Treatment of Diffuse Large B-Cell Lymphoma Continues to Evolve



Quick Guide to Terms

  • ABC = activated B-cell type
  • DLBCL = diffuse large B-cell lymphoma
  • EPOCH-R = etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin, plus rituximab
  • GCB = germinal center B-cell type
  • R-CHOP = rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone
  • RCHP = rituximab, cyclophosphamide, doxorubicin, and prednisone

Although the prognosis of patients with diffuse large B-cell lymphoma (DLBCL) has improved with R-CHOP—the addition of rituximab (Rituxan) to the cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy regimen—one-third of patients still relapse after therapy, and patients with the activated B-cell (ABC) genetic subtype have a poorer prognosis.

Auayporn Nademanee, MD, presented updates in the treatment of this disease at a City of Hope Hematologic Malignancies symposium held earlier this year in Las Vegas.1

“For patients with DLBCL, especially the ABC subtype, we don’t know what the best combination is yet,” said Dr. Nademanee, Jane & Mace Siegel Professor in Hematology & Hematopoietic Cell Transplantation and Director of the Matched Unrelated Donor Program at City of Hope, in Duarte, California. “Combining the R-CHOP regimen with another drug, such as lenalidomide [Revlimid] or ibrutinib [Imbruvica], appears promising, but we must wait for phase III trials, due to additional toxicity.”


Patients for whom R-CHOP fails continue to have poor outcomes. These are the patients we need to target and enroll in clinical trials. Further advances in personalized medicine may improve prognosis.
— Auayporn Nademanee, MD

“Most importantly, patients for whom R-CHOP fails continue to have poor outcomes,” Dr. Nademanee added. “These are the patients we need to target and enroll in clinical trials. Further advances in personalized medicine may improve prognosis.”

A Complex Disease

As Dr. Nademanee reported, ­DLBCL is the most common lymphoma, accounting for 25% to 30% of all non-Hodgkin lymphomas in the developed world.2 Genetic analyses have revealed the molecular heterogeneity of DLBCL tumors, which has led to classification into two subtypes based on cell of origin: germinal center B-cell (GCB) and activated B-cell (ABC).

“This is a very complex disease, which has different morphology, gene-expression profiles, and cell origins,” she explained. “When we see patients with DLBCL, it’s critical to understand the cellular origin of the disease.”

Although R-CHOP is the standard regimen, said Dr. Nademanee, one-third of patients relapse after therapy. One way to improve outcomes is to increase the intensity of regimens or include another drug in the R-CHOP backbone.

In patients older than 80 years, however, regular R-CHOP therapy may be too toxic, and a regimen with a decreased dose of CHOP (R-miniCHOP) has been shown to be safe and effective. Bendamustine in combination with rituximab has also been shown to be effective and less toxic than R-CHOP.

Ongoing Clinical Trials

Several randomized trials are currently researching new drugs to improve outcomes in DLBCL. A phase III randomized study3 of R-CHOP vs dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) showed no difference in overall response rates (89.3% vs 88.8%). Although survival curves were nearly identical, a greater percentage of patients in the dose-adjusted EPOCH-R arm discontinued treatment early due to adverse events (6.5% vs 1.5% in the R-CHOP arm).

“This study was planned to look at cell origin, but analysis has not yet been completed,” said Dr. Nademanee. “It’s possible that there are subsets of patients who may benefit from dose-adjusted EPOCH-R rather than R-CHOP.”

In patients with high-intermediate–risk/high-risk DLBCL, a phase II study of brentuximab vedotin (Adcetris) with R-CHOP is yielding positive results, especially in patients with CD30-expressing disease.4 Progression-free and overall survival rates appear encouraging in patients with CD30 expression, said Dr. Nademanee.

The study was originally designed to assess safety and activity between 2 doses of brentuximab vedotin (1.2 or 1.8 mg/kg) combined with R-CHOP. Due to significant neurotoxicity from the combination of brentuximab vedotin and vincristine, the study was amended to include the combination of brentuximab vedotin with RCHP (rituximab, cyclophosphamide, doxorubicin, and prednisone) as well.

Data from part 2 of the study show that brentuximab vedotin (1.8 mg/kg) plus RCHP is active as front-line therapy in CD30-expressing, high-intermediate–risk/high-risk DLBCL. Moreover, when combined with RCHP, brentuximab vedotin appears to be more tolerable than the combination with R-CHOP, Dr. Nademanee reported. The investigators observed no grade 3 neuropathy or motor neuropathy and a lower incidence of febrile neutropenia in the brentuximab vedotin/RCHP arm.

