Thomas Habermann, MD
With the R-CHOP chemotherapy regimen considered the backbone of therapy for treatment-naïve patients with non-Hodgkin lymphoma, researchers are now delving further into the genome to pave the way for therapeutic improvements.
The goal of current and novel therapies should be to achieve event-free survival (EFS) in patients at 24 months, particularly in diffuse large B cell lymphoma (DLBCL). Patients who reach that endpoint have a subsequent overall survival equal to that of age- and gender-matched members of the general population.
To help reach that goal, science is moving forward to finding new driver mutations in these heterogeneous diseases, to understand the effects of the microenvironment and of individual patient characteristics on survival, and to identify drugs that can target these factors.
Thomas Habermann, MD, professor of Medicine at the Mayo Clinic, presented a review of the evidence supporting these principles, during the 2016 International Congress on Hematologic Malignancies.
Supporting 24-Month EFS
The current standard of care for patients with DLBCL was established in a 2006 study, ECOG 4494,1
which demonstrated the value of adding rituximab to CHOP (prednisone, cyclophosphamide, vincristine, and doxorubicin), and then using rituximab as a maintenance therapy, in patients with aggressive non-Hodgkin lymphoma, compared with the less effective strategy of CHOP plus observation.
In a 2014 study of patients with DLBCL treated with first-line chemoimmunotherapy,2
EFS at 24 months was a predictor of survival rates akin to those in the general population, both in the United States and France. However, 21.7% of patients with this condition relapse before reaching that 2-year endpoint, another study showed. Among 107 patients in that study who underwent autologous stem cell transplant, 39 were alive at 2 years.
In a whole-exome analysis, certain acquired genomic alterations were associated with poor outcome after first-line chemoimmunotherapy in DLBCL.3
Specifically, 77% of patients who will fail to achieve EFS at 24 months can be identified in advance, based on a specific gene signature: a FOX01
mutation and gains in BCL6
, and RELB
Another gene, SLC22A16
, a doxorubicin transporter, was lost in half of those who did not achieve 24 months of EFS, the researchers found. That’s important because doxorubicin, an anthracycline, is considered a vital part of the R-CHOP regimen for patients with this disease, Habermann said.
Habermann and his colleagues have created a personalized way to help predict whether patients with these diseases will achieve 24-month EFS, through a nomogram looking at variables including age, performance status and the level of bulky disease. An electronic version of the nomogram is available online at http://www.qxmd.com
Seeking Better Treatments for DLBCL
Recent clinical trials have generated data demonstrating that a variety of drugs hold promise as potential treatments for non-Hodgkin lymphomas.
The BTK-targeted drug ibrutinib (Imbruvica), a tyrosine kinase inhibitor indicated for the treatment of chronic lymphocytic leukemia and other blood cancers, has shown promise in DLBCL. In a trial that reported results in 2015,4
37% of 80 participating patients with relapsed or refractory DLBCL categorized as activated B cell-like (ABC) experienced a complete or partial response, but only 5% of those with germinal center B cell-like (GCB) disease benefited, Habermann noted. Those with the highest likelihood of response had MYD88
mutations. Ibrutinib is now being tested in the disease in a phase III international trial.
When ibrutinib was combined with R-CHOP in an early trial,5
patients with CD20-positive B cell non-Hodgkin lymphoma achieved a 100% overall response rate, but most patients experienced side effects of grade 3 or greater, with neutropenia being the most common. A large phase III study, PHOENIX, launched in 2013 to compare R-CHOP with or without ibrutinib in patients with newly diagnosed non-GCB DLBCL.
R-CHOP is also being studied with the CD30-targeted antibody-drug conjugate brentuximab vedotin as a front-line therapy in patients with high-risk DLBCL.6
Results from the ongoing phase II study show a 12-month progression-free survival (PFS) rate of 82% in patients whose cancers are CD30-positive and a 56% PFS rate in those who are CD30-negative tumors.
The immunomodulatory agent lenalidomide affects multiple pathways that are important in B-cell malignancies, discouraging angiogenesis, modulating the tumor microenvironment, and acting directly against the tumor. According to one retrospective analysis,7
the drug, when combined with R-CHOP, can overcome the negative prognostic impact of non-GCB DLBCL that newly diagnosed patients in this subgroup face when given R-CHOP alone.