What is the recommended treatment regimen for a fit patient with high-risk diffuse large B-cell lymphoma (DLBCL) with MYC positivity and a high Ki-67 proliferation index?

Treatment Recommendation for High-Risk DLBCL with MYC Positivity in a Fit Elderly Patient

For a fit elderly patient with high-risk diffuse large B-cell lymphoma (DLBCL) with MYC positivity and high Ki-67, the recommended treatment is 6-8 cycles of R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone given every 21 days), with mandatory CNS prophylaxis using intravenous high-dose methotrexate rather than intrathecal administration alone. 1, 2

Primary Treatment Regimen

• Eight cycles of R-CHOP-21 is the established standard for patients aged 60-80 years with DLBCL, regardless of risk category 1, 2
• The regimen consists of rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², vincristine 1.4 mg/m² (maximum 2 mg), and prednisone 40 mg/m² on days 1-5, administered every 21 days 3, 4
• Do not use R-CHOP-14 (every 14 days)—a large randomized trial of 1,080 patients demonstrated no survival benefit over R-CHOP-21, with 2-year overall survival of 82.7% versus 80.8% (p=0.38) 3, 2

Critical Pre-Treatment Measures for High Tumor Burden

• Administer prednisone 100 mg orally for several days as "prephase" treatment before starting R-CHOP to prevent tumor lysis syndrome, particularly crucial given the high Ki-67 proliferation index 2, 5
• Ensure aggressive hydration and consider prophylactic allopurinol or rasburicase in this high-risk patient 2
• Assess cardiac function (left ventricular ejection fraction) before initiating anthracycline therapy 1

Mandatory CNS Prophylaxis

• CNS prophylaxis is absolutely required for high-risk patients with elevated LDH and/or multiple extranodal sites 1, 2
• Intravenous high-dose methotrexate is superior to intrathecal methotrexate alone and should be the preferred approach 1, 2
• The presence of MYC positivity (double-hit or triple-hit lymphoma) further increases CNS relapse risk, making prophylaxis non-negotiable 1

Supportive Care Requirements

• Prophylactic granulocyte colony-stimulating factor (G-CSF) is mandatory in all elderly patients treated with curative intent to maintain dose intensity 1, 2
• Avoid dose reductions due to hematological toxicity—this significantly compromises treatment efficacy and cure rates 1, 2
• Use G-CSF support rather than dose reduction if febrile neutropenia occurs 1, 2

Radiotherapy Considerations

• Consolidation radiotherapy to sites of bulky disease provides no proven benefit in the rituximab era and should not be routinely administered 1, 2
• Radiotherapy may be considered only for sites of residual PET-positive disease after completion of chemotherapy, with histological confirmation strongly recommended before proceeding 1

Response Evaluation Strategy

• Perform interim imaging after 3-4 cycles to assess response 1, 2
• PET scanning is highly recommended for post-treatment assessment to define complete remission according to revised response criteria 1
• If PET-positive after treatment completion, obtain histological confirmation before changing management, as false positives occur 1

Common Pitfalls to Avoid

• Do not reduce chemotherapy doses after prephase treatment due to cytopenias—this is the most common error that compromises cure rates 1, 2
• Do not use dose-dense R-CHOP-14 based on outdated pre-rituximab data—the definitive trial showed no benefit 3, 2
• Do not omit CNS prophylaxis in high-risk patients—intracranial relapse is devastating and largely preventable 1, 2
• Do not use intrathecal methotrexate alone for CNS prophylaxis—it is inadequate for high-risk disease 1, 2

Special Considerations for MYC-Positive DLBCL

• While more intensive regimens (R-ACVBP, dose-adjusted R-EPOCH) have been studied for high-risk disease, there is no established superior standard to R-CHOP-21 for patients aged >60 years 1, 2
• These patients should ideally be enrolled in clinical trials if available, but R-CHOP-21 with CNS prophylaxis remains the evidence-based standard outside of trials 1, 2
• High-dose chemotherapy with stem cell transplantation as first-line consolidation remains experimental and is not recommended outside clinical trials 1

Follow-Up Protocol

• History and physical examination every 3 months for year 1, every 6 months for years 2-3, then annually 1
• Blood count and LDH at 3,6,12, and 24 months 1
• CT imaging at 6,12, and 24 months after treatment completion 1
• Routine surveillance PET scanning is not recommended 1