New Treatment Strategies
Leukemia Insights - Summer 2007
We divide our patients based on IPSS category.
Treatment strategies for this group of patients include the PR1 vaccine, the combination of ATG and cyclosporine, the use of AMG531 (for patients with low platelets), deferasirox, and the combination of growth factors. One potentially very interesting compound is GX15-070ms, a small molecule Bcl-2 inhibitor. This agent has shown clinical activity in patients with CLL and MDS. Deregulated apoptosis is a hallmark of MDS and therefore the rationale for its approach.
In this group of patients, we are studying several different strategies. Together with the PR1 vaccine, we are using an oral or IV formulation of clofarabine at lower doses. Clofarabine, which is approved for children and relapsed ALL, also has activity in AML and higher-risk MDS. A new lower dose of clofarabine may result in an active and safe therapy for this group of patients. Third, prior studies have indicated that the combination of hypomethylating agent with a histone deacetylase inhibitor (HDAC) has significant activity in AML and MDS8.
Two studies are targeting this strategy in MDS. This includes a randomized study of decitabine with or without valproic acid, and the combination of vidaza with MGCD0103. The aim of the first study is to confirm that valproic acid adds to the activity of decitabine. This is an important study that will serve as the basis for other more powerful HDAC inhibitors. MGCD0103 is a new HDAC inhibitor with single agent activity in AML. It belongs to a new group of selective HDAC inhibitors. The combination of these two agents was reported to have a 30% response rate in patients with relapsed AML9.
Together with the clofarabine, dacogen ± valproic acid and vidaza + MGCD0103 studies described above, two other studies are available: the study of lenalidomide in patients with chromosome 5 alterations and a phase 2 study of single agent MGCD0103.
CMML is considered a distinct pathologic entity. For patients with non-proliferative disease, three specific treatment opportunities are available: 1) study of BMS-354825 (dasatinib); 2) phase 1 of Bay-43-9006 (sorafenib) and 3) a study of Velcade. The first two agents are multikinase inhibitors. Initial experience indicated activity in this setting.
Several studies are to be opened to patient accrual in the next few months. This includes:
Oral Vidaza. A new formulation of oral Vidaza is being developed. An ongoing study at M.D. Anderson Cancer Center is demonstrating that oral vidaza can be absorbed. Based on this data, we are planning a phase 1 study of oral vidaza for patients with MDS. This could result in the development of the first oral hypomethylating agent with the possibility of extended chronic oral use of therapy in MDS and potentially a breakthrough for these patients.
Single agent vorinostat for lower-risk MDS. Vorinostat (SAHA) is the first HDAC inhibitor approved for patients with cutaneous lymphoma. In an initial study vorinostat had activity in AML. Data from Europe has indicated that valproic acid (a neuroliptic with weak HDAC inhibitory activity) has moderate activity in MDS. If this concept is correct, the use of vorinostat may have significant activity.
Low dose subcutaneous decitabine. Decitabine has significant activity in intermediate-1 and above MDS, but its activity and toxicity profile is unknown in patients with lower-risk disease, in particular those with low risk. We have developed a new subcutaneous schedule of more weekly administration studies.
Other studies will include the use of LBH598, either alone or in combination for patients with MDS. LBH is a very potent HDAC inhibitor.