular lymphomagenesis of PTCLs, and through the development of new, more specific therapeutic molecules, one can hope in the coming years for more personalized medicine and improved patient prognosis. This review aims to provide an up-to-date overview of the current therapeutic approaches in nodal PTCLs.
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Affiliation(s)
- David Sibon
- Lymphoid Malignancies Department, Henri Mondor University Hospital, AP-HP, 94000 Créteil, France;
- Faculty of Medicine and Health, Campus Henri Mondor, Paris-Est Créteil University, 94000 Créteil, France
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20
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Horwitz SM, Ansell S, Ai WZ, Barnes J, Barta SK, Brammer J, Clemens MW, Dogan A, Foss F, Ghione P, Goodman AM, Guitart J, Halwani A, Haverkos BM, Hoppe RT, Jacobsen E, Jagadeesh D, Jones A, Kallam A, Kim YH, Kumar K, Mehta-Shah N, Olsen EA, Rajguru SA, Rozati S, Said J, Shaver A, Shea L, Shinohara MM, Sokol L, Torres-Cabala C, Wilcox R, Wu P, Zain J, Dwyer M, Sundar H. T-Cell Lymphomas, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2022; 20:285-308. [PMID: 35276674 DOI: 10.6004/jnccn.2022.0015] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoproliferative disorders arising from mature T cells, accounting for about 10% of non-Hodgkin lymphomas. PTCL-not otherwise specified is the most common subtype, followed by angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma, anaplastic lymphoma kinase-negative, and enteropathy-associated T-cell lymphoma. This discussion section focuses on the diagnosis and treatment of PTCLs as outlined in the NCCN Guidelines for T-Cell Lymphomas.
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Affiliation(s)
| | | | - Weiyun Z Ai
- 3UCSF Helen Diller Family Comprehensive Cancer Center
| | | | - Stefan K Barta
- 5Abramson Cancer Center at the University of Pennsylvania
| | - Jonathan Brammer
- 6The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | | | | | | | | | | | - Joan Guitart
- 11Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | - Ahmad Halwani
- 12Huntsman Cancer Institute at the University of Utah
| | | | | | | | - Deepa Jagadeesh
- 16Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | - Allison Jones
- 17St. Jude Children's Research Hospital/The University of Tennessee Health Science Center
| | | | | | - Kiran Kumar
- 19UT Southwestern Simmons Comprehensive Cancer Center
| | - Neha Mehta-Shah
- 20Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | | | | | - Sima Rozati
- 23The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
| | | | | | | | - Michi M Shinohara
- 27Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance
| | | | | | - Ryan Wilcox
- 29University of Michigan Rogel Cancer Center
| | - Peggy Wu
- 30UC Davis Comprehensive Cancer Center
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21
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Angelos MG, Ballard HJ, Barta SK. Advances and Personalized Approaches in the Frontline Treatment of T-Cell Lymphomas. J Pers Med 2022; 12:267. [PMID: 35207754 PMCID: PMC8874646 DOI: 10.3390/jpm12020267] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 02/05/2022] [Accepted: 02/08/2022] [Indexed: 02/05/2023] Open
Abstract
Peripheral T-cell lymphomas (PTCLs) are a rare and heterogenous subset of non-Hodgkin lymphoma characterized by an aggressive clinical course. Historically, the treatment of PTCLs have been analogous to that of aggressive B-cell lymphomas; however, it has been well-established that overall responses and complete remission rates are far inferior using near-identical chemotherapy strategies. Recently, there has been a plethora of newer agents designed to target distinguishing cellular and molecular features of specific PTCL subtypes. These agents have been proven to yield superior anti-lymphoma responses and, in some cases, overall survival in the relapsed, refractory, and frontline treatment setting. In this review, we will summarize and highlight the most influential clinical trials leading to the Food and Drug Administration (FDA) approval of several novel therapeutic agents against PTCL, with an emphasis on emerging studies and strategies to expand their potential use in the frontline treatment setting.
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Affiliation(s)
| | | | - Stefan K. Barta
- Department of Medicine, Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA; (M.G.A.); (H.J.B.)
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22
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Cencini E, Fabbri A, Mecacci B, Bocchia M. Role of lenalidomide in the treatment of peripheral T-cell non-Hodgkin lymphomas. World J Clin Oncol 2021; 12:882-896. [PMID: 34733611 PMCID: PMC8546656 DOI: 10.5306/wjco.v12.i10.882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 07/07/2021] [Accepted: 09/02/2021] [Indexed: 02/06/2023] Open
Abstract
T-cell lymphomas (TCLs) represent a group of lymphoid neoplasms characterized by an aggressive clinical course, even after an anthracycline-containing regimen. Novel agents for patients with relapsed/refractory TCL are urgently needed. Lenalidomide is an oral drug with immunomodulatory, antiangiogenic and direct antineoplastic effects. These peculiar mechanisms of action make TCL an attractive target for lenalidomide. We have identified five clinical trials in which lenalidomide monotherapy was investigated to treat TCL, including cutaneous TCL (CTCL) and adult T-cell lymphoma/leukemia (ATLL). In the ATLL-002 study, the overall response rate (ORR) was 42% and median progression-free survival (PFS) and overall survival were 3.8 mo and 20.3 mo, respectively. In a phase II trial for CTCL, ORR was 28% and median PFS and overall survival were 8 mo and 43 mo, respectively. For nodal peripheral TCL, ORR was between 10% and 43% in three clinical trials, with a median PFS of about 4 mo, even if some patients had a durable response. Overall toxicity is manageable and grade 3-4 events are mainly hematological and reversible. Combination strategies did not improve PFS. In conclusion, lenalidomide could represent a suitable treatment option for relapsed/refractory TCL, especially for neoplasms with a T-follicular helper origin, such as angioimmunoblastic TCL.
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Affiliation(s)
- Emanuele Cencini
- Unit of Hematology, Azienda Ospedaliera Universitaria Senese and University of Siena, Siena 53100, Italy
| | - Alberto Fabbri
- Unit of Hematology, Azienda Ospedaliera Universitaria Senese and University of Siena, Siena 53100, Italy
| | - Bianca Mecacci
- Unit of Hematology, Azienda Ospedaliera Universitaria Senese and University of Siena, Siena 53100, Italy
| | - Monica Bocchia
- Unit of Hematology, Azienda Ospedaliera Universitaria Senese and University of Siena, Siena 53100, Italy
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23
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Mehta‐Shah N, Lunning MA, Moskowitz AJ, Boruchov AM, Ruan J, Lynch P, Hamlin PA, Leonard J, Matasar MJ, Myskowski PL, Marzouk E, Nair S, Sholklapper T, Minnal V, Palomba ML, Vredenburgh J, Kumar A, Noy A, Straus DJ, Zelenetz AD, Schoder H, Rademaker J, Schaffer W, Galasso N, Ganesan N, Horwitz SM. Romidepsin and lenalidomide-based regimens have efficacy in relapsed/refractory lymphoma: Combined analysis of two phase I studies with expansion cohorts. Am J Hematol 2021; 96:1211-1222. [PMID: 34251048 DOI: 10.1002/ajh.26288] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 06/06/2021] [Accepted: 07/02/2021] [Indexed: 12/17/2022]
Abstract
Romidepsin (histone deacetylase inhibitor), lenalidomide (immunomodulatory agent), and carfilzomib (proteasome inhibitor), have efficacy and lack cumulative toxicity in relapsed/refractory lymphoma. We performed two investigator initiated sequential phase I studies to evaluate the maximum tolerated dose (MTD) of romidepsin and lenalidomide (regimen A) and romidepsin, lenalidomide, and carfilzomib (regimen B) in relapsed/refractory lymphoma. Cohorts in T-cell lymphoma (TCL), B-cell lymphoma (BCL) were enrolled at the MTD. Forty-nine patients were treated in study A (27 TCL, 17 BCL, 5 Hodgkin lymphoma (HL)) and 27 (16 TCL, 11 BCL) in study B. The MTD of regimen A was romidepsin 14 mg/m2 IV on days 1, 8, and 15 and lenalidomide 25 mg oral on days 1-21 of a 28-day cycle. The MTD of regimen B was romidepsin 8 mg/m2 on days 1 and 8, lenalidomide 10 mg oral on days 1-14 and carfilzomib 36 mg/m2 IV on days 1 and 8 of a 21-day cycle. In study A, 94% had AEs ≥Grade 3, most commonly neutropenia (49%), thrombocytopenia (53%), and electrolyte abnormalities (49%). In study B 59% had AEs ≥Grade 3, including thrombocytopenia (30%) and neutropenia (26%). In study A the ORR was 49% (50% TCL, 47% BCL, 50% HL). In study B the ORR was 48% (50% TCL, 50% BCL). For study A and B the median progression free survival (PFS) was 5.7 months and 3.4 months respectively with 11 patients proceeding to allogeneic transplant. The combinations of romidepsin and lenalidomide and of romidepsin, lenalidomide and carfilzomib showed activity in relapsed/refractory lymphoma with an acceptable safety profile.
