Abstract
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 according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. The method of Thall, Simon and Estey (Thall, Stat Med 1995) is used for toxicity monitoring.
Correlative studies: These include quantification of SLAMF7 highCD16 neg circulating monocytes by flow cytometry, measurement of serum interleukin-1 receptor alpha (IL-1Rα) concentrations and correlation of these with each other and with the mutant JAK2 allele burden, culture of human fibrocytes from peripheral blood mononuclear cells (PBMCs) in vitro, engraftment of BM cells from patients in non-obese diabetic, severe combined immunodeficient gamma (NSG) mice, and quantitation of fibrocytes in the BM of participants at baseline and every 6 cycles.
Current status: The study (clinicaltrials.gov identifier: NCT04517851) is ongoing; 2 participants have been enrolled and treated thus far. Updated enrollment information will be provided.
Bose: Astellas: Research Funding; Sierra Oncology: Honoraria; Constellation Pharmaceuticals: Research Funding; Novartis: Honoraria; Celgene Corporation: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Blueprint Medicines: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Kartos Therapeutics: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Pfizer: Research Funding. Jain: TG Therapeutics: Honoraria; Janssen: Honoraria; Servier: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Beigene: Honoraria; Adaptive Biotechnologies: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Pfizer: Research Funding; Cellectis: Honoraria, Research Funding; Fate Therapeutics: Research Funding; AstraZeneca: Honoraria, Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding. Pemmaraju: Roche Diagnostics: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; Springer Science + Business Media: Other; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Sager Strong Foundation: Other; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Plexxicon: Other, Research Funding; CareDx, Inc.: Consultancy; Aptitude Health: Consultancy; MustangBio: Consultancy, Other; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Incyte: Consultancy; Affymetrix: Consultancy, Research Funding; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Kantarjian: Amgen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Astra Zeneca: Honoraria; KAHR Medical Ltd: Honoraria; Ipsen Pharmaceuticals: Honoraria; Daiichi-Sankyo: Research Funding; Jazz: Research Funding; Immunogen: Research Funding; BMS: Research Funding; Astellas Health: Honoraria; AbbVie: Honoraria, Research Funding; Ascentage: Research Funding; Novartis: Honoraria, Research Funding; Aptitude Health: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Verstovsek: Blueprint Medicines Corp: Research Funding; Promedior: Research Funding; PharmaEssentia: Research Funding; Protagonist Therapeutics: Research Funding; CTI BioPharma: Research Funding; Celgene: Consultancy, Research Funding; Genentech: Research Funding; NS Pharma: Research Funding; Ital Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; Gilead: Research Funding; Sierra Oncology: Consultancy, Research Funding; Roche: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy.
Elotuzumab is a monoclonal antibody targeting SLAMF7, previously known as CS-1. It is approved for the treatment of multiple myeloma in combination with an IMiD and dexamethasone. This trial studies it as a single agent in patients with myelofibrosis.
