Amer Zeidan:

Hi, everyone. Good morning, good afternoon, good evening, wherever you are. Thank you so much for joining us. Welcome to VJHemOnc MDS Sessions, where today, our discussion is going to actually focus on the main highlights from ASH 2023 when it comes to novel drugs in the space, investigational drugs in early phase trials. So the discussion is really focused on early phase trials, not the advanced phase trials, so we’ll not be covering things like luspatercept, magrolimab, imetelstat. The focus will be on Phase I, Phase II drugs that looked interesting and potentially could enter into more advanced testing and hopefully at one point get approved. So my name is Amer Zeidan. I’m an associate professor of medicine at Yale University, and it’s a true pleasure to be joined by four of my colleagues and friends, all of them are experts in the field.

So Dr. Jan Bewersdorf is going to start us off with a presentation of the main highlights from the meeting, which will go for around 20, 25 minutes. Jan is a fellow at Sloan Kettering. He’s actually joining the faculty next year at Yale as an assistant professor in the myeloid malignancy field. We are also very happy to have Dr. Yasmin Abaza, who’s an assistant professor, also specialized in myeloid malignancies in Northwestern. Dr. Max Stahl who’s an instructor but should be really assistant professor in Dana-Farber. Again, very focused on MDS and myeloid malignancies. And Dr. Yazan Madanat who is an assistant professor in UT Southwestern. All of them are going to give their thoughts after the presentation by Dr. Bewersdorf, this is going to be done around 25 minutes where we discuss the panelists’ thoughts on those drugs and where do they fit in the field going forward. So we’ll start ahead with the presentation by Jan.

Jan Bewersdorf:

Thank you very much. Thanks everyone for joining this morning on the clinical updates from ASH as pertaining to early drug development in MDS. And before I get started, I just want to thank Dr. Zeidan and VJHemOnc for the kind invitation to speak here today and I’m really looking forward to sharing those updates as well as the subsequent panel discussion. As Dr. Zeidan already mentioned, I think we really want to focus a little bit more today on the novel investigational agents. However, I thought it would be important to get everyone on the same page and to put the subsequent slides into better context if I start off by a brief overview of the current treatment landscape of MDS. The slide shows a potential treatment algorithm for MDS that Dr. Zeidan and I recently published, but however, already there’s so much movement in the field that some of this is already outdated.

I would first like to draw your attention to the left-hand side of this algorithm, which shows the treatment algorithm for lower-risk MDS patients. Treatment of patients with lower-risk MDS is primarily supportive and focuses on the amelioration of cytopenias with anemia being the most common disease manifestation. Patients with symptomatic or transfusion dependent anemia have traditionally been treated with erythropoiesis stimulating agents or lenalidomide in the case if there’s a deletion 5q present. However, this entire treatment approach is already changing with the publication of recent clinical trials. However, as Dr. Zeidan mentioned in the interest of time and as the result have already published, as for many of the script, I would like to really refer you to those publications for further review and I’m not going to spend any additional time on those studies today. So we’re not going to cover updates from the COMMANDS trial or the IMerge trial of luspatercept and imetelstat respectively. Also, there was an interesting trial of TPO mimetics for treatment specifically of thrombocytopenia that was published last year.

The first agent I would like to discuss today is KER-050, which is also known as elritercept, which has a similar mechanism of action as luspatercept and acts as a ligand trap of TGF-ß ligands. At the 2023 ASH meeting, we saw results from ongoing Phase II study of KER-050 in patients with lower-risk MDS and the study schema is shown on this slide. Data at ASH were presented for 79 patients who were treated at the recommended Phase II dose. As you can see, most patients who were transfusion dependent, they had ring sideroblasts and multilineage dysplasia. However, the median EPO level was fairly low and only a quarter of the patients had previously received erythropoiesis stimulating agents, which is important when we put those results in context, especially with indirect comparisons against luspatercept. In the intention to treat population, the response rate was 50% and included red blood cell transfusion independence for at eight weeks and 39.1% of the patients. Responses were numerically better in patients with ring sideroblasts positive disease.

In terms of side effects, most adverse events were low grade and unrelated to treatment. The most common adverse events include dyspnea, diarrhea, and fatigue as you can see on the right-hand side of this slide. However, there’s only a Phase II trial that’s still ongoing in larger trials with an active comparator arm would be needed to see how KER-050 compares against luspatercept in terms of both safety and efficacy.

The second study I would like to highlight focuses on canakinumab. Canakinumab is an interleukin-1 beta inhibitor that’s approved for various rheumatologic conditions. And as there’s a strong overlap between immune dysregulation and certain subtypes of lower-risk MDS, canakinumab and other anti-inflammatory agents have been tested in patients with lower-risk MDS. In the single center Phase II trial conducted the MD Anderson, patients with lower-risk MDS or CMML, were treated with canakinumab as a single agent. Among 23 evaluable patients, four patients achieved hematologic improvement which lasted for a median duration of 8.5 months.

In the second study conducted by the group at Moffitt, canakinumab was added to darbepoetin in patients with lower-risk MDS who had previously been treated with erythropoiesis stimulating agents. However, in this trial there were no objective responses but there was also no new safety signal for this combination. So I think at this point it’s really unclear where this avenue of drug development will move further with other immunomodulatory drugs in clinical trials right now, but I think it will really need larger trials to see where these leads are.

