New Chemo-Free Trials for Relapsed/Refractory LBCL

Patients with relapsed or refractory non-Hodgkin lymphoma, like large B-cell lymphoma, often face limited treatment options. As research advances, more treatments are emerging to solve this issue and offer new treatments that effectively control the disease while maintaining manageable side effects and improving patients’ quality of life. 

Here, we review the recent and initial data of new promising agents for patients whose large B-cell lymphoma has returned after treatment or is no longer responding to treatment (relapsed/refractory).

New Chemo-Free Treatment Combination with Englumafusp Alfa and Glofitamab

A new combination therapy using englumafusp alfa and glofitamab is under investigation. This Phase 1 dose-escalation study included patients who had undergone at least one prior treatment. As of September 2024, the study has enrolled 134 patients, and it aims to determine the safety and effectiveness of this combination. 

Study Details 

Many participants had aggressive forms of lymphoma, and nearly half had previously received CAR-T cell therapy. Patients received glofitamab in a step-up dosing regimen, followed by englumafusp alfa in the second cycle. Both treatments were then administered every three weeks for up to 12 cycles. 

• At the time of the analysis, 67.5% of patients had responded to the combination, and 56.6% of patients achieved a complete response, meaning there were no detectable cancer cells
• The treatment also showed better outcomes in patients without prior CAR-T cell therapy, with improved response rates and longer response duration and progression-free survival.
• The most common side effect was cytokine release syndrome, which occurred in about 50% of the patients. 

This chemo-free, off-the-shelf treatment strategy may offer an effective alternative for patients with relapsed or refractory non-Hodgkin lymphoma, and a Phase 2 expansion study is currently underway to further explore its benefits, which we will cover as soon as results are available. 

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All-Oral Combination: Zabrutinib + Lenalidomide 

This Phase 1 dose-escalation/expansion study was conducted in Chinese patients who had undergone at least one prior systemic therapy and were ineligible for high-dose therapy or stem cell transplant. As of March 2024, 66 patients were enrolled, with a median follow-up of 16.5 months. 

Study Details

Many participants had advanced-stage disease, and 42% were classified as refractory. Patients received zanubrutinib (160 mg twice daily) plus lenalidomide in escalating doses (15, 20, or 25 mg). The recommended phase 2 dose (RP2D) of lenalidomide was determined to be 25 mg once daily.

• The overall response rate (ORR) was 58%.
• 42% of patients achieved a complete response (CR), meaning no detectable cancer cells.
• Median progression-free survival was 5.5 months, with a median duration of response of 14.9 months..

The most common side effects were related to low blood cell counts, including neutropenia (58%), which increases the risk of infections. However, these were generally manageable with medication and dose adjustments. 

The combination represents a promising chemotherapy-free treatment option, addressing an ongoing need for effective, easily administered therapies. 

A New Treatment: AZD0486 First-In-Human Trial 

A novel bispecific antibody, AZD0486, is being investigated as a potential treatment for relapsed/refractory diffuse large B-cell lymphoma. Designed to selectively bind CD19 on malignant B cells, AZD0486 aims to reduce cytokine release syndrome rates while maintaining strong antitumor activity. 

We interviewed the lead presenter of this trial, Dr. Sameh Gaballa, at the ASH conference, and he shared how this new antibody works and why it can be a revolutionary option for patients who have undergone multiple therapies.