New Strategies Explored in B-Cell Malignancies

Andre Goy, MD

The landscape in lymphoma management continues to evolve, with new therapies and approaches improving established treatment paradigms, according to Andre Goy, MD, chairman and director, and chief of the Lymphoma Division at John Theurer Cancer Center. Goy discussed recent advancements in mantle cell lymphoma and diffuse large B-cell lymphoma at the 2014 Chemotherapy Foundation Symposium.

Mantle Cell Lymphoma

In fit patients aged ≤65 years with mantle cell lymphoma (MCL), Goy said that dose intensive and/or high-dose chemotherapy regimens followed by autologous stem cell transplantation have demonstrated superiority to standard R-CHOP, with progression-free survival (PFS) extending beyond 5 years.

Induction regimens that include a high-dose version of the chemotherapy drug cytarabine are now considered the standard of care in younger patients. Studies involving younger patients have demonstrated 5-year event-free survival rates of 56% to 65% with induction regimens containing high-dose cytarabine.

Goy said the reason for the improved outcomes with the drug is that “cytarabine brings earlier and deeper CR (complete remissions),” and, “in younger patients with MCL, achieving an early and deep response (CR and molecular CR) translates into a longer PFS and survival advantage.” This is because in MCL, there is a relatively high-risk of relapse and patients frequently become chemo-resistant in the relapsed/refractory setting.

Several targeted agents have now been approved for heavily pretreated patients with relapsed/refractory MCL, including lenalidomide, bortezomib, and ibrutinib, Goy said. Ongoing trials are examining the potential of moving these agents into the frontline setting to be used in combination with a chemotherapy backbone.

Recently, bortezomib became the first targeted agent approved for MCL in the frontline setting. In October, the FDA approved first-line bortezomib in combination with VR-CAP (rituximab, cyclophosphamide, doxorubicin, and prednisone).

Researchers are also examining the potential of incorporating targeted agents in maintenance regimens following rituximab-chemotherapy.

In older patients (aged ≥65) with MCL, for whom standard of care is R-CHOP or BR (bendamustine plus rituximab), Goy said outcomes are “disappointing,” but he has hope that outcomes can improve.

“What I find really amazing—it’s palpable really—is that we are now really able to think, in the short term, of nonchemotherapy options in some of these elderly patients that will likely replace chemotherapy.”

Goy said that the next step to improving outcomes further in MCL would likely involve exploiting the heterogeneity of the disease to better stratify patients.

Diffuse Large B-Cell Lymphoma

In diffuse large B-cell lymphoma (DLBCL), Goy said the key research focus is moving beyond the current treatment standard of R-CHOP every 21 days for six cycles, or R-CHOP-21. While over 50% of patients are cured with this regimen, a significant number still relapse. Goy said that “relapses typically occur early, with 80% of relapses occurring in the first 3 years,” and the prognosis is poor for these patients.

To improve outcomes, researchers are examining higher intensity regimens and combination strategies with novel agents. Among the targeted agents being explored to improve on R-CHOP-21 in DLBCL are the BTK inhibitor ibrutinib, the Bcl-2 inhibitor ABT-199, IMiDs (lenalidomide), and proteasome inhibitors (bortezomib).

DLBCL is a heterogeneous disease and researchers hope to increase molecular understanding to enhance patient stratification and improve outcomes. At this point, three distinct subtypes of DLBCL have been established: germinal center, activated B-cell (ABC), and unclassified.

“Patients with the ABC subtype clearly do worse in terms of progress-free and overall survival,” Goy said. Several ongoing phase III studies are examining targeted agents, including bortezomib, lenalidomide, and ibrutinib, in patients with this poorer ABC prognosis.

Goy said the other mechanism by which researchers hope to improve upon R-CHOP-21 in DLBCL is with better predicators/evaluators to “better appreciate the depth and the quality of patient response.” Specifically, minimal residual disease (MRD) has emerged as a new concept in large cell lymphoma. MRD refers to the small number of malignant cells that remain after therapy when the patient is in remission and shows no symptoms or overt signs of disease. “MRD-negative might become a new endpoint for measuring patient outcomes,” said Goy.

Goy hinted at a potential future option in DLBCL management with data on chimeric antigen receptor (CAR) T-cell therapy, an immunotherapeutic option that has generated recent excitement in the hematology field. In research he conducted, Goy said that 4 of 7 patients with heavily pretreated refractory DLBCL had a complete response with anti-CD19 CAR T-cell therapy.

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