A session with experts Amer Zeidan, Valeria Santini, Rami Komrokji & Olatoyosi Odenike, who discuss the latest updates on lower-risk myelodysplastic syndromes.

Welcome to The MDS Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc). This exclusive discussion features leading experts Amer Zeidan, Valeria Santini, Rami Komrokji & Olatoyosi Odenike, who debate key topics in the treatment and management of MDS, including diagnostic approaches and challenges, current management options, and potential therapeutic options.

 

Diagnostic approaches and challenges

“I want to stress is the fact that you should also know how to interpret, how to evaluate allele frequency, and the role and the significance of the presence of the mutation in an elderly population like the one that constitutes the MDS patients. You may find clonal hematopoiesis that has not really a significance in terms of pathology and is not really diagnostic.”

– Valeria Santini

 

 

 

Current management options

“For luspatercept, as you alluded to obviously it’s approved by the FDA for patients with MDS ringed sideroblast, but there is probably benefit beyond that. In the PACE study that was led by our colleagues in Germany, with a similar compound that we studied in the past called sotatercept, there were responses outside the ringed sideroblast and even in the PACE study, you see that in any other splicing mutations there were responses.”

– Rami Komrokji

Potential therapeutic options

 

“I think that the future is much brighter now for our patients than it once was. We have many more therapies than we did before, drugs in our armamentarium. I am very curious about the potential role of some of the emerging immuno-therapy based approaches which, right now, are largely being studied in higher-risk disease, but we have immuno-molecules, for examples, that are target in the CD47, etc. Some of these are showing that they are reasonably well-tolerated, even in combination with other agents. I’m very curious about movement of such approaches into the lower-risk space.”

– Olatoyosi Odenike

Full Transcript

Amer Zeidan:
Hi, everyone. Thank you for joining us in this episode of MDS Sessions where we’ll be talking about the management and the diagnosis of lower-risk MDS including the current available options, but also some of the exciting new developments. Part of the focus will be on how the diagnosis of MDS, especially in early stages can be quite tricky, and take some advice from a very good group of experts that I’m very happy to be joined with today.

Amer Zeidan:
Today I have Dr. Valeria Santini, an associate professor of medicine and the director of the MDS section in the University of Florence. I have Dr. Olatoyosi Odeniki who is a professor of medicine and the director of the leukemia program at the University of Chicago. Last but not least, I have Dr. Rami Komrokji. Often known as Rami Komromji, but its Rami Komrokji, who is professor of medicine and the director of MDS and leukemia research at Moffitt Cancer Center. Thank you all for being with us today.

Amer Zeidan:
Maybe I can start with Valeria. Valeria, you’ve done a lot of work in the area of lower-risk MDS and I think one of the challenges that we often see in our patients is that until now we still get some patients who are diagnosed with lower-risk MDS who turn out to have other things, whether it’s vitamin deficiencies or drug effects of immune conditions. How often do you see that and what is your recommended diagnostic approach for people to do in general?

Valeria Santini:
This is a very good point to raise. In fact, in the past we were under-diagnosing the MDS status whereas now, everything that is anemia or cytopenia is MDS which, as you pointed out is not really true for many patients. There are many conditions and comorbid conditions that lead to chronic anemia as we know. You would be surprised in finding, as you mentioned, some vitamin deficiency, but most we have to recognize some specific cases like the multifactorial anemia of the elderly and that is a little bit difficult in fact because they may have dysplastic features in the marrow, they may have dyserythropoiesis, but this is not the dyserythropoiesis of MDS.

Valeria Santini:
Therefore, we require a very careful examination of the bone marrow aspirate indeed. Of course, hypothyroidism has to be ruled out and then, well, I don’t want to speak about renal insufficiency because it seems to be a clear thing to rule out immediately. But as a matter of fact, it is easy to say, not very easy to put in practice in your everyday clinic because there may be cases in which diagnosis is very, very difficult and I just want to mention the fact that sometimes even hemolytic anemia can be disguised as MDS. Reaching the diagnosis of MDS is far to be simple, and far to be straightforward.

Amer Zeidan:
Those are great points. Rami, how often do you check things like copper deficiency, LGL or PNH? Do you have a standard assay that you send on every single patient or do you do sequential testing based on the specific circumstances in which occasion presents?

Rami Komrokji:
I think on the points that Valeria raised, I agree with. What we used to do here, we used to have like a new patient panel for the MDS patients that we will check all those things. Most of the time because also we often serve as a consulting second opinion so we will get them all together. We’ll get B12, folate, iron levels, copper levels, PNH flow and LGL. I have to say that after one accumulating all this information on our database, it’s probably not cost-effective to do it on every single patient. I think it has to be targeted a little bit and now we do this.

