Peripheral T-cell lymphoma

Executive Summary

Peripheral T cell lymphoma (PTCL), a subtype of T-cell non-Hodgkin lymphomas (NHLs) that differs from the more prevalent cutaneous T-cell lymphomas, are a heterogeneous collection of illnesses with a dismal prognosis for the most part. Mature T-cell lymphomas are classified into four major groups depending upon the clinical criteria. Extranodal NK-/T-cell lymphoma is one type of NK-cell lymphoma. Patients with Peripheral T-cell lymphomas had a worse prognosis than those with aggressive B-cell lymphomas. Research on Peripheral T-cell lymphomas gene expression profiling has been reported. Gene expression profiling studies of more considerable patients have recently been conducted providing new insights into numerous Peripheral T cell lymphoma entities. Traditional cytogenetic studies have also shed light on copy number changes in Peripheral T-cell lymphomas. T-cell lymphomas have generally been treated with a combined chemotherapy regimen in the same way as B-cell lymphomas have been treated. New therapy techniques and the inclusion of novel medicines into conventional therapeutic regimens are required to enhance the result in Peripheral T-cell lymphomas patients. The use of immunoconjugates and monoclonal antibodies have been added to chemotherapy regimens in the case of Peripheral T-cell lymphomas. The use of antifolates is used as a treatment for peripheral T-cell lymphomas. Immunosuppressants and immunomodulators such as cyclosporine, bevacizumab, rituximab, lenalidomide, and thalidomide, are being investigated as single medicines in combination with chemotherapy. Also, subsets of Peripheral T-cell lymphomas patients will benefit from transplantation. Novel treatments for aggressive T-cell lymphomas are needed due to the poor results of CHOP-based regimens. Hence, the current state of Peripheral T-cell lymphoma categorization, prognosis, and therapy options have represented significant progress in the domain.

What is Peripheral T-cell lymphoma?

Peripheral T-cell lymphoma are a diverse group of clinically aggressive diseases with poor prognosis. Studies concentrating on PTCL are becoming more common, with the ultimate goal of bettering our understanding of disease biology and developing more effective treatments ​1​. However, the rarity of these subgroups is one of the challenges in identifying and investigating therapy alternatives in clinical trials. Various organizations have defined Lymphoma classifications, including the World Health Organization, which updated its category in 2008. This article gives a quick overview of the significant lymphoma categorization schemes and highlights the contributions of the International Peripheral T cell lymphoma Project.

The International Peripheral T-cell lymphomas Project’s contributions are highlighted on this page, which provides a concise review of the effective lymphoma categorization methods. Standard chemotherapy regimens and antifolates, conjugates, histone deacetylase inhibitors, monoclonal antibodies, nucleoside analogues, proteasome inhibitors, and signalling inhibitors are among them. As this analysis points out, the issue has morphed into an overabundance of medications and insufficient testing of patients. Future efforts to determine the optimal treatment solutions for people with PTCL will benefit from collaborative groupings.


Peripheral T-cell lymphomas (PTCL), a subtype of T-cell non-Hodgkin lymphomas (NHLs) that differs from the more prevalent cutaneous T-cell lymphomas, are a heterogeneous collection of illnesses with a dismal prognosis for the most part ​1​. The classification of Peripheral T cell lymphoma is problematic, resulting in a plethora of classification methods and a lack of molecular markers. The Rappaport system was used until the mid-1970s. The Kiel system, established in 19742, and the National Cancer Institute’s Working Formulation, adopted in the 1980s, are examples of older lymphoma classification systems.

T-cell lymphomas were first discovered as separate from B-cell lymphomas thanks to the work of Lukes, Collins, and Lennert in the 1970s, but this was initially met with scepticism. The International Lymphoma Study Group proposed the REAL classification (updated European-American Classification of Lymphoma Neoplasms) in 1994. It included the primary histologic, immunologic, and genetic characteristics of B- and T-cell neoplasms and Hodgkin lymphoma. 4 The International Lymphoma Study Group categorization of NHL was clinically evaluated in 1997. The results showed that the classification could be easily implemented and recognize clinically distinct kinds of NHL.

Inter Lymph, the International Lymphoma Epidemiology Consortium, presented a nested taxonomy of lymphoid neoplasm subgroups in 2007 ​2​. They used the World Health Organization’s (WHO) lymphoid neoplasm categorization and the International Classification of Diseases for Oncology to determine their type (3rd ed). In 2008, the WHO published the fourth edition of the WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. Many more Peripheral T-cell lymphomas subtypes are included in the new WHO classification. It may or may not assist doctors in determining the optimum therapy strategy for each subtype. The International PTCL Project is an international collaboration that better understands the distribution and consequences of aggressive T-cell lymphomas. Twenty-two institutions and over 1300 eligible patients from North America, Europe, and Asia took part in the study, and clinical and pathologic data on PTCLs identified and treated at their centres were submitted.

In 2008, the WHO classification for PTCLs was modified. The revised taxonomy introduced numerous new provisional disorders and enlarged certain existing diseases. The International PTCL Project is an international collaboration that better understands the distribution and consequences of aggressive T-cell lymphomas. In total, 22 institutions and over 1300 eligible patients from North America, Europe, and Asia took part in the study, and clinical and pathologic data on PTCLs identified and treated at their Centres were submitted.

In 2008, the WHO classification for Peripheral T cell lymphoma was modified. The revised taxonomy introduced numerous new provisional disorders and enlarged certain existing diseases.

