News

Article

MB-106 Shows Early Promise in BTKi-Refractory Waldenström Macroglobulinemia/LPL

Author(s):

Key Takeaways

  • MB-106 achieved a 90% overall response rate in heavily pretreated patients with Waldenström macroglobulinemia or lymphoplasmacytic lymphoma.
  • The therapy includes 4-1BB and CD28 costimulatory domains and a modified IgG1 spacer, enhancing its efficacy and safety.
SHOW MORE
Brian M. Till, MD

Brian M. Till, MD

The CD20-targeted CAR T-cell therapy, MB-106, showcased a favorable safety profile and elicited responses in heavily pretreated patients with Waldenström macroglobulinemia or lymphoplasmacytic lymphoma (LPL) who are refractory to BTK inhibitors, according to cohort data from a phase 1/2 study (NCT03277729) presented during the 2024 EHA Congress.1,2

In 10 evaluable patients, the overall response rate was 90%; this was comprised of 3 complete responses (CRs), 2 very good partial responses, and 4 partial responses. One patient achieved stable disease. Notably, 1 patient who achieved CR remained in remission for 31 months, and they experienced a rapid reduction in immunoglobulin level to normal range following exposure to the agent.

“MB-106, CD20-targeted CAR T-cell therapy, appears to be a safe and highly effective treatment for patients with BTK inhibitor–refractory Waldenström macroglobulinemia,” Brian M. Till, MD, associate professor in the Translational Science and Therapeutics Division and attending physician in Stem Cell Transplant Service and Immunotherapy Service at Fred Hutchinson Cancer Center, in Seattle, Washington, said in a poster presentation on the findings. “Based on these data, the FDA has granted MB-106 orphan drug status and [regenerative medicine advanced therapy] designation for the treatment of Waldenström [macroglobulinemia.]” Till is also an associate professor of medicine at the University of Washington.

Although CAR T-cell therapies have proven to be highly effective for several types of lymphoma, this modality has been minimally explored in Waldenström macroglobulinemia, Till noted in the poster presentation delivered during the meeting. The fully human, third-generation, CD20-targeted CAR T-cell therapy, MB-106, has 4-1BB and CD28 costimulatory domains, a modified IgG1 spacer that eliminates FcR binding, and a truncated CD19 transduction marker. The agent is under evaluation in the phase 1/2 trial, which enrolled patients with CD20-positive B-cell non-Hodgkin lymphoma.

To be eligible, patients needed to have previously treated Waldenström macroglobulinemia, large cell lymphoma with prior exposure to 2 lines of treatment, follicular lymphoma and mantle cell lymphoma (MCL) following at least 1 prior line of therapy (a BTK inhibitor if MCL), chronic lymphocytic leukemia who previously received a BTK inhibitor and/or experienced failure with venetoclax (Venclexta), and other previously treated B-cell non-Hodgkin lymphomas. Patients who were previously treated with CD19 CARs were allowed to enroll if normal B cells had recovered.

“The study initially required radiographically measurable disease, but the protocol was subsequently modified to remove this requirement and to base response on the [11th International Workshop on Waldenström’s Macroglobulinemia] criteria,” Till added. The data shared at the meeting were from the Waldenström macroglobulinemia cohort.

After a screening period, participants underwent leukapheresis. For approximately 10 days, the CAR T cells were produced. Patients then received lymphodepletion with cyclophosphamide and fludarabine, and bendamustine (Bendeka) was acceptable for clinical or supply reasons. After 36 to 96 hours of that treatment, they were infused with the CAR T-cell therapy. MB-106 was evaluated at the following dose levels: 1 x 105 cells/kg (dose level 0), 3.3 x 105 cells/kg (dose level 1), 1 x 106 cells/kg (dose level 2; n = 6), 3.3 x 106 cells/kg (dose level 3; n = 3), and 1 x 107 cells/kg (dose level 4; n = 1). Treatment was administered in the outpatient setting, with the exception of the first patient treated on each dose level. After 7 to 16 days, a tumor biopsy was performed.

“For the Waldenström cohort, who were treated later in the overall trial, the target dose level was dose level 4 for all the patients,” Till said. “Although due to manufacturing limitations, most patients received dose levels 2 or 3.”