The last trial that I would like to highlight in the lower-risk MDS space was abstract 1879 of the IDH2 inhibitor enasidenib. And as you’re probably aware, enasidenib has been approved for treatment of AML patients who have IDH2 mutations. IDH2 mutations are fairly rare in patients with lower-risk MDS, but with enasidenib there is a possibility for targeted therapy for those patients. Interestingly, preclinical studies have also shown that enasidenib can enhance erythropoiesis also in IDH2 wild-type patients. And these pre-Clinical observations then provide the rationale for a clinical trial of enasidenib in IDH2 wild-type patients.

In this Phase Ib/II study, enasidenib was found to be safe and resulted in trilineage hematologic improvement in one patient. However, it’s a small study, only seven patients were here involved and so it really remains to be seen what the efficacy is going to be in the larger study and if it differs by IDH2 mutation status which one might expect. However, the subset of patients with IDH2 mutant especially lower-risk MDS is small, which will make the conduct of such a clinical trial rather difficult.

And now with this, I would like to transition to higher-risk MDS where there were several interesting studies that I would like to highlight. Back to our treatment algorithm. In contrast to patients with lower-risk MDS, there has unfortunately been very little progress been made in terms of actual drug approvals for higher-risk MDS. Hypomethylating agents as monotherapy still remain a standard of care in a frontline setting of patients with MDS. As of today, the only potentially curative therapeutic modality for higher-risk MDS patients remains an allogeneic transplant. And although there have been multiple recent randomized placebo-controlled Phase III trials of HMA-based combinations, as I mentioned, HMA monotherapy still is a very reasonable standard of care option. Sometimes there’s off-label use especially in patients with higher-risk MDS and more than 10% blast of HMA-based combinations for example with venetoclax. And we’ll review some of the updated data from ASH for this momentarily.

This here is the trial that has been ongoing for a while now, which has azacitidine in combination with venetoclax in patients who are HMA naive and have higher-risk MDS. At the ASH 2023 meeting, we saw an update from this Phase Ib study of 107 patients that have been enrolled by now. The key study eligibility criteria and the study schema is shown on this slide. And of note for this trial, the primary endpoint was the complete remission rate per the IWG 2006 criteria with several key secondary endpoints as shown on this slide.

This slide in some form or another has been presented at prior meetings and again Dr. Garcia confirmed the results that were previously demonstrated and as you can see here, the combination led to a complete remission rate of 30% with a median duration of complete remission of 16.6 months. Responses also occurred fairly early in the treatment curves with a median time to complete response of 2.8 months, although there were also quite some delayed responses seen in a subset of patients as you can see here by the range up to 16 months.

However, it is also important to note that the majority of responses were marrow complete remission, so MCR, which was accompanied by hematologic improvement in only a subset of patients. This slide shows the overall survival from the time of treatment initiation and although the numbers are difficult to interpret in the absence of an active comparator arm, the 24 month overall survival rate of 51.3% and the median overall survival of 26% observed in the study are certainly promising. However, the results of the ongoing randomized VERONA trial of azacitidine plus venetoclax versus azacitidine plus placebo are eagerly awaited and hopefully will be available in the near future. Finally, the slide shows the safety data. It is important to note that the combination of azacitidine and venetoclax in MDS is associated with higher rates of adverse events despite an attenuated venetoclax dosing of 14 days per 28 day cycle.

And as you can see, serious adverse events occurred in about two thirds of patients and included infectious and febrile neutropenia and a significant proportion of patients. Furthermore, treatment emergent adverse events resulted in death in 15.8% of patients and the 60-day mortality rate was 6.5%. So we’ll have to see how this compares and in a randomized trial. However, there’s been increased interest in using venetoclax and azacitidine for blast count reduction, especially in patients who proceed on to receive an allogeneic bone marrow transplant. And in this abstract that focus on venetoclax and azacitidine as a bridge to allo-transplant.

A small study from Spain involved 23 patients who were treated with azacitidine and venetoclax prior to transplant. Eight of those patients had relapsed/refractory disease. The response rates and two year overall survival were fairly high in this study, higher than what we would see probably with historical controls. However, it’s important to note that this was a select cohort of patients. But nonetheless, this study suggests that AZA and venetoclax can be an effective way to potentially bridge patients to transplant, especially in the light of the shorter time to best response as we’ve seen from the study by Dr. Garcia.

The next abstract that I would like to highlight reported results from an ongoing Phase II study of IMM01 and azacitidine treatment-naive patients with higher-risk MDS. IMM01 is a SIRPα fusion protein, which blocks do-not-eat-me signals similar to anti-CD47 antibodies such as magrolimab. In this study, Yang and colleagues report the results of the first 22 patients evaluable for efficacy. They report an overall response rate of 81.8% with 36.4%, excuse me, of patients achieving a complete response. Higher grade treatment related adverse events were common and primarily hematologic in nature as you can see at the bottom of this slide. While encouraging, it remains to be seen how these data evolve with longer follow-up and with a larger sample size, especially given that the randomized Phase III trial of magrolimab plus azacitidine which recently reported to be negative.

There was another study of anti-CD47 antibodies. This is AK117 in combination with azacitidine and in this study 27 patients were evaluable for response, and of those 48.1% achieved a complete remission and another 29.6% had a marrow CR. So comparable in terms of numbers to the study I just showed on the previous slide. Adverse events were also comparable to other studies of anti-CD47 antibodies. However, I almost sound like a broken record, these findings will obviously have to be validated in larger controlled studies with extended follow up. This was another oral presentation by the group at MD Anderson trying to use immunotherapy for the treatment of patients with higher-risk MDS and this is vibecotamab which is a CD3-CD123 bispecific T-cell engaging antibody that was studied here in patients with HMA refractory MDS/CMML as well as patients with MRD positive AML.

