Genomic Quantification of MDS Responses to Decitabine
EvansMDS Discovery Research Grant 2018
One reason why progress has been slow in MDS is that clinical trials require lots of patients and they take a long time. The reason for this is that there is variability in outcomes between patients; some patients respond quickly, some respond slowly, and some do not respond at all. Therefore, in order to tell whether adding two drugs together works better than just using one of them alone, we need to compare responses and survival in large groups of patients. This helps minimize the impact of variability between patients, and hopefully provides a reproducible result regarding the relative effectiveness of the two regimens.
In this study, we hope to show that responses can be determined using mutation clearance and that this provides a more quantified end-point for an MDS study. If this hypothesis is correct, this could allow us to use fewer patients in MDS clinical trials.
We will approach this in two steps. First, we would like to determine whether MDS associated mutations can be found in the blood. MDS is a disease of the bone marrow and is usually associated with low blood counts. We found that MDS patients commonly have clonal mutations and that the vast majority of the bone marrow cells carry all these mutations even if the patient has very few bone marrow blasts. We looked for these mutations in the blood of 5 MDS patients. Surprisingly, we found the same mutations in the blood as in the marrow, and during treatment with decitabine, the mutations were eliminated just as they were from the bone marrow. These results are exciting, but only reflect MDS patterns in 5 patients. We will verify these initial results in a total of 39 patients to determine whether bone marrow mutations consistently can be found in the blood and whether mutation clearance from the marrow corresponds with clearance from the blood. If successful, this would mean that we might be able to quantify responses using blood and patients might be able to avoid some of their bone marrow biopsies.
Second, we would like to determine whether adding venetoclax to decitabine leads to better responses in MDS patients compared with decitabine alone. This will serve as our test case to determine if mutation quantification and clearance can be a more sensitive method of quantifying MDS responses. In our recent study of 10-day decitabine (decitabine given on days 1-10 of 28-day cycles) we found that responses were slow and that mutation clearance was incomplete. We think that if we could find a regime that leads to faster, deeper remissions, it would be a better therapy for MDS. We have set up a collaboration with Marina Konopleva at M.D. Anderson. She has opened a clinical trial treating patients with decitabine and venetoclax. The decitabine is given on days 1-10, just as we did. We will compare the rate and depth of mutation clearance from these patients with our patients, who were treated with decitabine alone. Specifically, we will look at whether the combination leads to better responses after cycles 1 and 2. This would provide an early end-point that could be quickly assessed on all patients in a study. If successful, this would provide a new treatment for MDS and would validate a new approach to quantify responses in a clinical trial that could use fewer patients, and thus allow us to test more combination approaches quicker.
Last, we will pool all this data together. All these patients will have been treated with decitabine, which is a common backbone for MDS clinical trials. We will provide these results as a database to other scientists so that they could compare mutation responses in their studies against our outcomes. This comparison might allow them to more accurately determine if a future combination was better than our current approaches.