How I Treat in Brief: Double-Hit Lymphoma

This month, Jonathan W. Friedberg, MD, MMSc, discusses the diagnosis and treatment of patients with double-hit lymphoma.

This material was repurposed from “How I Treat Double-Hit Lymphoma,” published in the June 9, 2017, edition of Blood.

  • Double-hit lymphoma is a high-grade diffuse large B-cell lymphoma with translocations involving MYC and BCL2 or BCL6.
  • Dose-adjusted R-EPOCH is an appropriate induction option for most patients with double-hit lymphoma.
  • FISH testing for double-hit status should be performed in newly diagnosed aggressive large B-cell lymphoma, but can be restricted to GCB subtype lymphomas and those that express MYC on immunohistochemistry.
  • Because patients with MYC-rearranged lymphoma have an increased risk of CNS involvement, baseline lumbar puncture and CSF sampling is recommended in most patients with double-hit lymphoma.
  • Novel approaches for the treatment of double-hit lymphoma include small molecule inhibitors of BCL2, bromodomain inhibitors, and anti-CD19 CAR T-cell therapy.

The 2016 revision of the World Health Organization (WHO) classification for lymphoma included a new category of lymphoma, separate from diffuse large B-cell lymphoma (DLBCL), termed high-grade B-cell lymphoma with translocations involving myc and BCL2 or BCL6. These lymphomas have been referred to as double-hit lymphomas.

Diagnosing and Evaluating Double-Hit Lymphoma

Double-hit lymphoma occurs in less than 10 percent of cases of DLBCL. These lymphomas are differentiated from the larger group of double-expressor lymphomas, which have increased expression of MYC and BCL2 or BCL6 by immunohistochemistry, by using variable cutoff percentages to define positivity (30-50% for MYC and 30-70% for BCL2 or BCL6).

The WHO emphasizes that there is no consensus on which large B-cell lymphomas should undergo testing for double-hit status. At our institution, every newly diagnosed aggressive large B-cell lymphoma is referred for fluorescence in situ hybridization (FISH) testing with an MYC break-apart probe, as well as for BCL2 translocation, t(14;18). If resources preclude this broad approach, most double-hit cases can be identified as being of the germinal center B-cell (GCB) subtype and expressing MYC on immunohistochemistry, so limiting testing to this group is an acceptable, albeit suboptimal, alternative.

Patients with double-hit lymphoma should undergo routine staging procedures, including baseline functional and anatomic imaging with positron emission tomography (PET) and computed tomography (CT) scans, bone marrow aspirate and biopsy, as well as serum testing for lactate dehydrogenase (LDH), liver and kidney function, HIV and hepatitis B, and cardiac function evaluation.

Patients with MYC-rearranged lymphoma have an increased risk of central nervous system (CNS) involvement or relapse in the CNS compared to other patients with DLBCL. I recommend baseline lumbar puncture and cerebrospinal fluid (CSF) sampling in most patients with double-hit lymphoma. Exceptions include patients who present with early-stage disease, in whom CSF involvement is much less common, or frail, older patients, in whom treatment with curative intent is challenging. CSF should always be analyzed with flow cytometry, given the substantially increased sensitivity of the test compared with routine cytologic analysis.

I only perform imaging of the brain in patients with double-hit lymphoma when they have neurologic symptoms or malignant cells in the CSF.

Treating Double-Hit Lymphoma

Patients with double-hit lymphomas have a poor prognosis when treated with standard chemoimmunotherapy. There are no published prospective trials in double-hit lymphoma, but retrospective studies strongly suggest that aggressive induction regimens may confer a superior outcome. However, double-hit lymphoma is associated with advanced age, meaning many of these aggressive regimens are not appropriate for affected patients.

De Novo Double-Hit Lymphoma

I treat most patients with double-hit lymphoma using the dose-adjusted R-EPOCH regimen (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin). I favor this regimen because it is tolerated well in patients <80 years old and has demonstrated improved outcomes compared with historic controls in several retrospective studies and in one small prospective study.

I consider adding four cycles of intrathecal methotrexate as CNS prophylaxis, particularly in patients with extranodal disease, high LDH, or other CNS risk factors. For patients with documented CNS involvement, I place an Ommaya reservoir for more intensive intrathecal therapy and use more aggressive systemic therapy incorporating high-dose methotrexate and high-dose cytarabine, alternating this with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone). Should these patients with CNS involvement obtain a remission, I consider consolidation with high-dose therapy and autologous hematopoietic cell transplantation (AHCT).

Exceptions to the use of dose-adjusted R-EPOCH include:

  • patients >80 years old
  • frail patients
  • patients with cardiac dysfunction that precludes anthracycline use

For these patients, I use an individualized approach, generally the mini R-CHOP regimen or R-CGOP (rituximab, cyclophosphamide, gemcitabine, vincristine, and prednisone).

Finally, for the small subset of patients with limited-stage DLBCL who present with double-hit lymphoma, but normal LDH, and no other clinical risk factors, I generally use a combined modality regimen of R-CHOP followed by radiation therapy consolidation, given the favorable prognosis and limited data supporting this approach.

Transformed Double-Hit Lymphoma

Double-hit lymphoma can occur in the setting of transformation of underlying indolent lymphoma, particularly follicular lymphoma, when this t(14;18) lymphoma acquires an MYC translocation. These patients are often older and extensively pretreated with various chemotherapy regimens. In patients who have not had prior anthracycline, I generally consider dose-adjusted R-EPOCH. For most other patients who have had prior anthracycline, I consider a salvage lymphoma regimen followed by AHCT.

Relapsed Double-Hit Lymphoma

The standard curative approach to the treatment of relapsed aggressive lymphoma in fit patients is to administer non–cross-resistant salvage chemotherapy followed by consolidation with high-dose therapy and AHCT, but outcomes in patients with MYC-rearranged disease are poor.

Based on results from retrospective analyses, if a patient with double-hit lymphoma was treated with intensive induction and still experienced progressive disease, I would refer him or her to a clinical trial involving novel agents rather than trying conventional salvage therapy. For patients with relapsed/refractory double-hit lymphoma who were treated with R-CHOP induction, I would consider salvage therapy, with plans for clinical trial referral if complete remission is not obtained.

Future Directions

Novel agents with promise in patients with double-hit DLBCL include small molecule inhibitors of BCL2, such as venetoclax, which has been studied in patients with relapsed lymphoma with limited activity in aggressive histologies. Several bromodomain inhibitors are also under investigation in MYC-associated lymphomas.

Anti-CD19 chimeric antigen receptor (CAR) T cells have significant clinical activity in patients with highly refractory DLBCL. At present, I consider a trial of CAR T cells a preferred option for fit patients with refractory double-hit lymphoma.


Friedberg JW. How I treat double-hit lymphoma. Blood. 2017;130:590-6.