For the purpose of this discussion and the topic at hand, I’m only going to focus on the MDS/CMML cohort and the rationale for the inclusion of these disease groups was that immunotherapy might be particularly effective in patients with a low disease burden state such as MRD-positive AML and MDS. This slide here shows the study schema of now patients were required to have a CD123 expression of at least 20% and the patients could not be eligible for an allo-transplant within 30 days of starting treatment. In cycle one, vibecotamab was administered at a lower priming dose on day one followed by a dose ramp up as you can see in the middle of this slide. And this was then continued weekly for a total of four 28 day cycles. The primary endpoints were the response rate in the MDS/CMML cohort.

This slide shows the safety data on the left-hand side as well as the efficacy data on the right-hand side of the slide. Higher grade adverse events among the 12 MDS/CMML patients enrolled were primarily related to infection, hepatotoxicity as well as infusion reactions. There was also one sudden death that was not further elaborated on during the presentation. In terms of efficacy, the best responses were marrow CR with hematologic improvement with five out of 12 patients per the IWG 2006 criteria, which translate into CRL or CR with limited hematologic recovery per the IWG 2023 criteria. Notably, all responses occurred early during the treatment course and neither CD123 expression nor the baseline bone marrow blast count predicted response.

The next abstract is a single center single arm Phase Ib/II study of selinexor in combination with azacitidine in patients with newly diagnosed higher-risk MDS, and the overall response rate here was reported at 78.6%, although most of those responses were marrow CRs. The side effect profile was as expected with this combination and primarily fluid hematologic as well as gastrointestinal adverse events. We previously already discussed IDH mutations in MDS and this here is another study by Dr. Cortes et al that used olutasidenib, which is an FDA-approved IDH inhibitor that is available for treatment of patients with relapsed/refractory IDH1-mutant AML. In this study, Cortes and colleagues presented that data from the ongoing study of olutasidenib monotherapy or in combination with azacitidine. And as you can see, response rates were quite encouraging in both combinations. However, grade three adverse events were fairly common and there was also one case of grade three differentiation syndrome, which is particularly relevant when we treat patients with IDH inhibitors. So as IDH mutations are fairly rare in MDS, larger randomized trials dedicated to patients with IDH mutant MDS will probably be difficult to conduct, but at least these data provides some rationale and some evidence for the off-label use of IDH inhibitors in MDS. Another drug that has been approved for the treatment of patients with AML and is now being evaluated in the MDS space is CPX-351, which is a liposomal formulation of cytarabine and daunorubicin that has been approved for the treatment of secondary AML, especially patients with AML with myelodysplasia-related changes. And in this study the group at MD Anderson conducted a Phase I/II study of lower doses of CPX-351 in HMA refractory patients with higher risk MDS/CMML. And this slide shows you the study design which used a conventional 3+3 dose-escalation scheme and then had a dose expansion phase where they had an additional 10 patients enrolled.

They ultimately enrolled 23 patients, 17 of those had MDS and the overall response rate was 59% per the IWG 2023 criteria and 71 per the IWG 2006 criteria. And as you can see, only a very small subset of patients achieved a true CR while most of their responses were either marrow CRs or CRLs subdivide as CR with lineage hematologic improvements of CRbi or a CRuni with uni lineage hematologic improvement. Febrile neutropenia occurred in about half of the patients and although the early mortality rates were low of 0% at four weeks and 4% at eight weeks and also the median overall survival just over a year at least compares favorable against historic controls of patients with HMA failure. However, that’s certainly a selected patient population and results will need to be validated in bigger studies.

The ABNL-Marro 001 is an ongoing international open-label trial that randomly allocates patients to different novel treatment combinations to really develop novel therapies specifically for patients with MDS/MPN overlap syndromes. The first arm of this trial was a combination of the selective JAK1 inhibitor itacitinib with oral decitabine and cedazuridine in patients with relapse refractory MDS/MPN overlap. The results presented at the ASH 2023 meeting were based on the 3+3 dose-escalation phase of this trial and there were no unexpected toxicities observed. Efficacy-wise, there were three out of seven patients that had a response including one CMML patient who actually had a complete remission. However it was an ongoing trial and we’re eagerly awaiting for the update.

Abstract 1876 was another single center Phase II study of combination therapy in patients with both HMA-naive and HMA-refractory MDS and CMML, and patients were treated here sequentially with cladribine, low-dose cytarabine and venetoclax followed by two cycles of consultation with AZA-Ven and then another two cycles with cladribine, low-dose cytarabine and venetoclax. And this slide shows you the study schema and the key inclusion criteria for your reference. This novel combination approach was generally found to be safe in the hands of our colleagues at MD Anderson and led to high response rates, especially in the HMA naive setting. However, response rates and survival in the HMA-refractory cohort were rather limited with a response rate of 20% and a median overall survival of about six months.

This is similar to IDH mutations where we have targeted therapies in AML that are approved. FLT3 mutations are also actionable for AML patients. However similar to IDH mutations, they’re rare in patients with MDS. However they do occur and targeted therapies will be of interest for patients. So in this Phase I/II study the group at MD Anderson combined azacitidine with the FLT3 inhibitor quizartinib in patients with MDS/MPN overlap with a FLT3 or CBL mutation. Patients with both HMA naive and HMA failure were eligible and the study scheme is shown again here on this slide.