Classification of Peripheral T-cell lymphomas

The WHO classification system divides mature T-cell lymphomas into four groups based on clinical criteria ​3​. The nodal, extranodal, and leukemic categories contain the majority of aggressive T-cell lymphomas. Peripheral T-cell lymphomas, not otherwise specified (NOS), which accounts for 25.9% of cases, anaplastic large cell lymphoma (ALCL), and angioimmunoblastic T-cell lymphoma are all included in the nodal lymphoma group (AITL). ALCL is further divided into two groups: ALK+ and ALK. ALK ALCLs are visually and immunophenotypically similar to ALK+ ACLs, but they lack ALK expression and have unique molecular characteristics.

According to the International PTCL study, ALK+ ALCL accounts for 6.6 per cent of PTCL cases, while ALK ALCL accounts for 5.5 per cent. Because the therapy and prognosis of cutaneous ACLs differ from those of systemic ACLs, they are classified as different disorders. AITL is the second-largest category in the International Peripheral T cell lymphoma Project, accounting for 18.5 per cent of cases. The lymphoepithelial cell variation differs from the others in that it is characterized by CD8+ T cells in the background and a predominance of epithelioid cells. The extranodal category includes several uncommon entities classified mainly through tissue tropism. 

Hepatosplenic T-cell lymphoma, which accounts for 1.4 per cent of all Peripheral T-cell lymphomas cases, is a disease that affects children and young adults ​4​. Immature or non-activated T lymphocytes infiltrate the liver, spleen, and bone marrow sinusoids, resulting in this tumour. Isochromosome 7q is a common chromosomal defect, and patients with Hepatosplenic T-cell lymphoma frequently have a dismal prognosis, with a median survival of fewer than two years. Young guys are more likely to develop the condition, which manifests as B-symptoms and cytopenia. CD2+, CD3+, CD4+, CD5+, CD7+, CD8+, or CD8 cells are common, and they may also express natural killer (NK) markers.

Enteropathy-associated T-cell lymphoma (EATL) is a type of T-cell lymphoma that affects 4.7 per cent of people. EATL is more common in areas where celiac disease is more prevalent, as indicated by the fact that it accounts for 5.8% and 9.1 per cent of Peripheral T-cell lymphomas in North America and Europe, respectively just 1.9 per cent in Asia ​5​. Pain, weight loss, and bowel perforation are common symptoms of the condition. The pleomorphic type is associated with celiac disease and is frequently CD3+, CD7+, and CD56, and the monomorphic type, which is CD56+ and often not associated with celiac disease, are the two morphologic types.

In up to 70% of EATL patients, chromosomal abnormalities include gains at chromosome 9q33-q34. Intestinal T- and NK-cell lymphomas are part of the spectrum of nasal-type NK-/T-cell lymphoma and are related to Epstein-Barr virus (EBV) infection in Asian nations. 17 Mucocutaneous T-cell lymphomas, nasal type NK-/T-cell lymphomas, and ALCLs can all present as intestinal lymphomas. Panniculitis-like T-cell lymphomas account for just 0.9 per cent of all Peripheral T cell lymphoma, and they are more common in men (75 per cent of cases) than in women, according to the International PTCL Project. Patients frequently have subcutaneous nodules that develop necrotic over time.

The neoplastic cells are usually CD3+, CD4+, and CD8+, with either TCR–/+ or TCR–/+, and they infiltrate surrounding the fat cells in a rim-like pattern. Because the outcome of patients with panniculitis-like T-cell lymphomas is much worse than that of patients with the type, they have been categorized as cutaneous T-cell lymphoma. Adult T-cell lymphoma (ATL) associated with human T-lymphotropic virus type I (HTLV-1), T-cell chronic prominent granular lymphocytic (LGL) leukaemia, aggressive NK-cell leukaemia, and T-cell prolymphocytic leukaemia are all included in the leukaemia group. The majority of patients with LGL leukaemia have an indolent disease frequently accompanied by neutropenia. Although aggressive NK-cell leukaemia and ATL have a dismal prognosis, immunosuppressive drugs are used to treat them.

Hydro is a vacciniform-like lymphoma, usually of T-cell origin, NK-cell lymphoma caused by mosquito bite allergy, and systemic EBV-positive T-cell lymphoproliferative disease of childhood, which is part of the spectrum chronic, active EBV infection, are all included in the WHO classification.

T-cell lymphomas are becoming more common. According to the United States Surveillance, Epidemiology, and End Results registry, the incidence of Peripheral T-cell lymphomas in the United States is 1 case per 100 000 persons. The International Peripheral T cell lymphoma Project discovered that nodal T-cell lymphomas are the most common subtypes around the world, with PTCL-NOS (25.9%) being the most common, followed by AITLs (18.5%) and ACLs (12 per cent). NK/T-cell lymphomas made up 10.4% of the total. Still, enteropathy-associated T-cell lymphomas (4.7%), Hepatosplenic T-cell lymphomas (1.4%), and panniculitis-like T-cell lymphomas (0.9%) were uncommon, even in this significant sample. There are regional variances in frequency among the common subtypes.

AITL is more prevalent in Europe than in Asia or North America; ALK+ ALCL is more common in North America; ALK ALCL is somewhat more common in Europe, and NK/T-cell lymphomas and ATL are more common in Asia. 23 The human leukocyte antigen DQ is intimately linked to the epidemiology of EATL, which results in either overt or silent celiac disease, a European condition. EBV-associated lymphoproliferative, T-cell, and NK-cell neoplasms are most common in Japan, Korea, Northern China, and Central and South American Native American populations. Males are more likely than females to develop NK-cell nasal and nasal-type lymphomas, more common in Asia and Latin America.

