Phase 2 Study of Brentuximab Vedotin in Patients with Advanced Systemic Mastocytosis

BACKGROUND: Brentuximab vedotin (BV) is a CD30-directed antibody-drug immunoconjugate consisting of an anti-CD30 antibody and the microtubule inhibitor monomethyl auristatin E (MMAE). BV is approved as a single agent for relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) and R/R systemic anaplastic large cell lymphoma, as well as post-auto-HSCT consolidation for high risk cHL. Prior studies have demonstrated both cytoplasmic and surface expression of CD30 on neoplastic mast cells (MC) in patients with systemic mastocytosis (SM), including advanced forms of the disease such as aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). BV produced apoptosis in CD30⁺ cell lines, as well as in primary neoplastic MCs derived from patients with CD30⁺ (but not CD30^-) SM. BV also downregulates IgE-induced histamine release from CD30⁺ mast cells (Blatt et al, Blood, 2015).

METHODS: We conducted a phase 2 investigator-initiated study to evaluate the efficacy, safety, and tolerability of BV in patients with CD30⁺ advanced SM. The goal accrual for stage 1 was 11 patients. Based on a Simon two-stage design, if 2/11 patients demonstrated a response per international consensus response criteria (IWG-MRT-ECNM; Gotlib et al, Blood, 2013), further accrual to a total of 26 patients would be undertaken. BV was dosed at 1.8 mg/kg intravenously every 3 weeks. BV was administered for a total of 8 cycles, or stopped earlier for disease progression, physician discretion, or unacceptable toxicity. Responders with subsequent loss of response could receive an additional 8 cycles of BV. Bone marrow (BM) biopsy samples and CD30 expression were centrally reviewed by one of the authors (TIG). The primary endpoint was overall response rate (ORR; CR + PR + clinical improvement [CI]). Secondary endpoints included evaluation of changes in BM MC burden, serum tryptase levels, and CD30 expression by flow cytometry. Total symptom scores (TSS) were assessed by a modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF). Adverse events were categorized and graded according to CTCAE 4.03.

RESULTS: Data cutoff for this analysis was July 25, 2017. 10 patients were enrolled; 3 ASM, 5 SM-AHN (CMML-1, n=3; MDS/MPN-U and CEL, each n=1), 2 MCL (one with CMML-1); median age (range) 72.5 years (40-84); M:F 4:6; all patients were positive for the KIT D816V mutation. The median number of prior therapies was 0.5 (0-2), excluding splenectomy (n=3). The median number of eligible IWG-MRT-ECNM organ damage findings at study entry was 1 (1-3). The median duration of follow-up was 114 days (13-242). The median number of treatment cycles was 5 (1-8), and two patients remained on treatment at the time of data cutoff. No responses were observed according to IWG-MRT-ECNM criteria. Of the 10 patients, 8 (80%) patients had stable disease (SD); 1 (10%) patient had progressive disease (PD); and 1 (10%) patient was not evaluable as a result of early death due to intracranial hemorrhage (ICH) from a mechanical fall considered unrelated to BV. Mean baseline CD30⁺ expression by flow was 67% (range 29-96%). There were no reductions in CD30⁺ MC or BM MC burden with treatment. Although the best median reduction in serum tryptase level was -29% among the 10 patients (range -5 to -38%), decreases in single patients were not durable and there was no correlation with CD30⁺ MC expression or BM MC burden. There was no significant decrease in TSS during the course of treatment.

The most common AEs (regardless of attribution) were primarily grade 1/2, and consisted of fatigue (40%), as well as diarrhea, abdominal pain/discomfort, infusion reaction, vomiting, cough, constipation, dyspnea, and depression (each 20%). One patient developed grade 2 from baseline grade 1 peripheral neuropathy. The majority of grade 3/4 AEs were hematologic, consisting of neutropenia (30%), anemia (20%), and thrombocytopenia (10%). Serious AEs included grade 5 ICH, grade 3 altered mental status and portal vein thrombosis (same patient), grade 3 rash, grade 3 epiglottitis, and grade 3 pleural effusion (each n=1). Reasons for early treatment discontinuation were PD (n=1), investigator discretion for lack of clinical benefit (n=3), and death due to ICH (n=1).

CONCLUSIONS: BV was well tolerated, but did not demonstrate clinical activity in this cohort of patients with CD30⁺ advanced SM.