Myelodysplastic Syndromes Treatment Update for 2023

So briefly with regard to myelodysplastic syndromes MDS, I just wanted to discuss some of the proposed changes to classification, as well as some of the changes and updates and low-risk myelodysplastic syndromes, as well as high-risk myelodysplastic syndromes. So in June of 2022, the molecular international prognostic score was proposed. This has been long awaited based.

Previously, we were using the I P S R. The problem with that system is that it didn’t include some of the important molecular findings that re leukemia were affecting outcome. So the purpose of the update is to incorporate some of the molecular findings that we know are so important in changing the management of these patients.

So this is from the paper and you can see here that in myelodysplastic syndromes MDS you see a large this is the frequency of mutated genes and cytogenetic abnormalities. And around 3000 myelodysplastic syndromes patients. And then in panel B, it specific leukemia says the various outcome, sorry, panel C is the outcomes. And you can see here that the SF three B one mutation is associated with the best.

and then the number of driver mutations you have re leukemia affects your prognosis. If you only have one mutation general, you tend to do better than if you have multiple negative prognostic driver mutations. So there you don’t have to memorize. The calculation, there’s an online calculator right there.

And you can see here that , each individual mutation is associated, is contributing to the risk factors of that patient. So now the risk groups are broken down to very low risk. Low risk and then very high risk. High risk. And then medium in the middle is the medium low and the median high. And this re leukemia breaks down that these groups are very.

clearly separated. And when you compare the I P S R to the molecular international prognostic score there is good concordance in the very high risk group and the very low risk group. It’s re leukemia the patients in the middle where, you and people who see myelodysplastic syndromes have known this for some time, that even if they are lower risk, you can see differences in their outcomes.

Switching gears to low risk myelodysplastic syndromes back in 2020

 

So switching gears to low risk myelodysplastic syndromes back in 2020, they presented the results of luspatercept for patients in low risk myelodysplastic syndromes. Recently they’ve produced a in demonstrating that the longer patients are on luspatercept they can have continued benefit for several years. And so right now, Luspatercept.

FDA approved, particularly in the lower risk myelodysplastic syndromes patient population who are transfusion dependent with SF three one mutations or ring that or less. And so in this case, they’re able to show that there was a continued benefit compared to placebo and that luspatercept in general is very well tolerated.

Compared to this is specific leukemia low transfusion dependent, high transfusion dependent, and then over leukemia and comparing placebo and luspatercept. There aren’t a lot of very specific increases in toxicity. So moving on to other agents that look like they have a lot of potential activity and lower risk myelodysplastic syndromes.

We’ve been waiting for the Imetelstat data

 

We’ve been waiting for the Imetelstat data. This is specific leukemia for patients who are heavily transfused, non Dell five q, low risk myelodysplastic syndromes who have already relapsed after ESA and so what’s unique, the unique mechanism of action of this drug is actu leukemia it’s tase inhibitor and it’s interferes specific leukemia with the binding of the.

The tase activity and it’s believed to be a disease modifying potential to selectively kill malignant stem cells and progenitor cells and help with normal red blood cells production. So in this phase two three trial they were randomized randomizing patients in the phase three, part two, the either placebo or.

Atomus stat. And then in order to qualify for the trial, patients had to have either I P S low or intermediate one. They had to be refractory to ESAs and have, or have an EPO level that was greater than 500, which would suggest they wouldn’t benefit from it. They had to be transfusion dependent and the primary endpoint was trans or red blood cells transfusion independence greater than eight.

And that secondary endpoints were related to safety, 24 week transfusion independence, as well as over leukemia survival, progression-free survival, and time to progression of acute myeloid leukemia. So the the meaning it had a meaningful and durable transfusion independent particularly with this therapy.

So at two years. So baseline characteristics of these patients, ab patients who were transfusion dependent for greater than a year was about 90% of people. And they did include patients who had seen prior luspatercept as well as ESAs. So people who were transfusion dependent for greater than one year, median time on study was 57 months.

The median duration was about 126 weeks. And median number of cycles was 27 cycles.