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Affiliation(s)
- Neha Mehta‐Shah
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
- Washington University School of Medicine in St. Louis St. Louis Missouri USA
| | - Matthew A. Lunning
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
- Department of Medicine University of Nebraska Medical Center Omaha Nebraska USA
| | - Alison J. Moskowitz
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Adam M. Boruchov
- Department of Medicine St. Francis Medical Center Hartford Connecticut USA
| | - Jia Ruan
- Department of Medicine Weill Cornell Medical Center New York New York USA
| | - Peggy Lynch
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Paul A. Hamlin
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - John Leonard
- Department of Medicine Weill Cornell Medical Center New York New York USA
| | - Matthew J. Matasar
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Patricia L. Myskowski
- Dermatology Service, Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Evan Marzouk
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Sumithra Nair
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Tamir Sholklapper
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Veena Minnal
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Maria L. Palomba
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - James Vredenburgh
- Department of Medicine St. Francis Medical Center Hartford Connecticut USA
| | - Anita Kumar
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Ariela Noy
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - David J. Straus
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Andrew D. Zelenetz
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Heiko Schoder
- Department of Radiology Memorial Sloan Kettering Cancer Center New York New York USA
| | - Jurgen Rademaker
- Department of Radiology Memorial Sloan Kettering Cancer Center New York New York USA
| | - Wendy Schaffer
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Natasha Galasso
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Nivetha Ganesan
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Steven M. Horwitz
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
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24
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Zain JM, Hanona P. Aggressive T-cell lymphomas: 2021 Updates on diagnosis, risk stratification and management. Am J Hematol 2021; 96:1027-1046. [PMID: 34111312 DOI: 10.1002/ajh.26270] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 06/08/2021] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Aggressive T-cell lymphomas continue to have a poor prognosis. There are over 27 different subtypes of peripheral T-cell lymphoma (PTCL), and we are now beginning to understand the differences between the various subtypes beyond histologic variations. MOLECULAR PATHOGENESIS OF VARIOUS SUBTYPES OF PTCL Gene expression profiling (GEP) can help in diagnosis and prognostication of various subtypes including PTCL-nos and anaplastic large cell lymphoma (ALCL). In addition, mutational analysis is now being incorporated in clinical trials of novel agents to evaluate various biomarkers of response to allow better therapeutic choices for patients. TARGETED THERAPIES There are many targeted agents currently in various stages of clinical trials for PTCL that take advantage of the differential expression of specific proteins or receptors in PTCL tumors. This includes the CD30 directed antibody drug conjugate brentuximab vedotin. Other notable targets are CD25, CCR4, inhibition of PI3kinase - m TOR and JAK/STAT pathways. The ALK inhibitors are promising for ALK expressing tumors. IMMUNOTHERAPIES Allogeneic stem cell transplant continues to be the curative therapy for most aggressive subtypes of PTCL. The use of checkpoint inhibitors in the treatment of PTCL is still controversial. The most promising results have been seen in cases of extranodal natural killer cell/T-cell (ENK/T) lymphomas and cutaneous T-cell lymphomas (CTCL). Bispecific antibody based treatments as well as CAR-T cell based therapies are in clinical trials.
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Affiliation(s)
- Jasmine M. Zain
- Department of Hematology/Hematopoietic Cell Transplantation City of Hope Medical Center Duarte California USA
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25
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Jan M, Sperling AS, Ebert BL. Cancer therapies based on targeted protein degradation - lessons learned with lenalidomide. Nat Rev Clin Oncol 2021; 18:401-417. [PMID: 33654306 PMCID: PMC8903027 DOI: 10.1038/s41571-021-00479-z] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/25/2021] [Indexed: 02/08/2023]
Abstract
For decades, anticancer targeted therapies have been designed to inhibit kinases or other enzyme classes and have profoundly benefited many patients. However, novel approaches are required to target transcription factors, scaffolding proteins and other proteins central to cancer biology that typically lack catalytic activity and have remained mostly recalcitrant to drug development. The selective degradation of target proteins is an attractive approach to expand the druggable proteome, and the selective oestrogen receptor degrader fulvestrant served as an early example of this concept. Following a long and tragic history in the clinic, the immunomodulatory imide drug (IMiD) thalidomide was discovered to exert its therapeutic activity via a novel and unexpected mechanism of action: targeting proteins to an E3 ubiquitin ligase for subsequent proteasomal degradation. This discovery has paralleled and directly catalysed myriad breakthroughs in drug development, leading to the rapid maturation of generalizable chemical platforms for the targeted degradation of previously undruggable proteins. Decades of clinical experience have established front-line roles for thalidomide analogues, including lenalidomide and pomalidomide, in the treatment of haematological malignancies. With a new generation of 'degrader' drugs currently in development, this experience provides crucial insights into class-wide features of degraders, including a unique pharmacology, mechanisms of resistance and emerging therapeutic opportunities. Herein, we review these past experiences and discuss their application in the clinical development of novel degrader therapies.
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Affiliation(s)
- Max Jan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Adam S Sperling
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Benjamin L Ebert
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Broad Institute of Harvard and MIT, Cambridge, MA, USA.
- Howard Hughes Medical Institute, Boston, MA, USA.
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26
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Liang D, Wei C, Zhang X, Yang J, Zheng Y, Du J, Wang L, Deng L. Efficacy of lenalidomide for relapsed or refractory T lymphoblastic lymphoma/leukemia after allogeneic hematopoietic stem cell transplantation. Leuk Lymphoma 2021; 62:2521-2525. [PMID: 33993826 DOI: 10.1080/10428194.2021.1919665] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
- Dan Liang
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Cong Wei
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoting Zhang
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jilong Yang
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yaling Zheng
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jingwen Du
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Liang Wang
- Department of Hematology, Beijing TongRen Hospital, Capital Medical University, Beijing, China.,Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University & Capital Medical University, Beijing TongRen Hospital, Beijing, China
| | - Lan Deng
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Department of Hematology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Epstein-Peterson ZD, Horwitz SM. Molecularly targeted therapies for relapsed and refractory peripheral T-cell lymphomas. Semin Hematol 2021; 58:78-84. [PMID: 33906725 PMCID: PMC8496899 DOI: 10.1053/j.seminhematol.2021.02.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/16/2021] [Accepted: 02/22/2021] [Indexed: 01/19/2023]
Abstract
The advent of molecularly targeted agents for patients with peripheral T-cell lymphomas (PTCL) has begun to change the therapeutic landscape in these diseases, especially for patients with relapsed or refractory disease. These agents, grounded in targeting numerous pathways or alterations related to disease pathogenesis, have shown promise across many PTCL subhistologies. Aided by significant advances in experimental techniques related to molecular biology, epigenetics, and immunology, more recent studies have begun elucidating mediators of resistance, both intrinsic and acquired, to inform future therapeutic advances. Defining and targeting these escape mechanisms through rational combination approaches will likely be important to continue to build on these promising advances and further improve clinical outcomes for patients facing PTCL.