The median patient age at baseline was 69.7 years (range, 51-79) and 30% were female. The median years since diagnosis was 14.5 years (range, 1-31). Moreover, patients were heavily pretreated, with a median number of prior lines of therapy received was 9, with a range of 1 to 12. All patients were previously exposed to a BTK inhibitor, which could have been ibrutinib (Imbruvica; 90%), acalabrutinib (Calquence; 20%), zanubrutinib (Brukinsa; 50%), or pirtobrutinib (Jaypirca; 10%). All patients had progressed on BTK inhibitors and 40% were intolerant.

All put 1 patient had a MyD88L265P mutation and 10% of patients were CXCR4 positive. At study entry, 80% of patients had anemia and 50% had thrombocytopenia. The median beta-2 macroglobulin was 4.1 mg/dL (range, 1.6-10.8). For half of patients, FDG-avid lymphadenopathy was present; 40% of patients had splenomegaly. The median IgM at baseline was 2461 mg/dL (range, 187-6461). Regarding risk category per the international prognostic scoring system for Waldenström macroglobulinemia, 60% had high-risk disease, 30% had intermediate-risk disease, and 10% had low-risk disease.

The most common grade 3 or higher adverse effects (AEs) reported before day 28 included leukopenia (grade 3, n = 1; grade 4, n = 5), neutropenia (n = 4; n = 5), lymphopenia (n = 1; n = 8), anemia (n = 4; n = 0), thrombocytopenia (n = 2; n = 1), hypotension (n = 2; n = 0), hypertension (n = 1; n = 0), fatigue (n = 1; n = 0), aspartate aminotransferase increase (n = 1; n = 0), alanine aminotransferase increase (n = 1; n = 0), and increased creatinine (n = 1; n = 0). Regarding infections, one case each of grade 2 pneumonia and grade 2 enterocolitis occurred before day 28. Additionally, 196 days after treatment, one patient died in remission of COVID-19 at 6.5 months after treatment.

Cytokine release syndrome occurred in 9 patients; 5 patients experienced a grade 1 event, and 4 patients experienced a grade 2 event. Moreover, tocilizumab (Actemra) and dexamethasone were given to 3 patients to manage this toxicity. Immune effector cell–associated neurotoxicity syndrome occurred in 1 patient and was grade 1 in severity.

References

  1. Till B, Baker K, Redman M, et al. High efficacy and favorable safety of CD20-targeted CAR-T therapy for BTK inhibitor-refractory Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL). HemaSphere. 2024;8(suppl 1):P1461.
  2. Mustang Bio announces favorable efficacy and safety data from complete Waldenstrom macroglobulinemia cohort of phase 1/2 clinical trial of MB-106, CD20-targeted autologous CAR-T therapy. News release. Mustang Bio, Inc. June 17, 2024. Accessed June 19, 2024. https://ir.mustangbio.com/news-events/press-releases/detail/180/mustang-bio-announces-favorable-efficacy-and-safety-data
Related Videos
Mazyar Shadman, MD, MPH
Craig Eckfeldt, MD, PhD, assistant professor, medicine, faculty, Microbiology, Immunology, and Cancer Biology PhD Graduate Program, Division of Hematology, Oncology, and Transplantation, the University of Minnesota Medical School
Mark Juckett, MD, professor, medicine, Division of Hematology, Oncology, and Transplantation, the University of Minnesota Medical School
Timothy Hughes, MD, MBBS, FRACP, FRCPA
Hannah Choe, MD, an expert on GVHD
Hannah Choe, MD, an expert on GVHD
Grzegorz S. Nowakowski, MD
Combination of Zanubrutinib + Venetoclax for Treatment-naive CLL/SLL With del(17p) and/or TP53: Preliminary Results From SEQUOIA Arm D
Preliminary Efficacy and Safety of the Bruton Tyrosine Kinase Degrader BGB-16673 in Patients With Relapsed or Refractory CLL/SLL: Results From the Phase 1 BGB-16673-101 Study
Results from the randomized phase 3 DREAMM-8 study of belantamab mafodotin plus pomalidomide and dexamethasone (BPd) vs pomalidomide plus bortezomib and dexamethasone (PVd) in relapsed/refractory multiple myeloma (RRMM)