 

The median duration was about 126 weeks. And median number of cycles was 27 cycles. So leukemia of this putting together that patients were able to remain on therapy and garner a benefit from. . So in this low risk myelodysplastic syndromes group, they were treated with the I stat. They were able to show that some of these patients had sustained transfusion independence over one year and were able to have continued benefit.

and when they initi leukemia started on therapies there was a mild increase in their hemoglobin, but that over time it didn’t seem like there was a sustained benefit. And so the median transfusion independence duration was 92 weeks, and so the median progression-free survival was reported at 34 months, and median over leukemia survival is at 56.

They were able to find correlatives showing a reduction in the SF three BK one V a F in these patients, particularly those who had the longer transfusion independence. So there were 11 patients on the trial that were transfusion independent for more than one year, and you could see that there was a clear reduction in the SF three BK one v a.

So they have demonstrated a very good safety signal and that in general the AEs were some reversible thrombocytopenia and neutropenia, but over leukemia well tolerated. So they’re waiting for the final readout of this, the phase three portion, which they anticipate this spring. And hopefully that’ll help.

Lead to an FDA approval of this drug shortly

 

Lead to an FDA approval of this drug shortly. Switching gears to myelodysplastic syndromes we fin leukemia have more options than just single agent Azacitidine. So briefly we have, HMA with Venetoclax HMA with magrolimab H HMA with Sabatolimab, which is a TIM-3 inhibitor . And then if patients have an I.

One or two mutation. There is data showing benefit in that patient population. If they have a RARA mutation, it looks like they would benefit from this tebar routine. And then rarely there are patients who are appropriate for induction style chemotherapy. So there is data, even you looking at it with CPX-351.

So this is the original data that was presented back in 2020, looking at Azacitidine and Venetoclax in higher risk myelodysplastic syndromes patients phase one B in general. The therapy that, that toxicities associated with this regiment are similar to what you would see with using Azacitidine Vene. In the acute myeloid leukemia patient population.

But not surprisingly, the myelodysplastic syndromes patient population is a little bit older and sometimes a little bit more frail. It was. Quite surprising to see 49% febrile neutropenia rates with this regimen because most myelodysplastic syndromes related therapies aren’t aren’t associated with those high rates of febrile neutropenia.

Not surprisingly, about 83% of patients on this regimen got neutropenia. And then of course some nausea, constipation, diarrhea, cytopenias

But then in terms of over leukemia response rate, 79% had an over leukemia response rate with median duration of about 12.9 months. And median time to CR about 2.6 months. So over leukemia, very similar to what you would see with the Azacitidine. Venetoclax. What is important to highlight though, is of course, in the myelodysplastic syndromes patient population, they only get the Venetoclax for 14 days versus the full 28 days initi leukemia with the acute myeloid leukemia patient population.

And that was adjusted because the, because of the higher rates of febrile neutropenia, median over leukemia survival was about 16.4 months. and 12 months survival rates were about 76%, 24 months, about 59. So I was looking for more updated re results on this trial, but hasn’t been presented for that particular trial.

But I was able to find a publication from the group from MD Anderson using the same regiment in their patient population. And in general, they were able to show the. grade three, four treatment emergent adverse events were about, were similar with neutropenia, about 39%, thrombocytopenia, about 39% lung infection, 30% febrile neutropenia, 17%.

 

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There were three patients who died related to sepsis, and this was deemed not related to their cancer treatment

 

There were three patients who died related to sepsis, and this was deemed not related to their cancer treatment or with the study drugs, but impressively an over leukemia response rate of about 87%. , the other regiment that’s become widely publicized. And we were part of this original work and have continued to be part of it here at UCI is looking at Azacitidine and Magrolimab.

This was presented at EHA in 2022. So for those who view, who don’t know about Mag Golimumab it’s a first in class CD 47. Macrophage immune checkpoint inhibitor. And you can actu leukemia, if I could get the video to work, you could see

No phagocytosis in this slide. And then when you add the anti CD 40 mab you can acute leukemia see.

This, the red cells being actu leukemia fide host into the macrophages or sorry the myelodysplastic syndromes cells being macro phagocytose into the macro.

Okay, how do I stop the video?

