Double-Hit Lymphoma: Many Treatment Strategies, No Standard of Care

Get Permission

Jonathon B. Cohen, MD

While we can have long-term survivors, patients who fail initial treatment are, in most cases, destined for a dismal outcome. You get one swing at bat. It’s important to figure out the most appropriate treatment.

—Jonathon B. Cohen, MD

"Double-hit lymphoma” represents a challenging malignancy without a standard-of-care treatment, although outcomes for some patients are better than was once believed, according to Jonathon B. ­Cohen, MD, Assistant Professor of Hematology and Medical Oncology at Emory University, Atlanta. Dr. Cohen shared his approach to double-hit lymphomas at the 2015 Debates and Didactics in Hematology and Oncology Conference, sponsored by Emory University, in Sea Island, Georgia.

Challenges in Evaluation

“The evaluation and identification of these patients is harder than it looks. I see many patients where there’s been a lot of discussion as to whether the patient truly has a double-hit lymphoma. The recent identification of [the] ‘double-expresser’ category makes it even more complicated,” said Dr. Cohen.

Double-hit lymphoma is characterized by the presence of concurrent MYC (myelocytomatosis oncogene) and BCL2 (B-cell lymphoma 2) gene rearrangements. Double-expresser patients stain positive on immunohistochemistry for MYC and BCL2 expression. With standard therapy approaches for non-Hodgkin lymphoma, such as R-CHOP (rituximab [Rituxan]/cyclophosphamide/doxorubicin/vincristine/prednisone), both patient types have a worse prognosis than patients without these alterations.

Recent availability of the MYC immunohistochemistry stain has increased the detection of double-expressers. In a 2012 study, 33% of patients were MYC-positive, 53% were BCL2-positive, and 18% expressed both genes.1 Overall survival was significantly better for the double-expressers than for the double-hit group, and both groups had worse outcomes than patients lacking these alterations.

Part of the challenge in evaluation and diagnosis is that double-hit lymphoma is not, by itself, a recognized lymphoma classification according to the World Health Organization (WHO). Many patients fall into the B-cell lymphoma unclassifiable category or have morphologically diffuse large B-cell lymphoma but are subsequently shown by fluorescent in situ hybridization to have a MYC plus BCL2 (or BCL6) gene rearrangement—the criteria for double-hit lymphoma status.

The upcoming WHO reclassification should clarify these categories, but in the meantime, any patient with aggressive non-Hodgkin lymphoma should be assessed by fluorescent in situ hybridization to evaluate for MYC and BCL2/6 gene expression to give optimal treatment, he added.

Wide Range of Treatment Approaches

“There are many approaches to treatment and no standard of care,” Dr. Cohen said. Key questions follow: What is the optimal induction regimen? Does stem cell transplant increase the chances for complete remission and long-term survival? The one universal truth, according to Dr. Cohen, is that R-CHOP alone is not adequate treatment, as it is unlikely to achieve long-term remission.

Some commonly employed, more intensive treatment options include the following regimens:

  • Dose-adjusted R-EPOCH (rituximab plus etoposide/prednisone/vincristine/cyclophosphamide/doxorubicin)
  • R-hyperCVAD (rituximab plus cyclophosphamide/vincristine/doxorubicin/dexamethasone alternating with methotrexate/cytarabine)
  • R-CODOX-M/IVAC (rituximab/cyclophosphamide/vincristine/doxorubicin/methotrexate) (etoposide/cytarabine/ifosfamide)

Dr. Cohen said for both double-hit and double-expressing patients, he favors dose-adjusted R-EPOCH, which is the only one of the three regimens that has been prospectively evaluated. The study on which he bases this preference, which was led by the National Cancer Institute, evaluated dose-adjusted R-EPOCH and found that progression-free survival at 14 months was 79% for all MYC-positive patients with non-Hodgkin lymphoma and 87% for the double-hit patients.2 Since newly diagnosed patients had to be stable enough to await the results of the fluorescent in situ hybridization assessment at the time of diagnosis, it is likely that very sick patients were not enrolled.

Dr. Cohen acknowledged, however, “This study suggests this regimen is very active. It’s still very early in follow-up, but these are encouraging data, and they look far better than our initial survival curves.”

Dr. Cohen also suggested that patients should be assessed for central nervous system involvement and considered for prophylaxis. If central nervous system disease is suspected at the time of diagnosis, he said he often alters his induction therapy. If there are no initial signs of central nervous system involvement, he uses prophylaxis, especially in MYC-positive patients.

Initial Treatment: Complete Response Is Key

The variability in current treatment choices is illustrated by a review of 49 patients with MYC-positive diffuse large B-cell lymphoma (29 with double-hit lymphoma) at The Ohio State University.3 Of them, 17% received R-CHOP, 28% received a “Burkitt-like regimen,” 48% received R-EPOCH, and 7% received another treatment; none received a transplant.

