Chemotherapy-Free Regimens for DLBCL

Chemoimmunotherapy is the standard of care treatment for patients with diffuse large B-cell lymphoma (DLBCL).

While this treatment is effective in 60–70% of patients, there are still some patients who relapse after treatment or are refractory to treatment. Additionally, due to the associated side effects of this treatment, it may not be suitable for older, frail patients. Chemotherapy-free regimens may be beneficial for these patients. 

What Are Chemotherapy-free Regimens?

Chemotherapy-free regimens describe a wide range of treatments that do not include chemotherapy.

Examples of chemotherapy-free treatments include:

• Targeted therapies 
• Immunotherapies, such as
  • Monoclonal antibodies
  • Bispecific antibodies
  • Chimeric antigen receptor (CAR) T-cells
• Immune modulators

When Are Chemotherapy-free Regimens Used?

Chemotherapy-free regimens are used in various situations, such as when standard chemotherapy hasn’t worked or for patients who are unable to receive chemotherapy. They may also be used as maintenance therapy for patients who are in remission after being treated with chemotherapy. Many chemotherapy-free regimens are still under investigation in clinical trials. 

Examples of Chemotherapy-free Regimens 

CAR T-cell therapies that target CD19 are an effective treatment for patients with relapsed/refractory DLBCL.

Three CAR T-cell therapies have been approved as a third-line treatment for patients with DLBCL:

• Axicabtagene ciloleucel (axi-cel)
• Tisagenlecleucel (tisa-cel) 
• Lisocabtagene maraleucel (liso-cel)

Axi-cel and liso-cel are also approved as a second-line treatment for patients with primary refractory or early relapsed DLBCL. Results from the ZUMA-7 and TRANSFORM trials showed that axi-cel and liso-cel, respectively, improved outcomes compared to standard treatment in this patient population. 

Bispecific antibodies, such as glofitimab and epcoritamab, which bind to both CD20 and CD3 proteins, are approved for the treatment of patients with relapsed/refractory DLBCL as a second-line therapy. These treatments have been associated with high response rates in clinical trials, though longer follow-up is needed to determine if they can cure DLBCL. Epcoritamab is particularly advantageous for older patients as it is administered under the skin rather than into the veins, like glofitimab.

Bispecific antibodies and CAR T-cells both have their similarities and differences when it comes to treating patients with DLBCL. 

Rituximab, an anti-CD20 monoclonal antibody, in combination with lenalidomide and ibrutinib, a BTK inhibitor, referred to as IR² regimen, has demonstrated efficacy in patients with relapsed/refractory DLBCL in clinical trials. This regimen may also benefit older, less fit patients who are ineligible for standard chemotherapy.

Tafasitamab, an anti-CD19 monoclonal antibody, combined with lenalidomide, an immune modulator, is approved for patients with relapsed/refractory DLBCL unsuitable for transplantation. This combination showed promising results in the L-MIND trial. 

The SMART Start trial has also investigated treating patients with this regimen prior to receiving standard chemoimmunotherapy, with promising initial results. 

Future Directions

While chemotherapy is the current standard of care for patients with DLBCL, chemotherapy-free regimens have shown that they can benefit patients for whom chemotherapy did not work.

Many of the regimens include new agents or combinations, and preliminary results suggest that they may benefit some patients as a first-line therapy, particularly patients unsuitable for intensive chemotherapy. As we learn more about the involvement of genetics in patients with DLBCL, more personalized treatments are being developed.

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Sources: 

• DLBCL 1L—What to Expect beyond R-CHOP?
• Guidelines for Patients - Diffuse Large B-Cell Lymphomas
• Treatment of Relapsed or Refractory Diffuse Large B-Cell Lymphoma: New Approved Options
• New treatment options in elderly patients with Diffuse Large B-cell Lymphoma