What is the optimal first‑line therapy for a newly diagnosed double‑expressor diffuse large B‑cell lymphoma in a fit adult?

Optimal First-Line Treatment for Double-Expressor DLBCL

For fit adults with newly diagnosed double-expressor DLBCL, standard R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone every 21 days) remains the recommended first-line therapy, with 6-8 cycles depending on age and risk stratification. 1, 2

Treatment Algorithm by Patient Age and Risk

Young Patients (<60 years) with Low-Intermediate Risk (aaIPI ≤1)

• Administer 6 cycles of R-CHOP-21 plus radiotherapy to sites of bulky disease (>5 cm) 1, 2
• Alternative option: R-ACVBP (rituximab, doxorubicin, vindesine, cyclophosphamide, bleomycin, prednisolone) every 14 days followed by sequential consolidation, which has shown superior survival compared to 8 cycles of R-CHOP 1, 2

Young Patients (<60 years) with High-Intermediate/High Risk (aaIPI ≥2)

• Administer 6-8 cycles of R-CHOP-21 2
• Consider enrollment in clinical trials, as no definitive standard exists for this high-risk subgroup 2
• Do NOT use dose-dense R-CHOP-14, as it has NOT demonstrated survival benefit over R-CHOP-21 2

Patients Aged 60-80 Years

• Administer 8 cycles of R-CHOP-21 with 8 total doses of rituximab, regardless of risk category 3, 1, 2
• If using R-CHOP-14,6 cycles with 8 rituximab doses are sufficient 2
• Consolidation radiotherapy provides no proven benefit in the rituximab era 3, 2

Patients Aged >80 Years

• Perform comprehensive geriatric assessment before treatment initiation 2
• R-CHOP can be used in fit patients up to age 80 3, 2
• R-miniCHOP (attenuated chemotherapy with rituximab) is appropriate for healthy patients over 80 2
• Consider substituting doxorubicin with etoposide or liposomal doxorubicin, or omitting it entirely after initial cycles in patients with cardiac dysfunction 2

Critical Pre-Treatment and Supportive Measures

Tumor Lysis Syndrome Prevention

• Administer prednisone 100 mg orally for several days as "prephase" treatment in patients with high tumor burden 1, 2
• Ensure adequate hydration and consider prophylactic allopurinol or rasburicase in highest-risk patients 2

Hematologic Support

• Avoid dose reductions due to hematological toxicity, as this compromises treatment efficacy 3, 1, 2
• Prophylactic G-CSF is indicated for febrile neutropenia in patients treated with curative intent and in all elderly patients 3, 1, 2

CNS Prophylaxis for High-Risk Patients

Double-expressor DLBCL patients with high-intermediate or high-risk IPI (particularly those with >1 extranodal site or elevated LDH) require CNS prophylaxis. 3, 1, 2

• Intravenous high-dose methotrexate is superior to intrathecal methotrexate alone 2
• Testicular lymphoma mandates CNS prophylaxis with contralateral testis irradiation 3, 1, 2

Why Double-Expressor Status Does NOT Change Standard Treatment

The available guidelines do not differentiate treatment recommendations for double-expressor DLBCL (MYC and BCL2 protein overexpression by immunohistochemistry) from standard DLBCL. 1, 2, 4 This is distinct from double-hit lymphoma (MYC and BCL2/BCL6 gene rearrangements), which carries a worse prognosis. 4 While double-expressor status may indicate higher risk, the current evidence-based approach is to treat according to age-adjusted IPI and clinical risk factors rather than molecular subtype alone. 1, 2

Response Assessment

• Perform imaging after 3-4 cycles and after completion of treatment 1, 2
• Use PET-CT with Deauville 5-point scale for post-treatment assessment 2
• Early PET (after 1-4 cycles) may have prognostic value but should not trigger treatment changes outside clinical trials 3

Common Pitfalls to Avoid

• Do NOT use R-CHOP-14 based on outdated pre-rituximab era data 2
• Do NOT reduce chemotherapy doses after prephase treatment unless absolutely necessary for life-threatening toxicity 1, 2
• Do NOT omit CNS prophylaxis in high-risk patients, particularly those with testicular involvement 3, 1, 2
• Do NOT skip comprehensive geriatric assessment in patients over 80 years before committing to full-dose therapy 2