The combination appeared to be safe, had an overall response rate of 69%. There was also one patient out of 11 with a complete remission and in general it seemed that patients with FLT3 mutations had a higher response and longer overall survival compared to patients with a CBL mutation, however, small subset, small numbers in this comparison. As mentioned previously, the BCL2 inhibitor venetoclax has really revolutionized the treatment of older patients with AML and might be available pending the results of the VERONA trial for patients with higher-risk MDS as well. There are other BCL2 inhibitors in this space. One that was presented at ASH is lisaftoclax, which is currently evaluated in a multi-arm trial in China. There were 115 patients total enrolled in this trial, 22 of those had MDS and in the MDS cohort the overall response rate was 70% with most of the responses actually being CRs in this group. Safety profile appeared comparable to what was being seen with venetoclax and essentially was limited to myelosuppression and some GI toxicity.

There is and there remains interest in immunotherapies with immune checkpoint inhibitors in MDS and AML despite recent series of trials that combined anti-CTLA4 as well as anti-PD-1 antibodies in MDS which had limited efficacy. So the field now has moved on more towards myeloid immune checkpoint inhibitors and one of these potential novel targets is Clever-1, which is a macrophage immune checkpoint receptor. Preclinical data suggests that blockade of Clever-1 with the monoclonal antibody bexmarilimab results in anti-tumor immune responses and the results of the ongoing Phase I/II study of bexmarilimab in combination with azacitidine in patients with AML and MDS were presented at last year’s ASH meeting. And the safety profile was notable for capillary leak syndrome and HLH in two patients. And then there were in terms of the efficacy in terms of MDS patients, there were five untreated MDS patients, four of which had a complete remission in the HMA refractory cohort responses were response rates were lower with only one patient achieving a CR out of five as well as two patients with marrow CR.

However, longer follow-up is needed and larger studies will be required to confirm those findings. And then the last abstract I would like to discuss today is a single arm open-label Phase II study of an anti-PD-1 antibody sintilimab in combination with decitabine in patients with treatment-naive high-risk MDS. 53 patients were enrolled in this trial and the overall response rate was 76.9% of an overall survival at two years of 54.8%. Immune related adverse events occurred in about a third of patients but all of which were reversible with glucocorticoids. And of this, I’ll stop here. This was quite a whirlwind tour I have to admit, but I’m really happy and looking forward to this discussion.

Amer Zeidan:

So maybe we can divide this into kind of two major areas to make things easier. One on the lower risk, which you presented a couple of abstracts I think on canakinumab and I think in a bigger sense on the inflammation targeting and inflammasome. There’s a number of those drugs including the IRAK inhibitors and other drugs that are also being studied both in lower-risk and high-risk. But also there’s a group of drug called pyruvate kinase agonists as well, which also are being studied in lower-risk MDS.

I don’t think there were presentations in ASH, but this field has been moving very fast after many years of only having ESA and lenalidomide, which was only used for del(5q) lower-risk MDS. Now we have luspatercept approved in the frontline setting, especially in patients with RS positive and after ESA failure. We have imetelstat which is in front of the FDA and potentially could be approved by June 2024 in the US and then we have those other agents. So it’s an exciting time with many drugs. But maybe I can start with Yasmin, what struck you on the lower-risk MDS presentations including both what Jan presented but in general in the field?

Yasmin Abaza:

Thank you, Dr. Zeidan and thank you for having me on this great meeting. So I think one of the nice presentations that struck me and Jan did a great job summarizing all and presenting all the abstracts. I think the KER-050 was one of the nice presentations in this ASH at least. It was nice to have another TGF-ß ligand inhibitor and it was nice too. One of the things that is interesting in this compound is that, or this agent is its ability to improve platelets and that was one of the things that struck me during their ASH presentation that they did have a nice rise in platelets and platelet recovery, which is…

I’m not a big fan of TPO mimetics and MDS and low-risk MDs. So it would be nice to have an agent that can increase platelets in patients who… That has been an ongoing issue. I know that the drug is really geared to be like luspatercept in improving anemia, but it’ll be nice to see if that kind of off-target activity can have the use in other aspects of cytopenias in lower-risk MDS. And it’ll be interesting to see how that plays in now with luspatercept being frontline. So it’s one of the things I think will be interesting to see how this drug is developed moving forward.

Amer Zeidan:

Yeah, I certainly think that having additional options from the same class certainly is always welcome. Actually I would point out that for luspatercept as well, there is some data about improvement in both neutrophil and platelet count in a small number of patients, but this was also observed with luspatercept. So I think while the predominant effect of those drugs seems to be on the erythroid lineage, they do seem to have some impact on neutrophils and platelets. And I guess based on the KER-050, this could be potentially a class effect that for sure might vary between the different agents in the class. But Max and Yazan feel free to jump in on your thoughts on the lower-risk. What is exciting for you and how do you see the field in terms of combinations, sequencing? Are we going to a multiple myeloma kind of situation where people are going from one drug to the next and hopefully live many years with the goal being transfusion independence and quality of life? Or are we going to try to cure some patients? What do you think we’re going to head forward?

