Chimeric antigen receptor T-cell (CAR-T) therapy is an approved treatment for several B-cell non-Hodgkin lymphoma (B-NHL) histologies but is investigational for Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL). Minimal data have been reported to date for CAR-T for WM/LPL. In addition to efficacy, a favorable safety profile is preferred for WM. CD20 is a proven therapeutic target for B-NHL, in naked and radiolabeled antibodies and promising activity with bispecific antibodies. CD-20 targeted CAR-T is another potential adoptive immunotherapy option that could be used instead of or in sequence with CD19 CAR-T. 

MB-106 is a 3rd-generation fully human CD20-targeting CAR-T with high response rates and a favorable safety profile in follicular lymphoma and other B-NHLs.  During the EHA 2024 conference, results of the WM cohort of phaseI/II clinical trial (NCT03277729) investigating safety and efficacy of MB-106 for high-risk B-NHLs were presented.

A single-institution study in which patients with relapsed/refractory B-NHLs including WM/LPL were eligible after confirmation of CD20 expression. Between 7/2021-2/2024, 10 patients with WM were enrolled and 9 treated with MB-106 (1 DL4, 4 DL3 and 4 DL2, 1 pending infusion), 8 were evaluable for response and toxicity at the data cut-off. 

The median age was 69.7 years (range 51-79), with 7 of 10 male. Median time from diagnosis was 14 years (range 1-31), and median prior treatment lines was 9 (range 1-12). All 10 patients had BTKi refractory disease (9 ibrutinib, 2 acalabrutinib, 5 zanubrutinib, 1 pirtobrutinib). MYD88L265P was present in 9/10 patients and 1 of 6 tested patients had a CXCR4 mutation. B2M was elevated in 7 of 10 patients; 5 patients had extramedullary disease (PET-avid adenopathy), 4 had splenomegaly. Median pre-CAR-T IgM was 2461 mg/dL (range 187-6461; ULN 350). 

Out of 10 evaluable patients, 9 developed CRS (4 grade 2, 5 grade 1), and 3 patients received tocilizumab and dexamethasone for CRS. No patients had grade 3 or 4 CRS. One patient had grade 1 ICANS. 

On day 28, 5 patients had grade 4 neutropenia, and 4 or more patients had grade ≥3 anemia, neutropenia, or thrombocytopenia. 

By IWWM-11, all 8 patients responded to treatment (3 CR, 2 VGPR, 4 PR, 0 MR, 1 SD, 0 PD). Of the 5 patients with FDG-avid adenopathy, all had a complete metabolic remission at day 28. Abnormal B cells in the marrow were absent by day 28 in 7 of 8 patients, and all patients experienced B cell aplasia. CAR-T expansion and persistence were robust. One patient died from complications of COVID-19, 196 days after treatment.

Conclusion 

Data from the study showed that CD20 CAR-T therapy (MB-106) for BTKi-refractory WM/LPL shows high efficacy and favorable safety with no grade 3-4 CRS and no grade 2 or higher ICANS. MB-106 has received orphan drug designation by the US FDA for WM, and a multicenter registrational phase II study is currently active in the US for WM.