T-cell lymphomas and viral associations

The frequency of endemic HTLV-1 and EBV infections are linked to the increased incidence of T-NK-cell lymphomas in East Asia. Gallo’s team discovered the HTLV-1 virus in a cell line derived from a patient with cutaneous T-cell lymphoma at the National Cancer Institute ​6​. Yoshida et al. in Japan found a retrovirus that was immunoreactive to sera from T-cell leukaemia patients at the same time ​7​. The unique genomic structure of HTLV-1 distinguished it from other animal retroviruses, resulting in a new retroviral group. HTLV-2, STLV, and BLV are all members of this viral family. Live infected T lymphocytes, such as T cells in breast milk, T cells in sperm, and new T cells in blood carriers of HTLV-1 proviruses, are assumed to be required for viral transmission. Angioimmun ATL is defined by a clonal increase of CD4+ T cells, often accompanied by a rash, lymph node and visceral involvement, and hypercalcemia. The HTLV-1 Tax protein and persistent nuclear factor-B activation are thought to be involved in T cell transformation in the early stages of ATL.

AITL has a polymorphous infiltration with medium-sized neoplastic cells, significant arborizing blood vessels, follicular dendritic cell proliferation, and scattered EBV+ B-cell blasts, among other characteristics. According to recent research, AITL is formed from the follicular helper T cells, a unique T-cell subset found in the germinal centre (TFH). The transformation of these TFH cells has been linked to 28-31 viruses. Aside from EBV, which is identified in B-cell blasts and is thought to have a role in developing EBV-associated B-cell lymphoma in some AITL patients, HHV6B, a human herpes virus, has been identified been found in about half of AITL cases. Although viral infection is most likely a symptom of underlying immunological dysfunction, EBV and HHV6B may affect cytokines, chemokines, and membrane receptors.

NK-cell lymphoma and T-cell lymphoma

Extranodal NK-/T-cell lymphoma is one type of NK-cell lymphoma. It is the nasal kind. Blastic NK-cell lymphoma is a type of lymphoma that affects the immune system ​8​. 10.4% of Peripheral T-cell lymphomas cases are aggressive NK-cell leukemia. Most NK-cell lymphomas have been identified and classified as lymphoid neoplasms by the World Health Organization (WHO); however, certain other NK-cell lineage neoplasms have yet to be organized. These diseases are examples of myeloid/NK-cell precursor acute leukemia, precursor NK-cell acute lymphoblastic leukemia, and chronic reactive NK-cell lymphocytosis. Nasal/NK-cell lymphomas and aggressive NK-cell leukemia tumor cells have been linked to EBV. Other factors, however, could be at play. The presence of epithelial carcinomas in 10 of 23 cases of NK-/T-cell lymphoma of the oral cavity in a recent Chinese study implies that other oncogenic drivers may be involved in addition to EBV.

T-cell lymphoma prognostic factors

In general, patients with Peripheral T-cell lymphomas had a worse prognosis than those with aggressive B-cell lymphomas. Overall survival (OS) and failure-free survival (FFS) with PTCL-NOS were both 10% at 10 to 15 years in the International T-cell Lymphoma Study ​9​.

When the International Prognostic Index (IPI) was applied to patients with aggressive T-cell lymphomas, it revealed that those with a high IPI score had a worse prognosis than those with a low IPI score, comparable to diffuse large B-cell lymphoma. Patients in the best prognosis category, on the other hand, did not have a good outcome, and those in the highest risk category had a very short survival. Patients with PTCL-NOS and AITL who had an IPI of 0 to 1 had a 5-year OS of 56 per cent and 50 per cent, respectively, whereas those with an IPI of 4 or 5 had a 5-year OS of 11 per cent and 25 per cent, respectively.

Patients with ALCL who had IPI 0 to 1 had excellent 5-year survival rates of 90 per cent and 74 per cent for ALK+ and ALK patients, respectively; however, patients with IPI 4 to 5 had a poor 5-year survival rate of 33 per cent and 13 per cent, indicating that IPI is a significant predictor, even in ALK+ patients. The IPI is not predictive of outcome in patients with ATLL, enteropathy-associated and Hepatosplenic T-cell lymphoma, or extra nasal NK-/T-cell lymphoma.

The prognosis index for Peripheral T-cell lymphomas, a new prognostic index specifically established for PTCL36, is similar to the IPI and includes age, lactate dehydrogenase, performance status, and then bone marrow involvement. The index segregated patients into more distinct prognostic groupings than the IPI when applied to PTCL-NOS patients. Twenty per cent of the 322 patients evaluated had no negative characteristics, 34 per cent had one, 26 per cent had two, and 20 per cent had three or more. Patients with no destructive prognostic features had a 5-year OS of 62 per cent, compared to 18 per cent for those with three or four negative prognostic markers.

Aside from traditional histology, chemokine expression and proliferative signatures, such as p53 and Ki-67, have been demonstrated to have predictive value. In one study, p53 was the most crucial prognostic predictor, and it was linked to the expression of P-glycoprotein, which confers chemotherapy resistance. Furthermore, BCL2- and BCL XL-associated proteins are expressed in 40-60% of Peripheral T-cell lymphomas patients. BCL2 is frequently hostile in ALK+ ALCL, but BCL2+ in other subtypes has a worse prognosis.

CXCR3 and CCR4 chemokine receptors were expressed in 63 per cent and 34% of PTCL-NOS tumours, respectively. CXCR3-positive/CCR4-negative chemokine expression was the most common in this study; multivariate analysis revealed that this phenotype was an independent prognostic factor and substantially predicted a poor prognosis in both PTCL-NOS and ALK-negative ALCL.

