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Treatment Options for Patients with Lower (Low & Intermediate-1 by IPSS) Risk Disease

Leukemia Insights - Winter 2008

One key aspect of patients with low risk disease is to differentiate between those with so-called “hypocellular” MDS (a minority of patients) and those with hypercellular disease. This also serves to emphasize the need for bone marrow biopsies when initially evaluating patients with MDS to assess cellularity. Current approaches include:

Protocol 2005-0115: Thymoglobulin and ATG

This study focuses on patients with hypoplastic MDS (bone marrow cellularity less than 20%). A response rate of 30% is being observed with an acceptable toxicity profile as we are using the rabbit ATG version.

Protocol 2007-0883: Low dose subcutaneous schedules of decitabine

Decitabine is one of the most active agents in higher risk MDS but current doses and schedules may be too intense for patients with lower risk MDS. We have developed a randomized phase II study of two schedules of SC decitabine, daily x 3 every month at a dose of 20 mg/m2 versus weekly x 3 every 4 weeks at the same dose. This study is specific for patients with lower risk disease and may provide a safer more efficient dose/schedule of decitabine in this patient population.

Protocol 2007-04005: Oral 5-azacitidine

5-azacitidine is very active in MDS and has been shown to improve survival in patients with higher risk disease. The main limitation is the need for several months to observe evidence of clinical benefit and the fact that currently treatment is considered indefinite. Because this agent is administered daily for 7 days either IV or subcutaneously, this becomes an issue when treating patients with MDS. Therefore the development of an oral formulation of this compound could have significant implications for our patients. We are part of a phase I study of an oral formulation of 5-azacitidine. Although the study is also open to patients with relapsed AML and MDS, patients with lower risk disease are also eligible. No significant toxicities have been encountered and clinical responses, including complete remission, are being observed. This study is a priority of the MDS program at MDACC.

Protocol 2006-0657: Lenalidomide & darbepoeitin in patients without del5q alterations

Lenalidomide is an extremely active agent in patients with anemia and alterations of chromosome 5 (del5q). The activity of this drug in patients without del5q alteration is less significant. Data from several investigators has indicated that the combination lenalidomide with growth factor may be synergistic. To study this issue, we have developed a study combining lenalidomide and darbepoetin focusing on patients for whom anemia is the main problem.

Protocols 2006-0722 and 2008-0249: AMG-531 (Romiplostim)

AMG-531 is a promising thrombopoiesis stimulating agent in MDS that has been recently approved for patients with ITP. The safety and response characteristics of this drug in MDS are not fully understood. At MDACC we have two studies using this drug. In the first one, AMG-531 is used in conjunction with decitabine. This is a very attractive combination that may reduce myelosuppression-related complications of decitabine. The second is a multicenter study of single agent AMG-531 for patients with MDS and thrombocytopenia that we expect will define the role of AMG-531 in lower risk MDS.

Upcoming studies in lower risk disease

Several studies are ready to be activated for patients with lower risk MDS. These concentrate on the development of several histone deacetylase (HDAC) inhibitors. Drugs like vorinostat3 have activity in AML. European investigators have reported clinical activity with weak HDAC inhibitors such as valproic acid in MDS4. Following this lead we are ready to open studies with LBH589, JNJ-26481585 and SBio939, three potent oral HDAC inhibitors. This class of drugs could become a new standard of care for patients with lower risk MDS.

© 2015 The University of Texas MD Anderson Cancer Center