|Year : 2020 | Volume
| Issue : 1 | Page : 74-75
T-cell lymphoma: Seeking triumph in the tumult
Department of Haemato-Oncology, Kingston Hospital NHS Foundation Trust; Lead for Commercial Education and Training, Haematology Institute, King's College Health Partners; King's College, London, UK
|Date of Submission||17-Dec-2019|
|Date of Decision||26-Dec-2019|
|Date of Acceptance||27-Dec-2019|
|Date of Web Publication||24-Feb-2020|
Kingston Hospital, Kingston upon the Thames, London
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Jayakar V. T-cell lymphoma: Seeking triumph in the tumult. Cancer Res Stat Treat 2020;3:74-5
Peripheral T-cell lymphomas (PTCLs) remain a hard nut to crack with their clonal heterogeneity and aggressive phenotype, plagued with poor progression-free survival (PFS) and overall survival (OS) rates in sharp contrast to their B-cell counterparts. However, the battle to gain inroads into their complex biology to engender personalized therapeutic algorithms has seen a few wins with abundant hope on the horizon!
Although this editorial presents a realistic narrative about the outcomes of T-cell lymphomas, it aspires to highlight the optimistic hot spots that deserve the reader's enthused attention.
Radhakrishnan's original article painstakingly maps the trajectory of 144 patients with PTCL treated at Cancer Institute (WIA) in Chennai, India, over 17 years. Most of their demographics are commensurate to previously published literature, with PTCL-not otherwise (NOS) being the most common subtype and ALK-positive anaplastic large cell lymphoma (ALCL) being the most buoyant with survival outcomes. The second retrospective observational cohort study from Malabar Cancer Centre in Kerala by Manuprasad et al. outlines the feasibility of outpatient-based salvage chemotherapy–gemcitabine, dexamethasone, and cisplatin in relapsed lymphoma inclusive of diffuse large B-cell lymphoma, Hodgkin's lymphoma, and PTCL. Again, the outcomes for their nine PTCL patients were dismal with both 2-year PFS and OS of 11%.
The lack of flow cytometry and immunohistochemistry data in both studies, possibly because of unavailability in their earlier cohort, makes any judgment about targeted treatment untenable. With universal expression in ALCL and variable expression in other subtypes, CD30 has emerged as a tangible robust target in PTCLs. Brentuximab vedotin (BV) is an antibody–drug conjugate consisting of an anti-CD30 monoclonal antibody linked to monomethyl auristatin E, which inhibits microtubules. The iconic ECHELON-2 study, a 452-patient international, randomized, double-blind, Phase III study compared BV combined with cyclophosphamide, doxorubicin, prednisone (CHP) to CHOP in patients with PTCL expressing CD30 in at least 10% of malignant cells by immunohistochemistry, demonstrated that patients treated with BV-CHP had an improvement in median PFS from 20.8 months to 48.2 months compared with CHOP.
Although the authors do allude to using crizotinib in four patients for targeting ALK-positive ALCL, the lack of use of brentuximab as a potent targeted agent, particularly in the relapsed setting due to financial constraints, remains lamentable. Since 2009, there have been three drugs other than BV that have been approved by the Food and Drug Administration for the treatment of relapsed PTCL: pralatrexate, romidepsin, and belinostat. We surmise that these were not available for use in both of these cohorts because of unimpressive response rates ~30% and prohibitive costs. Transplant numbers also seem to be lower in the relapsed setting in both these series, another deplorable epidemiological motif. Unavailability and access remain difficult issues around acquisition of these drugs in India, but a fightless submission to this Achilles heel would be a convenient and complacent argument against the use of effective drugs; not the right one. An active and scrupulous attempt to engage industry, perhaps to make these available for the deserving patient clientele, should be a realistic aspiration for cancer clinicians.
Collating data and championing for promising new agents in the setting of translational research for rare malignancies such as PTCL remain a formidable challenge, even in the Western world. Going forward, the authors should attempt to collaborate with other institutes with similar patient numbers in a prospective setting to bulk the cohort size and attract industry support for novel promising drugs.
Several druggable targets apart from CD30 and ALK in PTCL such as phosphoinositide-3-kinase, Janus kinase and signal transducer and activator of transcription proteins, spleen-associated tyrosine kinase, and inducible co-stimulator of the CD28 (B7) family are being actively explored with single and combination drugs in Phase I/II settings.
The way forward to making meaningful strides in the tumultuous terrain of T-cell lymphomas is going back to the bench and synergizing efforts with our basic science researchers. Better understanding of the biology of these diseases based on gene expression profiling, minimal residual disease evaluation (positron emission tomography–computed tomography and cell-free DNA), and modeling in patient-derived xenografts should help define mechanisms of response and resistance to therapy. An illuminant example of this is a novel gene expression profile in PTCL recently published by Heavican et al. that helps further subclassify forms of PTCL into four distinct groups according to the predominance of GATA3 expression, TBX21 expression, follicular T-cell lymphoma (FTCL) phenotype, and those not able to be classified. Those with PTCL-GATA3 subgroup had higher mutational complexity, including deletion of tumor suppressors such as p53, CDKN2A, PTEN, and FAS and gain of MYC and STAT3. These were associated with inferior survival. In contrast, those with the PTCL-TBX21 subgroup had less aberrant genomes but were more likely to have gains in cell cycle regulators and immune regulatory genes. Those who had FTCL phenotype had frequent mutations of genes regulating the epigenome (TET2, IDH2, and DNMT3A), as well as TCR and costimulatory signaling pathway mutations.
In conclusion, although both retrospective studies are a laudable effort in inspecting and reflecting on clinical practices in tenacious lymphoma subtypes (focusing on PTCL), several unmet needs prevail. A resolute interface between the bench and bedside along with collaborative multi-institute steering to optimize PTCL patient outcomes remains the only way to break the impasse staged by these aggressive T-cell lymphomas.
| References|| |
Radhakrishnan V. Clinicopathological characteristics, prognostic factors and outcomes in peripheral T-cell lymphoma: Experience from a single center in India. Cancer Res Stat Treat 2020;3:3-12. [Full text]
Vose J, Armitage J, Weisenburger D, International T-Cell Lymphoma Project. International peripheral T-cell and natural killer/T-cell lymphoma study: Pathology findings and clinical outcomes. J Clin Oncol 2008;26:4124-30.
Manuprasad A, Shenoy PK, Raghavan V, Shiljina KM, Nair CK. Gemcitabine, dexamethasone, cisplatin (GDP) salvage in relapsed lymphomas-A single institutional experience. Cancer Res Stat Treat 2020;3:13-8. [Full text]
Federico M, Bellei M, Luminari S, Horwitz SM, Montoto S, Emanuele Zucca E, et al
. CD30+ expression in peripheral T-cell lymphomas (PTCLs): A subset analysis from the international, prospective T-cell project. J Clin Oncol 2015;33:8552.
Horwitz S, O'Connor OA, Pro B, Illidge T, Fanale M, Advani R, et al
. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): A global, double-blind, randomised, phase 3 trial. Lancet 2019;393:229-40.
Philip CC, Mathew A, John MJ. Cancer care: Challenges in the developing world. Cancer Res Stat Treat 2018;1:58-62. [Full text]
Mehta-Shah N. Emerging strategies in peripheral T-cell lymphoma. Hematology Am Soc Hematol Educ Program 2019;2019:41-6.
Heavican TB, Bouska A, Yu J, Lone W, Amador C, Gong Q, et al
. Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma. Blood 2019;133:1664-76.