Project Details
Projekt
Repurposing doxycycline in the treatment of cardiac AL amyloidosis
Applicant
Professor Dr. Stefan Schönland
Subject Area
Hematology, Oncology
Term
from 2017 to 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 342064388
Systemic amyloidoses are rare diseases affecting approximately 1 in 100,000 persons each year. In systemic amyloidoses abnormal proteins deposit in organs and severely impair their function, causing death if not treated effectively. Light chain (AL) amyloidosis is caused by a small population of plasma cells. These cells produce light chains (LC) that form amyloid deposits. The heart is involved in three fourths of patients and is responsible for almost all the deaths occurring in the first 6 months after diagnosis. Current therapy of AL amyloidosis is based on drugs targeting the plasma cells producing the amyloid-forming LC. At present, most patients receive anti-plasma cell drug, bortezomib, as part of their initial treatment. However, bortezomib-based therapy can improve heart involvement only in less than one third of patients with AL amyloidosis, many patients (approximately one third) still die within 12 months from diagnosis. Early cardiac deaths remain an acute unmet need and the major determinant of overall outcome in this disease. Doxycycline is a widely used antibiotic that has been marketed for decades. This molecule has been studied in the laboratory, in animal models and, more recently, in small studies involving patients, for its potential of improving cardiac damage in amyloidosis. These studies showed that doxycycline disrupts amyloid deposits, reduces the amyloid load in a mouse model, and counteracts the toxicity exerted by amyloid-forming LCs on C. elegans. In a small clinical study, doxycycline was given to patients with cardiac AL amyloidosis during chemotherapy. This resulted in a remarkable improvement of survival compared to matched historical controls (i.e. similar patients who had received only anti-plasma cell therapy without doxycycline in the past). Based on these promising preliminary results, we designed the present clinical trial to assess whether the addition of doxycycline to standard bortezomib-based anti-plasma cell therapy can improve survival in patients with cardiac AL amyloidosis who were not previously treated. The rate of survival at 12 months will be compared in patients receiving doxycycline and in controls receiving standard antibiotic therapy, together with anti-plasma cell therapy. Patients will be assessed for parameters of plasma cell disease, heart involvement and possible involvement of other organs, as well as for quality of life. To make sure that patients who will receive doxycycline and those who will not have comparable severity of cardiac disease, patients will be stratified according to the stage of cardiac involvement. Patients with very advanced heart dysfunction will not be enrolled in the trial, because preliminary data indicate that doxycycline is of little or no benefit in these subjects. Patients will be randomized to receive doxycycline or standard antibiotics in combination with bortezomib-based anti-plasma cell therapy.
DFG Programme
Research Grants
International Connection
Canada, France, Italy, Spain, Turkey
