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SOHO 2020 | Treatment algorithm for low-risk MDS

Valeria Santini, MD, University of Florence, Florence, Italy, discusses the treatment algorithm of low-risk myelodysplastic syndrome (MDS) as well as the importance of genetic understanding of disease to guide treatment, including treating del5q mutated patients with lenalidomide as well as the significance of TP53 mutations. Prof. Santini also discusses the approval of luspatercept for the treatment of anemia in lower-risk MDS, as well as roxadustat, an oral HIF prolyl-hydroxylase inhibitor currently being evaluated in lower-risk MDS with anemia. This interview was recorded via an online conference call with The Video Journal of Hematological Oncology (VJHemOnc).

Transcript (edited for clarity)

As a matter of fact, we have much more options nowadays than we used to have some time ago. Therefore, the diagnosis and prognostic certification of lower-risk MDS patients must be as sophisticated as possible. That means that the evaluation of somatic mutation has to be taken into account and programmed every time. We need to establish a sequential therapy. So, the algorithm of treatment for low-risk MDS, it’s very broad...

As a matter of fact, we have much more options nowadays than we used to have some time ago. Therefore, the diagnosis and prognostic certification of lower-risk MDS patients must be as sophisticated as possible. That means that the evaluation of somatic mutation has to be taken into account and programmed every time. We need to establish a sequential therapy. So, the algorithm of treatment for low-risk MDS, it’s very broad. And it’s very articulated because we have of course, symptomatic anemia as the first and most frequent problem for lower-risk MDS patients. Beyond ESAs that have been used for decades and are still the first-line treatment for patients who have the criteria of response that is low endogenous EPO levels, better if lower than 200 units liter, not transfusion-dependent and a lower-risk, of course, without blasting the bone marrow. These are the patients that should be receiving EPO or biosimilar at the dose of 40,000 to 80,000 units a week.

Now, ESAs has been approved finally in Europe for treatment of symptomatic anemia, MDS. And we know also that although the majority of selected patients do respond, they will lose response after a while. And this is where it opens up the importance of evaluating the patients in the best way possible. We know, and we do treat patients with lenalidomide if they do have del5q and the response of del5q patients to lenalidomide is limited by the presence of TP53 mutation.

We learned in the last few months that a multi-hit, multi-allelic TP53 mutations are the ones that are responsible for loss of response or lack of response to lenalidomide and responsible for progression to AML. So this is what we should look for when we need to move from ESAs or when we already have a MDS del5q patient who received transfusion, we have to check for TP53 mutation. And in case the patient has only mono-allelic TP53 mutation. We may still, in my opinion apply lenalidomide as treatment. Otherwise we have to move to other treatment and we should always take into account the possibility to treat patients with transplant, even if for lower-risk it’s less recommended than in an earlier phase.

Last summer. In fact, another drug has been approved for anemia of transfusion dependent patients with lower-risk MDS. This is luspatercept, a subcutaneous agent that it has been approved for treatment of patients with ring sideroblast. That is more than 15% of rings that blast in the marrow or the presence of SF3B1 mutation and more than 5% as a ring sideroblast. So again, we have another important weapon or tool if you wish in the cure and treatment of anemia in low-risk MDS.

Of course there are more patients, even if ring sideroblast ones and MDS ones is very frequent. There are more patients who do not have these characteristics and still lose response to ESAs or never achieved a response, and should be treated with experimental drugs. Experimental drugs are the only option that is alternative to transfusions. And there are interesting ones like imetelstat, that is a telomerase inhibitor now under evaluation in Phase III and in the Phase II has shown a response in more than 45% of patients who had to factor it.

Speaker 1: (05:09)
So very interesting, a little bit of minor suppression. So we have to select patients who are not severely cytopenic for neutrophils and platelets, but it’s a very interesting agent. Another interesting agent under evaluation is roxadustat. Roxadustat is an inhibitor of the HIF alpha hydrolase. The epoxy inducible factor hydrolase, roxadustat is oral. And is in use in 38% of transfusion-independent in patients who did not respond to ESAs and have a low transfusion bottom, so very interesting and moment for low-risk patients with anemia, but there are other cytopenias like thrombocytopenia that still need to find a drug and a specific drug to be approved for low-risk MDS patients.

Eltrombopag and romiplostim have shown activity, lowering the hemorrhagic episodes and increasing the number of platelets in Phase II studies, but have not yet been approved. So the older drug eltrombopag, that is approved for ablastic anemia and ITP, and the romiplostim subcutaneous approved for ITP are still experimental for lower-risk MDS patients. There are other thrombohematic drugs that are under study.

And what is interesting is that if you have a patient with low-risk and more than one cytopenia, especially patients with anemia and thrombocytopenia, they should be treated with drugs like hypomethylating agents. Now in Europe, they are not approved. In the States and other countries widely use them as a second line treatment. The interesting part of these is that the oral azacitidine CC-486 has shown activity in a Phase III study that has been closed after several difficulties in involvement, and has shown activity in increasing platelets and red blood cells. But has some toxicity, especially for neutropenic patients, but is indeed a very interesting drug, whereas good results have been obtained by the MD Anderson group treating low-risk MDS patient with three days of standard dose of azacitidine or decitabine.

And therefore, I think that we will see more about oral drugs, also aspects that have not been yet published for lower-risk MDS patients. Of course, we are going towards what is called the total oral therapy, patients are elderly, they do not like to come to the hospital too often. Lower risk patients have a very long expectancy of life and longer, we hope. So it is very important to improve further their quality of life by providing oral drugs.

Finally, little is left, I would say for neutropenic patients, these are at present the most difficult ones to treat because there is not a specific drug, filgrastim G-CSF is of course very efficient, but it hasn’t shown an advantage when using prophylaxis. So it’s good to be used in neutropenic fever and just to be employed in the case of infections. As I mentioned, more experimental drugs are under evaluation, there is a lot of work because the patients with low-risk MDS are the majority of the MDS patients with a prolonged survival, the younger ones should be very carefully evaluated for an inherited predisposition and possibly move to transplant. Not very early, but surely program of transplant should be really designed carefully for the patients who are a little bit older and cannot undergo a transplant, or the risk of transplant is higher than the risk of transformation on MDS.

Not only cytogenetic and marrow cellularity, but also the presence of somatic mutation must be evaluated because this can help us also in experimental choice. For instance, IDH1 mutated patients with low risk MDS, could be enrolled in a study that has been promoted by the GFM, the French MDS group . And has become a European study and we are waiting for the first patients and the first results in this interesting approach. So I think it’s a very exciting moment for patients with the low-risk MDS.

And we still need, for instance, to understand the importance of immunosuppressive therapy, the selection of patients who could respond. I think there is a lot of work to be done and a lot of options and evaluation of agents that are still not yet well-known.


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