Maximilian Stahl:

Yeah, sure. Maybe I can start. I haven’t seen any curative approaches Amer with any of those agents, so I don’t think we’re there yet that we’re curing lower-risk MDS patients with those agents. But I do think there will be combination therapies of all those agents including ESA plus luspatercept, maybe luspatercept plus imetelstat. I think those approaches will be taken. I think one of the more promising agents that I saw that was not mentioned here was roxadustat. Actually I really like this agent not because only it has an interesting mechanism of action, which does not seem to overlap with a lot of the other agents being in HIFα inhibitor, but also it actually showed quite promising data.

Although the Phase III trial, the MATTERHORN trial was negative, but I think there was a lot of discussion in the field why that was negative and what patients were included. And those were mainly low transfusion burden patients and the placebo arm had a very high response rate. But I do think there’s a very promising agent and maybe with a better clinical trial design, this might be a very promising agent. So that would be one agent I would put high on my list mainly because it doesn’t have the same mechanism of action such as a TGF-ß trap and might be very good in combination with some of the agents that were mentioned.

Amer Zeidan:

No, I think that certainly is a reasonable idea. For fairness, Jan did include a slide about this drug and I had him take it out because we didn’t want to discuss failed Phase III trials, but I do agree with you that the Phase II for the drug were reasonable, but I think they included patients largely with very low kind of transfusion needs. And it wasn’t clear to me how much the drug, especially in the context of comparison against placebo, this was like a stunning finding in that trial to have a 33% transfusion dependence in placebo arm. So I agree with you that trial design was problematic and we’ll see if there are this drug or other drugs in the same class will move forward. But I agree the pathway potentially is active. Yazan, what do you think?

Yazan Madanat:

Hi everyone. So I think what’s exciting for me in lower-risk MDS is the ability to move drugs earlier and earlier in the patient’s disease trajectory. Now that we have a little bit more options, I think what was impressive in the elritercept trial is that they had 20% of patients with non-transfusion dependent and no other trials really in MDS have been designed to offer therapies for patients who are non-transfusion dependent. And I think patients who are symptomatic with lower-risk MDS, there’s nothing magical about a hemoglobin of nine versus 8.5 versus getting one unit of blood. I mean if they’re symptomatic, I think now we have a little bit more tools in our box to offer patients earlier and earlier therapies to make them live better even if we’re not helping them live longer. I think the other comment I would make on canakinumab is that it’s an exciting agent and we’re seeing some responses.

However, I think certain subsets of patients may benefit more and particularly looking at their genomic profiles, perhaps patients with TET2 positive disease where we see… I think that agent has potential but we need to use it not in all comers but in specific subsets of patients. And I would highlight one of the trials that Dr. Borate at Ohio State is carrying, investigating that agent in earlier stages than MDS in patients with clonal cytopenias of unknown significance. And so I think moving drugs into earlier stages of the disease may perhaps give it better efficacy and help patients live a better quality of life.

Amer Zeidan:

Thanks. I think that’s certainly the exciting direction the field is going to build up on what you said. There’s actually… I don’t believe there was an update in this ASH, but the Spanish group presented data with lenalidomide in patients who are not transfusion dependent with the hemoglobin of less than 12, but there were symptomatic but not needing transfusions and this was time limited therapy. They gave lenalidomide against placebo for two years of lenalidomide. And what they showed is a much longer period, I believe more than six years in terms of progressing to a point where the patients need transfusion independence compared to less than a year for patients who were in placebo. And now with luspatercept we have the ELEMENTS trial, which is a randomized Phase III, similar to COMMANDS looking in the frontline sitting in patients who are not transfusion-dependent but have symptomatic anemia.

So certainly the field keeps moving into earlier phases of treatment combinations. You touch on the issue of the CCUS and CHIP, which again, there’s a lot of active debate on where does the line separate between high-risk CCUS and low-risk CHIP, but certainly some of the same therapies that you could use potentially for lower-risk MDS potentially could and should be studied in higher-risk CCUS. So I think it’s a very exciting area with a lot of developments or earlier treatments in the disease course and combinations and sequencing is all very exciting. I think as Max alluded to, there is still no curative approach, but there is increased interest also in disease modifying drugs that potentially could reduce progression to acute myeloid leukemia and potentially prolonged survival. We don’t have a drug that does that in a definitive way yet, but I think there has been contrast made with luspatercept or I guess with the JAK inhibitors where the trials initially the randomized trials did not suggest an improvement overall survival, but with longer follow-up of the pivotal trials with ruxolitinib, there was a sense that there could be improvement in survival.

So some of that could happen with luspatercept with imetelstat, but clearly I think combinations and earlier therapies are very realistic at this point. Going in the last 10 minutes or so about the higher-risk MDS where the progress has not been as robust unfortunately in terms of new drugs. But that does not mean trials are not being done. A lot of trials are being done in the Phase III setting. Two trials actually have reported before ASH or around ASH that they have not made the primary endpoint but yet have not been presented. One was with magrolimab and the other one with sabatolimab. Both of those are press releases that the pivotal Phase III trial, which was AZA with sabatolimab or AZA with magrolimab versus AZA with placebo, each one of those trials had around 500 patients. They did not meet the primary endpoint despite encouraging data in Phase II settings.

But we have two remaining Phase III trials. One is VERONA with venetoclax, which is fully accrued and we’re waiting for results this year. Jan discussed the update from the Phase II data with more than 100 patients so far with venetoclax. And then we have the trial with tamibarotene, which is a RARA agonist. This is an ongoing Phase III trial, I believe the only ongoing Phase III trial. So what are your thoughts on some of the drugs that were mentioned? I think there was some updates on two promising CD47 agents, and again, people keep looking at this and thinking magrolimab, but there could be issues with the drug itself, there could be differentiators once we see the data, I think we’ll have a better sense, but maybe I can start in the reverse order now with you in terms of your thoughts about the higher-risk space, the abstracts that you have seen, what is exciting to you and how do you see the field moving forward?