Initi leukemia there was a the, in the phase one B, There is a priming that was determined to be necessary with Magrolimab, and that’s again, because one of the big side effects that has been noticed has been red cell anemia, which can be quite prompt in the initial dosing. So as you treat patients on this regimen, you started a very low dose.

Treat them twice a week initi leukemia. slowly increasing the dose till you get to the full dose by the end of the month, and then you’re able to proceed with twice a month Magrolimab at the full dosing. And then azacitidine. . Importantly, the patient population is very representative of what we see in the tertiary care centers with high risk factors and very high risk patients, as well as poor risk CY genetics.

And then what was noted was the 26% TP 53 mutations which is again, a very poor prognostic sign in myelodysplastic syndromes. Difficult to treat patient popul. . So the treatment related adverse events there was some constipation from cytopenia and then grade three anemia, which has been very important to track.

And there was acute leukemia one grade four anemia during this. There were 25% of patients who had infusion related reaction. 6% were at grade three and discontinuation of Magrolimab was only 6%. And Azacitidine was discontinued at about 7.4% of the time. As I mentioned, one of the major toxicities to monitor four is this on-target anemia.

It does look like it is related to when you initi leukemia start the therapy and. As the cells are accustomed, primed to the Magrolimab, then you don’t see as much anemia. There over leukemia it looked like there was a 0.7 grants per deciliter reduction in their first post-treatment. With the Magrolimab, however, there were patients who dropped three or even one.

Ca a couple cases of people who dropped their hemoglobin by four grams after one dose. So hence the strict monitoring, especially leukemia in the first month of therapy. 39 of patient percent of patients were transfusion dependent. This is their response rates. So the over leukemia response rates in TP 53 mutated patients was.

8% versus 68% in the tp 53 mutated patients. The CR rates were 30, 31% and 40%, and TP 53 mutated. And then the duration of response has been in 9.8 in the TP 53 wild type versus T 9.2 in the TP 53 mutated.

And then of course, the durations of responses is just a swimmer’s plot showing that you, there are patients who are now even three years out on this therapy tolerating it. So the medium median is 17.1 months. The median over leukemia survival hasn’t been reached and in the TP 53 mu wild type and in patients who are.

TP 53 mutated, it’s about 16.3 months. These patients were able to go to transplants and if they were in remission and obviously patients who went to transplant actu leukemia did better and had sustained remissions. And you can see here that they were able to document that the v a F of TP 53 going down with this therapy demonstrating that it is a disease-modifying.

So in general, it looks like that combination is well tolerated

 

So in general, it looks like that combination is well tolerated, particularly in patients who with high risk myelodysplastic syndromes and Low rates of people coming off therapy and it looks like it’s a promising therapy for patients with both TP 53 wild type as well as TP 53 mutated and median over leukemia survival, again, not reached in the composite group.

So this led to a phase three trial with a society Mar Golimumab that’s actu leukemia been fully accrued and we’re just waiting on outcomes for that data. Briefly, I just wanted to mention. the SBA in combination with hypomethylating therapy, which was actu leukemia a randomized phase two trial, placebo controlled.

Looking at TIM-3 inhibitor inhibition it’s a novel therapy because it’s targeting this TIM-3 inhibitor which is related to immuno myeloid regulat regulator, and it looks like it’s overexpressed and. Leukemia stem cells and blasts, but not in HSCs, normal. HSCs. So it looked like a re leukemia good target.

And the inclusion criteria was specific leukemia for ipss sr. High risk, very high risk or intermediate with greater than 5% blast. And they were randomized to either get this salum lab or placebo with, and it was well-balanced between the different groups. Unfortunately it did look like there was no additional benefit with this addi with two placebo with HMA alone.

With 8.6 months in the placebo with HMA versus 9.1 months. And although it looked like it was fairly well tolerated it didn’t appear to have additional benefit. There was a suggestion that and these are the survival, the changes in median progression-free survival. Pretty similar and not statistic leukemia different.