Rudiger et al. observed that the presence of > 70% transformed blasts, > 25% Ki67 proliferation, CD56 and CD30 expression, EBV infection, and background of > 10% CD8+ cells were poor prognostic markers in the PTCL-NOS group. Immunophenotyping is required to evaluate prognosis, according to the findings. In another study, a multivariate analysis of all prognostic parameters found that if the percentage of altered cells is > 70%, the hazard ratio for OS is 2.2 and 1.6 for FFS after correcting for IPI.40 The existence of the minor cell variation in ALCL patients has been linked to a worse prognosis. Finally, survival is harmed by the expression of cytotoxic chemicals.

Information about gene expression, cytogenetics, and comparative genomic hybridization

Research studies on Peripheral T-cell lymphomas gene expression profiling have been reported. The framework for understanding cell-of-origin and functional features of T-cell malignancies has been provided by expression profiling of pure normal T-cell subpopulations. These investigations have served to identify the regular counterpart of several distinct PTCLs, revealed mechanisms frequently changed in PTCLs, such as nuclear factor-B signaling and cell-cycle dysregulation, and underlined the importance of proliferation as a potential prognostic biomarker ​10​. However, most of these studies are underpowered to make conclusive judgments about survival prediction. Large sample sizes will be required to develop molecular outcome predictors in PTCL, which would necessitate international collaboration.

Gene expression profiling studies of more considerable patients have recently been conducted, and they have provided new insights into numerous PTCL entities ​11​. Iqbal et al. looked at 144 instances and were able to validate several earlier findings ​12​. Furthermore, they demonstrated that the microenvironment played a crucial role in AITL and generated a 15-gene outcome predictor that is substantially linked with survival and independent of the IPI. They also detected a subset of PTCL-NOS with cytotoxic properties and a worse survival rate.

Huang et al. used a combination of microarray analysis and array comparative genomic hybridization to study a significantly smaller number of extranodal NK/T-cell lymphomas of the nasal type ​13​. These researchers discovered significant differences in gene expression in these tumors compared to normal NK cells, including significant overexpression of granzyme H; evidence for overexpression of PDGFRA similar to PTCL-NOS; and a possible role for the novel tumor suppressor gene HACE1, which maps to the 6q21 region, in NK-/T-cell lymphomas.

Traditional cytogenetic studies have also shed light on copy number changes in Peripheral T-cell lymphomas. A recent study of PTCL-NOS, AITL, and ALK ALCL found periodic modifications linked to specific entities, such as gains of 5q, 21, and 3q in AITL, which are typically associated with chromosome 5 and 21 trisomies ​14​. There was also a lot of loss of genetic material on chromosome 6q. Gains of 1q and 3p were observed in ALK ALCL, while losses of 16pter, 6q13-21, 15, 16qter, and 17p13 were observed. 7q22-31, 1q, 3p, 5p, and 8q24qter exhibited constant gains, while 6q22-24 and 10p13pter showed steady losses. The OS was shorter in cases with a complicated karyotype.

Although the clonal expansion of TCR altered cells is seen in many subtypes of PTCL, this may not be the case in all cases of NK neoplasms. TCR rearrangements were found in 0.8 per cent to 1.2 per cent of cases in two recent investigations that looked into the lack of TCR rearrangements in these patients.

The researchers employed comparative genomic hybridization to look at genomic changes in patients with ALK+ and ALK ALCL. A study of 74 individuals discovered that ALK+ ALCL samples had gains of 17p and losses of 4q13-q21 and 11q14, whereas ALK pieces had more significant gains of 1q and 6p21.

Finally, considerable advancement in our understanding of the genetic complexity of Peripheral T-cell lymphomas will necessitate a collaborative international effort to examine multiple well-annotated cases utilizing next-generation sequencing techniques. This method, it is safe to assume, will give valuable information concerning recurrent mutations and new fusions that underpin the essential events in the biology of these tumours. To correctly document all physical changes, matched constitutional DNA will be required.

Methods of treatment for PTCL

T-cell lymphomas have generally been treated with a combined chemotherapy regimen in the same way as B-cell lymphomas have been treated. Although no randomized studies established that CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) was the best therapy, it was the most extensively utilized. A 5-year OS of 37 per cent was reported in a retrospective meta-analysis of 2912 patients treated with CHOP or CHOP-like regimens. Several organizations have tried more severe chemotherapy therapies for Peripheral T-cell lymphomas patients. For younger, fitter patients, the French Groupe d’Etude des Lymphomas de l’Adulte (GELA) employed ACVBP (dose-intensified doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone) plus consolidation with autologous stem cell transplantation (ASCT).

The German High-Grade Non-Hodgkin Lymphoma Study Study utilized several variants of CHOP, while an Italian group used high-dose sequential chemotherapy with ASCT. The M. D. Anderson Cancer Center used a combination of triple therapy and hyper-CVAD to treat patients (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone). According to the GELA, when compared to CHOP, ACVBP showed higher toxicity but better event-free survival and OS. In older patients, CHOP-14 outperformed CHOP-21 or CHOP with etoposide,68 and CHOP plus etoposide should be utilized in younger patients.

ALCL patients have a higher overall response rate (ORR) and 5-year OS rates than non-ALCL patients, with ORRs exceeding 75% and 5-year OS rates above 60%. Patients with ALK+ ALCL have the slightly better OS and FFS rates than those with ALK ALCL, but this could be due to an age difference, as ALK+ patients are often younger than ALK patients. Even in ALK+ ALCL patients, however, 5-year FFS rates were just 49%, indicating a clear need for novel medicines or subtype-specific treatments. It’s unknown why patients with severe T-cell lymphomas respond to standard B-cell lymphoma treatments less well. Data on the expression of P-glycoprotein and other drug resistance pathways in subgroups of patients, notably those with NK-/T-cell lymphomas, is still emerging.

