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Treatment Options for Patients with Higher (Intermediate-2 & High By IPSS) Risk Disease

Leukemia Insights - Winter 2008

Treatment of these patients still depends on age. Younger patients, particularly those with high risk disease are still considered for front-line induction chemotherapy approaches followed by allogeneic stem cell transplantation. For the older group of patients, which constitutes the majority, intensive chemotherapy is currently rarely indicated. Our strategies focus on development of active and safe treatments for newly diagnosed patients as well as those patients that have failed hypomethylating based therapies.

Protocols 2006-0977 and 2007-0835: Induction therapy approaches for younger patients with MDS

Traditional induction programs (i.e. “7+ 3” or IA) are relatively safe in patients younger than 60 years of age with induction mortality rates less than 10%. This type of approach followed by stem cell transplantation can be curative particularly in patients with diploid cytogenetics. Two phase II studies [IA + sorafenib (2006-0977) and IA + vorinostat (2007-0835)] are investigating the impact of adding a biological agent to standard induction approaches. So far, complete remission rates are extremely high with these programs and toxicities are not increased compared to the common experience with IA at MDACC. These biological agents are also used during consolidation and maintenance phases of the disease and may allow for long-term durable remissions in this difficult group of patients.

Protocols 2006-0686 and 2007-0882: Upfront therapy for older patients with MDS: combinations with decitabine

Data from our group has indicated that the combination of a hypomethylating agent and a histone deacetylase inhibitor has significant clinical activity and safety both in patients with higher risk disease and AML5,6. One finding from these studies is that responses appeared to be higher and faster with the combinations and that patients with higher valproic acid levels in blood tended to have better response. To confirm the role of valproic acid in combination with decitabine, we are conducting an NIH funded phase II randomized study of decitabine with or without valproic acid (2006-0686). The results of this study will define the role of valproic acid in the treatment of patients with higher risk MDS in combination with decitabine. Another important study incorporates mylotarg with decitabine. Data from several groups has indicated that this combination may be very active in MDS/AML as well as safe as it utilizes a lower dose of mylotarg (3 mg/m2 x 1). We are currently investigating the role of adding mylotarg to decitabine in study 2007-0882.

Therapy for patients that have received prior hypomethylating-based treatments

The use of 5-azacitidine and decitabine has been revolutionary for patients with higher risk disease. That said unfortunately most patients will eventually lose response. Therefore new strategies are needed for this group of patients. It should be noted that there is no current FDA approved treatment approach for these patients except the use of allogeneic stem cell transplants or intensive induction therapies. We are developing a number of strategies for this very specific clinical situation.

Protocols 2005-0536 and 2005-0535: Clofarabine

Clofarabine is a nucleoside analogue with significant activity in patients with ALL and AML either as a single agent or in combination with cytarabine. In view of this, two studies are evaluating the safety and activity of lower dose schedules of both an IV and an oral formulation of clofarabine. Preliminary results from these trials were presented at the 2007 ASH meeting. Of importance, it was noted in this analysis that this intervention was very successful (around 40% response rate) in patients with MDS that had received prior hypomethylating agent based therapy.

Protocol 2006-0943: Gimatecan

DNA topoisomerase I inhibitors (such as topotecan) are known to have significant activity in MDS. Gimatecan is an oral topo I inhibitor. 2006-0943 is a phase I study evaluating the safety and activity of this compound in patients that have received prior therapy for MDS.

Protocol 2007-0727: Sapacitabine

Sapacitabine is a new oral nucleoside analogue being developed at MDACC with activity in AML and an excellent toxicity profile. Based on this, we are currently conducting a study of lower doses of sapacitabine for patients with higher risk MDS. An active oral approach in this setting would be of great interest.

Protocol 2006-0293: Lenalidomide in higher risk del5q MDS

The role of lenalidomide in higher risk MDS is not well defined. In this study we use lenalidomide for patients with higher risk disease or AML and an alteration of chromosome 5.

Allogeneic Stem Cell Transplantation

The role of alloSCT in MDS is in evolution. Because most patients with MDS are older and may not have suitable related living donors, new transplant modalities are needed including those with lower intensity preparatory regimens. The Department of Leukemia collaborates closely with members of the Stem Cell Transplant Program at M. D. Anderson to evaluate patients for transplantation as soon as indicated.


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