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Affiliation(s)
- Zachary D Epstein-Peterson
- Lymphoma Service, Division of Hematologic Malignancies, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Steven M Horwitz
- Lymphoma Service, Division of Hematologic Malignancies, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
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Successful treatment with brentuximab vedotin for relapsed and refractory adult T cell leukemia. Anticancer Drugs 2021; 31:536-539. [PMID: 31934889 DOI: 10.1097/cad.0000000000000895] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Although treatments for adult T-cell leukemia/lymphoma in the past two decades have advanced, the current standard treatment for aggressive adult T-cell leukemia/lymphoma, particularly in patients who are not eligible for stem cell transplantation, remains inadequate; therefore, treatments to prolong the duration of remission and provide relevant benefits in terms of survival and quality of life are needed. Adult T-cell leukemia/lymphoma tumor cells express CD30 in some cases and the increased expression of CD30 is considered to be one of the causes of constitutive NF-κB activation in adult T-cell leukemia/lymphoma cells. Brentuximab vedotin represents a major breakthrough in the treatment of CD30-positive lymphomas. Elderly patients treated with chemotherapy generally have higher rates of grade 3 or 4 adverse events; however a retrospective analysis demonstrated the safety and efficacy of brentuximab vedotin in adults ≥60 years with relapsed and refractory CD30-positive lymphomas. We herein report the clinical effects of brentuximab vedotin and the significance of CD30 expression in an elderly refractory/relapse adult T-cell leukemia/lymphoma patient. CD30 expression is associated with disease progression in adult T-cell leukemia/lymphoma patients and brentuximab vedotin may be a new and promising treatment option for these patients. Further investigations on the use of brentuximab vedotin for adult T-cell leukemia/lymphoma are needed.
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29
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Pang Y, Chihara D. Primary and secondary central nervous system mature T- and NK-cell lymphomas. Semin Hematol 2021; 58:123-129. [PMID: 33906722 DOI: 10.1053/j.seminhematol.2021.02.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 02/03/2021] [Accepted: 02/22/2021] [Indexed: 12/29/2022]
Abstract
Primary central nervous system (CNS) mature T- and NK-cell lymphomas are rare, only comprising 2% to 3% of all primary CNS lymphomas. Among them, peripheral T-cell lymphoma, not otherwise specified, anaplastic large cell lymphoma (ALCL), and extranodal NK/T-cell lymphoma (ENKTL) are the commonly reported histological subtypes. Secondary CNS T-cell lymphoma generally affects about 5% of patients with T- or NK-cell lymphoma, with some exceptions. Acute and lymphomatous subtypes of adult T-cell leukemia/lymphoma (ATLL) have high risk of CNS progression, may affect up to 20% of patients; ALK-positive ALCL with extranodal involvement >1 also has high risk of CNS progression. However, the impact and the optimal methodology of CNS prophylaxis remain unclear in systemic T-cell lymphomas. There are little data on the treatment strategy of primary and secondary CNS T-cell lymphoma. Treatment strategy derived from B-cell CNS primary lymphoma is generally used; this includes induction therapy with high-dose methotrexate-based regimens, followed by high-dose chemotherapy with autologous stem cell transplant in fit patients. There are unmet needs for patients who are not fit for intensive chemotherapy. The prognosis after CNS progression in T-cell lymphoma is dismal with the median overall survival of less than 1 year. New agents targeting T-cell lymphomas are emerging and should be tested in patients with mature T- and NK-cell lymphoma who suffer from CNS involvement.
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Affiliation(s)
- Yifan Pang
- Medical Oncology Service, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Dai Chihara
- Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX.
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Abeyakoon C, van der Weyden C, Harrop S, Khot A, Dickinson M, Yannakou CK, Prince HM. Advances in Frontline Management of Peripheral T-cell Lymphoma. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2021; 21:368-378. [PMID: 33610499 DOI: 10.1016/j.clml.2021.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 01/12/2021] [Accepted: 01/16/2021] [Indexed: 10/22/2022]
Abstract
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphomas that are frequently associated with a poor prognosis. For many decades, the standard-of-care has been CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)-based therapy, but it is well-recognized that survival outcomes are unsatisfactory, especially when compared with B-cell lymphomas. Major recent advances in cancer diagnosis and management have the potential to significantly improve PTCL outcomes. These include: (1) improved diagnostic techniques that incorporate molecular genetic data to further refine diagnosis and subtyping; (2) the development of novel agents; and (3) improved monitoring modalities, such as 18F-fluorodeoxyglucose positron emission tomography-computed tomography scans and circulating tumor DNA. In this review, we aim to explore these 3 advances in the context of frontline management of PTCL.
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Affiliation(s)
- Chathuri Abeyakoon
- Department of Haematology, Epworth HealthCare, Melbourne, Victoria, Australia.
| | - Carrie van der Weyden
- Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Sean Harrop
- Department of Haematology, Epworth HealthCare, Melbourne, Victoria, Australia; Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Amit Khot
- Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria, Australia; Department of Haematology, Royal Melbourne Hospital, Melbourne, Victoria, Australia
| | - Michael Dickinson
- Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Costas K Yannakou
- Department of Haematology, Epworth HealthCare, Melbourne, Victoria, Australia
| | - H Miles Prince
- Department of Haematology, Epworth HealthCare, Melbourne, Victoria, Australia; Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria, Australia
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31
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Wolska-Washer A, Smolewski P, Robak T. Advances in the pharmacotherapeutic options for primary nodal peripheral T-cell lymphoma. Expert Opin Pharmacother 2021; 22:1203-1215. [PMID: 33524268 DOI: 10.1080/14656566.2021.1882997] [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] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Peripheral T cell lymphomas (PTCL) are a group of heterogenous hematologic malignancies derived from post-thymic T lymphocytes and mature NK cells. Conventional chemotherapy does not guarantee a good outcome. AREAS COVERED The article summarizes recent investigational therapies and their mechanism of action, as well as the pharmacological properties, clinical activity, and toxicity of new agents in the treatment of primary nodal PTCLs. The review scrutinized papers included in the MEDLINE (PubMed) database between 2010 and October 2020. These were supplemented with a manual search of conference proceedings from the previous five years of the American Society of Hematology, European Hematology Association, and American Society of Clinical Oncology. Further relevant publications were obtained by reviewing the references from the chosen articles. EXPERT OPINION PTCLs have proved difficult to treat and investigate because of their rarity. Studies of aggressive lymphoma, including a small proportion of T-cell lymphomas, found that any benefit from intensified traditional chemotherapy in patients with PTCL is accompanied by increased toxicity. However, the management of PTCL is beginning to change dramatically, thanks to the use of more sophisticated agents targeting the mechanisms of disease development.
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Affiliation(s)
- Anna Wolska-Washer
- Department of Experimental Hematology, Medical University of Lodz, Lodz. Poland.,Copernicus Memorial Hospital, Lodz. Poland
| | - Piotr Smolewski
- Department of Experimental Hematology, Medical University of Lodz, Lodz. Poland.,Copernicus Memorial Hospital, Lodz. Poland
| | - Tadeusz Robak
- Copernicus Memorial Hospital, Lodz. Poland.,Department of Hematology, Medical University of Lodz, Lodz. Poland
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Lemonnier F, Safar V, Beldi-Ferchiou A, Cottereau AS, Bachy E, Cartron G, Fataccioli V, Pelletier L, Robe C, Letourneau A, Missiaglia E, Fourati S, Moles-Moreau MP, Delmer A, Bouabdallah R, Voillat L, Becker S, Bossard C, Parrens M, Casasnovas O, Cacheux V, Régny C, Camus V, Delfau-Larue MH, Meignan M, de Leval L, Gaulard P, Haioun C. Integrative analysis of a phase 2 trial combining lenalidomide with CHOP in angioimmunoblastic T-cell lymphoma. Blood Adv 2021; 5:539-548. [PMID: 33496747 PMCID: PMC7839364 DOI: 10.1182/bloodadvances.2020003081] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 12/02/2020] [Indexed: 02/07/2023] Open
Abstract
Angioimmunoblastic T-cell lymphoma (AITL) is a frequent T-cell lymphoma in the elderly population that has a poor prognosis when treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy. Lenalidomide, which has been safely combined with CHOP to treat B-cell lymphoma, has shown efficacy as a single agent in AITL treatment. We performed a multicentric phase 2 trial combining 25 mg lenalidomide daily for 14 days per cycle with 8 cycles of CHOP21 in previously untreated AITL patients aged 60 to 80 years. The primary objective was the complete metabolic response (CMR) rate at the end of treatment. Seventy-eight of the 80 patients enrolled were included in the efficacy and safety analysis. CMR was achieved in 32 (41%; 95% confidence interval [CI], 30%-52.7%) patients, which was below the prespecified CMR rate of 55% defined as success in the study. The 2-year progression-free survival (PFS) was 42.1% (95% CI, 30.9%-52.8%), and the 2-year overall survival was 59.2% (95% CI, 47.3%-69.3%). The most common toxicities were hematologic and led to treatment discontinuation in 15% of patients. This large prospective and uniform series of AITL treatment data was used to perform an integrative analysis of clinical, pathologic, biologic, and molecular data. TET2, RHOA, DNMT3A, and IDH2 mutations were present in 78%, 54%, 32%, and 22% of patients, respectively. IDH2 mutations were associated with distinct pathologic and clinical features and DNMT3A was associated with shorter PFS. In conclusion, the combination of lenalidomide and CHOP did not improve the CMR in AITL patients. This trial clarified the clinical impact of recurrent mutations in AITL. This trial was registered at www.clincialtrials.gov as #NCT01553786.
