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Managing Low- and High-Risk Myelodysplastic Syndromes: Experts Address FAQs

Rami S. Komrokji, MD
Program Director

Senior Member, Vice Chair
Malignant Hematology
Section Head
Leukemia and MDS
H. Lee Moffitt Cancer Center & Research Institute
Department of Oncologic Sciences
University of South Florida
Tampa, Florida

Rami S. Komrokji, MD: consultant: AbbVie, Acceleron, Agios/Servier, Bristol-Myers Squibb/Celgene, Geron, Jazz, Novartis, PharmaEssentia, Taiho.

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Amy E. DeZern, MD, MHS

Associate Professor
Oncology and Medicine
The Johns Hopkins University School of Medicine
Baltimore, Maryland

Amy E. DeZern, MD, MHS: consultant: Bristol-Myers Squibb, CTI BioPharma, Geron, Novartis, Taiho.

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Amer Zeidan, MBBS, MPH

Associate Professor, Internal Medicine
Leader, Leukemia and Myeloid Disease Aligned Research Team (DART)
Director, Hematology Early Therapeutics Research
Yale Cancer Center and Smilow Cancer Hospital
Yale University School of Medicine
New Haven, Connecticut

Amer Zeidan, MBBS, MHS: consultant: AbbVie, Acceleron, Agios, Amgen, Aprea, Astellas, BeyondSpring, Boehringer Ingelheim, Cardiff Oncology, Celgene/Bristol-Myers Squibb, Daiichi Sankyo, Epizyme, Geron, Gilead Sciences, Incyte, Ionis, Janssen, Jazz, Kura, Novartis, Otsuka, Pfizer, Seattle Genetics, Syndax, Taiho, Takeda, Trovagene, Tyme; researcher: AbbVie, ADC Therapeutics, Amgen, Aprea, Astex, Boehringer Ingelheim, Cardiff Oncology, Celgene/Bristol-Myers Squibb, Incyte, Medimmune/AstraZeneca, Novartis, Otsuka, Pfizer, Takeda, Trovagene.

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Released: August 9, 2022

Key Takeaways:

  • Acute myeloid leukemia and myelodysplastic syndromes are distinct diseases, but recent diagnostic guideline updates have blurred the line between the two based on blast percentage
  • Tumor lysis syndrome is rare with venetoclax in myelodysplastic syndromes and acute myeloid leukemia; ramp-up dosing is not usually required
  • Use of CPX-351 off label may be considered for patients with myelodysplastic syndromes who can tolerate high intensity chemotherapy and have a short lead time for transplantation

In this commentary, adapted from a live satellite symposium at the 2022 American Society of Clinical Oncology Annual Meeting, expert faculty Rami S. Komrokji, MD; Amy E. DeZern, MD, MHS; and Amer Zeidan, MBBS, MHS answer audience questions on the management of myelodysplastic syndromes (MDS).

In your view, are acute myeloid leukemia (AML) and MDS one disease or distinct diseases?

Rami S. Komrokji, MD:
From my point of view, I do think they are distinct diseases, and they should be treated differently. As providers who treat patients with higher-risk MDS, we see patients denied treatment options intended for AML due to lack of approvals for MDS, even though many are likely to be active in MDS.  

I think with all myeloid diseases, there is a chronic phase, an accelerated phase, and then a leukemic phase, similar to what we know in chronic myelogenous leukemia and myelofibrosis. I think it is the same for MDS.

We should think of MDS without blasts and MDS with blasts as originating from a different biological clock, and then the disease progressed. There is lots of discussion now about which blast percentage we should use to define AML—should it be 20%, 30%, or 10% blasts—and at 10% that would potentially give some patients with MDS access to treatments available for AML.

Part of the difference lies in the biology of MDS, in that some patients are in an accelerated or blast phase, but the underlying bone marrow is not as healthy as with a patient with AML. So many of those patients will have different complications compared with those with de novo AML.

Amer Zeidan, MBBS, MHS:
I agree. It depends on the biology. Many patients who have excess blasts are closer to AML, and I think of patients who have <5% blasts as having a completely separate disease entity.

For patients who have >5% blasts, I tend to treat it as AML. We already do this with core binding factor leukemia. If a patient has a core binding factor translocation, we do not care about the blast percentage—we still treat it as AML. We also are trying to understand the implications of other factors, such as TP53 mutation.

So, I think it’s more about the biology of the disease. Particularly if patients have >10% blasts, I think of them as having AML. However, age and comorbidities also should be considered. The same way I would not give intensive chemotherapy to an older patient with AML who has comorbidities, I also would not do this for a patient with MDS.

Amy E. DeZern, MD, MHS:
I agree. I think you’ve both summed it up very nicely. It really comes down to the biology. The field is moving toward being more blast vague. Perhaps 10% will be the number.

Are any pivotal studies using the Molecular International Prognostic Scoring System (IPSS-M) for MDS risk stratification?

Rami S. Komrokji, MD:
I am not aware of clinical trials already adopting the IPSS-M model because it was just presented at the 2021 American Society of Hematology Annual Meeting. I am sure that for many ongoing studies, there will be an ad hoc analysis using this model. We need to see additional studies validating the model for risk stratification, but that will take time. It takes a few years to for new models to become the standard for clinical trials.

What triggers you to look for MDS in a patient with chronic cytopenia beyond the cytopenia?

Amy E. DeZern, MD, MHS:
For a patient who has pancytopenia and a less well‑controlled, systemic autoimmune process, I may or may not spend as much time looking for MDS. As we know, MDS is more common in men. So, if I have a male patient in his 70s and there is not a sufficient alternative explanation for chronic cytopenia, I would look for MDS. Although a bone marrow biopsy is not fun, it is a fairly easy diagnostic procedure to get a patient to their diagnosis.