Rami Komrokji:
Obviously the basic things, I think you always have to rule out B12 deficiency and stuff like that. We’ve looked at the PNH and most of the low-risk MDS, you rarely will find something that is really actionable or will explain the cytopenia unless there is some clinical indicators, such like any evidence of hemolysis, high NDH, low heptoglobin, that will make you think for PNH. We do observe a lot of LGL clones in MDS. We just published on this recently, maybe of, we say 20% of patients will have it. But again, most of the time, it’s like a by standard, an immune reaction. In some cases where you see severe cytopenia, some fibrosis in the bone marrow, doesn’t look straightforward like MDS, maybe checking LGL is helpful.

Rami Komrokji:
Then, finally for the copper, I really usually mostly emphasize checking it in patients with ringed sideroblast sub-type, especially if they have no evidence of somatic mutation like SF3B1. I always tell the fellows an anecdote. I saw a patient this year. He was one year on azacitidine and diagnosis labeled as MDS-RS but it was SF3B1 negative. The patient had trilineage cytopenia not just … which always takes this in your mind, it’s not usual for MDS-RS to have pancytopenia. The patient actually did have copper deficiency and with replacement counts recovered completely. In this subset with ringed sideroblast, if there is no SF3B1, I strongly recommend checking the copper levels, especially with risk factors for copper deficiency.

Amer Zeidan:
This is a great example and I actually use the same example often with copper and B12 deficiency. I’ve definitely seen cases like this and, of course, I think with EPO and other tablet replacements, that’s not a problem, but once you start thinking about HMAs, bone marrow transplant, this is, I think, a situation where you really want to be a hundred percent sure that this is a malignant process.

Amer Zeidan:
Along those lines, Toyosi, the use of molecular testing Rami was talking about, cost effectiveness, and there is a lot of variation, I think, in terms of using these next-gen sequencing panels and whether use a targeted one or do you use a big panel and which setting do you use it. Especially in lower-risk MDS where the issue is more to make the diagnosis potentially for the specific sub-type. What’s your typical approach of using next-gen sequencing? Do you have an institutional approach or is it something that each physician does on their own?

Olatoyosi Odenike:
I think it’s a mix of both. It’s evolved over time our approach to incorporate a next generation sequence in patients who are undergoing an evaluation for a potential MDS diagnosis. I will say that if we encounter a patient where we are strongly suspicious enough about their cytopenia as being potentially related to MDS, it triggers a bone marrow biopsy and aspiration. Along with that, we routinely send off an NGS panel. That would imply that we have by and large already ruled out other potential non-clonal causes. The cytopenias that we just described and that we feel strongly enough that the patient should get a bone marrow biopsy and so in the course on that, we will send off an NGS panel.

Olatoyosi Odenike:
We have an institutional panel which is clear approved and they’re about 150 genes on that so it’s a fairly broad panel. But it encompasses all of the usual ones that we would be curious about and so, I would say, in that context, we do that now on every patient where we’re suspecting a myeloid neoplasm including MDS.

Olatoyosi Odenike:
But I think it’s an open question as to whether this is something that we want to recommend broadly.

Amer Zeidan:
We have a similar process where we have an institutional panel. We do sometimes run into headaches because often they would cover it when it’s an MDS or any diagnosis, but in the context of the work-up, sometimes they tell you, “Well, you don’t know that the patient has MDS,” and you have to convince them that this is part of why I’m doing the assay because it helps me in the diagnostic evaluation.

Amer Zeidan:
Valeria, I think this is one aspect that may be different between Europe and the U.S., and probably other countries. I don’t know how easily it is to access some of those relatively readily for most patients. Maybe you can also tell us more about all these new acronyms, ICAS and SICAS, and how does that play in into your diagnosis of MDS? We are definitely seeing more patients sent to us with some mutation and some low counts and the primary referring doctor does not exactly, is this MDS, what is this.

Valeria Santini:
Yeah, that’s a very thing that is coming up very rapidly. Everybody knows that we have the possibility to study somatic mutation. Somatic mutation are an analysis that is required but it’s not sufficient to have a diagnosis of MDS. You have to know how to interpret the data. We have an institutional myeloid panel. It’s a little bit smaller than the one used in Chicago but we have at least 40 more frequently mutated genes that are evaluated. But I want to stress is the fact that you should also know how to interpret, how to evaluate allele frequency, and the role and the significance of the presence of the mutation in an elderly population like the one that constitute the MDS patients. You may find CHIP and then I come to the acronyms. You may find clonal hematopoiesis that has not really a significance in terms of pathology and is not really diagnostic.

