The Impact of Novel Agents in Non-Hodgkin Lymphoma Treatment

Anuja V. Abhyankar, MD Roswell Park Comprehensive Cancer Center

Non-Hodgkin lymphoma (NHL) comprises a heterogeneous group of lymphoid malignancies, with diffuse large B-cell lymphoma (DLBCL) being the most common aggressive subtype. Follicular lymphoma (FL) and mantle cell lymphoma (MCL) are among the more indolent forms. Treatment strategies that had remained unchanged for a long time have evolved rapidly in recent years with the incorporation of novel agents in the frontline and relapsed/refractory (R/R) settings.

Upfront Treatment for DLBCL

Frontline treatment for patients with DLBCL has typically been a combination of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Within the past few years, clinical trials investigating R-CHOP in combination with antibody-drug conjugates (ADCs) and bispecific T-cell engagers (BiTEs) have shown promise with improved survival outcomes.

• POLARIX (5-year update, ASH 2024): The trial showed Pola-R-CHP (polatuzumab vedotin, an ADC, plus rituximab, cyclophosphamide, doxorubicin, prednisone) improved progression-free survival (PFS) and disease-free survival compared with R-CHOP with fewer subsequent treatments and a comparable toxicity profile. Benefits were noted in certain exploratory subgroups, including activated B-cell subtype, IPI 3-5, double expressors, patients aged 60 years and older, and male patients.
• EPCOR-2: Epcoritamab (bispecific anti-CD3×CD20) plus R-CHOP demonstrated promising 2-year PFS and overall survival, durability of response, and activity across high-risk subgroups.
• EPCORE DLBCL-3: Epcoritamab monotherapy was effective in elderly patients unfit for intensive chemoimmunotherapy (anthracycline ineligible).

Relapsed/Refractory DLBCL

• ECHELON-3: Brentuximab vedotin plus lenalidomide-rituximab (BV plus R²) versus placebo plus R² in CD30-positive and -negative R/R DLBCL post two or more lines of therapy showed higher overall response rate (ORR) and complete response (CR) rates in the BV plus R² arm with a manageable toxicity profile.
• The combination of glofitamab (CD20×CD3 bispecific antibody) with polatuzumab vedotin also showed high efficacy, rapid responses, and activity in high-risk subgroups. Mosunetuzumab (CD20×CD3 bispecific antibody) plus polatuzumab vedotin has also shown similar results, with both regimens offering robust options in the post chimeric antigen receptor (CAR) T-cell therapy setting.

In addition, three other active regimens are used as treatment options in R/R DLBCL. Polatuzumab in combination with bendamustine and rituximab is time-limited and well-tolerated. However, bendamustine should be avoided prior to CAR-T. Moreover, the doublet therapy of tafasitamab and lenalidomide is active, but requires an intensive infusion schedule. While the ADC loncastuximab tesirine offers convenient dosing (q3 weeks), it’s important to watch adverse events, such as fluid overload and photosensitive rash.

Optimizing Outcomes in FL 

First-line treatment ranges for FL based on observation, as well as on grade and the patient profile. Options may include rituximab monotherapy, R², BR, or R-CHOP. 

In the relapsed/refractory setting, innovative treatment strategies include monoclonal antibodies, BiTEs, ADCs, and targeted therapies.

• inMIND: The phase 3 trial compared tafasitamab plus lenalidomide and rituximab versus placebo plus lenalidomide and rituximab in R/R FL. The tafasitamab arm showed improved ORR and CR rates compared with control. Benefit was observed across risk groups and there were similar rates of treatment interruptions and discontinuation.
• EPCORE NHL-2: Epcoritamab plus R² produced about an 80% CR rate, across high-risk cohorts POD24 and primary refractory disease. Phase 3 trial results could establish this as the next standard of care.
• Loncastuximab plus rituximab: The doublet demonstrated about a 97% ORR, 77% CR across risk groups, and 95% PFS at 12 months.
• Targeted agents:
  • Tafasitamab plus R²
  • Tazemetostat (for EZH2 mutation or selected wild-type cases)
  • Zanubrutinib plus obinutuzumab
  • CAR T-cell therapy and bispecific antibodies in later lines

Advances in MCL

For patients with MCL, Bruton’s tyrosine kinase inhibitors (BTKis) have entered the frontline setting as part of combination regimens for induction and maintenance. Intensive approaches include TRIANGLE, NORDIC, RBAC, HyperCVAD, and BOVen.

In the maintenance setting, patients who are minimal residual disease (MRD)-negative will receive maintenance rituximab, while those who are MRD-positive may be considered for autologous stem cell transplant or BTKi maintenance with rituximab.

When disease has relapsed, BTKi therapy—including pirtobrutinib—and CAR T-cell therapy are key considerations, while novel bispecific antibodies are currently in development.

CAR T-Cell and Novel Immunotherapies

The treatment landscape of DLBCL, FL, and MCL continues to evolve with CAR T-cell therapy and emerging immunotherapies.

Long-term follow-up from the ZUMA-5 trial demonstrated durable efficacy of axicabtagene ciloleucel in FL and marginal zone lymphoma, with a median PFS of 62.2 months. In FL specifically, the 5-year lymphoma-specific mortality was 15.6%.

A trial investigating odronextamab reported an ORR of 80% and a CR rate of 74% in patients with R/R FL after at least two prior lines of therapy. While cytokine release syndrome is a serious AE, it was generally mild in the trial population.

The WaveLINE-003 study, which evaluated the combination of zilovertamab vedotin with R-GemOx in R/R DLBCL revealed a CR rate of approximately 50%. However, treatment was associated with significant toxicity, prompting ongoing protocol modifications to improve tolerability.