Current challenges and novel treatment strategies in double hit lymphomas

Abstract

High-grade B-cell lymphomas with recurrent chromosomal break points have been termed 'double hit lymphoma' (DHL). The most commonly seen DHL is diffuse large B-cell lymphoma (DLBCL) with t(14;18) and t(8;14) or t(8;22) resulting in overexpression of BCL2 and MYC, respectively. The increased proliferation due to MYC overexpression, without the ability for an apoptotic brake as a result of BCL2 overexpression, results in 'the perfect storm of oncogenesis'. Thus this disease presents a number of diagnostic and therapeutic challenges for the hematologist. The first and foremost challenge is to recognize the DHL. As different morphological entities can be affected it is incumbent on pathologists and clinicians to maintain a high index of suspicion especially in disease that appears unusually aggressive or refractory to therapy. Diagnosis by fluorescence in situ hybridization (FISH) is a sensitive and specific method for detection of the disease but is time-consuming and expensive. While detection by immunohistochemistry (IHC) is sensitive and correlates with survival, standardized methods for this are not widely agreed upon. The second and equally important challenge in DHL is optimizing clinical outcome in a group of patients for whom the prognosis is widely regarded as poor. While improvements have been achieved by dose escalating standard chemotherapeutic regimens, many patients continue to do badly. Furthermore as a disease of aging many patients are unsuitable for dose-intensive chemotherapy regimens. There are now multiple novel targeted agents in various stages of clinical development that offer hope for better outcomes without undue toxicity. Among the most exciting of these developments include specific inhibitors of both BCL2 and MYC.

Keywords: BCL-2; MYC; diffuse large B-cell lymphoma; double hit lymphoma.

Figure 1.

Detection of DHL by FISH. The G-banded karyotype was 49,XY,+8,t(8;14)(q24;q32),+12, t(14;18)(q32;q21),+r[11]/46,XY[18]. (A) FISH using the LSI MYC (8q24) dual color break apart rearrangement probe (Vysis) showed two intact copies of MYC and one rearranged (split) MYC signal. In metaphases the rearranged 5’MYC signal (red) was located on the derivative chromosome 8 [der(8)der(8;14)] and the 3’MYC signal (green) was located on a derivative chromosome 14 [the der(14)t(8;14)]. (B) FISH using the LSI IGH/BCL2 t(14;18) dual color dual fusion translocation probe (Vysis) identified two IGH/BCL2 fusion signals: one on a derivative chromosome 14 [der(14)t(14;18)] and one on the derivative chromosome 18 [der(18)t(14;18)]. Additional IGH signals (green) were seen on the der(8)t(8;14) and the der(14)t(8;14). A BCL2 signal (red) was present on the intact chromosome 18. DHL, double hit lymphoma; FISH, fluorescence in situ hybridization.

Figure 2.

Detection of DHL by IHC. IHC of DH DLBCL is characterized by (A) diffuse growth of large B lymphoid cells on H+E with (B) high Ki-67, (C) high BCL2 and (D) high MYC expression. DH, double hit; DHL, double hit lymphoma; DLBCL, diffuse large B-cell lymphoma; IHC, immunohistochemistry.