Valeria Santini:
Today I heard a very beautiful presentation by [inaudible] and he showed data regarding CHIP. The presence of TEP2, SXL1, and DNM3A mutation, but also others, in elderly patients seem presented as much bigger than the 10-15% we are used to think of. Again, he presented the data in a large number of patients who were anemic. Some of them MDS, but indeed, many just anemic without MDS and with clonal hematopoiesis. 5% and 10% would be the threshold I would suggest to evaluate, to think more of MDS than CHIP. CHIP is the clonal hematopoiesis, known also as ARCH because it’s related to age.

Valeria Santini:
Then, we have the CCUS, the clonal cytopenia. Still, not MDS, because MDS has to have also a clear, as I mentioned before, morphology of the bone marrow. Then, the ICUS that are the ones we see quite frequently especially for neutropenia. Cytopenias that are of uncertain significance, and now we have to evaluate them with a follow-up and during time. I think we have a lot of acronyms but also a lot of attention to put in these patients because they may, in fact, evolve not only in MDS but also in time in leukemia, and they may have also cardiovascular problems, so we really have to pay attention to these findings.

Amer Zeidan:
Yeah, great points, Valeria. I think, especially for patients who have low blast count and when there isn’t chromosomal abnormality, those with normal karyotype, I think in these, assays can be helpful. I find it, actually, in my practice, very helpful to rule out MDS in some ways. If the next-gen sequencing is completely normal, since we know that more than 90% of patients will have some kind of molecular abnormality.

Amer Zeidan:
I had, actually, a couple of patients where they were referred for MDS and on the next-gen sequencing, when we did it, it was completely normal. In one of those patients, the B12 was normal on multiple assays, but because the clinical suspicion, the patient had some numbness, we ended up doing methylmalonic acid and it was actually sky-high. Again, a very unusual case and it turns out that B12 deficiency sometimes can be quite tricky. The B12 level can be quite tricky sometimes so I’ll say using that assay, I think that’s another good point to think about.

Amer Zeidan:
Rami, we spend a lot of time telling or educating in our talks, I know you do the same, that MDS is a cancer and it should not be thought of as a syndrome or pre-leukemia or anemia. How do you counsel patients with lower-risk MDS? Do you tell them it’s cancer? Do you get a lot of surprise in your clinic when patients hear that when they are coming for a second opinion?

Rami Komrokji:
Yeah, we do. We do discuss with the patients that this is type of blood cancer. But patients, sometimes, we have to reassure the patient that cancer is description of the underlying biology and cancer is a spectrum. Somebody who is lower-risk MDS, this is not a cancer that’s going to be life-threatening. As you recall, this was a problem in the past with the insurance companies denying many of the treatments for the patients because they would not recognize MDS as a cancer. I think patients need to know that because even if we’re going to talk about the lower-risk patients, the MDS does affect their survival, whether it’s direct or indirect with interaction with co-morbidities and I think … You and I published on this before that 25% of the patients we even labeled lower-risk MDS are going to probably unfortunately die within a couple of years. Again, it could be direct from the disease or indirect exacerbating co-morbidities. I think they need to know that. We discuss it. But then again, with some reassurance that it’s nothing that’s life-threatening on the short-term if they are lower-risk MDS.

Amer Zeidan:
Toyosi, after all of this and the diagnosis is made and you are looking at the risk-stratification and all these course that are out there and we have a bunch of them, which ones do you use clinically and how do you handle that intermediate risk group and the revised ideas as in your day to day practice?

Olatoyosi Odenike:
I tend to stratify my patients using both, with the IPSS and the IPSSR or revised IPSS. I consider a score of more than 3.5 in the revised IPSS as being sort of more on the higher-risk end of the spectrum. But I also pay a lot of attention obviously to how the patient is presented just in terms of being able to decide on what the therapeutic strategy is, what are the patients goals, what are their co-morbidities, what’s their primary cytopenia. For most patients in the lower-risk end of the spectrum, it’s usually anemia.

Amer Zeidan:
How about you, Valeria? Do you use any of those WHO prognostic scoring systems or the MD Anderson or any of those aside from the IPSS and revised IPSS?