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Affiliation(s)
- François Lemonnier
- Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Henri Mondor, Unité Hémopathies Lymphoïdes, Créteil, France
- Université Paris Est Créteil, INSERM, Institut Médical de Recherche Biomédicale, Créteil, France
| | - Violaine Safar
- Service d'Hématologie Clinique, Hospices Civils de Lyon, Pierre-Bénite, and Université Lyon 1, Lyon, France
| | - Asma Beldi-Ferchiou
- Université Paris Est Créteil, INSERM, Institut Médical de Recherche Biomédicale, Créteil, France
- Département d'Hématologie et d'Immunologie Biologique, Hôpitaux Universitaires Henri Mondor, AP-HP, Créteil, France
| | - Anne-Ségolène Cottereau
- Département de Médecine Nucléaire, Hôpital Cochin, AP-HP, Université Paris Descartes, Paris, France
| | - Emmanuel Bachy
- Service d'Hématologie Clinique, Hospices Civils de Lyon, Pierre-Bénite, and Université Lyon 1, Lyon, France
| | - Guillaume Cartron
- Département d'Hématologie Clinique, Centre Hospitalo-Universitaire de Montpellier, Unité Mixte de Recherche-Centre National de Recherche Scientifique 5535, Université de Montpellier, Montpellier, France
| | - Virginie Fataccioli
- Université Paris Est Créteil, INSERM, Institut Médical de Recherche Biomédicale, Créteil, France
- Département de Pathologie, Hôpitaux Universitaires Henri Mondor, Créteil, France
| | - Laura Pelletier
- Université Paris Est Créteil, INSERM, Institut Médical de Recherche Biomédicale, Créteil, France
| | - Cyrielle Robe
- Université Paris Est Créteil, INSERM, Institut Médical de Recherche Biomédicale, Créteil, France
- Département de Pathologie, Hôpitaux Universitaires Henri Mondor, Créteil, France
| | - Audrey Letourneau
- Institut de Pathologie, Centre Hospitalier Universitaire Vaudois et Université de Lausanne, Lausanne, Switzerland
| | - Edoardo Missiaglia
- Institut de Pathologie, Centre Hospitalier Universitaire Vaudois et Université de Lausanne, Lausanne, Switzerland
| | - Slim Fourati
- Université Paris Est Créteil, INSERM, Institut Médical de Recherche Biomédicale, Créteil, France
- Service de Virologie, Département Prévention, Diagnostic et Traitement des Infections, Hôpitaux Universitaires Henri Mondor, AP-HP, Créteil, France
| | | | - Alain Delmer
- Service d'Hématologie, Centre Hospitalier Universitaire, Reims, France
| | - Reda Bouabdallah
- Service d'Hématologie, Institut Paoli-Calmette, Marseille, France
| | | | - Stéphanie Becker
- Service de Médecine Nucléaire, Centre de Lutte Contre le Cancer Becquerel, Rouen, France
| | - Céline Bossard
- Université de Nantes, Center Hospitalier Universitaire Nantes, Département de Pathologie, INSERM Centre de Recherche en Cancérologie et Immunologie Nantes Angers, Nantes, France
| | - Marie Parrens
- Département de Pathologie, Hôpital Haut-Lévêque, Pessac, INSERM U1053, Université de Bordeaux, Bordeaux, France
| | | | - Victoria Cacheux
- Service d'Hématologie, Centre Hospitalier Universitaire, Clermont Ferrand, France
| | - Caroline Régny
- Service d'Hématologie, Centre Hospitalier Universitaire, Grenoble, France
| | - Vincent Camus
- Département d'Hématologie, Centre Henri Becquerel, Rouen, France; and
| | - Marie-Hélène Delfau-Larue
- Université Paris Est Créteil, INSERM, Institut Médical de Recherche Biomédicale, Créteil, France
- Département d'Hématologie et d'Immunologie Biologique, Hôpitaux Universitaires Henri Mondor, AP-HP, Créteil, France
| | - Michel Meignan
- LYSA Image, Hôpitaux Universitaires Henri Mondor, Créteil, France
| | - Laurence de Leval
- Institut de Pathologie, Centre Hospitalier Universitaire Vaudois et Université de Lausanne, Lausanne, Switzerland
| | - Philippe Gaulard
- Université Paris Est Créteil, INSERM, Institut Médical de Recherche Biomédicale, Créteil, France
- Département de Pathologie, Hôpitaux Universitaires Henri Mondor, Créteil, France
| | - Corinne Haioun
- Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Henri Mondor, Unité Hémopathies Lymphoïdes, Créteil, France
- Université Paris Est Créteil, INSERM, Institut Médical de Recherche Biomédicale, Créteil, France
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Zhu F, Li Q, Pan H, Xiao Y, Liu T, Liu X, Li J, Wu G, Zhang L. Successful Treatment of Chidamide and Cyclosporine for Refractory/Relapsed Angioimmunoblastic T Cell Lymphoma With Evans Syndrome: A Case Report With Long-Term Follow-Up. Front Oncol 2020; 10:1725. [PMID: 32984055 PMCID: PMC7481371 DOI: 10.3389/fonc.2020.01725] [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: 05/03/2020] [Accepted: 08/03/2020] [Indexed: 11/13/2022] Open
Abstract
Background Refractory/relapsed angioimmunoblastic T cell lymphoma (AITL) with Evans syndrome is a very rare condition with a poor prognosis. There is no evidence-based treatment strategy for refractory/relapsed AITL with Evans syndrome. Case Presentation A 51-year-old female was admitted to our hospital with multiple enlarged bilateral cervical lymph nodes, more than 1 week-long chest distress, and night sweats in July 2014. An excision biopsy of the left cervical enlarged lymph node revealed AITL. However, the patient showed resistance to the first-line chemotherapy for AITL and was diagnosed with refractory AITL. Complete remission was achieved after the salvage treatment with the combination of chemotherapy, radiotherapy, and immunomodulatory agent lenalidomide. Unfortunately, 12 months later, the patient suffered from disease progression and was diagnosed as refractory/relapsed AITL with Evans syndrome according to the laboratory findings and imaging. With the diagnosis of refractory/relapsed AITL with Evans syndrome, the patient received the first-line treatment for Evans syndrome including prednisone and intravenous immunoglobulin. The response to the first-line treatment for Evans syndrome was poor. The combination regimen of chidamide (30 mg, po, biw) and cyclosporine were administrated considering the treatment targeting simultaneously both refractory/relapsed AITL and Evans syndrome. The efficacy evaluation was complete remission. The last follow-up of the patient was April 30th, 2020, and no evidence of disease progression was observed. The overall survival of the patient was more than 70 months. Conclusion The treatment for refractory/relapsed AITL combined with Evans syndrome remains challenging to patients and physicians. The combination of chidamide and cyclosporine may be an effective and tolerable regimen for the intractable AITL with Evans syndrome case and more observations are necessary to identify the efficacy and safety in the future.