Rami S. Komrokji, MD:
I agree. If there is no other explanation for chronic cytopenia, I start thinking of MDS. For an older male with macrocytic anemia, MDS is one of the top 5 diseases on my mind.

Are there any hints that luspatercept can be disease modifying in lower‑risk MDS?

Amy E. DeZern, MD, MHS:
This is not yet clear, but some evidence suggests yes. Some patients on the MEDALIST trial who had long‑standing responses may have had some disease modification in different ways.

Does venetoclax have mechanisms of action other than the anti-apoptotic effect?

Amer Zeidan, MBBS, MHS:
There are none that I am aware of, but I suspect there could be. This is a common story that I have seen in MDS with hypomethylating agents, where we think the drugs work by one pathway, and they turn out to be working by different pathways. After many years, we still do not fully understand how they work. With lenalidomide, it seems like we discover a new mechanism of action every 5 years. I would not be surprised if the same thing is seen with venetoclax. 

Are any concerns about seizures or tumor lysis syndrome associated with venetoclax treatment for MDS?

Amer Zeidan, MBBS, MHS:
The interesting thing with MDS and AML, compared with chronic lymphocytic leukemia, is we generally do not see tumor lysis with venetoclax treatment. There is no ramp‑up in the phase III VERONA MDS study. The dose from the start was 400 mg, and we do not admit patients to the hospital who are receiving venetoclax because tumor lysis syndrome generally is not an issue.

The main issue, in my view, with venetoclax is the myelosuppression and infection complications. It is important to give the patients prophylactic antibiotics and to hospitalize them if they have an infection. Also, remember that these are older, frail patients who can easily get very sick with the venetoclax/azacitidine combination. So, we must be careful.

Rami S. Komrokji, MD:
I agree. When we started the protocol for venetoclax, even in AML, we were following the dose ramp-up. However, we went back and looked at approximately 300 patients, and as long as we didn't start when their white blood cell count was >25 x 109/L and gave patients hydration, we saw no tumor lysis. So, we stopped that dose escalation. I know the package insert says you should do it, but based on our experience and trials in MDS, we no longer do the ramp-up.

How do you see the role of CPX‑351 (cytarabine and daunorubicin) in MDS?

Amer Zeidan, MBBS, MHS:
I think this question builds on the earlier question of whether MDS and AML are distinct diseases. The 20% blast cut-off never made a lot of biological sense for many of us.

CPX-351 is approved by the FDA for the treatment of newly diagnosed therapy-related AML or AML with myelodysplasia-related changes in adults and pediatric patients 1 year or older. So, this would be for patients with 21% blasts or higher. So, I would consider CPX-351 for someone who has a transplant option, who is younger, who I think can tolerate intensive chemotherapy, and who has excess blasts.

However, I think one important thing to think about is how quickly the patient can get a transplant. CPX-351 is probably a good option if a patient can get to transplant relatively quickly, perhaps if they have a sibling donor and plans already are made. If it will take 3-4 months to find the donor, I would use a hypomethylating agent. My reasoning is that the patient may experience more toxicity with CPX-351, and the goal is to try to get the patient into a remission but also keep them in good shape for the transplant. We do not want to the patient to develop severe infectious complications or other major comorbidities before the transplant.

Do you think there will be uptake or use of CC-486 (oral azacitidine) in the community now given the availability of the drug? Is it going to be used off label in MDS?

Amy E. DeZern, MD, MHS:
The correct answer here is no, but there is some complexity here because oral azacitidine is available and approved for AML. I think we do not know the right dosing in lower‑risk disease such as MDS. The toxicity was very evident in that early part of the curve with early deaths, so I think we need to be quite thoughtful about its use off label. 

What do you think about the use of IRAK4 inhibitors in MDS?

Amer Zeidan, MBBS, MHS:
I think the data for the IRAK4 inhibitor emavusertib (CA-4948) are intriguing so far, especially in patients with splicing factor mutations. It is a drug for which we have very limited clinical data from a phase I/II trial (NCT04278768) in patients with relapsed/refractory AML or higher-risk MDS.

How do you manage patients with MDS after transplant relapse?

Amy E. DeZern, MD, MHS:
Managing MDS after transplant relapse certainly is a challenging situation. A lot—at least in our hands—is dependent on when the relapse occurs. If the patient has TP53-mutated disease and relapses before Day 100, there is very little that can be done in terms of therapy for that patient. But if it is a relapse beyond 6 months, there are data that the use of a hypomethylating agent followed by a donor lymphocyte infusion has some utility. In our institution, because we use haploidentical donors, if they relapse after 2 years, we have excellent outcomes with a nonmyeloablative second transplant. We have lots of discussion with the patient about whether they want to go through transplant again. Sometimes, maintenance azacitidine may offer some additional time while maintaining quality of life post transplant relapse.

What about hypoxia-inducible factor (HIF) inhibitors in lower‑risk MDS?

Amy E. DeZern, MD, MHS:
Roxadustat is an oral HIF prolyl hydroxylase inhibitor that is being studied in the phase III MATTERHORN trial (NCT03263091) for anemia‑predominant patients. It works by stabilizing HIF-1α that promotes erythropoiesis, and it probably can augment the hemoglobin. The results of the dose-selection stage of the MATTERHORN trial were published recently, and of 24 patients, 9 (37.5%) achieved transfusion independence, and there was a ≥50% reduction in red blood cell transfusions at 28 and 52 weeks. In addition, the drug was well tolerated at doses of 1.5-2.5 mg/kg 3 times a week.

Your Thoughts?
What challenges do you face in managing patients with MDS? Please answer the polling question and join the conversation by posting a comment in the discussion section.

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