Yazan Madanat:

Thank you, Amer. So yeah, I think the VERONA study results are obviously eagerly awaited. I think that’s probably one of the most promising trials in higher-risk MDS at the moment. From the data that the complete remission and even marrow CRS with hematologic improvements are quite impressive along with the survival data. What struck me was the death rate due to treatment emergent adverse events at 16%. And I wonder how the cytopenias are being managed in those patients and the use of prophylaxis for antifungal, antibacterial and antiviral because venetoclax, and we all have used it in acute myeloid leukemia, and those patients need very, very close monitoring and I think it’s important to highlight that it can be used safely but with extremely close monitoring of those patients. So I think the VERONA study is one of the most promising and we’re again eagerly awaiting the results.

I was impressed with the SIRPα inhibitor as well as the CD47 monoclonal antibody where we’re also seeing results that are very, very similar to the Phase I study using venetoclax for [inaudible 00:44:24] quite promising for those patients. Durability of remissions obviously is going to be something that’s important and how that impacts overall survival in that higher-risk population.

I think one thing to also keep in mind, and I know we tend to move to revised IPSS and molecular IPSS with all the new prognostic scoring systems coming out, but we have to remember that the original trials that got azacitidine approved used the original IPSS. And I struggled with that because… And I give you a quick example of one patient of mine with 10% blasts, normal cytogenetics and significant pancytopenia, that IPSS score would be intermediate one and I could never get her onto any higher-risk MDS trial. But we all agree that that patient has a higher-risk disease. I mean her revised IPSS would be five. But that’s to just contrast the patient population that was included in the AZA 001 trial as defined per IPSS as having higher-risk disease. So I think some of that may actually impact the results and outcomes of the studies that are newer and using revised IPSS or even molecular IPSS.

Amer Zeidan:

I think all of these are very good thoughts. Always strikes me actually when we discuss antibiotic prophylaxis. I think I have the same sense when someone is 21% plus everybody institutionally would be using triple prophylaxis, but once you have 19% plus it becomes at the discretion of the investigator because it’s high-risk and not AML. And I do think infections are something to worry about and to watch when you use any kind of myelosuppressive agents. Clearly, I agree with you VERONA, I think it’s very, very important.

I do think that the Phase II data that Jan presented, I don’t think Jan, you mentioned transplant rate, maybe I missed it, but 58% of those patients went to transplant. So for me, again, 26 months survival is very exciting as long as it holds up. But these are patients enrolled in tertiary specialized centers, many of them, 60% going to transplant is very high for MDS trials. So I think ultimately how do patients who do not proceed to transplant do and those probably with less than 10% blasts is going to be very, very important. Max, maybe I come to you in terms of what do you find exciting from the agents that Jan discussed and even outside of those agents in terms of the higher-risk MDS space?

Maximilian Stahl:

Yeah, I think honestly it’s very tough to say that there’s one particularly exciting agent. I think we have all seen it before again and again and with magrolimab it was the same story. Very high response rates, particularly if you use IWG 2006 criteria. If you use the new criteria, then I think often this response rate gets smaller and then you might not be quite as excited about some of those agents. So I think it’s very hard to say from a response rate to say, “Well, this is actually a promising agent.” I think with the newer response rate it’s helpful, but still we currently don’t have good prediction of what actually prolongs overall survival, particularly in a randomized setting. In terms of the CD47 agents, I think this is a very tough space because there are a lot of me-too CD47 agents, but I’m not sure they’re mechanistically very different from magrolimab.

They might target SIRPα, CD47, but I think there is accumulating evidence now in the preclinical world how important other parts of CD47 is, for example, the Fc receptor. That is very important in driving activity in mouse models. And I don’t see that yet being translated into a lot of the newer CD47 agents that are being tested. So I’m not so optimistic about those agents. I think some of the data that you present about the chemotherapy I think looks pretty good with CPX, although we use that already, I think frequently in patients who are HMA-refractory and close to AML as a bridge to transplant.

I think with all of those studies is the last point I make here is I think the most important things, I think Amer already mentioned this is how many people were transplanted. Because with those trials with very small number of patients, if the transplant rate is just a little bit different between trials, you might have very different data whether it’s promising or not. So I think that always needs to be taken in consideration.

Amer Zeidan:

Yeah, I would say even retrospectively we are seeing certainly very promising survival in our registry data piece called Validate, where 40% of patients actually have undergone transplant and the survival, the median survival is actually in the 20-month rang. So I think this is a very important thing and I completely agree that you have to think about these things when you evaluate Phase I and Phase II trials in terms of what is exciting and what is not. Yasmin, any thoughts?