Inventive approaches

New therapy techniques and the inclusion of novel medicines into conventional therapeutic regimens are required to enhance the result in Peripheral T-cell lymphomas patients ​15​.

Immunoconjugates and monoclonal antibodies

The anti-CD20 monoclonal antibody rituximab, when added to chemotherapy regimens like CHOP, has considerably improved B-cell lymphoma treatment outcomes. Alemtuzumab, iratumumab, siplizumab, zanolimumab, denileukin diftitox, and brentuximab vedotin are monoclonal antibodies, targeted immunoconjugates, and fusion proteins being studied in Peripheral T-cell lymphomas ​16​.

In one early research, alemtuzumab, an anti-CD52 monoclonal antibody, was reported in extensively treated patients with PTCL, with an ORR of 36%. Alemtuzumab has been used in PTCL with some success in combination with CHOP or EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin), with half of the patients having a complete response (CR). 73,74 In separate research, alemtuzumab was combined with CHOP, EPOCH, and IMVP16-PL (ifosfamide plus mesna, methotrexate, etoposide, and prednisone) in newly diagnosed PTCL patients,75 and alemtuzumab was combined with CHOP and ESHAP (etoposide, methylprednisolone, and high-dose cytarabine.

Despite the high overall response rates, the immunosuppressive effects of alemtuzumab have been linked to an increased risk of opportunistic infections. Patients in these studies have to be monitored for CMV reactivation regularly. A randomized trial comparing CHOP-14 to alemtuzumab-CHOP 14 is currently underway in a European intergroup study. 

In CD30+ ALCL, iratumumab and SGN-30, two anti-CD30 monoclonal antibodies, have effectiveness. 77,78 Both medications are synergistic or additive with traditional chemotherapy, according to in vitro research. 79-81 In patients with recurrent and refractory CD30+ lymphomas, brentuximab vetodin (SGN-35), an immunoconjugate of SGN-30 and monomethyl auristatin, has shown an ORR of 41% with a median response duration of 7.3 months. 82 In newly diagnosed ALCL patients, a trial is now being conducted to assess the combination of CHOP with brentuximab vetodin.

Siplizumab is a monoclonal anti-CD2 antibody. CD2 is an adhesion molecule found on activated T cells and NK cells and the majority of cells in T-cell lymphoma and leukemia patients. Siplizumab killed CD4+ and CD8+ T cells and NK cells but did not affect B cells. Siplizumab exhibited clinical activity in a phase 1 trial in patients with CD2+ lymphoproliferative illness, including complete responses (CRs) in two patients with LGL leukaemia, partial responses (PRs) in patients with ATL, and one PR in a patient with cutaneous T-cell lymphoma (CTCL).

A dose-escalation study following that resulted in a PR in a patient with NK-cell LGL and a CR in a patient with Peripheral T-cell lymphomas ​17​. However, siplizumab makes patients more likely to develop lymphoproliferative syndrome, which can be avoided using prophylactic rituximab—half of all T cells and most cutaneous t cell lymphoma and nodal PTCL cells express CD4. Anti-CD4 monoclonal antibody zanolimumab is used in both disease categories, while cutaneous t cell lymphoma clinical development is further. In a study of 21 PTCL patients, zanolimumab was active and well-tolerated, with a 24 per cent ORR. A phase 1/2 dose-escalation experiment in individuals with non-cutaneous CD4+ PTCL is now being conducted with zanolimumab coupled with CHOP.

Because AITL is characterized by overexpression of angiogenic factors such as VEGF, bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, will most likely have the most significant impact on AITL. The Eastern Cooperative Oncology Group studied bevacizumab with CHOP in a clinical trial for patients with PTCL or NK-cell neoplasms. At least one recurrent AITL patient achieved a CR after therapy with bevacizumab. However, preliminary trial results revealed a high rate of cardiac events linked to the treatment.

Denileukin diftitox, a fusion protein containing an IL-2 receptor-binding domain and diphtheria toxin, is effective in cutaneous and aggressive T-cell lymphomas. Denileukin diftitox at a dose of 18 g/kg per day for five days on a 21-day cycle revealed a response rate of 48 per cent in extensively pretreated patients with recurrent Peripheral T-cell lymphomas in a single-Centre phase 2 study at M. D. Anderson Cancer Center. Responses were seen in 4 of 10 PTCL-NOS patients, 2 of 3 AITL patients, and 2 of 2 ALCL patients. In this study, immunohistochemistry analysis of CD25 expression did not predict responsiveness to denileukin diftitox.

Based on these findings, a combination of denileukin diftitox and CHOP was tested in Peripheral T-cell lymphomas patients who had not been treated previously. A total of 49 patients were enrolled in this trial. On days 1 and 2 of each cycle, denileukin diftitox was given at a dose of 18 g/kg per day, followed by CHOP chemotherapy on day three and granulocyte colony-stimulating factor support on day 4 of each 21-day cycle. 90 The ORR was 86 per cent in 37 efficacy-evaluable patients (> 2 cycles) (CR 75 per cent). The median progression-free survival (PFS) was 15 months, and the predicted 2-year overall survival (OS) was 60%. A large randomized trial comparing CHOP to denileukin diftitox combined with CHOP is now underway.