Valeria Santini:
No. Actually, my approach is very similar. I just do IPSS because the drugs we are allowed to give are prescribed only if you have the IPSS, either lower or higher. But otherwise, I trust a lot IPSSR and I add, as we just mentioned also, the somatic mutation analysis. We do NGS and IPSSR and we try to find our way with these two tools. I don’t use the other stratification and the other risk assessments.

Amer Zeidan:
How about you Rami? As we know, none of those systems have any molecular abnormalities as part of them and aside that, actually will be one which we’ll talk about in a minute. Do you use those molecular alterations prognostically? Does your treatment decision differ if someone has ECXL1 or RUNX1 or some bad mutation when they have lower-risk MDS?

Rami Komrokji:
I think I select cases differently. Obviously, particularly as we were mentioning, the intermediate risk group. The question is always prognosis versus tailoring treatment accordingly and do we know that if we, for example, use hypomethylating agents with somebody with higher risk molecular features, we are going to ask them their natural history, and I’m not sure that we know that. But let’s say we have somebody who is an intermediate risk, a younger age. I want the edge but then I see high-risk mutation that’s also known to be overcome by transplant, then probably I’m going to be thinking more of transplanting somebody in that scenario. In general, yes, they upstage, I don’t know if we have enough evidence that all the treatments we apply will alter the natural history of that upstaging? But I think it’s important, for example, when you are considering allogeneic stem cell transplant, starting to think somebody is higher-risk to incorporate those. In the intermediate-risk, we look at other things, transfusion burden, presence of circulating blasts, mutations, to try to decide it’s the best time to go directly to transplant or just go step-wise in managing patients.

Amer Zeidan:
Toyosi, one last point on the diagnosis and prognostication before we go to treatment. How do you collaborate with your pathologists when you diagnose these patients? As you know, it’s quite tricky sometimes with these specific guidelines from the WHO about having more than 10% dysplasia in any particular line. It can be quite challenging in terms of especially if the karyotype is normal and the plate count is low and is there enough dysplasia or there isn’t enough dysplasia. Do you have direct conversation with the pathologist or do they generally feel comfortable calling it MDS?

Olatoyosi Odenike:
We do. We have a direct conversation with them on many of our patients because we do recognize that it’s complex, as we’ve just discussed. I do feel that pathologists do see a lot of cases so they tend, I think, to be often comfortable saying outright, “We think there’s enough here to call it MDS morphologically or not.” There are, of course, always gray zones where it seems like, “Uh, it may be MDS but not quite enough.” In those instances, they are often called in off on the report. We have a conversation about how the patient presented and so on, have we excluded everything we can exclude in terms of other non-MDS courses. Then, they usually waiting until they get the next-generation sequence analysis and, of course, the karyotype and all of that, before they stick their necks out one way or the other.

Olatoyosi Odenike:
I find that more and more, it’s becoming an integrated kind of approach where we try to get all of the pieces particularly those gray areas. Obviously, there are some cases where it’s going to be more obvious, but in those gray ones, we really try to work together and put all the pieces together and try to be as confident as we can be. As Valeria alluded to earlier, there will be patients who won’t be able to make that diagnosis and we are really, what I tell those patients is, “It’s pinch off time” We keep an eye on you when we aren’t sure because perhaps something might evolve that will make the diagnosis more overt.

Amer Zeidan:
Yeah, and I think it is important. As I said, I think some of the pathologists I think are more aggressive in their evaluation where they actually look at the patient history and they look at the assays and they look at what was done and what wasn’t done. Others might just look at the microscope. But I do think that integrated approach you mentioned is becoming more common and I think very helpful to kind of issue an addendum or finalization after you have the karyotype and the other resource basically to be somewhat more certain of the diagnosis.

Valeria Santini:
I just want to add a few words from the European side. If we do not have all the diagnosis and the morphology performed by a pathologist, hematologists in Europe just evaluate in the bone marrow’s layers and only the biopsies are given to the pathologist. The collaboration is there for the biopsies, but for the aspiration is our task. We spend a lot of time on the microscope. We know the patient, this is a good thing. I see basically all the bone marrow biopsy of my patients and therefore, I know them and I can really elaborate on the diagnosis. This is something that is present in Germany. In France, they don’t even do bone marrow biopsy for all the patients, for all their cases. We give a lot of attention to morphology for the moment. Then, of course, there will be immunophenotyping that is coming in even if there are a lot of issues there you have to have the real expert cytometrist that is analyzing your data from this. The most important thing to talk with is for the biopsy because still sometimes you really need to have the biopsy data to conclude your diagnosis.