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Affiliation(s)
- Fang Zhu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qiuhui Li
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huaxiong Pan
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yin Xiao
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Liu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xinxiu Liu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Juan Li
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Gang Wu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liling Zhang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Abstract
PURPOSE OF REVIEW IMiDs are a class of biologic agents with immunomodulatory, anti-angiogenic, and direct anti-cancer activities. This review summarizes current data on clinical development and application of IMiDs in non-Hodgkin lymphoma (NHL) subtypes, focusing primarily on lenalidomide, with additional discussion on managing common side effects. RECENT FINDINGS Improved upon the prototype thalidomide, the second-generation compound lenalidomide has enhanced immunological and anti-cancer properties with fewer side effects, while next-generation small molecule cereblon/E3 ubiquitin ligase modulator CC-122 is in early clinical studies. Lenalidomide is FDA-approved for treatment of relapsed/refractory mantle cell lymphoma as a single agent, as well as in combination with rituximab for R/R follicular lymphoma and marginal zone lymphoma. In addition, numerous clinical trials of lenalidomide, as single agent, in combination with anti-CD20 antibodies, or in combination with chemoimmunotherapy regimens, have shown promise in aggressive and indolent NHL in both the upfront and relapsed/refractory setting. As clinical trials with lenalidomide continue to find success in both indolent and aggressive lymphomas, IMiDs are poised to be important building blocks for combinatorial strategies with antibodies, chemotherapy, novel target agents, and emerging immunotherapy involving immune checkpoint inhibitors and chimeric antigen receptor T cell (CAR-T) therapy. Delineation of treatment-specific and disease-specific biomarkers is an important research objective to gain insight into potential mechanisms of action, and to guide future clinical development.
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Affiliation(s)
- Samuel Yamshon
- Division of Hematology and Medical Oncology, Department of Medicine, Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital, 1305 York Avenue, New York, NY, 10021, USA
| | - Jia Ruan
- Division of Hematology and Medical Oncology, Department of Medicine, Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital, 1305 York Avenue, New York, NY, 10021, USA.
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Abstract
BACKGROUND Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma, a malignant, chronic disease initially affecting the skin. Several therapies are available, which may induce clinical remission for a time. This is an update of a Cochrane Review first published in 2012: we wanted to assess new trials, some of which investigated new interventions. OBJECTIVES To assess the effects of interventions for MF in all stages of the disease. SEARCH METHODS We updated our searches of the following databases to May 2019: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We searched 2 trials registries for additional references. For adverse event outcomes, we undertook separate searches in MEDLINE in April, July and November 2017. SELECTION CRITERIA Randomised controlled trials (RCTs) of local or systemic interventions for MF in adults with any stage of the disease compared with either another local or systemic intervention or with placebo. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. The primary outcomes were improvement in health-related quality of life as defined by participants, and common adverse effects of the treatments. Key secondary outcomes were complete response (CR), defined as complete disappearance of all clinical evidence of disease, and objective response rate (ORR), defined as proportion of patients with a partial or complete response. We used GRADE to assess the certainty of evidence and considered comparisons of psoralen plus ultraviolet A (PUVA) light treatment as most important because this is first-line treatment for MF in most guidelines. MAIN RESULTS This review includes 20 RCTs (1369 participants) covering a wide range of interventions. The following were assessed as either treatments or comparators: imiquimod, peldesine, hypericin, mechlorethamine, nitrogen mustard and intralesional injections of interferon-α (IFN-α) (topical applications); PUVA, extracorporeal photopheresis (ECP: photochemotherapy), and visible light (light applications); acitretin, bexarotene, lenalidomide, methotrexate and vorinostat (oral agents); brentuximab vedotin; denileukin diftitox; mogamulizumab; chemotherapy with cyclophosphamide, doxorubicin, etoposide, and vincristine; a combination of chemotherapy with electron beam radiation; subcutaneous injection of IFN-α; and intramuscular injections of active transfer factor (parenteral systemics). Thirteen trials used an active comparator, five were placebo-controlled, and two compared an active operator to observation only. In 14 trials, participants had MF in clinical stages IA to IIB. All participants were treated in secondary and tertiary care settings, mainly in Europe, North America or Australia. Trials recruited both men and women, with more male participants overall. Trial duration varied from four weeks to 12 months, with one longer-term study lasting more than six years. We judged 16 trials as at high risk of bias in at least one domain, most commonly performance bias (blinding of participants and investigators), attrition bias and reporting bias. None of our key comparisons measured quality of life, and the two studies that did presented no usable data. Eighteen studies reported common adverse effects of the treatments. Adverse effects ranged from mild symptoms to lethal complications depending upon the treatment type. More aggressive treatments like systemic chemotherapy generally resulted in more severe adverse effects. In the included studies, CR rates ranged from 0% to 83% (median 31%), and ORR ranged from 0% to 88% (median 47%). Five trials assessed PUVA treatment, alone or combined, summarised below. There may be little to no difference between intralesional IFN-α and PUVA compared with PUVA alone for 24 to 52 weeks in CR (risk ratio (RR) 1.07, 95% confidence interval (CI) 0.87 to 1.31; 2 trials; 122 participants; low-certainty evidence). Common adverse events and ORR were not measured. One small cross-over trial found once-monthly ECP for six months may be less effective than twice-weekly PUVA for three months, reporting CR in two of eight participants and ORR in six of eight participants after PUVA, compared with no CR or ORR after ECP (very low-certainty evidence). Some participants reported mild nausea after PUVA but no numerical data were given. One participant in the ECP group withdrew due to hypotension. However, we are unsure of the results due to very low-certainty evidence. One trial comparing bexarotene plus PUVA versus PUVA alone for up to 16 weeks reported one case of photosensitivity in the bexarotene plus PUVA group compared to none in the PUVA-alone group (87 participants; low-certainty evidence). There may be little to no difference between bexarotene plus PUVA and PUVA alone in CR (RR 1.41, 95% CI 0.71 to 2.80) and ORR (RR 0.94, 95% CI 0.61 to 1.44) (93 participants; low-certainty evidence). One trial comparing subcutaneous IFN-α injections combined with either acitretin or PUVA for up to 48 weeks or until CR indicated there may be little to no difference in the common IFN-α adverse effect of flu-like symptoms (RR 1.32, 95% CI 0.92 to 1.88; 82 participants). There may be lower CR with IFN-α and acitretin compared with IFN-α and PUVA (RR 0.54, 95% CI 0.35 to 0.84; 82 participants) (both outcomes: low-certainty evidence). This trial did not measure ORR. One trial comparing PUVA maintenance treatment to no maintenance treatment, in participants who had already had CR, did report common adverse effects. However, the distribution was not evaluable. CR and OR were not assessable. The range of treatment options meant that rare adverse effects consequently occurred in a variety of organs. AUTHORS' CONCLUSIONS There is a lack of high-certainty evidence to support decision making in the treatment of MF. Because of substantial heterogeneity in design, missing data, small sample sizes, and low methodological quality, the comparative safety and efficacy of these interventions cannot be reliably established on the basis of the included RCTs. PUVA is commonly recommended as first-line treatment for MF, and we did not find evidence to challenge this recommendation. There was an absence of evidence to support the use of intralesional IFN-α or bexarotene in people receiving PUVA and an absence of evidence to support the use of acitretin or ECP for treating MF. Future trials should compare the safety and efficacy of treatments to PUVA, as the current standard of care, and should measure quality of life and common adverse effects.