LMB-2 is a single-chain monoclonal anti-Tac (anti-CD25) antibody conjugated to Pseudomonas toxin. In phase 2 trials, LMB-2 showed clinical activity in CLL, cutaneous t cell lymphoma, and hairy cell leukaemia. Although ATL is the most responsive Peripheral T-cell lymphomas subtype to LMB-2, clinical responses have been confined to rapid disease progression and immunogenic reactions after > 95 per cent tumour shrinkage. 91 LMB-2 will be administered following fludarabine and cyclophosphamide treatment in phase 2 clinical trial for this cohort. The FDA just licensed romidepsin in 2009 to treat established and refractory cutaneous t cell lymphoma, based on a 34 per cent ORR in two clinical trials.

The median time to progression was 8.3 months in early disease and 6.4 months in more advanced disease, with a median response length of 15 months (range 1-20+). The individuals with relapsed and refractory PTCL completed a phase 2 study of romidepsin. 95 The National Cancer Institute and nine extramural locations enrolled 43 PTCL patients in this phase 2 open-label, multiarm, multicenter trial. Thirty-one of the 43 patients underwent two cycles of treatment. There had been an average of 3.9 past therapies.

The overall objective response rate was 39%, with 55% of patients receiving at least two rounds of therapy. For all patients, the median duration of response was 8.3 months (range: 1.6 months to 4.8+ years). A multicenter, global phase 2B registration study of romidepsin at the same dose and schedule in relapsed and refractory PTCL has recently been published. The ORR was 26% with 15% CR by radiographic evidence in 130 patients with a median of two prior treatments. The median response time was 12 months, and the most common side effects were gastrointestinal and constitutional issues and thrombocytopenia.

Belinostat, an HDAC inhibitor produced from hydroxamic acid, has been tested in intravenous and oral forms. Belinostat was given intravenously at 1000 mg/m2 every three weeks to 53 patients, 19 of whom had refractory PTCL and 29 had refractory cutaneous t cell lymphoma. In PTCL, the objective response rate was 32% with 2 CR and a median response time of 8.9+ months, while in cutaneous t cell lymphoma, the accurate response rate was 14% with a response duration of 9.1 months. Belinostat is now being studied in a multicenter phase 2 registration trial in relapsed PTCL patients and a cohort dose-escalation study in patients with relapsed lymphoma.

Combinations of HDAC inhibitors with topoisomerase inhibitors, bortezomib, and cytotoxic chemotherapeutic medicines have been shown to have additive and synergistic action in vitro. Clinical trials are being conducted to see how effective these combinations are in T-cell lymphomas.


Pralatrexate is a new folate antagonist whose activity is linked to attaching to the decreased folate carrier. The ORR for pralatrexate in a phase 1/2 dose-escalation trial in refractory lymphoma patients was 31%, with response durations ranging from 3 to 26 months. Patients with T-cell lymphomas had a 54 per cent response rate in that study. The PROPEL experiment was started as a result of these promising results. In this study, individuals with relapsed or refractory Peripheral T-cell lymphomas were treated with pralatrexate once a week for six weeks on a seven-week cycle. On average, prior therapy was three, and 63 per cent of patients had no response to their most recent treatment.

The response rate was 29%, and the median response time was 10.1 months. Five patients with relapsed or refractory PTCL who responded to pralatrexate as a single therapy underwent stem cell transplantation. Mucositis was reported in 70% of patients, and thrombocytopenia was reported in 40%. Pralatrexate was approved by the US Food and Drug Administration in September 2009 as a single drug for the treatment of relapsed or refractory PTCL patients. Several recent studies have examined the potential synergy between pralatrexate and other active drugs in T-cell lymphoma. A phase 1 trial combining pralatrexate and gemcitabine is currently being conducted.

Immunosuppressants and immunomodulators

Cyclosporine is an immunosuppressive drug that works by inhibiting the nuclear factor of the activated T-cell transcription complex, which activates genes that code for cytokines and cell surface molecules involved in cell-to-cell communication and death. Patients were given cyclosporine in a phase 2 experiment since AITL is characterized by immunological dysregulation. Two-thirds of the patients (3 CRs, 5 PRs) reacted; however, four died. The Eastern Cooperative Oncology Group ran a phase 2 cyclosporine trial in AITL, but it was closed early due to insufficient enrollment ​18​.

Other immune-modulating and antiangiogenic drugs, including bevacizumab, rituximab, lenalidomide, and thalidomide, are being investigated as single medicines in combination with chemotherapy. Twenty-four relapsed Peripheral T-cell lymphomas patients completed a phase 2 study of lenalidomide at a dose of 25 mg/m2 daily for 21 days of a 28-day cycle. With a PFS of 95 days, the overall response rate was 30%. In 20% and 33% of individuals, toxicities included neutropenia and thrombocytopenia.

Analogues of nucleosides

Chemotherapeutic drugs known as nucleoside analogues primarily hinder DNA replication and repair. In Peripheral T-cell lymphomas, the most effective pyrimidine nucleoside analogue is gemcitabine. It’s been used as a single agent and in combination with alemtuzumab and bortezomib. Cladribine, fludarabine, clofarabine, and nelarabine are purine nucleoside analogues. Cladribine and fludarabine have shown efficacy in PTCL, and clofarabine and nelarabine are currently being tested in clinical studies in T-cell lymphoma.

The best therapeutic options for patients with NK/T-cell lymphoma have yet to be determined. Researchers conducted a phase 1/2 study of concurrent chemoradiotherapy for Japan’s untreated localized NK/T-cell lymphoma. Extranodal NK/T-cell lymphoma of the nasal type is usually resistant to CHOP and has a high expression level of the multidrug resistance gene P-glycoprotein. Patients in this study received radiotherapy and chemotherapy, including carboplatin, etoposide, ifosfamide, and dexamethasone. The 2-year OS was 78 per cent after a median follow-up of 32 months. It was superior to the previous control method of radiation alone (45 per cent).