So this was unfortunate. It did look like the combination arm was associated with a better duration of response, but that wasn’t set up as their primary endpoint, unfortunately. And they are looking at patients who had lower blast counts and seeing if they benefited more from this combination therapy.

because we know with immunotherapy sometimes it can take a few months to see the full benefit of the therapy. So moving on. So this is a newer agent. It’s a rah. Targeted. So if patients have RARA positive acute myeloid leukemia or myelodysplastic syndromes, that isn’t present, that’s not something that’s usu leukemia present on Foundation One Testing.

It looks like there is a benefit to adding this TEMA Barine to their h HMA therapy. And what’s involved is basic leukemia taking their blood exposing it to. A two-day turnaround time to get the RNA and then doing testing specific leukemia for this rah positive positivity or negativity. And in l patients with this mutation, they found a 67% over leukemia response rate, a 67% transfusion independent rate, and 61% CR I rate.

And just moving ahead. We are part of the trial looking at this in the high-risk myelodysplastic syndromes setting. So specific leukemia newly diagnosed high-risk myelodysplastic syndromes. Patients who have this RARA positivity are randomized to either get getting the study agent with HMA or placebo with HMA and then looking at their CR rates.

I’d like to encourage people to refer patients in if they are looking. Newer therapy for high-risk myelodysplastic syndromes patients, and we’d be very happy to screen them for this trial and if eligible looks like they re leukemia do benefit from this therapy. To summarize what we have in myelodysplastic syndromes in upfront myelodysplastic syndromes, we have the if they’re RAH positive With high risk myelodysplastic syndromes, we have this tatami barine with hypomethylating therapy versus placebo.

And then if they are IDH mutated we have this compound that’s coming out of Huntington medics H M P L three oh. In relapse setting, we have several other options. If there are IDH mutated, we have the HPL 3 0 6 or the Olaparib, and if they’re low risk factors we have a clinical trial that is looking at this R 2 89 and lower risk myelodysplastic syndromes after two prior lines of.

I wanted to highlight the results of e ECOG 1910

 

Just very briefly, I wanted to highlight the results of e ECOG 1910. So we were participating in this trial as well and it’s a randomized phase three trial, looking at incorporating Blinatumomab nitum into upfront therapy for newly diagnosed pH negative a l. Patients got inductions one and two of standard chemotherapy and then had a bone marrow cells biopsy if it looked like they were it, they were then randomized to either include Blinatumomab or chemotherapy or go directly to TR transplant.

And the, obviously the FDA approval ofatumumab in the MRD setting led to an amendment that demonstrated that leukemia patients that. MRD Positive had to get Blinatumomab. So this is specific leukemia for patients who were MRD negative, getting Blinatumomab and can you see a benefit? And so the patients that were enrolled between 30 to 70, the median age was 51.

The C R I rate was 81%. Okay, got it. . Impressively the over leukemia survival rates this is what I wanted to get to. The median over leukemia survival in the patients who got Blinatumomab, nitum or chemo was not reached versus 71.4 months with the chemotherapy arm. And it’s very exciting results. For us we’re looking forward to seeing more in this setting, but I think it’s definitely potenti leukemia practice changing and leading awards to moving immunotherapy even further.

Even earlier in therapy, relapse-free survival rates were also not reached. And so I think that we’ll look forward to seeing more results of this in the future, but I’d like to of open up and see if anybody has any questions.

 

About the Author: Deepa Jeyakumar, MD

Hematologist-oncologist Dr. Deepa Jeyakumar is a board-certified physician at UCI Health who focuses on bone marrow transplantation, stem cell therapy, and the detection and treatment of blood malignancies. Her clinical interests are in the treatment of patients with myelomas, lymphomas, leukemias, and myelodysplastic syndromes.

At Philadelphia, Pennsylvania’s Lewis Katz School of Medicine of Temple University, Jeyakumar received her medical degree. She finished her internal medicine residency at the University of Illinois Medical Center in Chicago, then pursued fellowships at Tufts Medical Center in Boston, Massachusetts, and Stanford University in Palo Alto, California, both in hematology/oncology and bone marrow transplantation.

She has authored or co-authored a large number of articles, posters, and abstracts in addition to a chapter on acute myelogenous leukemia in one of the best books on cancer survivorship.

At the Chao Family Comprehensive Cancer Center at UCI Health, Jeyakumar sees patients.