Amer Zeidan:
I think some places in the U.S. do that although I think the general shift has been more that pathologists will make for the different, I think, reasons within the U.S. Is this still the case, Valeria, even with more junior faculty? Fellow are being trained to diagnose themselves or is this also starting to shift in … ?

Valeria Santini:
Yes, we spend our energy to teach them how to recognize dysplastic cells, but also in general for morphology. I know it’s getting more and more difficult because the load of assistance on our patients is big and it’s very hard to spend time in the microscope like in the past. But we still spend quite a long time for now with our undergraduate, but mostly with graduate students who are fellows who spend time in the hematology department.

Amer Zeidan:
I think another aspect in the U.S. is, I think in Europe, the medical oncologist is a completely separate specialty from hematology, while in the U.S. it’s quite often that people do both and I think that somewhat also affects that. Having that enough experience in the lab.

Amer Zeidan:
So, the diagnosis is made, Valeria, and you’ve done a lot of work on erythropoiesis-stimulating agents which I think is one of the most commonly, probably the most commonly-used treatment for MDS, because anemia for lower-risk is, I mean, a problem that we encounter. I want to ask you about specific situations where they are not clear-cut. If you have a patient who has an erythropoietin level of more than 500 where we know that ESA does not work as well and has frequent transfusion need. This is a situation where I see often in my clinic and we know that the ESA does not work very well. But I sometimes end up using it because it’s always easy to use, it doesn’t have a lot of side effects, and the patients are generally not too excited about the alternatives when we discuss with them. Do you do this approach or do you not use it when you think that it’s unlikely that it’d work?

Valeria Santini:
I judge on the case. If the patient is elderly or very co-morbid and has a lot of problems, maybe I can try even to use erythropoietic stimulating agents. Otherwise, if the erythropoietin level is really high, like more than 500 units which is very rare case, I must say, then I don’t even try and I propose immediately an alternative treatment which, in Europe, can be an experimental treatment because we are not allowed to prescribe hypomethylating agent in lower-risk MDS. As a matter of fact, very few patients have very high levels of erythropoietin, but some may have, and extremely rare patients may not tolerate erythropoietin that we have been using for decades for hundreds of patients and without any problem. In that case, I just switch off those experimental treatment or chelation and transfusions if there are other co-morbidities not allowing experimental treatment.

Amer Zeidan:
Rami, one of the things we see with the ESA and the community is the dosing issue. What is the most common issues do you think people should think about when they do those ESAs for lower-risk MDS patients?

Rami Komrokji:
In the U.S.A. also, we see the fact that erythropoietin or the darbepoetin, and I think that the difference between them is probably dosing. You have just to have the right dosing. In general, we see under-dosing a little bit. In the U.S.A., I think patients should be getting somewhere between 40-60,000 the equivalent of the short-acting erythropoietin. Give it 8 to 12 weeks try before assessing if it’s working or not. I tend, a lot of the times, to start with the higher dose and then go down just to shorten that duration and be certain rather dose escalating. I would start sometimes with 60, and then go down. We hold if the hemoglobin goes above 12, we restart if it’s below 11. But I think it’s really that some of the patients come or if they’re getting erythropoietin, we treat for weeks or they are getting 10,000 units I think that’s totally inadequate dosing, in MDS particularly.

Amer Zeidan:
Yes, that’s a great point because I think some people go with the renal dosing which we know is much, much lower than what typically use in MDS. I guess, on the opposite end of the spectrum, Toyosi, I have seen patients in my clinic who are getting ESAs whether they are at the good doses or the lower doses, but they are on the ESA for two years and they are still being transfused once every month. You cannot figure out exactly why they are continuing the ESAs. Some people say, well, it’s making the people feel better. Other people say, “Well, we think the frequency has reduced.” Of course, there is no real way to know. What do you do in those situations? Have you ever added GCSF or some of those other interventions before you switched trial or some other agent?

Olatoyosi Odenike:
I haven’t in general added growth factors. For such patients, I have usually viewed it as evidence of inadequate response and I’ve generally encouraged them to think of alternative therapies, clinical trials, see if it’s available. If a clinical trial is not available, depending on the patient in front of me, it’s either supportive care or hypomethylating agent. It’s really someone much older who doesn’t want to assume all the risks of HMA therapy. I’ve been okay with those patients getting transfusions. But if it’s someone who, I think, from a co-morbid point of view can tolerate azanucleosides, I’m inclined to do that then I have generally done that.

