Talazoparib for Cohesin-Mutated AML and MDS With Excess Blasts

This research study is testing if Talazoparib is an effective treatment for patients with AML and MDS that have a mutation in the cohesin complex.

This research study is a Pilot Study, which is the first time investigators are examining this study drug for a selected subgroup of patients with AML and MDS whose disease features a mutation in the cohesin complex. The FDA (the U.S. Food and Drug Administration) has approved Talazoparib as a treatment for certain kinds of breast cancer. It is not currently approved for treating your disease. Talazoparib is a drug that stops the activity of a protein called poly (adenosine diphosphate \[ADP\]-ribose) polymerase or PARP. PARP is involved in repairing damage to the DNA within your cells. DNA is the set of instructions found within all of your cells that tells them how to behave. The DNA is damaged all the time by things around in the environment, and is repaired by several different methods, one of which uses PARP. When PARP is turned off by Talazoparib in the normal cells, other methods can still work to repair damage to DNA. However, in some cancer cells these other methods are broken and cannot be used. When PARP is turned off by Talazoparib in these cancer cells, DNA damage cannot be repaired and leads to the death of the cancer cells. Talazoparib is a drug that is safe and active in breast cancer and gynecologic cancers. However, there were no responses among 33 unselected patients with hematologic malignancies, including 21 with AML (acute myeloid leukemia) and 4 with MDS (myelodysplastic syndrome), when they received treatment with Talazoparib by itself. It is not known if there were any patients with cohesin-mutations that were on the clinical trial (these mutations are rare). In this research study, the investigators are testing if Talazoparib is an effective treatment for patients with AML and MDS that have a mutation in the cohesin complex. The cohesin complex is made up of a group of proteins that are critical for normal DNA replication activity. Mutations in the cohesin complex occur in patients with MDS/AML and may represent a new therapeutic target. In a chemical screen experiment in a Dana-Farber Cancer Institute laboratory, the investigators found that leukemia cells featuring a mutated cohesin complex were sensitive to Talazoparib (meaning the leukemia cells went away after treatment with Talazoparib) by a mechanism called synthetic lethality (this means that the lab experiments showed that leukemia cells with a mutation in cohesin were dependent on PARP activity to survive; when inhibiting PARP with a PARP inhibitor like Talazoparib, the leukemia cells died). The investigators thus identified Talazoparib to be a possible treatment for actual patients with MDS or AML that have a mutation in cohesin complex.