Adjuvant Doxycycline to Enhance Anti-Amyloid Effects: Results from the DUAL Phase 2 Trial

Abstract

Background: Doxycycline use is associated with improved outcomes in amyloidosis in retrospective studies. Methods: This phase 2 trial of doxycycline (registered under clinicaltrials.gov: NCT02207556) in newly diagnosed light chain (AL) amyloidosis enrolled 25 patients with systemic AL amyloidosis on treatment with doxycycline for 1 year along with chemotherapy. Outcomes of interest included mortality, organ response, and hematologic response rates at 1 year. Findings: The median age was 62 years, 64% were male, and 68% had the AL lambda subtype. Patients had Mayo 2012 stage 3 in 24% and stage 4 in 28%. Cardiac involvement was present in 60% of patients, renal involvement in 72%, and 60% patients had 3 or more organs involved. Target organ was cardiac in 14(56%), renal in 7(28%), hepatic in 1(4%) and soft tissue in 3(12%). At 1 year, mortality was 20% (95% confidence interval, 8.9-41.6%) and organ response was 36% (18-57%). Hematologic response in 1-year survivors was 100%, including 30% complete and 55% very good partial response. Autologous hematopoietic cell transplant was performed in 60%; among transplanted patients, day-100 transplant-related mortality was 0. Doxycycline use was safe and not attributed to any grade 2 or higher toxicity. Interpretation: In addition to an unprecedented low 1-year mortality, doxycycline use was safe and associated with high transplant utilization rate. We thus contend that doxycycline should be considered in newly diagnosed AL patients in the first year, particularly among patients with advanced disease and cardiac involvement. Trial Registration: clinicaltrials.gov: NCT02207556 Funding Statement: This study was funded by the American Cancer Society Institutional Research Grant # 86-004-26, the Research and Education Program Fund, a component of the Advancing a Healthier Wisconsin endowment at the Medical College of Wisconsin and Clinical and Translational Science Institute, and by a K23 HL141445 (AD). Declaration of Interests: AD- Grant funding: Sanofi, EDO Mundipharma, TeneoBio, Takeda, Amgen; Honoraria: Prothena, Pfizer, Imbrium, Akcea BD- Grant funding and Honoria- Takeda, Celgene, Janssen, Amgen and Sanofi PH- Grant funding and honoraria – Takeda, Celgene, BMS, Janssen, Kite. Juno, Pharmacyclics and Karyopharm. AS, KEF, SC, MP, DW have no conflicts to report. Ethics Approval Statement: The study was performed after approval by the Medical College of Wisconsin Institutional Review Board in accordance to the provisions of the Declaration of Helsinki guidelines. All patients provided written informed consent.