Targeted agents interact with specific pathways necessitating patient selection based on either cell of origin, mutation status, or both. We will be treating ‘double hit’ lymphomas differently as a result of these factors.
—Leo I. Gordon, MD
The R-CHOP regimen (rituximab [Rituxan] plus cyclophosphamide, doxorubicin, vincristine, and prednisone) was a major advance in treating diffuse large B-cell lymphoma, but experts are seeking to up the ante and identify ways to continue to improve outcomes beyond that achieved with R-CHOP.
“We are rapidly moving beyond R-CHOP for all patients. In 2014, clinical and biological features drive therapy. We believe that determination of cell of origin is essential for patient selection. Targeted agents interact with specific pathways necessitating patient selection based on either cell of origin, mutation status, or both. We will be treating ‘double hit’ lymphomas differently as a result of these factors,” stated Leo I. Gordon, MD, Abby and John Friend Professor of Cancer Research and Professor of Medicine at Robert H. Lurie Cancer Center of Northwestern University, Chicago.
At the National Comprehensive Cancer Network (NCCN) 9th Annual Congress on Hematologic Malignancies, Dr. Gordon discussed studies suggesting that several newer agents, including lenalidomide (Revlimid), ibrutinib (Imbruvica), and bortezomib (Velcade), can overcome the adverse impact of non–germinal center B-cell diffuse large B-cell lymphoma.1
Work has been going on for 2 decades on identifying adverse risk factors in diffuse large B-cell lymphoma. In 1995, Dr. Gordon and colleagues reported that elevated lactate dehydrogenase (LDH) was associated with reduced survival.2
“Even in the rituximab era, LDH level trumps International Prognostic Index [IPI] in terms of predictability,” Dr. Gordon stated. Other important markers for survival in the rituximab era include CD5 expression and Ki-67. Translocation of c-MYC on fluorescence in situ hybridization is associated with increased risk of central nervous system involvement, and high levels of c-MYC as well as low levels of HLA-DR predict survival in diffuse large B-cell lymphoma, he explained.
A six-gene model is able to predict longer survival (LMO2, BCL6, FN1) and shorter survival (CCND2, SCY3, BCL2), he continued.
More recently, “double hit” lymphomas, which include high-grade lymphomas with dual chromosomal rearrangements in MYC and BCL2 or, less commonly, BCL6, were identified and found to be associated with a worse survival.
With the increasing number of factors that predict for poor survival, the search is on for targeting both lymphoma cells and the microenvironment. “Successful targeted therapy needs to identify the biologic ‘Achilles heel’ of the tumor to alter clinical outcomes,” Dr. Gordon explained. “A number of different approaches are being explored.”
One important advance is the identification of two different subtypes in diffuse large B-cell lymphoma: activated B-cell or germinal center B-cell lymphoma. These cells predict distinct diseases with different outcomes. Different pathways are activated in these subtypes, and recurrent mutations identify potential targets, Dr. Gordon told listeners. Activated B-cell lymphoma carries a much worse prognosis than germinal center B-cell lymphoma, he added.
A new assay called Lymph2Cx can accurately identify cells of origin using NanoString technology and thereby predict overall and progression-free survival.3 This 20-gene predictive test costs $40, can be done in less than 36 hours, and can be performed on frozen paraffin-embedded samples. It retains prognostic power compared with Affymetrix gene-expression profiling of fresh tissue, Dr. Gordon noted.
Strategies Under Study
Lenalidomide added to R-CHOP (ie, R2-CHOP) is a promising investigational strategy. In a phase II trial of 21 elderly untreated patients with diffuse large B-cell lymphoma, the addition of lenalidomide on days 1 to 4 to R-CHOP21 (ie, R-CHOP given over 3 weeks) was found safe, feasible, and effective, with an overall response rate of 86% and complete response rate rate of 86%.4 At a median follow-up of 22 months, 2-year overall survival was 92%, and 2-year progression-free survival was 73%. This regimen was moved into phase III trials.
