Understanding Double-Hit Lymphomas and Optimizing Management

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While most double-hit lymphomas are high risk, a small subset looks like typical large cell lymphoma, and their prognosis is good.
— Jeremy S. Abramson, MD

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Double-hit lymphomas are a challenging subset of high-grade B-cell lymphomas, previously characterized histologically as diffuse large B-cell lymphoma or B-cell lymphoma unclassifiable with intermediate features between diffuse large B-cell lymphoma and Burkitt lymphoma. Expert guidance in their management was offered by Jeremy S. Abramson, MD, Clinical Director of the Center for Lymphoma, Massachusetts General Hospital and Assistant Professor of Medicine, Harvard Medical School, Boston, at the 2016 Pan Pacific Lymphoma Conference in Koloa, Hawaii.1

The World Health Organization (WHO) pathologic diagnosis of double-hit/triple-hit lymphomas changed in 2016 to eliminate Burkitt lymphoma. The new definition is “high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6.” Dr. Abramson added: “These lymphomas are high grade both histopathologically and cytogenetically, and this is important.”

Double- and triple-hit lymphomas constitute 3% to 10% of diffuse large B-cell lymphomas but are more frequent among the former Burkitt lymphoma category (2008 WHO classification). They may occur de novo or, in about 20% of cases, as a transformation from follicular lymphoma. Double-hit lymphomas are usually seen in the context of a complex karyotype containing multiple numerical and structural aberrations.

The majority of double-hit lymphomas (about three-quarters) are marked by MYC plus BCL2 translocations; BCL6 translocation is less common. Double-hit lymphomas and the triple-hit type (MYC/BCL2/BCL6) have a similar prognosis. “They all do relatively poorly,” Dr. Abramson admitted.

What Is Not a Double-Hit Lymphoma?

Dr. Abramson described lymphomas that are not double-hit lymphomas:

  • Diffuse large B-cell lymphomas with a MYC rearrangement without rearrangements of BCL2 or BCL6
  • Morphologically small B-cell lymphomas, ie, follicular lymphoma, without high-grade histology
  • Diffuse large B-cell lymphomas with expression—but not rearrangements—of MYC and BCL2: these are double-expressor lymphomas, and their prognosis is better than double-hit lymphomas
  • Diffuse large B-cell lymphoma with amplifications or extra copies of MYC, BCL2, and BCL6 (although this is controversial, as they have a common pathway).

Researchers from The University of Texas MD Anderson Cancer Center described 40 patients with other MYC/BCL2 structural abnormalities, a subset they labeled “atypical double-hit lymphomas.” Most (n = 22) had BCL2 translocation with extra copies of MYC; others (n = 15) had extra copies of MYC and BCL2 without translocations; and a few (n = 3) had MYC translocations with extra copies of BCL2.2

“Compared to double-hit lymphomas, atypical cases like these are more likely to have diffuse large B-cell lymphoma morphology and normal LDH [lactate dehydrogenase],” he said.

Clinically, patients with double-hit lymphomas usually present at an advanced stage and commonly have extranodal involvement and a high IPI [International Prognostic Index] score. Bone marrow is positive in about half the cases, and many patients have leukemic or circulating disease, which is not often seen with typical diffuse large B-cell lymphoma.

Results From Previous Studies

In early retrospective studies, only about 10% of high-risk patients achieved long-term survival, but historic series are limited based on selection bias, since only the most aggressive cases clinically and histologically were evaluated for MYC translocations in the first place. In the modern era when MYC testing is performed more broadly, lower risk cases are being identified with an improved prognosis. Patients with limited-stage disease and low IPI scores fare better, whereas those with bone marrow involvement do worse, explained Dr. Abramson. Individuals with typical diffuse large B-cell lymphoma morphology also appear to have better outcomes than those with Burkitt-like features.

A 2014 multicenter retrospective study of 311 patients with double-hit lymphoma showed median progression-free survival to be 11 months and median overall survival to be 22 months.3 At 2 years, a “tail of the curve” showed about 40% of patients were free of disease progression, and close to 50% were still alive.

“The outcomes were far better than we saw with previous analyses,” he noted, adding fluorescence in situ hybridization (FISH) analysis identify double-hit lymphoma in otherwise low-risk patients, who have a greater than 50% chance of cure.

Can Poor Prognosis Be Predicted?

The same multicenter study found that odds ratios for worse survival were leukocytosis (1.7), LDH > 3 times the upper limit of normal (1.7), advanced Ann Arbor stage (1.6), and central nervous system (CNS) involvement (2.0). In a risk model incorporating these four factors, overall survival at 6 years ranged from > 95% in patients without any of these factors to < 40% in those with two to four of them (P < .0001).3

“While most double-hit lymphomas are high risk, a small subset looks like typical low-risk large cell lymphoma, and their prognosis is good,” concluded Dr. Abramson.