Unlike nucleoside analogues, metabolic enzyme inhibitors deoxycoformycin (pentostatin) and forodesine do not incorporate DNA. Forodesine inhibits phosphorylase, raising the deoxyguanosine triphosphate pool, while pentostatin inhibits adenosine deaminase, increasing the deoxyadenosine triphosphate pool. In cutaneous t cell lymphoma, both medicines have demonstrated some efficacy. A 53 per cent overall response rate was reported in a phase 1/2 research with oral forodesine in relapsed and refractory CTCL patients, and a phase 2 trial was completed.

Inhibitors of the proteasome

Bortezomib, a proteasome inhibitor, is effective as a single treatment in patients with relapsed or refractory cutaneous t cell lymphoma. Bortezomib had a 67 per cent ORR in a phase 2 study in relapsed cutaneous t cell lymphoma or Peripheral T-cell lymphomas patients, with two CR and no grade 4 toxicity. The GELA reported that 29 patients were withdrawn early due to toxicity in a phase 2 study of bortezomib plus ACVBP treatment in 57 untreated PTCL patients. The ORRs were comparable to those of ACVBP alone. Bortezomib has been used in conjunction with gemcitabine and doxorubicin, and new research suggests that bortezomib and pralatrexate may have synergistic effects in T-cell lymphoma patients.

Inhibitors of signaling

Enzastaurin is a protein kinase C inhibitor that works in part through the AKT pathway. Enzastaurin decreases cell proliferation, causes tumor cell death, and suppresses tumour-induced angiogenesis in cutaneous t cell lymphoma cell lines by targeting the PI3K/AKT pathways. Enzastaurin is now being tested in two phases 2 trials: one for patients with various forms of NHL, such as PTCL and CTCL, and another for patients with relapsed cutaneous t cell lymphoma.

Treatment options for ATL and NK/T-cell lymphomas caused by HTLV-1

Twenty (77%) of the 26 patients with an assessable response attained a CR, with one PR. The ORR for this study was 81 per cent. Mucositis caused by radiation was the most common grade 3 nonhematologic harm (30 per cent). According to the researchers, concurrent chemoradiotherapy with multidrug resistance-non related drugs and etoposide is a safe and effective treatment for localized nasal NK/T-cell lymphoma ​19​.

L-asparaginase is combined with ifosfamide, etoposide, dexamethasone, and methotrexate in a novel treatment for advanced NK-/T-cell lymphomas (SMILE). P-glycoprotein overexpression in NK/T-cell lymphomas has been linked to chemoresistance and poor outcomes following CHOP-based regimens, with 5-year survival rates of 20% or less in patients with the advanced-stage illness. Yong et al. used L-asparaginase, vincristine, dexamethasone, and involved-field irradiation to treat 18 patients who were refractory to CHOP and reported a response rate of 55% and a 5-year OS of 55%. A 67 per cent response rate is reported in a phase 1 study increasing methotrexate plus etoposide.

The SMILE regimen was studied in individuals with newly diagnosed stage IV or relapsed refractory NK-/T-cell lymphomas in a prospective phase 2 experiment. 116 29 (74%) of the 39 patients completed the treatment course. Four cases achieved complete remission (CR) in 15, partial remission in 14, and early death due to infection. The ORR and CR, respectively, were 74 per cent (95 per cent CI, 58 per cent -87 per cent) and 38 per cent (95 per cent CI, 58 per cent -87 per cent). Infection was the most common grade 3 nonhematologic harm (41 per cent).

Conventional chemotherapy regimens have consistently yielded unsatisfactory results. VCAP (vincristine, cyclophosphamide, doxorubicin, and prednisone), AMP (doxorubicin, ranimustine, and prednisone), and VECP (vindesine, etoposide, carboplatin, and prednisone) were tested in phase 3 Japanese research against CHOP-14 in ATL. VCAP-AMP-VECP was superior to VCAP-AMP-VECP in newly diagnosed aggressive ATL patients. A phase 2 trial is being planned to see if allogeneic stem cell transplantation after induction with the VCAP-AMP-VECP regimen may extend the median survival time beyond 13 months, which is currently the case with the VCAP-AMP-VECP regimen.

Patients with acute or lymphomatous ATL have been observed to respond to interferon and zidovudine in up to 50% of cases. One hundred sixteen individuals with acute ATL, 18 patients with chronic ATL, 11 patients with smouldering ATL, and 100 patients with ATL lymphoma were assessed in a recent meta-analysis. The five-year OS rates for 75 patients who received first-line antiviral therapy (P =.004), 20 for 77 patients who received first-line chemotherapy, and 12% for patients who received first-line chemotherapy followed by antiviral therapy were:

  • 46% (P =.004).
  • 20% for 77 patients who received first-line chemotherapy.
  • 12% for 55 patients who received first-line chemotherapy followed by antiviral therapy.

Patients with acute, chronic, or smouldering ATL, according to the authors, benefited considerably from first-line antiviral medication.

With antiviral medication, 82% of patients with acute ATL survived five years, while 100% of patients with chronic and smouldering ATL survived five years. First-line antiviral medication significantly increased OS (hazard ratio = 0.47; 95 percent CI, 0.27-0.83; P =.021), according to multivariate analysis. However, future prospective investigations are required due to selection bias in this retrospective analysis. Finally, in Japan, KW-0761, a humanized anti-CCR4 antibody, has shown potential as a single drug in treating ATL. In phase 1 research, KW-0761 was used to treat relapsed patients with CCR4-positive ATL and PTCL.

