Compared to B-NHL, Peripheral T cell Lymphomas: 

• Present in more advanced disease 
• Poorer performance status 
• Frequent B symptoms 
• Frequent paraneolastic features such as eosinophilia, HLH etc 
• Higher incidence of autoimmune phenomenon 

PTCL-NOS, includes those cases that do not belong to any of the better defined entities 

Epidemiology: 

• Account for 6% of all NHL 
• Usually seen in adults 
• Common in men 
• Median age- 61 years 
• PTCL-NOS accounts for 50% of all PTCLs. 

Etiology: 

• Risk factors include HTLV1 and EBV infections 

Clinical Features: 

• Bulky lymphadenopathy 
• B symptoms 
• Common extranodal involvement 
• Sometimes- HLH 

Investigations: 

• Lymph node biopsy- Features seen in PTCL- NOS are
  • Diffuse infiltrates of tumor cells with effacement of normal nodal architecture 
  • Very broad cytological spectrum mainly medium to large sized cells 
  • Nuclei are irregular, pleomorphic and may be hyperchromatic with prominent nucleoli 
  • Clear cells and RS like cells often present 
  • High endothelial venules increased 
  • An inflammatory, polymorphous background seen. 
• Immunohistochemistry:
  • T-Cell associated antigens are positive, but there can be loss of one or more antigens (Especially CD7) 
  • Positive- CD45, CD43, CD3
  • 80%  are CD4 + / CD8 –
  • 20% are CD4 – / CD8+ 
• Molecular studies: Clonal rearrangement of the T cell receptor gene 
• Cytogenetics: 
  • Loss of 9p, 5q or 12p.  
  • Gains of 7q, 17q.  
  • Complex cytogenetic abnormalities 
  • t (5:9)- Fusion of IL2 inducible T cell kinase with spleen tyrosine kinase 
• Hemogram- Eosinophilia 
• LDH- Increased 

Prognosis: 

• Generally Poor 
• Overall 5 year survival- 30%  
• T Cell specific International Prognostic Index score: One point given to each of these: 
  • Age >60 years 
  • Raised S. LDH levels 
  • PS- 2-4 
  • Stage III or IV 
  • Extranodal involvement > 1 site 

• Other poor prognostic markers include: 
  • High Ki 67 expression 
  • Extranodal disease 
  • Expression of cytotoxic molecules- TIA-1, Granzyme-B, nm23-H1 protein 
  • TP53 gene abnormality 
  • Chemokine receptor expression- Ex: CCR4 
  • B Symptoms 
  • Bulky disease- >10cm 
  • Raised CRP levels 
  • Platelet count <1,50,000/cmm 
• Loss of 5q, 10q and 12q carry better prognosis 

Pretreatment Work-up for PTCL NOS: 

• History 
  • B-Symptoms 
• Examination 
  • LN: 
  • Spleen: 
  • Full skin exam: 
• WHO P. S. 
• BSA 
• IHC 
• BMA and Bx 
• CT (CAP)/ PET 
• Stage 
• Hemoglobin 
• TLC, DLC 
• Platelet count 
• LFT - Bili- T/D      SGPT:       SGOT: Albumin:    Globulin: 
• Creatinine 
• Electrolytes: Na:       K:       Ca: Mg:        PO4:  
• Uric acid: 
• LDH 
• Beta2 microglobulin 
• HIV:
• HBsAg:
• HCV: 
• HTLV 1 Serology (In high risk population) 
• UPT 
• IPI score 
• ECHO (If anthracyclines planned) LVEF-               %
• Chemotherapy consent after informing about disease, prognosis, cost of therapy, side effects, hygiene, food and contraception
• Fertility preservation
• PICC line insertion and Chest X ray after line insertion
• Tumor board meeting and decision
• Attach supportive care drug sheet
• Inform primary care physician

Treatment Plan for PTCL-NOS:

Indications for CNS prophylaxis

• High IPI score
• High LDH
• Involvement of extranodal site

Other Treatment Options: Targeted therapies

• Sipilizumab:
  • Anti CD2 antibody
  • 0.4-1.2mg/kg- biweekly- for total of 8 doses
  • It triggers T cell apoptosis
• Anti-CD3 antibodies
  • Muromonab: Causes high INF alpha release with severe cytokine syndrome, hence not used
  • Visilizumab: Engages CD3, but does not cause release of TNF alpha
• Zanolimumab:
  • Anti CD4 antibody
  • Has cytotoxic and antiproliferative activity
  • Given biweekly for 6 weeks
  • Dose: early stage: 560mg, Late stage: 980mg
• Alemtuzumab- Anti CD52 antibody
• Brentuximab: Anti CD30 antibody
• Daclizumab- Anti CD 25 antibody
• Anti CD 194 antibody

Recent advances:

Allogeneic hematopoietic stem cell transplantation for NK/T-cell lymphoma: an international collaborative analysis