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Affiliation(s)
- Arash Valipour
- Department of Dermatology, Venereology and Allergology, Johann Wolfgang Goethe-University Hospital, Frankfurt am Main, Germany
- Evidence-Based Medicine Frankfurt, Institute of General Practice, Goethe University, Frankfurt, Germany
| | - Manuel Jäger
- Department of Dermatology, Venereology and Allergology, Johann Wolfgang Goethe-University Hospital, Frankfurt am Main, Germany
- Hautklinik, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany
| | - Peggy Wu
- Department of Dermatology, University of California Davis, Sacramento, CA, USA
| | - Jochen Schmitt
- Center for Evidence-Based Healthcare, Faculty of Medicine Carl Gustav Carus, Technischen Universität (TU) Dresden, Dresden, Germany
| | - Charles Bunch
- c/o Cochrane Skin Group, The University of Nottingham, Nottingham, UK
| | - Tobias Weberschock
- Department of Dermatology, Venereology and Allergology, Johann Wolfgang Goethe-University Hospital, Frankfurt am Main, Germany
- Evidence-Based Medicine Frankfurt, Institute of General Practice, Goethe University, Frankfurt, Germany
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Zhu J, Yeoh EM, Maeda Y, Tobinai K. Efficacy and safety of single-agent pralatrexate for treatment of angioimmunoblastic T-cell lymphoma after failure of first line therapy: a pooled analysis. Leuk Lymphoma 2020; 61:2145-2152. [PMID: 32536233 DOI: 10.1080/10428194.2020.1765232] [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] [Indexed: 10/24/2022]
Abstract
Angioimmunoblastic T-cell lymphoma (AITL) is a histological subtype of peripheral T-cell lymphoma associated with a poor prognosis. This post-hoc pooled analysis aims to provide insight about the efficacy of pralatrexate monotherapy in a subset of twenty-nine patients with relapsed or refractory (r/r) AITL drawn from two prospective registration trials completed in China and Japan. After a median of two prior lines of therapy, an overall response rate of 52% (15/29 patients; 95% CI 0.34, 0.70) was demonstrated. The estimated median duration of response, progression free survival (PFS) and overall survival (OS) were 6.4 months (196 days), 5.0 months (151 days), and 18.0 months (548 days), respectively. Grades 1-3 mucositis was observed in twenty-three patients (79.3%); and hemato-toxicity in twenty-six (89.7%) patients. Results of this analysis corroborate with data from two previously reported US retrospective cohorts, supporting the potential benefits of pralatrexate monotherapy in patients with r/r AITL.
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Affiliation(s)
- Jun Zhu
- Peking University Cancer Hospital and Institute, Beijing, China
| | - Ee Min Yeoh
- Mundipharma Singapore Holdings Pte Ltd, Singapore
| | | | - Kensei Tobinai
- Department of Hematology, National Cancer Center Hospital, Tokyo, Japan
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Abstract
PURPOSE OF REVIEW Peripheral T cell lymphomas (PTCLs) are a heterogeneous group of non-Hodgkin lymphomas with inferior prognosis compared with their B cell counterparts characterized by frequent relapses, resulting in a median 5-year survival of approximately 30%. Their diverse clinicopathologic features challenge existing treatment paradigms that treat all patients uniformly. Here we review recent advances in the treatment of these diseases. RECENT FINDINGS While current treatment still relies largely on combination chemotherapy, the introduction of more effective novel and targeted therapies has improved outcomes in certain subtypes. Increasing understanding of the underlying biology of PTCL has prompted further subclassification by genetic and molecular subgroups. Overall, the most significant advances in PTCL management have resulted from improved understanding and classification of the biology of PTCL. Ongoing development of subtype-specific targeted therapies will be essential to improve long-term outcomes of patients with these diseases.
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Affiliation(s)
- Pamela B Allen
- Winship Institute of Emory University, 1365 Clifton Rd NE, Suite 4400, Atlanta, GA, USA
| | - Barbara Pro
- Department of Medicine, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 676 N. St. Clair Street, Suite 850, Chicago, IL, 60611, USA.
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Marchi E, O'Connor OA. The rapidly changing landscape in mature T-cell lymphoma (MTCL) biology and management. CA Cancer J Clin 2020; 70:47-70. [PMID: 31815293 DOI: 10.3322/caac.21589] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 10/01/2019] [Accepted: 10/15/2019] [Indexed: 02/06/2023] Open
Abstract
Historical advances in the care of patients with non-Hodgkin lymphoma (NHL) have been restricted largely to patients with B-cell lymphoma. The peripheral T-cell lymphomas (PTCLs), which are rare and heterogeneous in nature, have yet to experience the same degree of improvement in outcome over the past 20 to 30 years. It is estimated that there are approximately 80,000 and 14,000 cases, respectively, of NHL and Hodgkin lymphoma per year in the United States. As a subgroup of NHL, the PTCLs account for 6% to 10% of all cases of NHL, making them exceedingly rare. In addition, the World Health Organization 2017 classification describes 29 distinct subtypes of PTCL. This intrinsic diversity, coupled with its rarity, has stymied progress in the disease. In addition, most subtypes carry an inferior prognosis compared with their B-cell counterparts, an outcome largely attributed to the fact that most treatment paradigms for patients with PTCL have been derived from B-cell neoplasms, a radically different disease. In fact, the first drug ever approved for patients with PTCL was approved only a decade ago. The plethora of recent drug approvals in PTCL, coupled with a deeper understanding of the molecular pathogenesis of the disease, has stimulated the field to pursue new avenues of research that are now largely predicated on the development of novel, targeted small molecules, which include a host of epigenetic modifiers and biologics. There is an expectation these advances may begin to favorably challenge the chemotherapy paradigms that have been used in the T-cell malignancies.
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Affiliation(s)
- Enrica Marchi
- Department of Medicine, Center for Lymphoid Malignancies, Columbia University Medical Center, College of Physicians and Surgeons, New York, New York
| | - Owen A O'Connor
- Department of Medicine, Center for Lymphoid Malignancies, Columbia University Medical Center, College of Physicians and Surgeons, New York, New York
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Liu X, Shang Y, Li L, Zhang X, Li Z, Zhang M. Gemcitabine, cisplatin, prednisone, and thalidomide for relapse and refractory peripheral T-cell lymphoma: a retrospective study from China. Cancer Manag Res 2019; 11:8277-8284. [PMID: 31571985 PMCID: PMC6749983 DOI: 10.2147/cmar.s215585] [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: 05/13/2019] [Accepted: 08/16/2019] [Indexed: 11/23/2022] Open
Abstract
Background Peripheral T-cell lymphoma (PTCL) is often prone to relapse and progression even after formal first-line treatment, and there is no standard regimen for second-line treatment. What is more, the activity of thalidomide against this type of lymphoma is unknown. Purpose The objective of this study was to evaluate the efficacy and safety of GDPT regimen in the treatment of relapsed/refractory peripheral T-cell lymphoma. Patients and methods In this retrospective study, gemcitabine, cisplatin, prednisone, and thalidomide (GDPT) combination regimen was used as salvage protocol for PTCL that failed in first-line treatment for 29 patients and it was scheduled to give 6 cycles of GDPT therapy in order to better evaluate the efficacy unless there was evidence of disease progression, unacceptable toxicities, or refusal by the patient. Results After a total of 106 cycles of GDPT regimen were administered, the result showed that the disease control rate (DCR) achieved 82.8% and overall response rate (ORR) reached 69.0% with 34.5% complete remission (CR) and 34.5% partial remission (PR). The median progression-free survival (PFS) was 10.0 months (95% CI 6.6-13.4) and median OS was 28.0 months (95% CI 19.2-36.8). And the 1-year PFS rate and 1-year OS rate were 43.6% and 64.6%, respectively. Both hematologic and non-hematologic toxicities were moderate and well tolerated. There was no treatment-related death. Conclusion Thalidomide in combination with gemcitabine, cisplatin, prednisone regimen is a new promising approach to treating patients with relapse and refractory PTCL.