Amer Zeidan:
Valeria, you’ve done also a lot of work on lenalidomide and you led in one of the Phase III trials in the non-deletion 5q, which is the most common form of lower-risk MDS. Assuming you don’t have those insurance or availability restrictions in that same exact patient we just discussed, someone with an EPO level of more than 500 and needing frequent transfusions, would you use lenalidomide or would you use hypomethylating agent or what would you use in this situation?

Valeria Santini:
As I mentioned to you, both drugs in non del 5q are off label. In Europe, you may prescribe them by asking to the health authorities the permission to use them because hypomethylating agents are, of course there, but you can’t prescribe and you can’t dose them. The same for lenalidomide. What I do usually is I use hypomethylating agents off label if the patient has another cytopenia aside from anemia. As a matter of fact, they do respond pretty well, as you know because you use them, but you have to continue. It’s a chronic therapy and this is giving some problems sometimes in terms of compliance. For lenalidomide, in our Phase III study, we showed that the patients who respond with transfusion independence are the patients who have the lower-level of endogenous EPO, lower than 100 units liter. They may respond, as a matter of fact, for a long time as some of my patients still are on treatment. There are some side effects to take into account, so I think both drugs may be considered. The hypomethylating agents I use only for patients who have other cytopenias, whereas lenalidomide is strictly for only anemic patients.

Rami Komrokji:
If I may add a little bit, because we have almost the liberal use of the two agents here. I usually think of lenalidomide patients with isolated anemia as Valeria mentioned. Even if they have a concomittant cytopenia that doesn’t need treatment as the platelet is 60 or 70, those patients typically don’t respond to lenalidomide. We restrict such use for patients that are just with isolated anemia post-ESA failure. We do sometimes combine it with Procrit. We have the U.S. inter-group study based on some work we’ve done in the past that sometimes you do see higher responses or maybe it’s a little bit more durable with the combination.

Rami Komrokji:
The other thing that I tried to do and that’s a work I published also in the past is looking at the sequence. If I have the choice for somebody who is purely anemic, I will go first with len plus Procrit rather than aza because we see almost to what Valeria reported, around 30% responses if we use it after ESA. But if we use it after HMA failure, the responses dropped down to 10%, while the responses to HMAs are preserved whether they were used before or after len. Obviously in the del 5q, I think that standard of care nobody argues about it, but in the non-del 5q, I would use len for pure anemia patients plus minus Procrit, but before HMAs. But if there is concomitant cytopenia, I totally agree with Valeria. We move to hypomethylating agent. In younger patients, obviously, just always do a good reminder for everybody that there are subset of patients that do well with ATG plus minus cyclosporine as well.

Amer Zeidan:
Toyosi, on the same front, again, HMA, lenalidomide here. With the availability of the oral hypomethylating agent in the U.S., both of them approved in the last few months, would you consider using an oral hypomethylating agent for a lower-risk MDS or would you not use this at this point?

Olatoyosi Odenike:
I think at this point I would hold off. There are ongoing phase, at least one ongoing trial that I’m aware of in lower-risk MDS using the oral decitabine and oral cedazuridine combination. I would be more inclined to put such a patient on a trial than doing off-label. Because I think it’s an open question right now as to what the ideal dose would be in a lower-risk MDS patient. There, we are trying to work the fine line of benefit versus toxicity. Can we get a dose that would be less myelosuppressive while still preserving the potential for this to be effective? I think that this is best addressed in the context of a clinical trial wherever possible. I would try to wait for the results for the trial or get the patient on the trial if they were eligible rather than doing it off-label.

Amer Zeidan:
I follow the same approach not using them for the time being until we have more data. Valeria, assuming you get the health authorities authorize the use of hypomethylating agent in someone anemic. We have data-

Valeria Santini:
Only anemic?

Amer Zeidan:
Yeah. Someone who’s anemic, mostly. We have data from MD Anderson with three days of HMAs and we have data that still going to work on with 10 days, and we have everything in the middle. Where do you stand on that spectrum of how do you dose a drug?

Valeria Santini:
As a matter of fact, as I mentioned, we don’t use it so frequently but the MD Anderson data with the attenuated dose, as they call or it’s better to call them with a shorter scale up of three days, they have wonderful response rates. In the 60% so apparently, and even more. Apparently, this approach that is a little bit counterintuitive because we learn that we have to use it for longer time, lower dose, to induce the hypomethylating effect. Now we have standard dose for a shorter time, so it’s a little bit different from our conception, our idea of this treatment.