Also, patients with low IPI scores and earlier-stage disease have more favorable outcomes, and patients who achieve a complete response to induction have a 60% chance of cure.4

Achieving Complete Response

Dr. Abramson addressed whether more complete response could be achieved with more intensive therapy, such as dose-adjusted (DA) EPOCH-R (etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin, rituximab [Rituxan]). Progression-free survival may be improved with more intensive regimens. Dr. Abramson’s center prefers DA-EPOCH-R over a more traditional Burkitt-like regimen, which may be difficult for older patients to tolerate. DA-EPOCH-R also been shown to produce the highest response after induction and the longest progression-free and overall survival among several regimens.3,5

Update on Double-Hit Lymphomas

  • Approximately 5% of diffuse large B-cell lymphomas are “double-hit lymphomas,” meaning they have translocations in both MYC and BCL2 and/or BCL6.
  • Prognosis is generally poor for patients with double-hit lymphomas, although there is a subset who may achieve long-term survival. Achievement of complete response to induction is the best predictor of a good outcome.
  • Intensive regimens may prolong remission but have not been shown to improve overall survival.
  • DA-EPOCH appears to be an effective treatment for many patients with double-hit lymphomas.

Multivariable analyses, however, have not shown that intensive regimens improve overall survival.3,4 Although approximately 50% of patients can achieve long-term survival, there are no obvious differences between intensive chemotherapy and R-CHOP (rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone).

The role of consolidation with high-dose chemotherapy and autologous stem cell transplantation also remains unclear, with no significant benefit shown over observation in retrospective analyses. The achievement of complete response to induction remains the most important treatment-related factor for outcome, said Dr. Abramson.

Choice of Initial Therapy

“Treatment intensification appears to improve complete response rates and progression-free survival, without an obvious impact on overall survival. The standard of care for initial therapy is undefined, and treatment must be individualized,” Dr. Abramson said.

At present, his empiric approach is:

  • Young patients: Burkitt-like approach, such as DA-EPOCH-R, R-HyperCVAD (rituximab and cyclophosphamide/doxorubicin/vincristine/dexamethasone), or R-CODOX-M/R-IVAC (rituximab and cyclophosphamide/doxorubicin/vincristine/methotrexate/cytarabine)/(rituximab/etoposide/cytarabine/ifosfamide);
  • Older patients: DA-EPOCH-R;
  • Patients with low-risk features (uncommon): R-CHOP or DA-EPOCH-R, with radiotherapy for limited-stage disease;
  • All patients: Consider CNS evaluation and prophylaxis;
  • High-risk patients: Consider upfront stem cell transplant consolidation.


Approximately 25% of diffuse large B-cell lymphomas are the high-risk subset of double-expressors, without translocations but with immunohistochemical expression of the MYC and BCL2 proteins. Without translocations, their prognosis is worse than that of routine DLBLC—about a 50% overall survival rate—but better than that of double-hit lymphomas. With R-CHOP, their 3-year overall survival is approximately 50%. MYC protein expression without BCL2 expression, however, does not predict an inferior outcome.

“Despite worse outcomes with R-CHOP for this high-risk subset as compared to other diffuse large B-cell lymphomas, there is no evidence that other regimens perform better,” indicated Dr. Abramson. “This is even more of a data-free zone than double-hit lymphoma, but clinical trials are being developed for these patients.”

Prospects for Targeted Therapies

Advances in understanding double-hit and double-expressing lymphomas have painted a brighter therapeutic future. The BCL2 inhibitor venetoclax (Venclexta) shows promise; BET bromodomain inhibition and histone deacetylase inhibition are other avenues for these subtypes.

Promising non–subtype-specific agents include anti-CD19 CAR T cells, programmed cell death protein 1 (PD-1)/ programmed cell death ligand 1 (PD-L1) inhibitors, novel antibody-drug conjugates, bispecific antibodies such as blinatumomab (Blincyto), and the first-in-class inhibitor of nuclear export compound selinexor. For double-expressors, most of which fall into the activated B-cell type of diffuse large B-cell lymphoma, targeting the cell of origin could prove effective with ibrutinib (Imbruvica) or lenalidomide (Revlimid), and mutationally directed therapy. ■

Disclosure: Dr. Abramson is a consultant for AbbVie, Gilead, Kite Pharma, and Seattle Genetics.


1. Abramson JS: What is really a double-hit or triple-hit DLBCL? 2016 Pan Pacific Lymphoma Conference. Presented July 20, 2016.

2. Li S, Seegmiller AC, Lin P, et al: B-cell lymphomas with concurrent MYC and BCL2 abnormalities other than translocations behave similarly to MYC/BCL2 double-hit lymphomas. Mod Pathol 28:208-217, 2015.

3. Petrich AM, Gandhi M, Jovanovic B, et al: Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: A multicenter retrospective analysis. Blood 124:2354-2361, 2014.

4. Li S, Saksena A, Desai P, et al: Prognostic impact of history of follicular lymphoma, induction regimen and stem cell transplant in patients with MYC/BCL2 double hit lymphoma. Oncotarget. May 19, 2016 (early release online).

5. Dunleavy K, Fanale M, LaCasce A, et al: Preliminary report of a multicenter prospective phase II study of DA-EPOCH-R in MYC-rearranged aggressive B-cell lymphoma. 2014 ASH Annual Meeting. Abstract 395. Presented December 8, 2014.