This retrospective analysis examined the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with relapsed/refractory natural killer/T-cell lymphomas (NKTCL). The study included 135 patients who underwent allo-HSCT between 2010 and 2020.  The three-year progression-free survival (PFS) and overall survival (OS) rates were 48.6% and 55.6%, respectively. Shorter time interval between diagnosis and allo-HSCT and transplantation not in complete or partial response were associated with reduced PFS. Pre-transplant treatment with programmed cell death protein 1 (PD-1/PD-L1) inhibitors did not affect graft-versus-host disease or survival. 

https://doi.org/10.1038/s41375-023-01924-x

CHOEP plus lenalidomide as initial therapy for patients with stage II–IV peripheral T-cell lymphoma

In this phase II study, a novel induction strategy for nodal-based peripheral T-cell lymphoma (PTCL) was evaluated using lenalidomide in combination with CHOEP chemotherapy. Patients received standard doses of CHOEP along with 10 mg of lenalidomide on days 1–10 of a 21-day cycle for six cycles. Among 39 evaluated patients, the objective response rate after six cycles was 69%, with complete response in 49% and partial response in 21%. However, hematologic toxicity, including febrile neutropenia, was a significant issue, leading to treatment discontinuation in some cases. Despite these challenges, the estimated 2-year progression-free and overall survival rates were 55% and 78%, respectively. 

https://doi.org/10.1111/bjh.18885

Romidepsin Plus CHOP in patients with previously untreated peripheral t-cell lymphoma

The final analysis of the Ro-CHOP phase III trial, conducted 5 years after the last patient enrolled, showed that romidepsin plus CHOP did not significantly improve progression-free survival (PFS) or overall survival (OS) compared to CHOP alone as first-line treatment for peripheral T-cell lymphoma. However, in an exploratory analysis, the Ro-CHOP arm demonstrated a significantly longer median PFS in the follicular helper T-cell lymphoma subgroup. Second-line treatments were administered to 251 patients after relapse or progression, with brentuximab vedotin showing a potential benefit in disease control, even after adjusting for histology and prognostic factors.

https://doi.org/10.1200/JCO.23.0168

Long-term outcome of peripheral T-cell lymphomas

Peripheral T-cell lymphomas (PTCLs) are diverse haematological cancers with generally poor outcomes, although some patients achieve long-term disease control. The International T-cell Lymphoma Project (ITCLP) provided data on 735 patients with a 10-year follow-up. The overall response rate to first-line therapy was 68%, with 5- and 10-year survival rates of 49% and 40%, respectively. Survival beyond 5 years was high (84%), but lymphoma was still the leading cause of death (67%) in the 5- to 10-year period. Factors such as age >60 years and poor performance status were linked to worse outcomes.

https://doi.org/10.1111/bjh.19433 

Chidamide maintenance therapy versus autologous stem cell transplantation versus observation as a post-remission choice in adult patients with peripheral T-cell lymphoma

Tucidinostat (also known as chidamide) is a histone deacetylase inhibitor developed in China. This Phase 2 trial evaluated peripheral T-cell lymphoma (PTCL) patients treated with autologous stem cell transplantation (ASCT), chidamide maintenance, or observation after first-line chemotherapy. The 3-year progression-free survival (PFS) rates were 85.6% (ASCT), 80.8% (chidamide), and 49.4% (observation). Chidamide maintenance improved both PFS and overall survival compared to observation. Multivariate and propensity score matching confirmed the superior PFS in the chidamide group. 

https://doi.org/10.1007/s00277-024-05708-w

Role of upfront autologous transplant for peripheral T-cell lymphoma patients achieving a complete remission with first-line therapy

This meta-analysis evaluated the role of upfront autologous stem cell transplantation (ASCT) in patients with peripheral T-cell lymphomas (PTCL) who achieved first complete remission (CR1) post-chemotherapy. Across 17 studies with follow-ups ranging from 22 to 94 months, ASCT showed trends towards improved progression-free survival (PFS) and overall survival (OS) compared to chemotherapy alone. Importantly, for transplant-eligible patients in CR1, ASCT significantly improved both OS (HR=0.59, p=0.03) and PFS (HR=0.61, p=0.0004). The benefit was especially notable in angioimmunoblastic T-cell lymphoma (AITL) patients, suggesting ASCT may be most effective for this subgroup.

https://doi.org/10.1038/s41409-024-02254-x

Autologous or allogeneic transplantation in patients with peripheral T-cell lymphoma

The phase III (Autologous or Allogeneic Transplantation in Patients With Peripheral T-Cell Lymphoma) AATT study found that in younger PTCL patients, event-free survival (EFS) and overall survival (OS) were similar between autologous (autoSCT) and allogeneic stem cell transplantation (alloSCT) as consolidation treatments. Seven-year EFS rates were 38% for alloSCT and 34% for autoSCT, while OS rates were 55% and 61%, respectively. AlloSCT showed a strong graft-versus-lymphoma effect with lower relapse rates but higher nonrelapse mortality (NRM) than autoSCT. AlloSCT remains the preferred option for younger, transplant-eligible patients with relapsed/refractory PTCL but is not recommended as a first-line consolidation.

https://doi.org/10.1200/JCO.24.005