“These results support further evaluation of brentuximab vedotin with front-line therapy for DLBCL,” she said. “Although the trial is on hold, these are very exciting data, which show improved prognosis for patients with high-risk disease.”

Lenalidomide Maintenance

REMARC, a phase III trial assessing the benefit of lenalidomide maintenance after response to R-CHOP in previously untreated patients (aged 60–80 years), showed statistically significant and clinically meaningful improvement in progression-free survival (ClinicalTrials.gov identifier: NCT01122472). Patients receiving lenalidomide maintenance after R-CHOP had a median progression-free survival of 54 months, compared to 38.6 months for placebo.

Treatment Update for DLBCL

  • The R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy regimen remains the standard of care for diffuse large B-cell lymphoma, especially in patients with the germinal center B-cell (GCB) subtype.
  • Patients with the non-GCB type have a poorer prognosis and should be enrolled in clinical trials.
  • The new regimens of R-CHOP plus lenalidomide or R-CHOP plus ibrutinib “appear promising” but must await phase III trials.

“This is the first report showing that use of an immunomodulatory agent as maintenance therapy prolongs progression-free survival for patients with DLBCL after R-CHOP,” said Dr. Nademanee. “However, at a median follow-up of 52 months, analysis of overall survival found no difference between the lenalidomide and placebo arms.”

Other Approaches

For patients with the ABC (or non-GCB) subtype, prognosis is poor, said Dr. Nademanee, but recent studies suggest that lenalidomide maintenance may also improve outcomes. In elderly patients with untreated DLBCL, a phase II study of lenalidomide plus R-CHOP21 (ie, administered every 21 days) led to increases in progression-free and overall survival with acceptable toxicity.5

“This is very exciting,” said Dr. Nademanee, “but we’re waiting for the phase III trial to see if this turns out to be positive.”


It is a challenge to be a generalist these days, especially in the area of blood cancer treatment. As the science evolves, you need the opinion of physicians who work on a daily basis focused on these disease entities and are aware of the evolution of treatment options.
— Steven T. Rosen, MD

A phase Ib study demonstrated that ibrutinib at 560 mg can be given safely with R-CHOP as front-line therapy for non-GCB DLBCL.6 A phase III study comparing ibrutinib plus R-CHOP vs R-CHOP alone is underway.

Finally, in patients who relapse, said Dr. Nademanee, overall survival is low, so prevention is key. A phase III study of ibrutinib vs placebo after autologous stem cell transplantation is currently recruiting participants with relapsed or refractory ABC-type disease.

Future studies with treatment based on cell of origin/molecular profile, targeted therapy, and availability of biomarkers will allow the possibility of individualized risk-adapted therapy, she concluded.

“The field is evolving more rapidly than ever, and precision medicine is going to make it even more complicated,” said Steven T. Rosen, MD, Provost and Chief Scientific Officer and Director of the Comprehensive Cancer Center and Beckman Research Institute at City of Hope. “It is a challenge to be a generalist these days, especially in the area of blood cancer treatment. As the science evolves, you need the opinion of physicians who work on a daily basis focused on these disease entities and are aware of the evolution of treatment options.” ■

Disclosure: Dr. Nademanee is on advisory boards for Seattle Genetics and Gilead. Dr. Rosen reported no potential conflicts of interest.

References

1. Nademanee A: Updates in treatment of diffuse large B cell lymphoma. City of Hope Presents: How the experts treat hematologic malignancies. Presented March 17, 2017.

2. Armitage JO, Weisenburger DD: New approach to classifying non-Hodgkin’s lymphomas: Clinical features of the major histologic subtypes. Non-Hodgkin’s Lymphoma Classification Project. J Clin Oncol 16:2780-2795, 1998.

3. Wilson WH, Jung S, Pitcher BN, et al: A phase III randomized study of R-CHOP vs DA-EPOCH-R and molecular analysis of untreated large B-cell lymphoma: CALGB/Alliance 50303. 2016 ASH Annual Meeting. Abstract 469. Presented December 4, 2016.

4. Budde LE, Halwani AS, Yasenchak C, et al: Results of an ongoing phase II study of brentuximab vedotin with RCHP as frontline therapy in patients with high-intermediate/high-risk diffuse large B cell lymphoma (DLBCL). 2016 ASH Annual Meeting. Abstract 104. Presented December 3, 2016.

5. Nowakowski GS, LaPlant B, Macon WR, et al: Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-cell lymphoma: A phase II study. J Clin Oncol 33:251-257, 2015.

6. Younes A, Thieblemont C, Morschhauser F, et al: Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: A non-randomized, phase 1b study. Lancet Oncol 15:1019-1026, 2014.



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