A Pilot Study of the Anti-SLAMF7 Monoclonal Antibody, Elotuzumab, in Myelofibrosis

Background: Prior work from our group has shown that fibrocytes, the cells driving bone marrow (BM) fibrosis in patients with primary myelofibrosis (PMF), are neoplastic (clonal) and derived from monocytes (Verstovsek, J Exp Med 2016). These findings led to the clinical development of PRM-151 (recombinant human pentraxin-2) as an anti-fibrotic agent for patients with myelofibrosis (MF) (Verstovsek, EHA 2019). Our observations were extended by others to show that thrombopoietin receptor (MPL) activation induces fibrocyte differentiation and that blood monocytes highly expressing MPL and signaling lymphocyte activation molecule family member 7 (SLAMF7) were possible fibrocyte precursors (Maekawa, Leukemia 2018). Furthermore, patients with JAK2V617F+ MF have a significantly elevated SLAMF7 high monocyte percentage, which correlates with the JAK2V617F allele burden (Maekawa, Blood 2019). Finally, elotuzumab, a SLAMF7-targeting monoclonal antibody, inhibited the differentiation of MF patient-derived fibrocytes in vitro and romiplostim-induced MF and splenomegaly in vivo. Study design and methods: This is a single-institution, investigator-initiated, pilot phase 2 study of elotuzumab monotherapy in patients with JAK2V617F+ PMF or post-polycythemia vera/essential thrombocythemia MF who need treatment but are not candidates for JAK inhibitor therapy. Baseline BM fibrosis grade must be 2 or 3 per the European consensus (Thiele, Haematologica 2005). Prior JAK inhibitor treatment is permitted. Elotuzumab is dosed intravenously weekly at 10 mg/kg per dose for the first 8 doses, followed by 20 mg/kg every 4 weeks, per the label for its use in multiple myeloma in combination with pomalidomide and dexamethasone. Patients may continue elotuzumab until disease progression or unacceptable toxicity, up to a maximum of 36 cycles. Premedication and management of infusion reactions are carried out according to the elotuzumab package insert. Spleen and liver sizes are measured by palpation and the MPN-SAF-TSS questionnaire (Emanuel, J Clin Oncol 2012) is administered on day 1 of each cycle. Patients receive a BM biopsy at screening and every 6 cycles while on-study. Plasma cytokines are measured at baseline and every 3 cycles while on-study. The primary endpoint is overall response rate according to the revised IWG-MRT-ELN criteria (Tefferi, Blood 2013). A total of 15 patients are planned to be enrolled. Elotuzumab is provided by Bristol-Myers Squibb. Adverse events are graded a