Evaluating the Long-term Safety and Tolerability of Imatinib in Patients With Lymphangioleiomyomatosis (LAM)

Overview

Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease that appears to behave like a slowly growing cancer. Since clinical progression is very slow, new blood tests have been used to speed the time required to find safe and effective medications. A large National Institute of Health study called MILES showed that sirolimus (also known as Rapamycin) improved lung function in individuals with LAM. Since most individuals with LAM and impaired lung function are now on sirolimus, future studies may prove more difficult. Laboratory studies suggested that Imatinib mesylate (imatinib), an FDA-approved drug for leukemia, initiates LAM cell death. A pilot trial with imatinib titled "Imatinib Mesylate for the treatment of Lymphangioleiomyomatosis" - (LAMP-1) was funded by the Department of Defense in 2016, and documented (1) the safety of use of tyrosine kinase inhibitors in patients with LAM; (2) the safety of concurrent use of tyrosine kinase and mTOR inhibitors; and, (3) short term variability in vascular endothelial growth factor D (VEGF-D) - a LAM biomarker, as a response to therapies. Due to the short-term LAMP-1 trial, LAMP-2 will be a longer-term 6-month clinical study evaluating the safety and tolerability of imatinib in patients with LAM. Patients that participate in the trial will come in for 5 office visits and check-up phone calls every 2 weeks over the course of 6 months.

Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease that is due to a very slow growing cancer that proliferates via unopposed activity of the mTOR pathway. A large NIH study (MILES) found that sirolimus (Rapamycin) that inhibits the mTOR pathway improved lung function and quality of life compared to placebo in LAM. Sirolimus has been shown to cause growth suppression but not apoptosis of LAM cells in culture. Additionally, not all patients with LAM have a clinical effect with sirolimus. Recently, imatinib mesylate has been shown to induce LAM cell apoptosis, raising the possibility of more lasting therapy for LAM. Currently, most LAM patients are on sirolimus and attempts to find sirolimus naive patients have not been successful for other studies. LAM cells use the mesenchymal PDGF receptor pathway for proliferation, similar to certain leukemias and slow growing neoplasms. Laboratory studies suggested that Imatinib mesylate (imatinib), an FDA approved drug for leukemia, initiates LAM cell death. A pilot trial with imatinib (LAMP-1) was funded by the DOD in 2016, and documented (1) the safety of use of tyrosine kinase inhibitors in patients with LAM; (2) the safety of concurrent use of tyrosine kinase and mTOR inhibitors; and, (3) short term variability in VEGF-D as a response to therapies. Concurrent cell-based research studies during this time showed equally efficacious tumoricidal activity of nilotinib in vitro. Due to the short-term LAMP-1 trial, the investigators propose a longer-term clinical study evaluating the safety and tolerability of imatinib in patients with LAM.