What is the recommended first‑line treatment and work‑up for a treatment‑naïve, medically fit adult with proliferative peripheral T‑cell lymphoma and Eastern Cooperative Oncology Group performance status (ECOG) 0‑2?

First-Line Treatment and Work-Up for Proliferative Peripheral T-Cell Lymphoma

For a treatment-naïve, medically fit adult with proliferative peripheral T-cell lymphoma and ECOG 0-2, the recommended first-line treatment is 6 cycles of dose-dense CHOEP (cyclophosphamide, hydroxydaunorubicin, vincristine, etoposide, prednisone) given bi-weekly, followed by autologous stem cell transplantation in chemosensitive patients. 1, 2

Initial Diagnostic Work-Up

Tissue Diagnosis:

• Perform excisional lymph node biopsy with comprehensive analysis including Pan-T-cell markers, subset markers, B-cell markers, proliferation markers, and specialized markers based on suspected subtype 2
• Obtain TCR gene rearrangement analysis and ALK translocation detection to distinguish ALCL ALK+ from ALK- disease 2
• Perform EBER in situ hybridization for EBV evaluation, as EBV positivity affects prognosis and treatment selection 1, 2

Staging Evaluation:

• Complete blood count with differential, comprehensive metabolic panel including LDH and uric acid 1, 2
• Screen for HIV, HTLV-1, hepatitis B and C 1
• PET/CT of chest, abdomen, and pelvis 1, 2
• Bone marrow aspirate and biopsy 1, 2
• Cardiac assessment (MUGA scan or echocardiogram) before anthracycline-based therapy 2
• Full skin examination 2

Risk Stratification:

• Calculate International Prognostic Index (IPI) score, which remains the standard prognostic tool 1, 2
• Document male sex as an additional adverse prognostic factor 1, 2

Treatment Algorithm by Age and Histologic Subtype

For Patients ≤60 Years Old:

The evidence-based approach is 6 courses of bi-weekly CHOEP followed by autologous stem cell transplantation in chemosensitive patients, which achieves an overall response rate of 82% with 51% complete response 1, 2. This regimen demonstrates 5-year overall survival of 70% for ALCL ALK-, 52% for angioimmunoblastic T-cell lymphoma (AITL), and 47% for PTCL-NOS 1, 2.

Critical Exception - ALCL ALK+ with Low-Risk IPI:

• For ALCL ALK+ patients with low or low-intermediate IPI scores, consolidation with autologous transplant is NOT recommended, as these patients achieve favorable outcomes with chemotherapy alone (5-year failure-free survival 60-80%) 1, 2
• ALCL ALK+ patients with high-risk profile (IPI >2) should receive autologous stem cell transplant consolidation 1

For Patients >60 Years Old:

Standard CHOP (without etoposide) is recommended due to excessive toxicity of CHOEP in older patients 1, 2. The addition of etoposide is mostly feasible only in younger patients, with toxicity being a limiting factor beyond age 60 1.

For Stage I Disease (Rare):

• Administer shortened chemotherapy schedule (3 courses) followed by involved-site radiotherapy at 40 Gy 1
• Higher radiation doses (40 Gy preferred over 30 Gy) are needed due to lower radiosensitivity of PTCLs compared to B-cell lymphomas 1

Consolidation Strategy

Autologous Stem Cell Transplantation:

• Upfront autologous transplant in chemosensitive patients is associated with improved overall survival based on population-based data 1
• This represents an evidence-based approach adoptable outside clinical trials 1
• Transplant eligibility should be determined by age, IPI score, and comorbidities 1

Response Evaluation Schedule

• Perform radiological assessment after every 2-4 cycles of therapy, at treatment completion, and whenever response is questioned 2
• PET/CT is increasingly used for restaging, though residual FDG-avid lesions lack specificity and biopsy confirmation is recommended 1

Critical Pitfalls to Avoid

Do Not Use Anthracycline-Void Regimens:

• Platinum and gemcitabine combinations (e.g., PEGS regimen) have shown disappointing results with only 39% overall response rate and 14% 2-year progression-free survival 1
• Despite ongoing debate about anthracyclines in PTCL, anthracycline-void regimens have failed to demonstrate superiority to CHOP/CHOEP outside clinical trials 1

Avoid Standard CHOP in Younger Fit Patients:

• CHOP alone (without etoposide or transplant consolidation) yields inferior outcomes in younger patients who can tolerate dose-intensified approaches 1

Do Not Delay Transplant Evaluation:

• Early identification of transplant-eligible patients is essential, as chemosensitivity to induction therapy determines transplant candidacy 1

Alternative Approaches for Frail Patients

For patients not eligible for intensive chemotherapy schedules, consider less toxic approaches such as gemcitabine monotherapy or bendamustine 1. However, these are palliative strategies with limited efficacy.

Clinical Trial Consideration

Whenever possible, inclusion in a clinical trial is strongly recommended given the heterogeneity of PTCL and ongoing efforts to improve outcomes 1.