Adjuvant doxycycline to enhance anti-amyloid effects: Results from the dual phase 2 trial

Anita D'Souza, Aniko Szabo, Kathryn E Flynn, Binod Dhakal, Saurabh Chhabra, Marcelo C Pasquini, Dorothee Weihrauch, Parameswaran N Hari, Anita D'Souza, Aniko Szabo, Kathryn E Flynn, Binod Dhakal, Saurabh Chhabra, Marcelo C Pasquini, Dorothee Weihrauch, Parameswaran N Hari

Abstract

Background: Although, doxycycline use is associated with improved outcomes in amyloidosis in retrospective studies, evidence from clinical trials is limited.

Methods: This phase 2 trial of doxycycline (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 a low 1-year mortality, doxycycline use was safe and associated with high transplant utilization rate. We thus contend that doxycycline should be studied in a placebo-controlled study in newly diagnosed AL patients in the first year, particularly among patients with advanced disease and cardiac involvement.

Keywords: Doxycycline; Early mortality; Systemic light chain amyloidosis.

Conflict of interest statement

AD- Grant funding and honoraria- Sanofi, EDO Mundipharma, TeneoBio, Takeda, Prothena, Pfizer, Imbrium, Akcea BD- Grant funding and Honoria- Takeda, Celgene, Janssen, Amgen and GSK PH- Grant funding and honoraria – Takeda, Celgene/BMS, Janssen, Amgen, Sanofi, and Karyopharm MP- Honoraria- Kite, Novartis, BMS, Celgene, Amgen, Medigene, Pfizer KEF- Grant- Jazz, Incyte AS, SC, DW have no conflicts to report

© 2020 The Author(s).

Figures

Fig. 1
Fig. 1
Kaplan-Meier estimates of overall survival.
Fig. 2
Fig. 2
Longitudinal Change in PROMIS scores over study period.

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