Patterns of Failure in Patients With Double Hit or Double Expressor Lymphomas: Implications for Radiation Therapy

Int J Radiat Oncol Biol Phys. 2018 Apr 1;100(5):1126-1132. doi: 10.1016/j.ijrobp.2018.01.041. Epub 2018 Jan 31.


Purpose: Lymphomas with MYC and either BLC2 or BCL6 rearrangements or MYC and BCL-2 protein overexpression, classified as double-hit (DHL) or double-expressor (DEL) lymphomas, respectively, are associated with poorer response to standard immunochemotherapy. Optimal therapy is not clear, and little information exists on the contribution of consolidative radiation therapy in these patients. This study describes the patterns of failure of DHL/DEL in relation to initial sites of disease and indications for radiation therapy in unselected diffuse large B-cell lymphoma (DLBCL).

Methods and materials: A retrospective single-institution study of all patients with diagnoses of non-Hodgkin lymphoma between 2011 and 2015 was performed. DHL status was determined by fluorescence in-situ hybridization, and DEL status was determined by immunohistochemistry. Progression-free survival (PFS) was calculated from the end of chemotherapy using the Kaplan-Meier method. Cox modeling was used for multivariable analysis.

Results: Screening of 275 DLBCL patients yielded a 53-patient cohort, including 32 patients with DHL, 10 with DEL, 9 with a triple rearrangement, and 2 triple expressors. Of the 26 patients whose disease progressed, 15 had primary refractory disease. The remaining 11 failures were relapses after complete response to initial chemotherapy. Of those failures, 6 (55%) occurred at initially involved site(s), and 4 (36%) were isolated initial site relapses. Consolidative radiation therapy was associated significantly with improved PFS on multivariable analysis (hazard ratio 0.17, 95% confidence interval 0.02-0.94, P = .04).

Conclusions: DHL/DEL are associated with high relapse rates, which preferentially occur at initially involved sites. Among patients achieving complete response to chemotherapy, consolidative radiation therapy was associated with improved PFS. This provides a rationale for the continued role of radiation therapy in the treatment of DHL and DEL and requires validation in a larger cohort.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Murine-Derived / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Cyclophosphamide / administration & dosage
  • Doxorubicin / administration & dosage
  • Etoposide / administration & dosage
  • Female
  • Gene Rearrangement
  • Genes, myc / genetics*
  • Humans
  • Kaplan-Meier Estimate
  • Lymphoma, Large B-Cell, Diffuse / drug therapy
  • Lymphoma, Large B-Cell, Diffuse / genetics*
  • Lymphoma, Large B-Cell, Diffuse / radiotherapy*
  • Male
  • Middle Aged
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Prednisone / administration & dosage
  • Prognosis
  • Progression-Free Survival
  • Proto-Oncogene Proteins c-bcl-2 / genetics*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins c-bcl-6 / genetics*
  • Proto-Oncogene Proteins c-myc / metabolism
  • Retrospective Studies
  • Rituximab / administration & dosage
  • Treatment Failure
  • Vincristine / administration & dosage
  • Young Adult


  • Antibodies, Monoclonal, Murine-Derived
  • BCL2 protein, human
  • BCL6 protein, human
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-bcl-6
  • Proto-Oncogene Proteins c-myc
  • R-CHOP protocol
  • Rituximab
  • Vincristine
  • Etoposide
  • Doxorubicin
  • Cyclophosphamide
  • Prednisone

Supplementary concepts

  • EPOCH protocol