Cerebral cavernous malformation (CCM) is a common vascular abnormality of the brain, affecting 0.1%-0.5% of people. It often causes recurrent brain hemorrhages, epilepsy, and neurological impairments, with surgery being the main treatment. However, surgery carries high risks for patients with multiple lesions or lesions in critical areas, and no effective pharmacological treatment is available. CCM is linked to mutations in genes like CCM1, CCM2, CCM3, or MAP3K3, which activate the MEK5-ERK5-KLF2/4 pathway, disrupting endothelial function. Immune cell infiltration, particularly plasma cells with high CD38 expression, suggests a role for humoral immunity in CCM. Depleting B cells in mouse models reduced lesions and hemorrhages, but broad B cell depletion is risky.
To find a safer treatment, researchers tested anti-CD38 monoclonal antibodies in mice, showing that targeting CD38 reduced CCM lesion formation. Given the success of CD38-targeted therapies like daratumumab in treating multiple myeloma, this study proposes evaluating daratumumab for CCM in a single-center trial with 10 adult patients to assess its safety and efficacy.
Age ≥ 18 years;
Diagnosed with familial cerebral cavernous malformation (familial CCM) (diagnosis requires at least one of the following: multiple CCMs or ≥2 family members with CCM);
Presence of clinical symptoms or history of symptomatic events: intracerebral hemorrhage, stroke, permanent or transient neurological deficits, seizures, disability, or any other neurological symptoms associated with cavernous malformations;
Deemed unsuitable for surgical resection by a physician;
Stable familial CCM lesions not requiring intervention;
Presence of metal implants or other contraindications to MRI;
History of statin therapy within the past 6 months;
History of beta-blocker therapy within the past 6 months;
Single group
Daratumumab
DrugParticipants receive intravenous daratumumab (16 mg/kg weekly for 8 weeks), diluted in 1000 mL (first dose) or 500 mL (subsequent doses) of saline, with infusion rates escalated stepwise from 50 to 200 mL/h under vital sign monitoring. Premedication (antihistamines/analgesics) is administered 30 minutes prior to each infusion to mitigate reactions.
Incidence of severe infusion-related reactions (IRRs)
Incidence of severe infusion-related reactions (IRRs) (defined as any adverse reaction directly caused by the injection procedure or drug administration, including fever, chills, hyperhidrosis, headache, bronchospasm, myalgia, arthralgia, hypotension, hypertension, etc., where the reaction persists without rapid resolution after symptomatic treatment and/or infusion interruption, recurs after initial improvement, or results in clinical consequences requiring hospitalization).
Change in total lesion volume on MRI during treatment
Change in total lesion volume on MRI during treatment (specifically comparing post-treatment SWI \[Susceptibility Weighted Imaging\] sequence imaging with baseline imaging).
Incidence of neutropenia during treatment
Incidence of neutropenia during treatment (defined as absolute neutrophil count \[ANC\] \<1 × 10⁹/L accompanied by a single temperature measurement \>38.3°C or persistent temperature ≥38°C for over 1 hour).
Incidence of anemia during treatment
Incidence of anemia during treatment (defined as hemoglobin \[Hgb\] below the lower limit of normal).
Incidence of cytokine release syndrome (CRS) during treatment
Incidence of cytokine release syndrome (CRS) during treatment (defined as temperature ≥38°C not attributable to other causes, assessed according to the American Society for Transplantation and Cellular Therapy \[ASTCT\] consensus criteria).
Incidence of moderate IRRs
Incidence of moderate IRRs (defined as adverse reactions directly caused by injection or drug administration that resolve rapidly after symptomatic treatment and/or infusion interruption).
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