What is the recommended treatment regimen for a patient with high-risk Diffuse Large B-Cell Lymphoma (DLBCL) and MYC positivity?

Treatment Recommendation for High-Risk DLBCL with MYC Positivity

For a young patient (<60 years) with high-risk DLBCL (aaIPI ≥2) and MYC positivity, you should use DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) for 6 cycles with CNS prophylaxis, as this regimen produces superior outcomes compared to R-CHOP in MYC-rearranged lymphomas. 1

Evidence Supporting DA-EPOCH-R in MYC-Positive DLBCL

The most compelling evidence comes from a prospective phase 2 study specifically designed for MYC-rearranged aggressive B-cell lymphomas, which demonstrated:

• 48-month event-free survival of 71.0% and overall survival of 76.7% in 53 patients with MYC-rearranged lymphomas treated with DA-EPOCH-R 1
• This included both single-hit (MYC alone) and double-hit (MYC plus BCL2/BCL6) lymphomas with similar excellent outcomes 1
• The study population had high-risk features: 81% with stage III-IV disease and 49% with high-intermediate or high IPI scores 1

A more recent multicenter phase 1/2 trial further validated this approach in MYC-associated DLBCL:

• 2-year progression-free survival of 78.2% and overall survival of 83.6% in patients with double-hit and double-expressor lymphomas treated with lenalidomide plus DA-EPOCH-R 2
• The overall response rate was 90.9% with complete response rate of 83.6% 2
• Patients had median age 65 years with 69% having IPI ≥3 2

Why Not Standard R-CHOP?

Standard R-CHOP is inadequate for MYC-positive DLBCL. Multiple retrospective studies demonstrate worse outcomes with R-CHOP in patients with MYC rearrangement compared to those without, with improved outcomes observed after more intensive treatment 1. The guidelines acknowledge that "R-CHOP gives poor outcomes for double-hit lymphomas" and that "only preliminary results have suggested better results with more intensive regimens" 3.

For young high-risk patients (aaIPI ≥2), the guidelines explicitly state there is no current standard with sufficient efficacy, and these patients should preferably be treated in clinical trials 3. When standard R-CHOP is used in this population, it is acknowledged as suboptimal 3.

Treatment Protocol Details

Administer DA-EPOCH-R as follows:

• 6 cycles of dose-adjusted chemotherapy with rituximab 375 mg/m² on day 1 of each cycle 1
• The dose-adjustment is based on nadir blood counts, escalating or de-escalating doses to maintain therapeutic intensity while managing toxicity 1
• Mandatory CNS prophylaxis given the high-risk features 1

Critical Pre-Treatment Measures

• Administer prednisone 100 mg orally for several days as prephase treatment to prevent tumor lysis syndrome, particularly important in MYC-driven lymphomas with high proliferative rates 4, 5
• Ensure adequate hydration and consider prophylactic allopurinol or rasburicase 4
• Screen for hepatitis B (HBsAg and anti-HBc) before initiating rituximab 6

Expected Toxicity Profile

DA-EPOCH-R has manageable toxicity:

• Grade 4 neutropenia occurs in approximately 53% of cycles 1
• Grade 4 thrombocytopenia in 13% of cycles 1
• Febrile neutropenia in 19% of cycles 1
• Prophylactic G-CSF is justified for febrile neutropenia in patients treated with curative intent 3, 4

The lenalidomide-enhanced regimen showed similar toxicity: grade ≥3 neutropenia (67%), anemia (67%), thrombocytopenia (49%), and neutropenic fever (35%) 2.

Alternative Consideration: R-ACVBP

If DA-EPOCH-R is not available, R-ACVBP (rituximab, doxorubicin, vindesine, cyclophosphamide, bleomycin, and prednisolone) given every 2 weeks followed by sequential consolidation is an alternative intensive regimen that has shown improved survival compared to R-CHOP in young patients 3, 4. However, this was studied in the general young low-intermediate risk population, not specifically in MYC-positive disease 3.

Common Pitfalls to Avoid

• Do not use standard R-CHOP-21 in MYC-positive high-risk DLBCL, as retrospective data consistently show inferior outcomes 1
• Do not use R-CHOP-14 (dose-dense every 14 days), as it has not demonstrated survival benefit over R-CHOP-21 and is not appropriate for this high-risk population 3, 4
• Do not omit CNS prophylaxis in high-risk patients with MYC-positive disease 1
• Do not reduce chemotherapy doses due to hematological toxicity unless absolutely necessary, as this compromises efficacy—use G-CSF support instead 3, 4

Cost Considerations in Real-World Practice

While DA-EPOCH-R is more expensive than R-CHOP (mean cost USD 106,940 vs USD 58,509), the comparable or superior clinical outcomes justify the increased expense in this high-risk population 7. The investment in intensive upfront therapy is warranted given the poor salvage rates if initial treatment fails.