Tailoring front-line therapy in diffuse large B-cell lymphoma: who should we treat differently?

Abstract

Although there have been significant insights into the biology of diffuse large B-cell lymphoma (DLBCL) over recent years, progress in our therapeutic approach has been disappointing over the same timeframe. This is not for want of trying. In 2017, R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) remains the "gold standard," despite all of our insights into cell-of-origin and other subgroups. We have traditionally used clinical risk factors to tailor our therapies and have tested intensification of chemotherapy with little success. We are now in an era of testing therapies according to the molecular phenotype of the individual's tumor. Many phase 1/2 studies have looked at adding targeted agents to conventional R-CHOP with some promise. The phase 3 data are now starting to emerge. Are we ready yet to modify our standard of care and have we reached an era of precision medicine in DLBCL? The answer to this is "not yet." The exception is perhaps patients with the newly defined World Health Organization category of high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6, the so-called double- and triple-hit lymphomas. In these tumors there has been a move away from R-CHOP to more intensified regimens, however, has not been based upon rigorous prospective evaluation but review of retrospective datasets. This article will review the molecular subgroups of DLBCL, interventional strategies, and the outcomes of these interventions to date.

Figure 1.

REMoDL-B. (A) Study schema. Patients initiated a first cycle of R-CHOP while the molecular work-up was performed, thus not selecting for patients with less-aggressive phenotypes. The novel agent, bortezomib, was only introduced at the second cycle in randomized patients. (B) PFS by molecular phenotype. Percentages are 30-month PFS. Unc, unclassifiable.

Figure 2.

PFS (A) and OS (B) in elderly patients in first remission of DLBCL randomized to either lenalidomide or placebo maintenance. Results from the REMARC study. Reprinted from Thieblemont et al with permission.

Figure 3.

Model assessing clinical risk according to MYC and BCL2 Status in DLBCL. The risk of treatment failure is proportional to the degree of MYC and BCL2 expression. The 5% of patients with the poorest outcome are shown in red and have the highest level of MYC and BCL expression as a result of translocation immunoglobulin loci. Reprinted from Sesques and Johnson with permission.

Figure 4.

(A) Relapse-free survival by front-line regimen in those patients with double-hit lymphoma who achieve a first CR by induction regimen. (B) Relapse-free survival by front-line regimen and in receipt of an autologous stem-cell transplant. Reprinted from Landsburg et al with permission.

Figure 5.

OS of patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone according to the presence of concurrent expression of MYC and BCL2 proteins (MYC⁺/BCL2⁺) or the presence of concurrent MYC and BCL2 translocations. Reprinted from Johnson et al with permission.