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Expert Answers to Clinician Questions Regarding Optimal Management of Patients With Myelodysplastic Syndrome

Guillermo Garcia-Manero, MD

Professor, Division of Cancer Medicine
Chief, Section of Myelodysplastic Syndromes
Division of Cancer Medicine
Department of Leukemia
The University of Texas MD Anderson Cancer Center
Houston, Texas

Guillermo Garcia-Manero, MD, has disclosed that he has received funds for research support from Bristol-Myers Squibb and consulting fees from Bristol-Myers Squibb and Taiho.

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Rami S. Komrokji, MD

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, has disclosed that he has received consulting fees from AbbVie, Acceleron, Bristol-Myers Squibb, Geron, Incyte, and Jazz and fees for non-CME/CE services from Agios, Bristol-Myers Squibb, and Jazz.

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Jamile Shammo, MD, FASCP, FACP

Professor of Medicine and Pathology
Division of Hematology, Oncology, and Stem Cell Transplant
Director, MDS/MPN/Aplastic Anemia Program 
Rush University Medical Center
Chicago, Illinois

Jamile Shammo, MD, FASCP, FACP, has disclosed that she has received funds for research support from AbbVie, Alexion, Bristol-Myers Squibb, CTI, Incyte, Kartos, Novartis, Onconova, and Telios; consulting fees from Alexion, Apellis, Bristol-Myers Squibb, Incyte, and Novartis; has received fees for non-CME/CE services from Alexion, Bristol-Myers Squibb, Incyte, and Sanofi; and has stock/ownership interest from AbbVie, Baxter, and Takeda.

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Released: January 11, 2021

This commentary features expert answers to learner questions from a live CCO Webinar on the optimal management of patients with myelodysplastic syndromes (MDS). Topics include: the use of oral decitabine vs IV decitabine, del(5q) in MDS, investigational therapies for MDS, and other treatment challenges in MDS. The answers below are responses provided by the Webinar faculty of Guillermo Garcia-Manero, MD; Rami S. Komrokji, MD; and Jamile Shammo, MD, FASCP, FACP. They have been edited for clarity.

Is oral decitabine equivalent to standard IV decitabine in patients with higher-risk MDS?

Guillermo Garcia-Manero, MD:
Oral decitabine, which is a combination of decitabine plus the cytidine deaminase inhibitor cedazuridine, is pharmacologically identical to IV decitabine. The FDA approved this combination in July 2020 for the treatment of adults with MDS, including previously treated or untreated, de novo or secondary MDS with certain subtypes (ie, refractory anemia with or without ringed sideroblasts or excess blasts, and chronic myelomonocytic leukemia) as well as intermediate-risk and high-risk International Prognostic Scoring System groups.

Approximately 200 patients have been treated with this compound in clinical trials, and it has shown a virtually identical pharmacokinetic and pharmacodynamic profile as IV decitabine.

New data from a trial by Savona and colleagues in patients with MDS and chronic myelomonocytic leukemia (N = 133) suggests that the response rate for oral decitabine is at least comparable to what is shown with IV decitabine, and the survival rates shown in this and other trials with oral decitabine are equivalent or greater than IV decitabine. Oral decitabine is becoming a standard of care in our practice; we are living through COVID-19, trying not to bring those patients into the office, and we now have 2 oral hypomethylating agents to help lessen the need for visits: oral decitabine for MDS and oral azacitidine for acute myeloid leukemia. I strongly believe that these 2 oral agents are going to play a greater role in our armamentarium vs the IV alternatives, and patients are increasingly demanding this. In addition, many doublets with other drugs are increasingly focused on oral combinations that will be very important as regimens easier to administer than parenteral therapy, particularly for older patients.

Do you delay cycles based on cytopenia during the first 4 cycles with oral decitabine?

Guillermo Garcia-Manero, MD:
Clinicians should follow the same approach with oral decitabine that is used with IV decitabine. As each decitabine tablet is a full dose, adjusting doses with oral decitabine varies from IV decitabine, but there are strategies for that, such as adjusting the number of days of treatment. My concern is that patients may believe that because oral decitabine is a tablet that you take once daily for approximately 5 days, that it is not chemotherapy. We are trying to educate our patients to understand that they need to treat their oral regimen like IV chemotherapy, including seeing their clinicians on the first day of dosing and adhering to the treatment schedule at home in order to receive essentially the same dosing of chemotherapy per month that they were getting with the IV injections.

Is oral decitabine equivalent to standard IV azacitidine in patients with higher-risk MDS?

Guillermo Garcia-Manero, MD:
I don’t think that you can extrapolate oral decitabine data to IV azacitidine data. We should be aware, however, that, like oral decitabine, there is an investigational drug called ASTX030 that combines oral azacitidine with cedazuridine. It is possible that in the future, this oral azacitidine combination may pharmacologically emulate IV azacitidine.  If that happens, the question will be whether you can go from the standard of care in higher-risk disease to new oral azacitidine. That will be very interesting to see, but we are not there yet.

Do you use dexamethasone in lower-risk MDS?

Rami S. Komrokji, MD:
The only patient scenario in which we will sometimes use dexamethasone is in patients with del(5q) after lenalidomide failure. Studies have shown that the mechanism of resistance in these cases is increased P53 expression, not mutation, and dexamethasone downregulates that. In my experience with a small group of 8 patients with this scenario, 5 were able to achieve some response, but none had cytogenetic changes. Response is typically short lived, but it can be a possible option in patients with del(5q).

