What Is High-Grade B-Cell Lymphoma with MYC and BCL2/BCL6 Rearrangements?

High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements is an aggressive and rare subtype of non-Hodgkin lymphoma. Often referred to as “double-hit” (MYC plus one other) or “triple-hit” (MYC, BCL2, and BCL6), this form of lymphoma is characterized by chromosomal translocations that activate oncogenes associated with rapid cell growth and survival.

These genetic rearrangements drive uncontrolled proliferation of malignant B-cells, making the disease more resistant to standard treatment and associated with a poorer prognosis compared to other diffuse large B-cell lymphomas (DLBCL).

Who Is Affected?

This lymphoma typically affects older adults, often those over age 60, but it can occur in younger individuals as well. It is slightly more common in males and may present either as a new primary diagnosis or as a transformation of a lower-grade lymphoma, such as follicular lymphoma.

Clinical Presentation

Patients often present with:



  • Rapidly growing lymph nodes or masses




  • B symptoms (fever, night sweats, weight loss)




  • Extranodal involvement (e.g., bone marrow, central nervous system, gastrointestinal tract)




  • Advanced-stage disease at diagnosis



Because of its aggressive nature, early diagnosis and prompt initiation of treatment are essential.

Diagnosis

Accurate diagnosis requires histological examination and cytogenetic testing of biopsy tissue. The diagnostic process includes:



  • Immunohistochemistry (IHC): Confirms B-cell lineage and expression of markers like CD20, CD10, BCL6, and Ki-67 (high proliferation index).




  • Fluorescence in situ hybridization (FISH): Detects MYC, BCL2, and BCL6 gene rearrangements.




  • Bone marrow biopsy and PET/CT scan: Assess extent of disease.




  • Lumbar puncture: Often done to evaluate CNS involvement due to high risk of central nervous system spread.



The World Health Organization (WHO) classifies this disease as “High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements”, distinguishing it from DLBCL not otherwise specified.

Treatment Approaches

This aggressive lymphoma typically does not respond well to standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), which is used for most DLBCLs. More intensive regimens are required.

Common first-line regimens include:



  1. DA-EPOCH-R (Dose-Adjusted Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin, Rituximab):



    • More effective than R-CHOP for double/triple-hit lymphomas.




    • Administered as a continuous infusion over 5 days per cycle.






  2. HyperCVAD (Cyclophosphamide, Vincristine, Doxorubicin, Dexamethasone) ± Rituximab:



    • Alternating with high-dose methotrexate and cytarabine, particularly in younger patients.






  3. CNS prophylaxis:



    • Intrathecal methotrexate or systemic high-dose methotrexate may be given due to high risk of CNS involvement.






  4. Stem Cell Transplantation (ASCT):



    • Considered in first remission for eligible patients, especially those with high-risk features.





Relapsed or Refractory Disease

Options for patients with relapsed or refractory high-grade B-cell lymphoma may include:



  • CAR T-cell therapy (e.g., axicabtagene ciloleucel, lisocabtagene maraleucel):



    • Offers durable responses in heavily pretreated patients.






  • Targeted therapies:



    • Trials investigating agents like BCL2 inhibitors (e.g., venetoclax), BTK inhibitors, and bispecific antibodies.






  • Clinical trials:



    • Strongly encouraged due to limited standard options and poor outcomes with traditional salvage therapies.





Prognosis

The prognosis for high-grade B-cell lymphoma with MYC and BCL2/BCL6 rearrangements is significantly poorer than for other types of DLBCL. Survival rates vary, but:



  • Median overall survival may be less than 2 years without intensive treatment.




  • Early response to therapy and achieving complete remission are key prognostic factors.




  • Stem cell transplant or CAR T-cell therapy may improve long-term outcomes for select patients.



Conclusion

High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements represents a challenging subtype of lymphoma that demands aggressive treatment and careful monitoring. Thanks to ongoing research, newer therapies such as CAR T-cells and novel agents offer renewed hope for improved survival. Early identification through genetic testing and referral to a lymphoma specialist or academic center can help ensure patients receive optimal care.

If you or a loved one has been diagnosed with this rare and aggressive lymphoma, discussing all available options — including clinical trials — with a hematologist-oncologist is essential.