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Chronic Lymphocytic Leukemia
Olaptesed pegol (NOX-A12) with bendamustine and rituximab: a phase IIa study in patients with relapsed/refractory chronic lymphocytic leukemia
Ferrata Storti Foundation
Haematologica 2019 Volume 10410):2053-2060
‡This paper is dedicated to the memory of our colleague Prof. Michael Steurer, an extraordinary scientist and physician appre- ciated for his empathetic commitment to his patients, who recently passed away.
Michael Steurer,1‡ Marco Montillo,2 Lydia Scarfò,3 Francesca R. Mauro,4 Johannes Andel,5 Sophie Wildner,1 Livio Trentin,6 Ann Janssens,7 Sonja Burgstaller,8 Anna Frömming,9 Thomas Dümmler,9,10 Kai Riecke,9 Matthias Baumann,9,10 Diana Beyer,9 Stéphanie Vauléon,9 Paolo Ghia,3 Robin Foà,4 Federico Caligaris-Cappio3 and Marco Gobbi11
1Division of Hematology and Oncology, Innsbruck Medical University, Innsbruck, Austria; 2Department of Hematology, Niguarda Cancer Center, Niguarda Hospital, Milan, Italy; 3Università Vita-Salute San Raffaele and IRCCS Istituto Scientifico San Raffaele, Milan, Italy; 4Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy; 5Medical Dept. 2, County Hospital, Steyr, Austria; 6Department of Medicine, Hematology and Clinical Immunology Branch, University of Padua, Padua, Italy; 7Department of Hematology, Universitaire Ziekenhuizen Leuven, Leuven, Belgium; 8Department of Internal Medicine IV, Wels-Grieskirchen Hospital, Wels, Austria; 9NOXXON Pharma, Berlin, Germany; 10current affiliation: Mologen AG, Berlin, Germany and 11Haematology Clinic, Department of Internal Medicine, University of Genoa, and Ospedale Policlinico S. Martino, Clinica Ematologica, Genoa, Italy
ABSTRACT
Olaptesed pegol (NOX-A12) is a pegylated structured L-oligoribonu- cleotide that binds and neutralizes CXCL12, a chemokine tightly regulating the life cycle of chronic lymphocytic leukemia cells. The resulting inhibition of CXCR4 and CXCR7 signaling reduces the protective activity of the bone marrow and lymph node microenvironment. CXCL12 inhibition mobilizes chronic lymphocytic leukemia cells into the circulation and prevents their homing into the protective niches. In this phase I/II study, 28 patients with relapsed/refractory chronic lymphocytic leukemia were treated with olaptesed pegol in combination with bendamustine and rituximab. Combination treatment was preceded by single escalating pilot doses of olaptesed pegol in the first ten patients for evaluation of safety and pharmacokinetics. Peak concentrations and systemic exposure of olaptesed pegol were dose-linear; plasma elimination was monophasic with a 53.2 h half-life. A rapid increase in circulating chronic lymphocytic leukemia cells was observed already 1 h after administration of olaptesed pegol and lasted for at least 72 h. Single-agent treatment was well tolerated and no dose-lim- iting toxicity was observed. The combination regimen yielded an overall response rate of 86%, with 11% of patients achieving a complete response and 75% a partial response. Notably, all ten high-risk patients, including four with a 17p deletion, responded to treatment. The median progression- free survival was 15.4 (95% confidence interval: 12.2, 26.2) months while the median overall survival was not reached with >80% of patients alive after a median follow-up of 28 months. Olaptesed pegol was well tolerated and did not result in additional toxicity when combined with bendamus- tine and rituximab (ClinicalTrials.gov identifier: NCT01486797). Further clini- cal development of this novel CXCL12 inhibitor is thus warranted.
Introduction
Olaptesed pegol (NOX-A12) is a novel, pegylated L-oligoribonucleotide, a so- called Spiegelmer®, which binds and neutralizes the chemokine CXCL12 (stromal cell-derived factor-1, SDF-1) with high affinity and specificity. As a result, it inhibits CXCL12 signaling through both of its receptors, CXCR4 and CXCR7.1,2 In healthy
Correspondence:
MARCO GOBBI
gobbi@unige.it
Received: September 19, 2018. Accepted: May 9, 2019. Pre-published: May 16, 2019.
doi:10.3324/haematol.2018.205930
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