In patients with del(5q) and higher-risk anemia, in addition to hypomethylating agent (HMA), would you add lenalidomide to improve their anemia?

Jamile Shammo, MD, FASCP, FACP:
I am not in favor of combining azacitidine and lenalidomide in higher-risk MDS. There was initially promising phase II data from a small study combining HMA and lenalidomide in patients with higher-risk MDS (6% del[5q]), but subsequent SWOG data that compared the combination vs single-agent azacitidine or azacitidine plus vorinostat showed no significant difference in efficacy between groups. I think it is difficult to put 2 myelosuppressive agents together because you usually have to reduce the dosing due to toxicity, thereby reducing efficacy. I prefer combinations in which you have one myelosuppressive drug and add another class of drug that doesn’t amplify the same toxicities, so that you can take advantage of both.

Is there a role for FLT3 inhibitors in the subset of patients with MDS with FLT3 mutations?

Guillermo Garcia-Manero, MD:
There is a subset of patients with higher-risk MDS that, when they progress after HMA therapy, they may acquire FLT3 mutations. We still don’t know if they acquire them at progression or if the mutations were dormant and become activated by previous treatment. Clinically, an increase in white blood cell counts at this time may indicate the presence of a FLT3 or RAS mutation. In our experience, patients with MDS who have FLT3 mutations at the time of HMA failure can be rescued if you use a FLT3 inhibitor. There are no approvals for this, but I think it is to the patient’s benefit to use a FLT3 inhibitor to target that FLT3 mutation. So in patients with HMA failure and a high white count, check for the FLT3 mutation.

Is there a role for intravenous immunoglobulin (IVIg) and prednisone for treating transfusion-dependent lower-risk MDS patients?

Jamile Shammo, MD, FASCP, FACP:
We have all had patients with MDS and immune thrombocytopenia purpura (ITP), and these are not easy patients to treat. The only time I use IVIg and prednisone is if I feel that there is a cytopenia that may be immunologically mediated, but you have to be absolutely certain that this is truly immunologically mediated, and sometimes it is a diagnosis of exclusion. I have used prednisone, or dexamethasone, without IVIg in cases of ITP or suspected immune-mediated ITP, but there has to be a lot of workup that goes into that before selecting that treatment.

Do you use low-dose cyclosporine in lower-risk MDS?

Jamile Shammo, MD, FASCP, FACP:
I have used low-dose cyclosporine when I feel that the cytopenias seem to be far out of proportion to what I see in the bone marrow, for example, if you see severe reduction in the platelet counts, severe reduction in the neutrophils, perhaps hypocellularity, and you don’t see much dysplasia. Then I might use immunosuppressive therapy. I have a few patients who had deletion 13q, and there are some very small subset reports in the literature suggesting that immunosuppressive therapy might work for those patients. I have been using cyclosporine and the thrombopoietin receptor agonist eltrombopag for those patients with some success.

Rami S. Komrokji, MD:
If you encounter patients with severe thrombocytopenia, especially isolated thrombocytopenia in lower-risk MDS, which is uncommon, there are reasonable data with eltrombopag from the Italian group showing response in approximately 25% of patients.

Are there immune-related adverse events with TIM-3 inhibitors?

Guillermo Garcia-Manero, MD:
This is an interesting question. If you consider the data with the PD-1 and CTLA-4 immune checkpoint inhibitors, we see risk of considerable novel toxicities such as pneumonitis and colitis. In my experience with TIM-3 inhibitors, I have seen less severe toxicity than I have with PD-1 and CTLA-4 inhibitors. But as with any immunotherapies, including TIM-3 inhibitors and CD47 inhibitors currently in clinical trials, you have to remain alert for possible immune reactions, and quickly respond with steroids, particularly if you suspect any severe toxicities such as pneumonitis or colitis.

Do you foresee treatment combinations with immune checkpoint inhibitors in MDS in the setting of HMA failure?

Guillermo Garcia-Manero, MD:
I think we need to let that data mature, but eventually there will be a triplet with immune checkpoint inhibitors in MDS. First, there will be a very powerful doublet, such as azacitidine plus a drug of another class, perhaps venetoclax or pevonedistat. Next, we will have a triplet, where you will have the HMA doublet together with an immunotherapy.

Should we investigate treating clonal cytopenia of undetermined significance (CCUS) and inflammation to avoid progression toward MDS?

Rami S. Komrokji, MD:
That is a great question, and yes, I think it is a direction we should take. Dr. Garcia-Manero and I have done several studies together to target inflammation in lower-risk MDS, and most of the time, we have not seen responses that we had anticipated because many of these patients already had HMA failure. I think if we are going to target the inflammatory pathway, it should be done earlier in the disease process. Once the disease is so clonal and we acquire so many other mutations, I don’t know how much we will achieve by targeting the inflammation. CCUS might be an ideal stage to investigate, as CCUS has a 50% rate of progression to MDS. One interesting approach currently being investigated is using vitamin C earlier in the disease, such as in the international EVITA trial examining the impact of vitamin C on CCUS and other lower-risk myeloid malignancies (NCT03682029) or later in the disease in combination with azacitidine, as in the trial at the Cleveland Clinic combining azacitidine plus vitamin C in patients with MDS or acute myeloid leukemia and TET2 mutations (NCT03397173). Earlier treatment of inflammation in this disease is worth further exploration.

Your Thoughts
What are your most pressing questions about the care of your patients with MDS? Please let us know in the discussion box below.

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