Phase 2 study of panobinostat with or without rituximab in relapsed diffuse large B-cell lymphoma

Area of Science:

• Oncology
• Pharmacology
• Genetics

Background:

• Diffuse large B-cell lymphoma (DLBCL) often harbors mutations in histone-modifying enzymes (HMEs).
• Histone deacetylase inhibitors (HDIs) show potential in DLBCL, with preclinical data suggesting synergy with rituximab.

Purpose of the Study:

• To evaluate the response rate and toxicity of panobinostat (a pan-HDI) with or without rituximab in patients with relapsed or refractory DLBCL.
• To identify molecular correlates of response and non-response to panobinostat treatment.

Main Methods:

• A randomized phase 2 study involving 40 patients with relapsed/refractory DLBCL.
• Sequencing of candidate genes and whole exomes in relapse tumor biopsies.
• Quantification of circulating tumor DNA (ctDNA) in serial plasma samples.

Main Results:

• Eleven of 40 patients (28%) responded to panobinostat; rituximab did not improve response rates.
• Median duration of response was 14.5 months, with 6 of 11 responders remaining progression-free.
• MEF2B mutations were significantly associated with response.
• A significant increase in ctDNA at day 15 post-treatment strongly predicted lack of response (71.4% sensitivity, 100% specificity).

Conclusions:

• Panobinostat can induce durable responses in a subset of patients with relapsed DLBCL.
• Early prediction of treatment response is possible through MEF2B mutation status or ctDNA level changes at day 15.