Abstract
5 min readAbstract Background: Waldenström's macroglobulinemia (WM) is a rare, indolent B-cell lymphoproliferative disorder characterized by expansion of clonal IgM-secreting cells (Advani P, et al. Hematol Oncol Stem Cell Ther. 2019;12:179-188). While ibrutinib is the only Bruton tyrosine kinase inhibitor (BTKi) currently approved by the US FDA and EMA for WM, other BTKi's are currently under investigation. More than 90% of patients with WM have somatic mutations in MYD88, and 30%-40% of these patients have activating mutations in CXCR4WHIM (Xu L, et al. Br J Haematol. 2016;172:735-744; Treon SP, et al. Blood. 2014;123:2791-2796). CXCR4WHIM in WM is associated with high serum IgM level, symptomatic hyperviscosity, earlier time to treatment, and inferior response to approved and investigational BTKi (Schmidt J, et al. Br J Haematol. 2015;169:795-803;Tam C, et al. Blood. 2020; 136:2038-2050). Inhibition of CXCR4 can sensitize CXCR4WHIM-expressing cells to ibrutinib (Cao Y, et al. Leukemia. 2015;29:169-176). Mavorixafor is an oral small-molecule antagonist of CXCR4. In vitro data have shown that mavorixafor inhibits CXCL12 binding and extracellular signal regulated kinase hyperactivation for CXCR4 mutations. Aims: To report on an early assessment of the safety and clinical response of mavorixafor in combination with ibrutinib after ≥6 months (6 cycles) of treatment in patients with MYD88 and CXCR4WHIM WM. Methods: This is an ongoing phase 1b, open-label, multicenter, single-arm study (NCT04274738) examining intrapatient dose escalation, safety, pharmacokinetics (PK), and pharmacodynamics of mavorixafor in combination with ibrutinib (target N=18). Eligibility includes age ≥18 years, clinicopathological WM diagnosis, consensus criteria indication for treatment, measurable disease, 0-3 prior therapies, and confirmed MYD88 and CXCR4WHIM mutations. Patients are initiated on mavorixafor 200 mg (low-dose) and ibrutinib 420 mg, both oral and once-daily. Mavorixafor escalation to 400 mg (mid-dose) occurs after 28 days if no dose-limiting toxicities (DLTs) are observed and to 600 mg (high-dose) after 400 mg is deemed safe (<2/6 DLTs). Patients are followed for adverse events (AEs), and change from baseline in IgM, Hgb, PK, WBC counts, and clinical responses. Results: At data cutoff of June 15, 2021, 10 patients have enrolled, with 9 dosed and 9 continuing on study. Both 200-mg and 400-mg mavorixafor doses in combination with ibrutinib were deemed safe. Dosing at 600 mg is ongoing. Median duration of treatment was 198 days. A total of 107 AEs were observed (79% grade 1). Of 92 AEs with complete assessment for causal relationship to study drugs, 9 were deemed related to mavorixafor only, 13 to ibrutinib only, and 18 to the combination. One DLT was observed, consisting of grade 3 hypertension attributed to combination therapy. Two grade 2 AEs attributed to mavorixafor only led to drug interruption (7-8 days). Overall response rate for evaluable patients (minor response or better) was 100% (N=8). Four of 8 patients achieved major response; 1 of 8 patients achieved very good partial response. All 9 patients showed decrease in serum IgM while on treatment, with IgM levels normalizing in 1 patient after 4 months' treatment. For all patients treated for ≥6 months (N=7), median absolute serum IgM level decreased to 31.04 g/L at 6 months from pretreatment level of 46.23 g/L . Mean Hgb increased by >20 g/L, with Hgb approaching normal levels in these 7 patients. Mavorixafor and ibrutinib exposures were consistent with previous reports (de Jong J, et al. Cancer Chemother Pharmacol. 2015;75(5):907-916), and combination treatment increased peripheral lymphocytes, neutrophils, and monocytes in all 9 patients. Conclusion: Our findings as of June 2021 in patients with WM carrying both MYD88 and CXCR4WHIM mutations show that mavorixafor in combination with ibrutinib is well tolerated. Mavorixafor and ibrutinib exposures were consistent with previous single-agent studies, suggesting no drug-drug interactions, and mavorixafor exposures tracked with increases in key WBC counts. All evaluable patients demonstrated at least a minor response. Combination of mavorixafor with ibrutinib led to rapid, clinically meaningful, and durable decrease in IgM levels and increase in Hgb levels. These ongoing studies support the feasibility of combining ibrutinib with mavorixafor to improve responses in MYD88 CXCR4WHIM WM. Disclosures Treon: BMS: Consultancy, Research Funding; Self: Patents & Royalties: Holder of multiple patents related to testing and treatment of MYD88 and CXCR4 mutated B-cell malignancies; Pharmacyclics: Consultancy, Research Funding; Dana Farber Cancer Institute: Current Employment; Janssen: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; X4: Research Funding. Buske: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding. Thomas: Genentech: Research Funding; X4 Pharma: Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; Ascentage Pharma: Research Funding. Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding. Branagan: CSL Behring: Consultancy; Adaptive: Consultancy; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dimopoulos: BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Beigene: Honoraria; Amgen: Honoraria. Gavriatopoulou: Genesis: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; GSK: Honoraria. Cadavid: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Garzon: X4 Pharmaceuticals: Consultancy. Tang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Seyffert: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Garg: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Ali: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Taveras: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Chen: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Matous: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.
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