The most important factor in their outcomes was not whether they were MYC-positive or double-hit, but whether they achieved a complete remission. After 4 years of follow-up, virtually all patients with complete remission remained alive, compared with none of the patients failing to achieve a complete remission, noted Dr. Cohen, a study co-investigator.

“This speaks to the fact that while we can have long-term survivors, patients who fail initial treatment are, in most cases, destined for a dismal outcome,” he commented. “You get one swing at bat. It’s important to figure out the most appropriate treatment.”

Transplant After Induction Therapy

What has been less well established is whether consolidation and stem cell transplant provide further benefit. MD Anderson researchers retrospectively evaluated 129 patients with double-hit lymphoma receiving a range of treatments and found that 2-year event-free survival was highest (> 60%) among the R-EPOCH cohort.4

Upfront transplant did not influence event-free and overall survival among patients who achieved a complete remission, although the curves did separate at 2 years in this nonrandomized study. “The findings suggest, at least, that front-line transplant in all likelihood does not hurt,” he commented.

In a small study from British Columbia, 19 patients received R-CODOX-M/IVAC treatment followed by stem cell transplant.5 This aggressive approach resulted in a 2-year progression-free survival of 60% and overall survival of 82%. “The findings would suggest this is an additional reasonable regimen for double-hit lymphoma,” Dr. Cohen offered.

A multicenter study of 311 patients further evaluated induction regimens and transplant.6 Patients received R-CHOP (32%), R-hyperCVAD (21%), R-EPOCH (21%), R-CODOX-M/IVAC (14%), and other regimens (13%), and 17% received an autologous transplant at first complete remission.

Intensive induction, as compared with R-CHOP, was also significantly associated with improved progression-free survival (approximately 50% at 4 years; P = .001). Progression-free survival was highest with R-hyperCVAD (approximately 60% at 4 years; P = .0016). After adjustments for several high-risk features identified in the study, intensive induction also significantly improved overall survival.

Although stem cell transplant did not significantly improve survival (P = .140), the curves did separate, he noted, “suggesting there may be some benefit, though it was done in the minority of patients, who were self-selected to get to transplant. The role of transplant has not been established; therefore, I discuss the pros and cons with each ­patient.”

In support of transplant, one could argue that transplant in first complete remission is generally low risk, that extrapolating from other studies suggests high-risk patients may benefit, and that when patients relapse after initial therapy, their outcomes are very poor (so preventing relapse is critical). Against transplant, one could argue that prospective studies are lacking and that patients who achieve complete remission after induction may well remain in remission and not ever need a transplant.

“The question has not been answered as to whether after intensive treatment, patients still need transplant,” he reiterated. “I typically consider transplant in patients with double-hit lymphoma who have several other IPI [International Prognostic Index] risk factors. However, those who are not otherwise high risk who achieve a [complete remission] with intensive therapy can likely be observed.”

What is clearer is that with an appropriate intensive regimen, outcomes for patients with double-hit lymphoma “are not nearly as bad as we initially thought,” Dr. Cohen said. “The curve flattens out at about 40% [6 months post diagnosis], and some patients are likely cured. Hopefully, with better treatment, we can move that bar higher.” ■

Disclosure: Dr. Cohen has served on advisory boards for Pharmacyclics, Millennium/Takeda, Seattle Genetics, and Celgene. He has received research funding from BMS and Pharmacyclics.


1. Johnson NA, Slack GW, Savage KJ, et al: Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 30:3452-3459, 2012.

2. 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.

3. Cohen JB, Geyer SM, Lozanski G, et al: Complete response to induction therapy in patients with Myc-positive and double-hit non-Hodgkin lymphoma is associated with prolonged progression-free survival. Cancer 120:1677-1685, 2014.

4. Oki Y, Noorani M, Lin P, et al: Double hit lymphoma: Br J Haematol 166:891-901, 2014.

5. Sun H, Savage KJ, Karsan A, et al: Outcome of patients with non-Hodgkin lymphomas with concurrent MYC and BCL2 rearrangements treated with CODOX-M/IVAC with rituximab followed by hematopoietic stem cell transplantation. Clin Lymphoma Myeloma Leuk 15:341-348, 2015.

6. 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.

Related Articles

Dr. Cohen’s Approach to Managing Double-Hit Lymphoma

  • All patients with aggressive non Hodgkin lymphoma should be evaluated for MYC and BCL2/6 gene expression, if possible, by fluorescent in situ hybridization and immunohistochemistry.
  • Several intensive treatment regimens are available. Dr. Cohen favors dose-adjusted R-EPOCH for patients with...