Valeria Santini:
I don’t know whether this can be an approach that can be applied to many patients because I have some very small experience in this sense. I would speak, again, I would study it more in depth and I would like to see a clinical trial so to compare the standard schedule to the attenuated dose and see whether they are equivalent or one is better than the other.

Amer Zeidan:
Rami, maybe I can ask you to comment on the same issue since MDS Clinical Research Consortium which Moffit belongs to, I think, have looked at that issue as well. But also maybe you can tell us about use of luspatercept which you’ve also been involved and endorsed in the same exact patients, someone with anemia and with a high EPO level, but not your typical patient with sideroblast for which the label is there. Would you use it in this situation?

Rami Komrokji:
For the hypomethylating agents, obviously, I think the standard in the U.S.A. in the lower-risk had become the five days based on Dr. Lion’s paper few years ago showing similar responses to the 522 or the 525 and less toxicity. As Valeria mentioned, there is also the MD Anderson pilot Phase II is promising. We just finished, actually, the accrual to that study through the consortium where 200 plus patients were randomized between first early start versus waiting patient becomes transfusion dependent, second versus five days aza, three days decitabine, three days aza. I think that will answer the question.

Rami Komrokji:
In practice, because we were part of the study, to be honest, sometimes I will use it in some older patients. Patients that like it in attenuated schedule with success but I think to generalize that we will need the results from this study if it shows that three days is as good as five, that will be much easier and it makes sense to do that in the lower-risk.

Rami Komrokji:
For luspatercept as you alluded to obviously it’s approved by the FDA for patients with MDS ringed sideroblast, subtype it’s a erythroid maturating agent, I think that’s the term now we are using to describe it or it promotes the term erythroid differentiation. It’s a neutralizing antibody for the TGF-b ligands. The label is for sideroblast but there is probably benefit beyond that. In the PACE study that was led by our colleagues in Germany, with a similar compound that we studied in the past called sotatercept, there were responses outside the ringed sideroblast and even in the PACE study, you see that in any other splicing mutations there were responses. Even in patients with no splicing mutations, there were responses. Obviously, it is not easy to get the drug approved in that setting, even in the U.S.A. to be honest at this point. Many times what happens in those patients that we are currently dealing with, it’s like they have prior len or hypomethylating agents so we also don’t have data about the responses post that. In general, if patients are having transfusion dependent they will not do well.

Rami Komrokji:
But what we are trying to move forward with luspatercept is really up front. We have the COMMAND study that we are trying to randomize patients between ESA and luspatercept. For those patients that actually have a little less chance to respond to ESA, maybe identifying that group to that it will become the upfront strategy. Yes, sometimes we try to use it off the label in the non-RS subtype but it’s mainly have been restricted since the approval in that category except on clinical trials.

Amer Zeidan:
Thanks for this comprehensive review Rami. Of course, the last option that we use and we and you have looked at is the use of immunosuppressive therapy. I think there is some good data as well in the right setting. Do you see, for the interest of time, because this is a great discussion and time is running quickly, I want to discuss a little bit about some of the new agents. One interesting agent, imetelstat which I know you do also quite a bit of myelofibrosis and MPN work and this drug interfaces both MDS and MPN. What’s your sense of the Phase II was just published in GSAO, and there’s an ongoing Phase III, what’s your sense of this drug and the patients that could be candidates for it should it become available?

Olatoyosi Odenike:
My overall sense is that the drug is a little bit cumbersome to use. It’s what my experience had been. We participated in the myelofibrosis trials and then to some degree in some of the earlier iterations of the MDS trial. There does seem to be a signal in patients who are lower-risk MDS who have not responded to the typical agents that we would use such as ESA therapy. I think I would be very curious about what the results would be in a randomized setting to really so gauge the level of benefit. To me, it’s an agent that’s a little bit slightly more challenging to use than some of the other agents that we’ve described so far so I think therein lies the challenge. But the early phase trials were promising just in terms of the potential for specifically this patient population.

Amer Zeidan:
Another drug that’s in advanced Phase III trial is roxadustat which works in the hypoxia-inducible factor pathways. I think in the last segment and the last few minutes I just want to get some sense from the group about where do you see the management of lower-risk MDS is going in a few years. It sounds that for a long time we really have not mostly focused on symptoms, survival was not generally the goal, quality of life, and we did not have really then a lot of drugs and things are changing. Maybe starting with Valeria, how do you see things going in the next few years for lower-risk MDS?

