Dr Castillo on Acalabrutinib Plus Rituximab in Patients With Anti-MAG IgM Peripheral Neuropathy

Jorge J. Castillo, MD, clinical director, Bing Center for Waldenström Macroglobulinemia, institute physician, Dana-Farber Cancer Institute, associate professor of medicine, Harvard Medical School, discusses preliminary data from a phase 2 study (NCT05065554) of acalabrutinib (Calquence) plus rituximab (Rituxan) in patients with Waldenström’s Macroglobulinemia or IgM symptomatic anti-myelin associated glycoprotein (MAG)–mediated peripheral neuropathy.

The prospective, single-arm study was designed to evaluate the efficacy of BTK inhibition plus CD20 directed therapy as a novel treatment for patients with anti-MAG peripheral neuropathy, Castillo begins. Patients with an anti-MAG antibody and an IgM monoclonal gammopathy or Waldenström’s Macroglobulinemia; and a predominantly sensory demyelinating PN with a modified Rankin score of 1 or more with progressive symptoms or a score of 2 or more were enrolled onto the study. Treatment consisted of 100 mg of continuous oral acalabrutinib administered twice daily, plus weekly rituximab in cycles 1 and 4. The first 8 patients enrolled onto the study were included in this analysis. Interestingly, MYD88 mutations occurred in 6 patients but none were CXCR4 mutated, Castillo notes.

Results showed that the combination of acalabrutinib and rituximab demonstrated early activity in patients with IgM-related anti-MAG peripheral neuropathy, Castillo reports. Among the 7 evaluable patients, the overall response rate based on IWWM-11 criteria was 86%, he details. Categorical responses included 2 very good partial responses, 1 partial response, 3 minor responses, and 1 occurrence of stable disease. Additionally, 57% of patients showed improvement in their I-RODS score, with a median improvement of 0.5 points, he adds. The median time on treatment was 175 days (range 28-510), indicating a favorable duration of response.

Regarding safety, the treatment regimen was deemed well tolerated. However, 1 patient had to be removed from the trial after 28 days due to a grade 3 elevation in ALT. Two other grade 3 adverse effects occurred, including a rituximab-related infusion reaction and syncope unrelated to treatment, but these were deemed reversible.

Overall, these findings may provide a framework for the development of novel and more effective therapeutics in anti-MAG peripheral neuropathy, Castillo says. Additional data from more detailed neurologic assessments are expected to provide further insights, Castillo states, adding that long-term data will hopefully show that this regimen can induce responses to improve patients' quality of life. The trial is ongoing and enrollment continues.