Yasmin Abaza:

No, I agree with Max completely. I’m not as enthusiastic about the CD47 SIRPα. We keep trying the same pathway, it’s not really working. So I think we need to change. Either we change what we do with it or how we do it. Either we combine it with a PD-1 or a TIM-3. We need to attack maybe the immune system by different mechanisms rather than just doing it one way or doing it in a different way, like a BiTE where it can target CD47 or something along those lines where we’re just not using a naked antibody. It’s just not at the current time with the magro being the biggest example, it’s just not working. I agree with the CPX and the cladribine I’m not really as excited with the chemotherapy-based regimen in these patients. These are very old cytopenic patients, the MDS marrow is not as good reserve as an AML marrow, so the account recovery is not as good. So I’m not really as… We have data that you published on adding in venetoclax in HMA in the relapsed/refractory setting into these are good responses I believe, and that a paper was in American Journal of Hematology had a 20% rate of patients that went to transplant. So you can maybe get them to transplant by doing something using an HMA backbone. I don’t also see using cladribine-based regimen as a frontline when we have azacitidine approved in the frontline setting.

So I think it’s nice. It’s nice, definitely great effort. I just don’t know if that’s how it’s going to change MDS. I think one of the studies that, although it’s a very small study that maybe has promises using a BiTE, the CD123-CD3 BiTE, that pathway may be something promising. Maybe if we can have other ages that work on the same pathway, maybe we’ll see some activity, especially if we maybe push in the frontline setting where some of these, using them earlier is better with an HMA backbone. But again, as Max and everyone said higher-risk MDs is we are hitting a wall with it at the current time and we need to be more creative I think and trying to break this issue with no standard of care except for HMA.

Amer Zeidan:

Yeah, I think each time you think about some of those agents, I guess for the CD47, it is the issue that the pathway itself. I think the preclinical science, as Max was saying, I think for the most part is robust, but I think translating it to the humans have been I think particularly challenging. There are differences in addition to the pathway. Clearly the drugs are right. So I think most of the newer CD47s do not cause the same issue with the hemagglutination and the anemia. So I guess we have to see the data and whether the issue was efficacy or safety or anemia. So clearly I think we’re interested to see bigger studies. In my mind, I think if you have a Phase II trial that has at least 80 patients, 80 to 100 patients and maintain a CR above 40%, in my mind that is something that is potentially exciting.

With the idea similar to what Max said that or Yazan, I think one of you said is that durability. So it has to be, in my opinion, durable and maybe doing more of this before going to Phase IIIs might make more sense rather than just jumping to a randomized Phase III after a 30, 40 patient study with a limited follow-up to minimize these failures of Phase IIIs or ultimately, I guess similar to the ICC approach, start calling MDS with excess blasts MDS/AML and using some of the AML drugs if we cannot get dedicated drugs. But clearly, I think the IDH inhibitors Jan covered both some data about enasidenib and which is IDH2 inhibitor and olutasidenib, which is another IDH1 inhibitor in addition to the only approved one, which is ivosidenib, an IDH1 inhibitor in the relapsed/refractory setting. So those are active drugs, but the problem is that these mutations are rare, not more than 2 to 3% in patients with MDS.

So I think clearly there’s a need for mutation agnostic treatments in those patients outside of the IDH and FLT3 mutations. Some of the new exciting agents in AML are menin inhibitors, I think this also remains to be seen how do these translate into kind of MDS, although we don’t see the typical mutations that are associated with the responses with the HOXA9 over expression like the NPM1 and the MLL rearrangements. So in the last few minutes, any final thoughts? I’ll start with you Yazan, and then go around. And Jan, I’ll give you the chance to speak. You presented for us, but you didn’t give us your own thoughts. I’ll also give you a chance to speak at the end in terms of your thoughts about the data that you just presented. Yazan, do you want to start?

Yazan Madanat:

Sure, yeah. One last thought about the PD-1, I think there was sintilimab that data presented in combination with decitabine. That’s the first PD-1 inhibitor that’s immunotherapy that’s showing some great responses, at least in a small early-phase trial with 76% overall response rate. So I think that agent may have promise, but I don’t know why or how it works or functions differently than other PD-1 or PDL-1 inhibitors that have been tried extensively in MDS and AML. But it might be a different, again, target or targeting a slightly different mechanism of action.

Amer Zeidan:

I had the same struggle with like you when this was presented because we certainly have looked at a number of PD-1/PDL-1s, and it wasn’t clear to me if this one is any difference. So I guess as we were just saying, longer follow up on that study with more patients. I think we’ll clarify if these responses will hold up. Max.

Maximilian Stahl:

Yeah, I think maybe one thing I want to mention is, apart from the clinical trials is I think the importance of transplant, I think we recognize this more and more, and I think particular in patients where we sometimes say they should not be transplanted, maybe they can be transplanted. I see this frequently in clinical practice when arbitrary cutoffs for blast percentages are made. And I think all of us in our group know that there’s not great data of recommending really any blast percentage cutoff for pre-transplant for MDS patients.

And the same, I see a lot for TP53 mutated patients where a lot of patients are not being taken to transplant. Although we know the outcomes are poor with transplant, but they’re still better than without transplant. So I do think a lot of therapies need to be closely coordinated with transplant and maybe we need to move some therapies more in the post-transplant setting. So get people to transplant quicker and then focus on the maintenance setting to prevent relapses. So I think that would be one thing that I would put a lot of attention to is coordinating clinical trials closely with transplant.

Amer Zeidan:

And I think this is very important because as you were saying, we cannot cure these patients currently with anything we have. So maybe the approach should be thinking about how we can transplant more of those patients safely and then give them a chance. Total therapy approach maintenance is clearly not a standard, but I do use it on occasion. I’m sure some of you do use it on occasion with the idea to try to delay relapse and see if graft-versus-leukemia effect might help some patients to be cured out of the disease. Yasmin.

