In the World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissues, high-grade B-cell lymphomas include diffuse large B-cell lymphoma and its numerous subtypes, B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell and Burkitt lymphoma, and Burkitt lymphoma. However, it is becoming increasingly clear that morphologic heterogeneity is only part of the picture and that many of these lymphomas are biologically driven by equally complex variations in genetics and protein expression (see Table 1). It is also becoming clear that specific genetic abnormalities and/or patterns of protein expression can be clinically relevant and have an impact on prognosis and treatment choice—even with lymphomas that appear similar morphogically.
|Proportion of Lymphomas (References)|
|Morphology||Genetic Double Hit||Only MYC-Positive||Double Expressers of BCL-2 and MYC Protein by IHC||Ki-67 ≥ 90%|
|DLBCL||0%-12% (Johnson 2009, Caponetti 20133)||3%-8% (Johnson 2009, Caponetti 20133)||29%-44% (Green 2012, Aukema 20115)||7%-8% (Mead 2008, Savage 20097)|
|High-grade B-cell lymphoma with features intermediate between DLBCL and Burkitt lymphoma||9% (Perry 20138)||36% (Perry 20138)||NA||61% (Perry 20138)|
|Burkitt lymphoma||<1% (Swerdlow 20081)||∼100% (Swerdlow 20081)||<20% (Swerdlow 20081)||∼100% (Swerdlow 20081)|
Abnormalities involving the myc avian myelocytomatosis viral oncogene homolog (MYC) and B-cell chronic lymphocytic leukemia/lymphoma 2 (BCL-2) genes and/or overexpression of MYC protein and the BCL-2 protein have been the subject of numerous recent reports describing the biologic behavior and prognostic factors in these subsets of high-grade B-cell lymphomas. The worst prognosis generally has been associated with what have been termed “double-hit” lymphomas. This label is usually given to lymphomas with rearrangements of MYC and BCL-2, but some reports apply the term “double-hit” to lymphomas with rearrangements of any 2 of the 3 genes MYC, BCL-2, and BCL-6. Histologic subtypes of lymphoma that have had “double hits” identified include diffuse large B-cell lymphoma, B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, and follicular lymphoma. “Double hits” appear to be most frequent in B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, they are observed in a minority of diffuse large B-cell lymphomas, and they appear to be rare in follicular lymphoma.
To make matters even more complicated, recent reports have used the label “double hit” or “double expressers” for lymphomas that overexpress MYC and BCL-2 protein but either do not have the genes rearranged, or the lymphomas were not tested for the presence of such rearrangements. Patients with high-grade B-cell lymphomas that express both MYC protein and BCL-2 protein seem to have a worse prognosis than those with lymphomas that do not overexpress these proteins, but they probably fare better than patients who have lymphomas with genetic double hits. Patients with high-grade B-cell lymphomas who have a genetically defined double hit have an extremely poor prognosis (the median survival in most series is <1 year), and these patients often progress on therapy.[5, 9, 10] The optimal treatment for these patients is unclear, but 1 recent report suggested that combined etoposide, doxorubicin, vincristine plus cyclophosphamide, prednisone, and rituximab (EPOCH-R) might be associated with a better outcome for tumors that express both MYC and BCL-2 protein; however, this was not observed in a recent, large, multicenter analysis for genetically defined double-hit lymphomas. Also, in a prospective validation of the outcomes with combined cyclophosphamide, vincristine, doxorubicin, cytarabine, methotrexate/etoposide, ifosfamide, and cytarabine (CODOX-M/IVAC) in Burkitt lymphoma, a small number of cases from that review were determined to be double-hit diffuse large B-cell lymphomas and were uniformly fatal within 5 months, suggesting that current chemotherapy regimens for aggressive lymphomas like Burkitt lymphoma may be inadequate for many of these double-hit lymphomas.
The prognosis for patients with diffuse large B-cell lymphoma and an isolated MYC translocation or overexpression of MYC protein is more difficult to discern in our opinion. Although several publications that investigated the presence of MYC translocations have demonstrated inferior outcomes,[13, 14] many of those included in their cases at least a small proportion of double-hit lymphomas (before their potential significance was recognized), or the authors did not investigate for the presence of a BCL-2 or BCL-6 translocation. Thus, some of those publications may have included undiagnosed double-hit lymphomas. In our data from the University of Nebraska Medical Center in 208 patients with diffuse large B-cell lymphoma, the 5-year survival rate was 31% for patients with double-hit lymphomas; 47% for patients with either MYC, or BCL-2, or BCL-6 rearrangements; and 71% for patients with an isolated MYC rearrangement.
The article by Cohen et al in this issue of Cancer addresses another important issue regarding patients with either MYC rearrangements or a combination of MYC rearrangement and the t(14; 18) translocation as evidence of a BCL-2 rearrangement. Those authors observed that patients who did not achieve complete remission had a very short survival, but that a majority of the patients who did achieve a complete remission had durable remissions. This applied both to patients with double-hit lymphomas and to those with an isolated MYC rearrangement. This result is similar to a report presented at the 2013 American Society for Hematology (ASH) annual meeting using transplantation in remission, but another report indicated a high relapse rate in complete responders with or without transplantation.
How should these data be applied in the care of patients with diffuse large B-cell lymphoma and B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma who have either an isolated MYC rearrangement or a double-hit lymphoma involving both MYC and BCL-2? On the basis of our experience, we treat patients who have isolated MYC rearrangement with either EPOCH-R, which is our first choice in patients who have a very high proliferative rate (ie, a Ki-67 level ≥90%), or combined rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP-R), and we expect an outcome equivalent to what we observe in other patients with diffuse large B-cell lymphoma. For patients with double-hit diffuse large B-cell lymphoma or B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, we favor using EPOCH-R and offer patients who achieve a remission (and could tolerate the treatment) an autologous hematopoietic stem cell transplantation in remission. Although previous reports suggest that, even after achieving a complete remission, patients with double-hit lymphomas have poor outcomes, this report in Cancer suggests that, for some of these patients who achieve a complete remission with frontline chemotherapy, high-dose therapy and autologous transplantation may not be indicated. We have anecdotally observed a dramatic but short-lived response to ibrutinib in a patient with a double-hit lymphoma who had progressed through at least 5 prior chemotherapy regimens. This is obviously a patient population in which novel targeted therapies need to be tested in combination with chemoimmunotherapy in the front-line setting, because the proportion of patients who progress early is so high, and because many of them do not appear to be salvageable with further conventional chemotherapy regimens.