The ORR for this study was 31% (5 of 16; 95 per cent CI, 11%-59%). There were no dose-limiting side effects, and no anti–KW-0761 antibodies were found. 120 Recently, a phase 2 trial for patients with relapsed ATL was completed. The ORR was 54% with 7 CR in 27 patients (14 acute, six lymphomatous, and seven chronic ATL). Cytopenias (lymphopenia 96%, neutropenia 33%), skin rash (52%), and moderate transaminitis were toxic.


According to several retrospective investigations, there are subsets of Peripheral T-cell lymphomas patients who will benefit from transplantation ​20​. In patients with histologies other than ALK+ ALCL and patients with moderate or high IPI scores, the National Cancer Consortium Network recommends transplantation as a consolidation option after the initial remission. The presence of disease at transplantation is a strong predictor of success, especially in autologous transplantation. Patients in chemo sensitive remission have better outcomes, whereas only 25% to 30% of refractory patients improve. OS and FFS are, on average, 34% and 18%es with 5-year results.

Individuals with recurrent disease saw only a minor benefit (5-year OS of 36%) with autologous transplantation, while patients transplanted in the first remission saw a 5-year OS of 76%.

A prospective German study of PTCL patients who had chemotherapy and up-front autologous transplantation has been published. 4 to 6 cycles of CHOP were followed by mobilizing therapy with either dexaBEAM (dexamethasone, carmustine, melphalan, etoposide, and cytarabine) or ESHAP (dexamethasone, carmustine, melphalan, etoposide, and cytarabine) (etoposide, methylprednisolone, cytarabine, and cisplatin). Myeloablative chemoradiotherapy and ASCT were then used on patients in total or partial remission.

Two-thirds of the patients (66%) showed a positive response to chemotherapy and were given ASCT. The estimated 3-year OS and PFS for patients in CR were 48% and 36%, respectively, at a median follow-up duration of 33 months. Patients who did not respond to chemotherapy and did not receive ASCT had a poorer prognosis, with a median survival of fewer than two years. Autologous transplantation’s effect in second or subsequent remission is less clear.

In the United States, there are currently no randomized studies comparing the outcomes of autologous versus allogeneic transplantation. Lymphoma organizations are launching a significant lymphoma research project in the Nordic and German countries. Furthermore, the Center for International Blood and Marrow Transplant Research is now doing a database review comparing allogeneic and autologous transplants in patients with Peripheral T-cell lymphomas. In a retrospective single-institution analysis comparing autologous and allogeneic transplantation, autologous transplantation performed in the first remission produced the best results. In contrast, allogeneic transplantation performed better for patients with refractory or relapsed illnesses. More research is needed to determine which subsets of PTCL patients will benefit most from allogeneic or ASCT.

Treatment options for PTCL that are based on scientific evidence

Novel treatments for aggressive T-cell lymphomas are needed due to the poor results of CHOP-based regimens. The National Cancer Consortium Network has developed evidence-based treatment regimens for T-cell lymphoma patients and divides them into stages ​21​. Chemotherapy should be followed by involved-field radiation for early-stage patients with localized illnesses. Except for those with a low IPI, all patients are consolidated with ASCT. The only subtype of ALCL with a good prognosis is ALK+ ALCL, which should not be transplanted in the first remission.

According to new research, ALK+ patients with a high IPI may be an exception to this norm. In prospective studies, where up to 40% of patients do not achieve complete remission and hence cannot be consolidated by transplantation, new approaches are required. The use of histopathologic features to guide first-line therapy selection is not yet widespread, but it should be considered. For nodal T-cell lymphomas, the conventional treatment is CHOP-based therapy (PTCL-NOS, AITL, and ALCL). Individualized regimens for extranodal subtypes are possible. 

The distinction between the type and the type, which is currently included in the category of cutaneous T-cell lymphoma, should be made for panniculitis-like T-cell lymphoma. The patients can be treated with single-agent treatments or combination chemotherapy and have a good prognosis. Overall, cutaneous T-cell lymphomas have a poor prognosis and should be treated aggressively with chemotherapy and transplantation.

On the other hand, hepatosplenic and intestinal T-cell lymphomas have a terrible prognosis. In one trial, 26 patients with enteropathy-associated T-cell lymphoma were given CHOP and then methotrexate, followed by ifosfamide, etoposide, and Epirubicin. 128 patients (n = 33) underwent transplantation after achieving CR. PFS and OS were 52% and 60% for transplanted enteropathy-associated patients, respectively. Patients with NK/T-cell lymphoma have also had poor outcomes with CHOP-based regimens. Hence, alternate regimens like SMILE and asparaginase combos are aggressively evaluated for these patients.

In patients with poor prognosis subtypes such as NK-/T-cell and T-cell lymphomas, the effect of autologous vs allogeneic stem cell transplantation has not been determined. In a retrospective study, these subtypes performed worse following autologous transplantation than the more frequent PTCL-NOS and AITL subtypes. As a result, consolidation with allogeneic stem cell transplantation should be considered in patients who have suitable donors.

Finally, it is clear from this overview of the current state of Peripheral T-cell lymphomas categorization, prognosis, and therapy options that significant progress has been made. Although the lack of available medicines was formerly a barrier to PTCL treatment, the advent of innovative therapeutics necessitated the development of paradigms to combine these drugs with improving response rates and durability of responses. Based on the success of the chronic lymphocytic leukaemia and mantle cell lymphoma consortiums, North American scientists have founded the North American PTCL Collaborative Group, which will work with the International PTCL Project to explore innovative therapeutic techniques to enhance PTCL outcomes. Patients with newly diagnosed PTCL can now register in an international registry. A global tissue bank has also been established to collect adequate amounts of clinically annotated and well-characterized specimens.


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