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Affiliation(s)
- Xiangli Liu
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, People's Republic of China
| | - YuFeng Shang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, People's Republic of China
| | - Ling Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, People's Republic of China
| | - Xudong Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, People's Republic of China
| | - Zhaoming Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, People's Republic of China
| | - Mingzhi Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, People's Republic of China
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Zain JM. Aggressive T-cell lymphomas: 2019 updates on diagnosis, risk stratification, and management. Am J Hematol 2019; 94:929-946. [PMID: 31119775 DOI: 10.1002/ajh.25513] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 05/17/2019] [Accepted: 05/21/2019] [Indexed: 12/26/2022]
Abstract
INTRODUCTION Aggressive T-cell lymphomas continue to have a poor prognosis. There are over 27 different subtypes of peripheral T-cell lymphoma (PTCL) and we are now beginning to understand the differences between the various subtypes beyond histologic variations. MOLECULAR PATHOGENESIS OF VARIOUS SUBTYPES OF PTCL Gene expression profiling can help in diagnosis and prognostication of various subtypes including PTCL-nos and anaplastic large cell lymphoma. In addition, mutational analysis is now being incorporated in clinical trials of novel agents to evaluate various biomarkers of response to allow better therapeutic choices for patients. TARGETED THERAPIES There are many targeted agents currently in various stages of clinical trials for PTCL that take advantage of the differential expression of specific proteins or receptors in PTCL tumors. The most promising is the CD30 directed antibody drug conjugate brentuximab vedotin. This has recently been approved by the Food and Drug Administration for the upfront treatment of CD30 expressing PTCLs in combination with cyclophosphamide, doxorubicin, and prednisone chemotherapy. Other notable targets are CD25, CCR4 tag, PI3kinase inhibitors, and JAK/STAT inhibitors. Anaplastic lymphoma kinase (ALK) inhibitors are promising for ALK expressing tumors. IMMUNOTHERAPIES The use of checkpoint inhibitors in the treatment of PTCL is still controversial. The most promising results have been seen in cases of extranodal natural killer cell/T-cell lymphomas and cutaneous T-cell lymphomas. For all other subtypes, immune checkpoint inhibitors should be used with extreme caution and only in the context of a clinical trial. Allogeneic stem cell transplant continues to be the curative therapy for most aggressive subtypes of PTCL.
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Affiliation(s)
- Jasmine M. Zain
- Department of Hematology/Hematopoietic Cell TransplantationCity of Hope Medical Center Duarte California
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Stuver RN, Khan N, Schwartz M, Acosta M, Federico M, Gisselbrecht C, Horwitz SM, Lansigan F, Pinter‐Brown LC, Pro B, Shustov AR, Foss FM, Jain S. Single agents vs combination chemotherapy in relapsed and refractory peripheral T-cell lymphoma: Results from the comprehensive oncology measures for peripheral T-cell lymphoma treatment (COMPLETE) registry. Am J Hematol 2019; 94:641-649. [PMID: 30896890 DOI: 10.1002/ajh.25463] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 02/18/2019] [Accepted: 03/12/2019] [Indexed: 11/11/2022]
Abstract
Single agents have demonstrated activity in relapsed and refractory (R/R) peripheral T-cell lymphoma (PTCL). Their benefit relative to combination chemotherapy remains undefined. Patients with histologically confirmed PTCL were enrolled in the Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment (COMPLETE) registry. Eligibility criteria included those with R/R disease who had received one prior systemic therapy and were given either a single agent or combination chemotherapy as first retreatment. Treatment results for those with R/R disease who received single agents were compared to those who received combination chemotherapy. The primary endpoint was best response to retreatment. Fifty-seven patients met eligibility criteria. At first retreatment, 46% (26/57) received combination therapy and 54.5% (31/57) received single agents. At median follow up of 2 years, a trend was seen towards increased complete response rate for single agents versus combination therapy (41% vs 19%; P = .02). There was also increased median overall survival (38.9 vs 17.1 months; P = .02) and progression-free survival (11.2 vs 6.7 months; P = .02). More patients receiving single agents received hematopoietic stem-cell transplantation (25.8% vs 7.7%, P = .07). Adverse events of grade 3 or 4 occurred more frequently in those receiving combination therapy, although this was not statistically significant. The data confirm the unmet need for better treatment in R/R PTCL. Despite a small sample, the analysis shows greater response and survival in those treated with single agents as first retreatment in R/R setting, while maintaining the ability to achieve transplantation. Large, randomized trials are needed to identify the best strategy.
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Affiliation(s)
- Robert N. Stuver
- Division of Hematologic Malignancies and and Bone Marrow Transplantation, Beth Israel Deaconess Medical Center Boston Massachusetts
| | - Niloufer Khan
- Memorial Sloan Kettering Cancer Center New York New York
| | | | - Mark Acosta
- Spectrum Pharmaceuticals, Inc. Irvine California
| | | | | | | | | | | | - Barbara Pro
- Robert H. Lurie Comprehensive Cancer Center Chicago Illinois
| | | | | | - Salvia Jain
- Division of Hematologic Malignancies and and Bone Marrow Transplantation, Beth Israel Deaconess Medical Center Boston Massachusetts
- Harvard Medical School Boston Massachusetts
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Ng SY, Jacobsen ED. Peripheral T-Cell Lymphoma: Moving Toward Targeted Therapies. Hematol Oncol Clin North Am 2019; 33:657-668. [PMID: 31229161 DOI: 10.1016/j.hoc.2019.04.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Therapeutic advances for peripheral T-cell non-Hodgkin lymphoma (PTCL) have lagged behind their B-cell NHL counterparts in part because novel agents to treat PTCL have been developed empirically. The recent clinical success of brentuximab-vedotin suggests that novel therapies for PTCL can significantly improve outcomes when properly targeted. Aberrancies in T-cell receptor, Jak/STAT, and DNA methylation pathways play critical roles in T-NHL pathogenesis based on genomic studies and preclinical experimental validation. New strategies targeting these pathways in patients with PTCL are underway, and this clinical trial experience will possibly contribute to additional improvements in outcome for patients with these diseases.
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Affiliation(s)
- Samuel Y Ng
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
| | - Eric D Jacobsen
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA
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Abstract
PURPOSE OF REVIEW Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T-cell and natural killer (NK)-cell neoplasms in the WHO 2016 classification. Patient prognosis is poor when treated with CHOP, and there is an unmet need for new drugs. Several agents have been developed for PTCL, and their use is the subject of this review. RECENT FINDINGS Phase 2 studies demonstrated the activity of new drugs in Relapsed/refractory PTCL. Only four compounds were approved by the food and drug administration: romidepsin and belinostat, which are epigenetic modifiers, the antifolate agent pralatrexate, the immuno-conjugate brentuximab vedotin. New combinations have been tested, but the results were disappointing. Given the latest progress in biology, targeted agents are evaluated in different subtypes of PTCL. Relapsed anaplastic large-cell lymphoma exhibits improved prognosis with the approved anti-CD30 drug conjugate brentuximab vedotin. Localized nasal NK/T is treated with radiotherapy and nonanthracycline chemotherapy with L-asparaginase. Recently, immune checkpoint inhibitors demonstrated activity in NK/T lymphoma and can be used in elderly patients. SUMMARY Treatment remains a challenge for PTCL, and several targeted drugs provide new approaches. Progress will be made incrementally in the different subtypes. One of the critical situations facing new drugs is the ability to run robust clinical trials in rare diseases.
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Ma H, O’Connor OA, Marchi E. New directions in treating peripheral T-cell lymphomas (PTCL): leveraging epigenetic modifiers alone and in combination. Expert Rev Hematol 2019; 12:137-146. [DOI: 10.1080/17474086.2019.1583102] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Affiliation(s)
- Helen Ma
- Center for Lymphoid Malignancies, Division of Hematology and Oncology, Department of Medicine, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY, USA
| | - Owen A. O’Connor
- Center for Lymphoid Malignancies, Division of Hematology and Oncology, Department of Medicine, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY, USA
| | - Enrica Marchi
- Center for Lymphoid Malignancies, Division of Hematology and Oncology, Department of Medicine, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY, USA
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A case of AITL complicated by EBV-positive B cell and monoclonal plasma cell proliferation and effectively treated with lenalidomide. Int J Hematol 2019; 109:499-504. [PMID: 30604313 DOI: 10.1007/s12185-018-02587-6] [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: 08/10/2018] [Revised: 12/27/2018] [Accepted: 12/27/2018] [Indexed: 12/14/2022]
Abstract
Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma with an aggressive clinical course and poor prognosis after conventional chemotherapy, for which there is no current standard of care. We describe here an 87-year-old woman with AITL, whose clinical diagnosis was complicated by the presence of B immunoblasts positive for Epstein-Barr virus in the lymph nodes and monoclonal plasma cells in the bone marrow at initial presentation. Rebiopsy of the lymph node led to the correct diagnosis of AITL with concurrent smoldering plasma cell myeloma. She was treated with several courses of conventional chemotherapy, resulting in progressive disease, and then switched to the immunomodulatory drug lenalidomide, which used in Japan for the treatment of multiple myeloma. Lenalidomide was effective in controlling both AITL and plasma cell myeloma.