Yasmin Abaza:

I do agree with Max on the need for total therapy approach and try to address higher-risk MDS closer to an AML category where we do quickly post-transplant maintenance. I think for immunotherapies, I think that we need to maybe rethink how to use immunotherapies. We invest enough time and effort into it. There’s data from the solid tumors, for instance, they’re combining CD47 and PD-1s together and there’s some activity in that solid tumor. Can that be translated into myeloid malignancies? I think that’s something that we need to maybe consider. And the other question is how much cytoreduction do I need prior to stem cell transplantation? How quickly do you need to move patients to transplant, especially if you’re going to consider post-transplant maintenance. So I think there’s still a lot of work that that needs to be done to optimize care for higher-risk MDS.

Amer Zeidan:

Thank you. I think that’s an excellent summary. Jan, you started the episode today and you get to close it. So your thoughts on the slides that you presented and also the ideas that you’ve been hearing.

Jan Bewersdorf:

Yeah, thanks. And I really enjoyed the panel discussion today. I think there’s a lot of reason to be optimistic. I think there’s been a lot of development in the field. The one thing that I would like to add to everything that was already said, which I totally agree with, is that I think we are learning more about the underlying disease biology. We already talked about the overlap of immune dysregulation in MDS, we talked about IDH inhibitors, we talked about maybe FLT3 inhibitors, menin. And I think the field may actually have to move away from a one-size-fits-all approach and think about this more on a molecularly defined, genetically defined disease. And we’ve already seen this with SF3B1 mutations and luspatercept we’ve seen it reflected in WHO classification. I think that the field might actually benefit from moving this even further.

We have large group of splicing mutations where we unfortunately don’t have really effective drugs in the space yet, but I think there might be something more coming. We’ve seen data from mutation, IDH mutations. I think it might actually be beneficial if you think as a field more about the genetic composition of the disease and then potentially even do basket trials with MDS and AML patients overlapping. And I think that can be an interesting avenue when we think about drug development more in a bigger picture in a longer run. But I think based on what we’ve seen at ASH, I think there’s reason to be optimistic for sure.

Amer Zeidan:

Yeah, these are also very important tools like the idea of precision individualized oncology and treating those patients. And I think working with our industry colleagues, when these trials are being designed, there’s always a tendency to try to be as inclusive as possible in terms of putting as many patients on trials versus going for the subsets that might be more likely to benefit. And actually in this approach, this is what worked with luspatercept initially, where the plan was to go with RS positive. We know now that it works regardless in the frontline setting, but certainly the activity is enriched in RS positive patients.

And if the original trial was not done this way, who knows if the drug would kind of move forward. So I think this is an important consideration and certainly can energize more research because once you have a drug approved, even in a smaller subset of patients, it can certainly lead to exploring the drug in different settings, in combinations, earlier settings, et cetera. So thank you so much. This was a great discussion and I hope the audience will enjoy it and looking forward to having you join us for another episode of MDS sessions at VJHemOnc in the future. Thank you so much.

Amer Zeidan: Consultancy: Schrödinger, Notable, Chiesi, Mendus, Otsuka, Foran, Syros, ALX Oncology, Kura, Seattle Genetics, Servier, Boehringer-Ingelheim, Jazz, Orum, Geron, Syndax, Gilead, Zentalis, BeyondSpring, Incyte, Pfizer, Celgene/BMS, Janssen, Amgen, Agios, Daiichi Sankyo, Tyme, Taiho, AbbVie, Ionis, Takeda, Genentech, Epizyme, Lox Oncology, Novartis, Astellas, BioCryst, Regeneron; Honoraria: Schrödinger, Notable, Chiesi, Mendus, Otsuka, Foran, Syros, ALX Oncology, Kura, Seattle Genetics, Servier, Boehringer-Ingelheim, Jazz, Orum, Geron, Syndax, Gilead, Zentalis, BeyondSpring, Incyte, Pfizer, Celgene/BMS, Janssen, Amgen, Agios, Daiichi Sankyo, Tyme, Taiho, AbbVie, Ionis, Takeda, Genentech, Epizyme, Lox Oncology, Novartis, Astellas, BioCryst, Regeneron; Research Funding: Foran, Shattuck Labs, Astex.

Maximilian Stahl: Consulting: Boston Consulting; CME: Novartis, Curis Oncology, Haymarket Media, Clinical care options (CCO); Advisory board: Novartis, Kymera, Sierra Oncology, GSK, Rigel, BMS, Sobi. Maximilian Stahl served on the advisory board for Novartis, Kymera, Sierra Oncology, GSK, Rigel, BMS, Sobi; consulted for Boston Consulting and Dedham group and participated in GME activity for Novartis, Curis Oncology, Haymarket Media and Clinical care options.

Yasmin Abaza: Consulting/Advisory: BMS, Kite, Pfizer, Servier, Astellas, Rigel, Geron; Research Funding: ALX Oncology, Biosight, Curis, Biomea, Novartis, AbbVie

Yazan Madanat: YFM has received honoraria/consulting fees from BMS, Kura Oncology, BluePrint Medicines, GERON, OncLive and MD Education, VJHemOnc and Medscape Live. YFM participated in advisory boards and received honoraria from Sierra Oncology, Stemline Therapeutics, Blueprint Medicines, Morphosys, Taiho Oncology, SOBI, Rigel Pharmaceuticals and Novartis. YFM received travel reimbursement from Blueprint Medicines, MD Education, and Morphosys.