New Approaches for Patients with Higher Risk MDS
Leukemia Insights - Summer 2010
The prognosis of patients with higher (IPSS intermediate-2 and high) risk MDS has improved significantly since the advent of the hypomethylating (HM) agents. Although the results with these two agents are encouraging, median survival of patients is still less than 24 months. More importantly the prognosis of patients that fail hypomethylating agents is very poor. Their median survival is less than 5 months and patients tend to be refractory to most conventional modalities. It is our opinion that most patients in this situation should be treated in a clinical trial when possible. The main objectives of the research program at MD Anderson for patients with MDS are twofold: development of new therapies that could improve outcomes in previously untreated patients and the development of therapies for patients that have failed a HM agent. The following are examples of these:
Combination epigenetic therapy
Results from several groups have demonstrated that the combination of a HM agent with an HDAC inhibitor is synergistic in vitro. Pilot phase II studies have also indicated that this type of approach is safe and active in patients with MDS and AML. To test this concept, we are currently conducting several studies of such combinations: a randomized clinical trial of single agent decitabine versus decitabine and valproic acid, the combination of 5-azacitidine and LBH589, and a study combining 5-azacitidine and vorinostat. This last study is open to patients who are not candidates for other regimens because they have impaired renal or hepatic functions, poor performance status, or have other active malignancies.
Initial results of this trial are that this combination is safe and has activity in this group of patients that do not qualify in general for other therapeutic alternatives.
New hypomethylating agents: oral 5-azacitidine
An oral hypomethylating agent could provide significant benefit to patients with MDS. Not only would this be a more convenient approach to treatment but it would also allow the development of different schedules and potentially truly chronic use. At MD Anderson we have been developing an oral formulation of 5-azacitidine. Results of the initial phase I trial of oral 5-azacitidine were presented at ASH 2009. The drug was administered daily for 7 days following one cycle of standard subcutaneous 5-azacitidine to allow for intra-patient PK and PD analysis and the maximally tolerated dose (500 mg) was defined with the dose limiting toxicity being diarrhea. This GI toxicity is probably related to the fact that the formulation used contains a significant amount of mannitol. Response rates in patients that had received at least 7 cycles of therapy were in excess of 40%. Doses below the MTD (400 to 500 mg daily x 7) of oral 5-azacitidine have been very well tolerated.
Based on extensive PK analysis, we are now investigating 15 to 30 day schedules as well as twice and three times a day administration. This study is open to patients with MDS, including previously untreated, and AML. Additional studies of other formulations of oral 5-azacitidine are ongoing at MD Anderson. A study with oral decitabine has also been recently opened at MD Anderson.
Other epigenetic combinations
The combination of 5-azacitidine and lenalidomide has recently been shown to be safe and active in MDS. Recent reports have also indicated that high dose lenalidomide (50 mg orally daily) has significant single agent activity in AML. Based on this, we are currently conducting a phase I trial of this combination using standard dose 5-azacitidine with dose escalation of lenalidomide in patients with MDS with or without deletion of chromosome 5q.
Another approach to enhance activity of HDAC inhibitors is via inhibition of the NF-kB pathway. Data from our collaborator Dr. Steven Grant at Virginia Commonwealth University has demonstrated that the combination of an HDAC inhibitor with bortezomib has significant activity in leukemia. We are now currently conducting an NIH-funded trial of the combination of PDX1010, an oral HDAC inhibitor, and bortezomib in patients with MDS and AML.
This study is specifically supported by the NCI and will allow us to understand the molecular and clinical implications of this type of combination therapy.
New agents in MDS
Patients for whom hypomethylating-based therapy is no longer effective
A number of non-hypomethylating nucleoside analogues are being developed for patients with MDS. These include clofarabine and sapacitabine. Both agents have significant activity in previously untreated patients and particularly in patients that have received prior HM therapy. Dr. Faderl reported data at ASH 2009 showing that oral clofarabine on a daily x 5 schedule had significant activity in patients with MDS including those who had received prior hypomethylating based therapy.
Two other agents being studied in this group of patients are AR-67 and ARRY-520. AR-67 is a novel DNA topoisomerase I inhibitor, a class of agents that have demonstrated significant activity in the past in patients with MDS. ARRY-520 inhibits kinesin spindle protein or KSP and this approach has been shown to have antileukemia activity in preclinical models and to be safe in patients with advanced leukemia.
Specific situations & opportunities for patients with MDS
Access to multiple other trials in the Department of Leukemia offer the opportunity of other phase I trials for specific situations. Although Flt-3 and JAK2 mutations are relatively infrequent in MDS, patients with these features can be treated with specific targeted interventions. This includes the use of Flt-3 inhibitors and a number of JAK2 inhibitors. Also alternative higher dose schedules of lenalidomide are being explored in patients with alterations of chromosome 5.
Finally the group of patients with so-called hypoplastic MDS are currently being recognized as a different subset of patients that may not be candidates for standard therapies in MDS such as hypomethylating therapy or other forms of chemotherapy. Most investigators are focusing on immune manipulation in these patients using ATG combinations and more recently the use of alemtuzumab and these studies are also ongoing at MD Anderson.
The role of allogeneic stem cell transplantation & high dose chemotherapy in MDS
Although the median age of patients with MDS is 70 to 75 years, a significant fraction of patients are younger and may be potential candidates for more intense therapies including transplantation. The Leukemia Department works closely with the Department of Stem Cell Transplant at MD Anderson allowing for rapid evaluation and referral of such patients.
Finally, even though the role of AML-like chemotherapy programs is debatable in MDS, it is obvious that younger patients can benefit from this type of approach, particularly those with diploid cytogenetics and a potential opportunity for transplantation. Current front line studies at MD Anderson include combinations using vorinostat, an HDAC inhibitor, or sorafenib, a Flt-3 inhibitor, or the incorporation of clofarabine to front line strategies. These studies may allow us to develop more effective induction/consolidation approaches both in MDS and AML.