Treatment failure due to intracerebral stem cell-like behavior of glioblastoma (GBM) cells: A reason for targeted maintenance therapy with imatinib (I) and hydroxyurea (H)? An analysis of study DE21 and DE40 (Ambrosia)

Abstract

2048 Background: As the role of normal glia cells is not totally understood the behavior of glioblastoma cells can be described as stem cell like, able to migrate along intra cerebral cords and eluding established treatment including surgery, irradiation and chemotherapy. As PDGF-R signaling seems to play a role in GBM proliferation, PDGF-R signal transduction inhibition with I was analyzed. While monotherapy of I was not effective in GBM, the combination of I plus H (I/H) showed efficacy in a small number of progressive patients (pts), with stable disease (SD) being the main result. The role of H in this concept and the optimal treatment setting for I plus H is not clear so far. Methods: We conducted two trials: study DE21, a single-center, Phase II study to analyze the effect of I/H as maintenance treatment (MT) in patients with SD; and the multi-center, randomized, phase III, open-label, cross-over design study DE40 to analyze the efficacy of I/H versus H as induction treatment in pts with progressive disease (PD). In DE21, 30 SD GBM pts post-radiotherpy (RT) and at least one chemotherapy regimen received I 600 mg/day with H 1,000 mg/day. In DE40, 240 recurrent pts, post-temozolomide failure, received either I 600 mg/day plus H 1,000 mg/day, or H 1,500 mg/day. Results: Characteristcs of both patient populations were typical. Performance status was 0, 1 or 2. Toxicity was moderate without grade IV toxicity in both studies. In DE21 22/30 pts were in stage of SD after at least one progression. In DE21 mean progression-free survival (PFS) was 7.5 months, 36 months PFS was 17%, 4 of these 5 pts with at least one prior relapse. In DE40 mean PFS was 7 weeks, 12 months PFS less than 5%. Conclusions: The results show that MT with I/H in SD pts is superior to the treatment of PD pts. As at least in part GBM cells show a stem cell-like behavior in the brain, treatment strategies can be divided into a remission inducing strategy followed by a MT for detectable or undetectable residual disease, thus preventing these GBM cells from proliferating. For some GBM pts I/H seems to be a durable MT while the role of I/H in remission induction is inferior. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Pharma Novartis Pharma Novartis Pharma Novartis Pharma