Valeria Santini:
Finally, as you mentioned, we have something new to propose to our patients beside the supportive care. I think that as Rami mentioned, luspatercept has still a lot to tell us because we have to use the drug in a different setting than ringed sideroblast. Maybe the percentage of response will be lower. But frontline would be a challenge and in Europe, a new trial is starting proposed by our German colleagues in which luspatercept is used in non-transfusion dependent patients. That’s something we still have to know, how to use at it’s best because it’s a new drug, but I think this is something leading us a little bit further with treatment of anemic patients.

Valeria Santini:
But again, different approaches and probably a more refined immuno-suppressive therapy, we disregarded it for two long. I think this is something we should consider a little bit more when choosing therapies. I suppose new drugs are coming along the way and we will have a lot of work to do in the next few years.

Amer Zeidan:
Rami, what do you think? Probably some combinations are probably also are going to be in the horizon.

Rami Komrokji:
I think one of the things is first, we have to redefine our goals. Because we always have focused on alleviating cytopenias transfusion dependence. I think it’s still reasonable. But I do believe that when we restore effective erythropoiesis, we do have impact on patients’ outcome indirectly even maybe. We have to start studying who are the patients that really we should be aiming for that always rather than just settling down for the transfusion-dependents. I think our philosophy or goal for identifying patients at higher-risk should be revised a little bit.

Rami Komrokji:
Then, obviously, I think even what we lump as lower-risk are really a very heterogeneous group where the effect in erythropoiesis is totally different. Now, we know, for example, SS3B1 mutant MDS is almost separate category. You have the deletion 5q and I think as we learn more, whether they dissect those groups into more homogenous group where we understand the real defect in erythropoiesis and target that.

Rami Komrokji:
There are some agents like, I think, we talked about the imetelstat that is early on and it’s an IV drug given every four weeks, but in the early studies, there is some suggestions and it’s more subset of patients and it may change the, for example, the allele burden for the SF3B1. We may start having some medications that may have impact.

Rami Komrokji:
Then, as you mentioned, finally trying to find the combination of those therapies. Obviously, many times in the past, we had only limited options so we combine them without a good rationale. But I think as we move forward, maybe we’ll have it a bit more rational to combine things together. I’m sure that we’re going to see a lot of the combinations with luspatercept, for example, coming forward, some of them with good rationale, some of them just maybe combinations based on clinical activity. But I think it’s exciting at least that we have at least three or four drugs with activity now in the lower risk. Hopefully, we’ll optimize their use with the coming clinical trials.

Amer Zeidan:
Toyosi, what do you think? Do you think lower risk MDS could become like diabetes or hypertension where our patient can live with that many, many years without fail?

Olatoyosi Odenike:
That would be so nice. I think that the future is much brighter now for our patients than it once was. As you’ve heard from our esteemed colleagues on the line, we have many more, more than we did before, drugs in our armamentarium. I am very curious about the potential role of some of the emerging immuno-therapy based approaches which, right now, are largely being studied in higher-risk disease, but we have immuno-molecules, for examples, that are target in the CD47, etc. Some of these are showing that they are reasonably well-tolerated, even in combination with other agents. I’m very curious about movement of such approaches into the lower-risk space. I’m trying to figure out what the relative impact that will have on our patients. It’s a very exciting time to be caring for patients with MDS and trying to think through these very interesting questions.

Amer Zeidan:
Thank you so much. Thank you so much to all of you. This was a great discussion and a lot of great insights. We could probably spend hours talking about all these drugs and the new directions. Hopefully, I’ll have you in the future for another discussion especially after some of the new data gets released in ASH and the other meetings. Thank you so much everyone and I look forward to see you in the next episode. Thank you.

Olatoyosi Odenike:
Thank you.

Rami Komrokji:
Thank you.

Olatoyosi Odenike:
Bye.

Amer Zeidan:
Bye.

The MDS Channel

 

Explore the latest updates in MDS, including expert interviews from major international congresses, podcasts and e-learning.

Disclosures

Amer Zeidan – Consulting fees from Boston Biomedical, PTC Therapeutics, Agios, Celgene/Bristol-Myers Squibb, Abbvie, Astellas, Novartis, Daiichi Sankyo, Trovagene, Seattle Genetics, Amgen, Pfizer, NewLink Genetics, Jazz, Takeda, Genentech, Blueprint, Kura Oncology, Kite, Amphivena, Trillium, Forty Seven/Gilead

Valeria Santini – Advisory board: Novartis, Menarini, Geron, Celgene/BMS, Takeda, Astex, Janssen

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