How common is MDS that is found to be resistant to treatment with the commonly used hypomethylating agents (HMA), azacitidine (Vidaza®), and decitabine (Dacogen®)?
The overall response rate to HMA based therapy is about 40% to 60%. The landscape is changing slightly, particularly with the use of combination therapies, where we are getting closer to 60% to 80% overall response rates for MDS patients in clinical trials. But that still means about 25% or more patients are experiencing no improvement with these agents. This of course applies mostly to higher-risk MDS patients, because we don’t usually treat lower-risk category patients upfront with these agents. However, we have learned that patients that have not responded to HMA directed therapy (whether they are low or high risk MDS) have poor outcome/survival.
What is the difference between MDS that is refractory to hypomethylating agents and recurrent MDS that returns after successful or partially successful treatment? Is there any understanding of why some MDS is initially resistant to these drugs and why other MDS shows an encouraging response at first, but becomes less effective later?
It is important to identify what we mean when use the words ‘refractory’ and ‘resistant’. My view is that there is a difference, and MDS that is refractory to hypomethylating agents means that patients do not respond to the treatment at all no matter how long they have been exposed to the therapy. In that scenario, we often refer to such patients as ‘primary refractory’ patients. If there has been some response to treatment with a hypomethylating agent with a meaningful benefit (such as transfusion independence) or a larger benefit (like complete remission) with subsequent loss of that response, that is defined as resistant MDS. Biologically, there may be some difference in the MDS that is refractory versus that which initially had a response and then became resistant to treatment. I would say that the biology of refractory MDS dictates that those clinical situations are harder to treat and have worse clinical outcome(s).
Is it known why some MDS is resistant to these two quite similar drugs? Are there instances where one drug fails and the other does not?
There are a few ways to envision the mechanisms of resistance to hypomethylating agents (HMA). One is that there is a decreased transport of either drug into the cell. The transporter used for this is a human nucleoside transporter, known as an hNT. If a cancer cell wants to avoid the toxicity of the agent, then it will find a way to mutate the transporter and thus, decrease the ability of the agent to get into the cancer cell. Another mechanism of resistance would be inactivation of the drug by disruption of key enzymes needed to activate the drugs when they enter the cell that we mentioned earlier (UCK and DCK). If the cancer cell inactivates that key enzyme (UCK/DCK) needed for drug activation, then the agent won’t be activated and therefore won’t be able to kill the cancer cell.
Cells can also learn how to increase the elimination of the HMA drug. If the cancer cell increases the ability to break down the active HMA by increasing cytadine deaminase (CDA) levels, the cancer cell can decrease its exposure to the drug by directly eliminating it, and then the cancer cell has a growth advantage and can avoid the threat from the HMA. There are some researchers that believe there are differences in men and women with regard to CDA activity and that gender affects the likelihood of response to these agents.
Other things to consider are epigenetic mechanisms of resistance. If there’s heavy methylation on the DNA strand, the HMA drug don’t work as well in that setting because it’s so cumbersome and hard to reverse the methylation burden. It is also thought that these agents can work through immune modulation through up-regulation of PD-1, PD-L1, and up-regulation of regulatory T cells. This may come into play, but is still an area of active investigation.
Is there a way to predict what patients may be refractory to treatment with hypomethlyating agents?
The researchers wanted to know if the expression of the enzymes that activate azacitidine (UCK1 and UCK2) predicted clinical response(s) to azacitidine. They looked at a cohort of 57 MDS patients, and their data showed there was a higher UCK 1 mRNA expression in those patients who responded to azacitidine, as compared to those patients who did not. They also found that patients with a lower UCK1 expression had a shorter median overall survival than high UCK 1 expression -- 19 months compared to 49 months. This seemed to be a valuable way to evaluate and predict who may have a longer response or improved survival to HMA directed therapy. Confirming this hypothesis in a prospective manner will help support this research and may help us direct therapeutic choices for our future patients.
It would be great to have markers that help us identify which patients are going respond to specific therapies. We need to do more research with regard to this. We currently have tools like the International Prognostic Scoring System (IPSS) and (IPSS-R), which help with the prognosis for a patient with MDS. Mutation status of specific genes is another tool that is coming to the forefront for evaluating patients with MDS. For example, MDS that harbors a p53 mutation has a worse prognosis than those without a p53 mutation.
We are incorporating these molecular tools in prospective studies for our MDS patients so we can better understand prognosis and hopefully better guide treatment selections for our patients.
What follow-up treatments are there for MDS that resists therapy with hypomethylating agents, and does the next type of treatment selected depend on the risk category or classification of the MDS?
We know that high risk patients have poor outcomes after failing hypomethylating agents, and poor outcomes in the low and intermediate categories have also recently been demonstrated. For those patients, what can we do? Some patients go to a higher dose of HMA therapy, or just switch to the “other HMA” hoping that using a different kinase pathway (UCK/DCK) will help. Some patients are progressing from MDS to AML and they move to a more aggressive approach like intensive induction chemotherapy with the hope to get to bone marrow transplant. And for other patients, enrolling onto a clinical trial is available to them and offers a therapy that they would not otherwise have access to.
Clinical trials that are focusing on novel combinations may be the best options for patients with refractory or relapsed MDS. (i.e.; PD1 inhibitor plus an HMA or single agent PD1 inhibition). All the options should be discussed with each individual patient if appropriate. It is really the patient and his/her physician’s choice to figure out what is best to for that individual patient.