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Abstract
There are a number of rare T-cell lymphoma subtypes that may be encountered in clinical practice. In recent years, improved immunohistochemical techniques and molecular tumor profiling have permitted refinement of some of the diagnostic categories in this group, as well as the recognition of distinct conditions not previously well elucidated. In this chapter, we cover the diagnostic and clinical features of some of the more common of these conditions, including subcutaneous panniculitis-like T-cell lymphoma, cutaneous gamma-delta T-cell lymphoma, enteropathy-associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma, CD4-positive small/medium T-cell lymphoproliferative disorder, and acral CD8-positive T-cell lymphoma. Given the rarity of these conditions, optimal treatments approaches are not always well established, not least as data from large-scale clinical trials are lacking. In this chapter, we aim to provide a summation of current thinking around best treatment, as well as highlighting some controversies in the management of these diagnoses.
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Affiliation(s)
- C van der Weyden
- Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia.
| | - C McCormack
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
- Department of Dermatology, St Vincent's Hospital, Fitzroy, Australia
- Department of Oncology, Sir Peter MacCallum, The University of Melbourne, Parkville, Australia
| | - S Lade
- Department of Oncology, Sir Peter MacCallum, The University of Melbourne, Parkville, Australia
- Department of Anatomical Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - R W Johnstone
- Department of Oncology, Sir Peter MacCallum, The University of Melbourne, Parkville, Australia
- Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - H M Prince
- Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia
- Department of Oncology, Sir Peter MacCallum, The University of Melbourne, Parkville, Australia
- Epworth Healthcare, Melbourne, Australia
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Ma H, Davarifar A, Amengual JE. The Future of Combination Therapies for Peripheral T Cell Lymphoma (PTCL). Curr Hematol Malig Rep 2018; 13:13-24. [PMID: 29397528 DOI: 10.1007/s11899-018-0432-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW Peripheral T cell lymphoma is a rare heterogeneous group of diseases which are characterized by poor outcomes to treatment and short overall survival. In the past decade, several new therapies targeting T cell biology have been approved in the relapsed setting. These new therapies, such as pralatrexate, romidepsin, belinostat, and brentuximab vedotin, have begun to make their way into practice. Despite these advances, outcomes have not changed dramatically. In recent years, efforts have been made to incorporate these new therapies into combination strategies to treat this challenging disease entity. Herein we will review some of the latest developments. RECENT FINDINGS With the new WHO classification, discrete entities of PTCL are now being identified by molecular and phenotypic markers. This new classification is critical to our ability to define disease entities which may respond to certain classes of targeted therapy. Some such mutations include genes controlling epigenetics (TET2, IDH2, DNMT3A, RHOA, CD28). As such, epigenetic therapies such as histone deacetylase (HDAC) inhibitors have become the platform to which other novel therapies or chemotherapy has been added. Early phase clinical studies have demonstrated that combination therapy with romidepsin plus other agents known to have activity in T cell lymphoma have enhanced clinical benefit for this group of diseases. In addition, the antibody drug conjugate, brentuximab vedotin has been shown to have potent activity in T cell lymphomas expressing CD30. This drug is being studied as well with other targeted therapies and chemotherapy in an effort to improve response rates and progression-free survival. Although T cell lymphomas remain a highly challenging group of diseases to treat, new efforts to leverage drugs that discretely target the biology that drives T cell lymphomagenesis in combination provide hope that improved outcomes may be realized in the near future.
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Affiliation(s)
- Helen Ma
- Center for Lymphoid Malignancies, Division of Hematology and Oncology, Department of Medicine, Columbia University Medical Center, 51 West 51st Street, Suite 200, New York, NY, 10019, USA
| | - Ardy Davarifar
- Center for Lymphoid Malignancies, Division of Hematology and Oncology, Department of Medicine, Columbia University Medical Center, 51 West 51st Street, Suite 200, New York, NY, 10019, USA
| | - Jennifer E Amengual
- Center for Lymphoid Malignancies, Division of Hematology and Oncology, Department of Medicine, Columbia University Medical Center, 51 West 51st Street, Suite 200, New York, NY, 10019, USA.
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Tse E, Kwong YL. Immunologic Milieu of Mature T-Cell and NK-Cell Lymphomas-Implications for Therapy. Curr Hematol Malig Rep 2018; 13:37-43. [PMID: 29396703 DOI: 10.1007/s11899-018-0437-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
PURPOSE OF THE REVIEW T-cells and natural killer (NK) cells share the same ontogeny, and lymphomas derived from them are clinically diverse, occurring in nodal and extranodal sites. In addition to inherent properties of these lymphomas, their microenvironment also impacts on pathogenesis and response to therapy. An understanding of the milieu of T-cell and NK cell lymphomas has important implications on treatment. RECENT FINDINGS Components of the microenvironment include tumour-associated macrophages (TAM), non-neoplastic T-cells and B-cells, eosinophils, dendritic cells, endothelial cells and blood vessels. TAM typically undergoes M2 polarization, promoting angiogenesis and inhibiting anti-tumour cellular immunity. In lymphomas of follicular helper T-cell derivation, increased B-cell proliferation occurs, which may in turn enhance neoplastic T-cell growth. The expression of immune checkpoint ligands on TAM, dendritic cells or lymphoma cells induces an immunosuppressive environment conducive to neoplastic proliferation. Strategies against this complex cellular and immunologic microenvironment have shown promises. These include the use of signal transduction inhibitors, monoclonal antibodies against chemokines or non-neoplastic microenvironmental cells, immunomodulatory drugs and immune checkpoint blockade. As T-cell and NK cell lymphomas are highly heterogeneous, clinical trials to demonstrate efficacy of a given therapeutic approach requires careful design aiming at enriching patient populations who will best respond. Targeting of the immunologic milieu in T-cell and NK-cell lymphomas offers exciting challenges and opportunities.
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MESH Headings
- B-Lymphocytes/immunology
- B-Lymphocytes/pathology
- Cell Proliferation
- Dendritic Cells/immunology
- Dendritic Cells/pathology
- Humans
- Lymphoma, Extranodal NK-T-Cell/immunology
- Lymphoma, Extranodal NK-T-Cell/pathology
- Lymphoma, Extranodal NK-T-Cell/therapy
- Lymphoma, T-Cell, Peripheral/immunology
- Lymphoma, T-Cell, Peripheral/pathology
- Lymphoma, T-Cell, Peripheral/therapy
- T-Lymphocytes, Helper-Inducer/immunology
- T-Lymphocytes, Helper-Inducer/pathology
- Tumor Microenvironment/immunology
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Affiliation(s)
- Eric Tse
- Department of Medicine, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong, China
| | - Yok-Lam Kwong
- Department of Medicine, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong, China.
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50
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Van Der Weyden C, Dickinson M, Whisstock J, Prince HM. Brentuximab vedotin in T-cell lymphoma. Expert Rev Hematol 2018; 12:5-19. [DOI: 10.1080/17474086.2019.1558399] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Affiliation(s)
| | - Michael Dickinson
- Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - James Whisstock
- ARC Centre of Excellence in Advanced Molecular Imaging, Biomedicine Discovery Institute, Department of Biochemistry, Monash University, Melbourne, Australia
| | - H. Miles Prince
- Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia
- Epworth Healthcare, Richmond, Australia
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