Should high-risk diffuse large B-cell lymphoma (DLBCL) with MYC positivity be treated like Burkitt lymphoma?

Should High-Risk DLBCL with MYC Positivity Be Treated Like Burkitt Lymphoma?

No, high-risk DLBCL with MYC positivity should not routinely be treated with standard Burkitt lymphoma regimens, but rather requires more intensive therapy than R-CHOP, with dose-adjusted EPOCH-R being the most reasonable approach for most patients, particularly those over 60 years. 1, 2

Key Distinction: MYC-Positive DLBCL Is Not Burkitt Lymphoma

• DLBCL with MYC rearrangement represents approximately 10% of DLBCL cases and has inferior outcomes with standard R-CHOP therapy, but it remains a distinct entity from Burkitt lymphoma. 2

• The 2010 NCCN guidelines explicitly recognize that it may not always be possible to distinguish between DLBCL and Burkitt lymphoma, and when distinction is unclear, aggressive therapy is appropriate in selected cases. 1

• However, ESMO guidelines from 2015 clearly state that while R-CHOP gives poor outcomes for double-hit lymphomas (MYC plus BCL2 and/or BCL6 rearrangements), only preliminary results suggest better results with more intensive regimens, and clinical trials are required. 1

Treatment Approach Based on Patient Age and Fitness

For Younger, Fit Patients (Age <60 years):

• Burkitt-type intensive regimens may be feasible and should be considered, including CODOX-M/IVAC or hyper-CVAD with rituximab. 1, 2

• These regimens include high-dose methotrexate, cytarabine, and CNS prophylaxis as integral components. 1

• The 2010 NCCN guidelines note that CHOP is explicitly not adequate therapy for Burkitt lymphoma, and this principle extends to MYC-rearranged aggressive B-cell lymphomas. 1

For Older Patients (Age ≥60 years) or Those Unable to Tolerate Burkitt Regimens:

• Dose-adjusted EPOCH-R is the most reasonable approach, as it is effective in both DLBCL and Burkitt lymphoma, and retrospective studies suggest efficacy in MYC-rearranged DLBCL with or without BCL2 translocation. 2

• Most patients with MYC-positive DLBCL are older than 60 years and have poor tolerability of standard Burkitt regimens, making DA-EPOCH-R a more practical option. 2

• Preliminary prospective data for DA-EPOCH-R in MYC-rearranged DLBCL are very encouraging, though mature data are still awaited. 2

Critical Prognostic Factors to Consider

Double-Hit and Triple-Hit Lymphomas:

• Concurrent rearrangements of MYC and BCL2 and/or BCL6 (double-hit or triple-hit) are associated with extremely aggressive behavior and very poor outcomes. 2, 3, 4

• Double-hit lymphomas have a median overall survival of only 4.5 months, which is significantly inferior to both Burkitt lymphoma (p=0.002) and IPI-matched DLBCL (p=0.04). 4

• IGH/BCL2 fusion, double-hit score (MYC and BCL2 co-expression), and double-hit translocation are pathological prognostic factors for poor progression-free survival. 3

MYC Expression Without Rearrangement:

• MYC overexpression alone (without translocation) combined with BCL2 overexpression (dual expressors) also confers poor prognosis, though the evidence for specific treatment approaches is less clear. 1

• High Ki-67 proliferation index (>60%) and BCL2 positivity (>50%) are independent prognostic factors for poor overall survival in DLBCL. 5

Essential CNS Prophylaxis

• CNS prophylaxis is strongly recommended given the high rate of CNS involvement and progression in MYC-rearranged lymphomas. 2, 4

• Checking cerebrospinal fluid by cytology and flow cytometry at initial diagnosis should be considered. 2

• CNS disease was present in 45% of double-hit lymphoma patients at presentation in one series. 4

• Intrathecal therapy should be incorporated into the treatment regimen. 1

Role of Stem Cell Transplantation

• There is no consensus on consolidation stem cell transplantation in first remission, and no retrospective studies have demonstrated benefit. 2

• Autologous stem cell transplant may be considered for relapsed/refractory disease or early relapse. 1

Common Pitfalls to Avoid

• Do not use standard R-CHOP for MYC-rearranged DLBCL or double-hit lymphomas - outcomes are consistently poor across multiple studies. 1, 2, 3, 4

• Do not assume all MYC-positive cases are the same - distinguish between MYC rearrangement alone, double-hit (MYC + BCL2/BCL6 rearrangements), and dual expressors (protein overexpression without rearrangement). 1, 2

• Do not overlook CNS prophylaxis - the CNS relapse rate is substantially higher than standard DLBCL. 2, 4

• Do not delay treatment to obtain complete molecular characterization - if FISH results are pending but clinical suspicion is high, initiate more intensive therapy rather than R-CHOP. 1

Recommended Diagnostic Workup

• Assessment of MYC and BCL2 rearrangement using interphase FISH is recommended in newly diagnosed patients treated with curative intent. 1

• Immunohistochemistry should include CD10, BCL2, BCL6, Ki-67, and MYC protein expression. 1

• FISH for MYC, BCL2, and BCL6 rearrangements should be performed to check for double-hit or triple-hit status. 1