A phase 2 study of brentuximab vedotin in patients with CD30-positive advanced systemic mastocytosis

Abstract

There is an unmet need for effective therapies for advanced systemic mastocytosis (advSM). CD30 is expressed on the surface of neoplastic mast cells (MC) in more than 50% of patients with advSM. Brentuximab vedotin (BV) is a CD30-directed antibody-drug conjugate with preclinical evidence supporting both an antineoplastic effect and an attenuation of immunoglobulin E-associated mediator release. These observations are the basis for this phase 2 trial of BV monotherapy (1.8 mg/kg IV every 3 weeks up to 8 cycles) in patients with CD30-positive advSM. The primary objective was to determine the efficacy of BV according to International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (IWG-MRT-ECNM) response criteria. Secondary objectives included evaluation of safety, changes in bone marrow (BM) MC burden, serum tryptase level, flow cytometric quantification of MC surface expression of CD30, and self-reported symptom burden. The trial enrolled 10 patients with a diagnosis of CD30+ advSM (aggressive SM, SM with an associated hematologic neoplasm [SM-AHN], or mast cell leukemia [MCL]) with 1 or more signs of SM-related organ damage. According to IWG-MRT-ECNM criteria, none of the patients demonstrated better than stable disease with BV. In addition, there were no significant reductions in BM MC burden, serum tryptase levels, or MC surface expression of CD30. Self-reported symptom scores showed no durable improvement with BV treatment. We conclude that BV is not active as a single agent in CD30+ advSM. This trial was registered at www.clinicaltrials.gov as #NCT01807598.

Conflict of interest statement

Conflict-of-interest disclosure: J.G. received funding from Seattle Genetics, Inc. for the conduct of this phase 2 trial. Pathology testing (T.I.G.) was performed at TriCore Reference Laboratories (Albuquerque, NM) supported by Seattle Genetics, Inc. The remaining authors delcare no competing financial interests.

© 2019 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Baseline and on-treatment MC CD30 expression and BM MC burden. CD30+ BM MCs (A), assessed by multiparameter flow cytometry on the aspirate specimen, as well as BM MC burden (B), BM MC burden, assessed by immunohistochemistry on the core biopsy specimen, did not show significant reductions when compared with pretreatment baseline by Wilcoxon matched pairs signed rank test (i). Pre- and posttherapy assessments are represented for individual patients (i) and for the entire cohort (ii) with each biomarker. Box plot boundaries represent the 75th and 25th percentiles; whiskers denote maximum and minimum values, (+) denotes the cohort’s mean, and symbols represent individual patient values. EOT, end of treatment; FCM, multiparametric flow cytometry; IHC, immunohistochemistry.

Figure 2.

Changes in serum tryptase levels on BV therapy. Serum tryptase activity level, represented for each patient as a percentage change relative to their pretreatment baseline, did not show durable reductions over the course of treatment. Patient 3 discontinued treatment after cycle 4 because of progressive disease, with subsequent values obtained during posttherapy monitoring shown within the dashed line box.

Figure 3.

Changes in patient-reported symptoms on BV therapy. Composite symptom burden assessments using the MPN-SAF TSS-10* (A) and modified MSAF** (B) did not show significant change over time (r2 ∼0) by 1-way analysis of variance with a posttest for linear trend (i). Individual patients’ assessments (ii) did not show a consistent trend over time. *Composite of patient-reported scores on 10 items (0-10 scale each, with higher indicating worse): worst fatigue, concentration, early satiety, inactivity, night sweats, itching, bone/muscle pain, abdominal discomfort, weight loss, and fever. **Composite of patient-reported scores on 10 items (0-10 scale each, with higher indicating worse): pruritus, dizziness, headache, worst fatigue, flushing, abdominal discomfort, diarrhea, bone/muscle pain, concentration, and depression.