New Approaches to Patients With Lower Risk MDS
Leukemia Insights - Summer 2010
Patients with IPSS low or intermediate-1 disease are usually grouped together in the so-called lower risk category. These account for close to 75% of patients with MDS. This is a particularly difficult group of patients as it includes individuals with very benign conditions and long expected survivals and minimal risk of transformation to AML and patients with very poor prognosis and very high risk of transformation.
The Lower-Risk Specific MDS model is used at MD Anderson to differentiate these patients (Table 2). One of the main emphases of our current therapeutic program is the development of new strategies specific for patients with lower-risk disease but poor predicted survival. Examples of several of these trials are summarized below.
Table 2: MD Anderson Lower-Risk Specific Model
Diploid or del(5)q only
|Marrow Blast (%)||<4|
Targeting the p38 MAPK pathway: A phase I trial of ARRY-614
p38 MAPK is involved in hematopoietic stem cell function. In vitro inhibitors of this pathway have been shown to stimulate hematopoiesis and have potential therapeutic benefit in patients with lower risk disease. ARRY-614 is a new oral molecule that inhibits p38 MAPK. This study is specific for patients with lower risk MDS that are transfusion dependent. So far toxicity has been minimal with this compound and hematologic responses are being observed in the initial phase of this trial. This is an option for transfusion dependent patients that are not responding to growth factor support.
Histone deacetylase inhibitors
Histone deacetylase (HDAC) inhibitors are a relatively new class of agents with activity in cutaneous lymphoma and potentially leukemia. In vitro, these agents have the capacity to induce cell differentiation and therefore there is significant interest in studying these agents in lower risk MDS. Because HDAC inhibitors are oral and have excellent toxicity profile, they are attractive for this group of patients. We are currently investigating two of these agents: LBH589 and JNJ-26481585.
LBH589 is a very potent oral hydroxamic acid derivative being explored in a number of leukemias and lymphomas. This phase II trial explores the activity of this agent in patients with low or int-1 disease that are transfusion dependent. The drug is administered three times a week and patients are not required to stay in Houston for a prolonged period of time.
JNJ-26481585 is a novel HDAC inhibitor that in vitro has an excellent antileukemia activity profile with minimal effect on normal hematopoietic tissues. We are currently conducting a phase I trial with extensive pharmacokinetic and dynamic monitoring to assess the safety and tolerability of this compound in both MDS (all risks) and AML.
New schedules of hypomethylating agents
Both 5-azacitidine and decitabine are approved for patients with MDS. That said current schedules of these agents, that are very effective in patients with higher-risk disease, are frequently associated with severe myelosuppresion. This may preclude their use in patients with lower-risk disease for whom this degree of myelosuppression may not be acceptable. Because of the clinical activity of these agents, we have been interested in evaluating very low dose schedules of hypomethylating agents in patients with lower risk MDS. We just completed a study of decitabine comparing two different schedules: 20 mg/m2 subcutaneous daily x 3 every month or the same dose weekly times three also every month.
This study, which was presented at ASH 2009, demonstrated that the daily x 3 schedule was superior to the weekly. Although complete response rates were modest (less than 10%), close to 70% of patients achieved stabilization of disease and significant improvements in transfusion requirements. More importantly this very low dose schedule was extremely well tolerated with few complications from myelosuppresion. Based on these encouraging results, we are now designing a phase II trial of very low dose 5-azacitidine (50 mg/m2 daily x 3) in transfusion dependent patients with lower risk disease. This will serve as the basis for a planned study of oral 5-azacitidine that will be discussed in this issue.