In a second study of 47 evaluable patients, R2-CHOP achieved an 83% complete response rate and 15% partial response rate (98% overall response rate) in a group of newly diagnosed patients with CD20-positive, stage II to IV, diffuse large B-cell, or grade 3 follicular lymphoma.5
“This regimen of lenalidomide plus R-CHOP is well tolerated, including in the elderly. The efficacy appears promising when compared with R-CHOP. Most interesting is that the addition of lenalidomide may ameliorate the negative effect of non–germinal center B-cell phenotype on outcome.
Ibrutinib also appears to be active in relapsed/refractory activated B-cell diffuse large B-cell lymphoma, but not as much in other molecular subtypes, Dr. Gordon continued. A phase III trial is underway to validate the effect of R-CHOP plus ibrutinib vs R-CHOP plus placebo in non–germinal center B-cell diffuse large B-cell lymphoma.
Bortezomib is another drug that may be exploitable according to cell-of-origin subtype. R-CHOP plus bortezomib was studied as initial therapy for 40 patients with diffuse large B-cell lymphoma and adverse prognostic factors, including high stage, elevated LDH, intermediate and high IPI, and non–germinal center B-cell subtype.6 Early data showed no significant difference in overall survival or progression-free survival from what would have been expected for patients with germinal center B-cell histology.
At least two studies are planned to compare newer regimens vs R-CHOP and evaluate results according to cell-of-origin subtype: the PYRAMID trial in non–germinal center B-cell diffuse large B-cell lymphoma and the REMoDL-B trial in patients with activated B-cell or germinal center B-cell disease.
Other approaches in preliminary investigations include antibody-drug conjugates plus rituximab. For example, one study is comparing rituximab-CD22 antibody-drug conjugate vs rituximab-CD79b antibody-drug conjugate in 41 patients with relapsed/refractory follicular lymphoma and 81 with relapsed/refractory diffuse large B-cell lymphoma.7 SGN-CD19A is another antibody-drug conjugate in early clinical trials. ■
Disclosure: Dr. Gordon reported no potential conflicts of interest.
1. Gordon LI: Diffuse large B-cell lymphoma: Treatment beyond R-CHOP. NCCN Annual Congress on Hematologic Malignancies. Presented September 20, 2014.
2. Gordon LI, Andersen J, Colgan J, et al: Advanced diffuse non-Hodgkin’s lymphoma: Analysis of prognostic factors by the international index and by lactic dehydrogenase in an intergroup study. Cancer 75:865-873, 1995.
3. Scott DW, Wright GW, Williams PM, et al: Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue. Blood 123:1214-1217, 2014.
4. Nowakowski GS, LaPlant BR, Reeder C, et al: Combination of lenalidomide with R-CHOP (R2CHOP) is well-tolerated and effective as initial therapy for aggressive B-cell lymphomas: A phase II study. American Society of Hematology Annual Meeting. Abstract 689. Presented December 10, 2012.
5. Chiappella A, Franceschetii S, Castellino A, et al: Rituximab-CHOP21 plus lenalidomide (LR-CHOP21) is effective and feasible in elderly untreated diffuse large B-cell lymphoma (DLBCL): Results of phase II REAL07 study of the Fondazione Italiana Linfomi (FIL). American Society of Hematology Annual Meeting. Abstract 903. Presented December 11, 2012.
6. Ruan J, Martin P, Furman RR, et al: Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma. J Clin Oncol 29:690-697, 2011.
7. Morschhauser F, Flinn I, Advani RH, et al: Preliminary results of a phase II randomized study (ROMULUS) of polatuzumab vedotin (PoV) or pinatuzumab vedotin (PiV) plus rituximab (RTX) in patients (Pts) with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). ASCO Annual Meeting. Abstract 8519. Presented May 31, 2014.