Practical Approaches to the Treatment in High- or Very High-Risk MDS Patients

Dr. Richard A. Larson
Richard A. Larson, MD
Professor of Medicine
University of Chicago
Chicago, Illinois

The subset of patients with high-risk MDS are often older patients who may not be eligible for more intensive treatments. Read a recent interview with Dr. Larson where he reviews the IPSS and IPSS-R criteria used to define these patients. He will also review risk factors associated with high-risk MDS and the goals of therapy. Lastly, he discusses key genetic mutations that should be addressed, including emerging agents that are of potential interest in this group of patients.

Can you please describe a patient with high- or very high-risk MDS?

It is important to note that this high-risk subset of myelodysplastic syndromes (MDS) often occurs in older patients, specifically a group of patients who may not be eligible for more intensive treatments, although therapy should not be determined by age alone.1 We define high- or very high-risk MDS based upon the International Prognostic Scoring System (IPSS) that was revised in 2012 and now called the IPSS-R.2,3 Patients fall into the high-risk and very high-risk categories by having increased myeloblasts in the bone marrow or having unfavorable cytogenetic features in bone marrow cells. Both of those characteristics are also shared by acute myeloid leukemia (AML), so from my perspective, we are often talking more about an evolving AML because these patients have a significantly greater risk of progressing to actual AML.3,4,5 Looking at the IPSS-R score, patients that fall into the very-high and high-risk categories have overall median survivals in the range of 1 to 1.5 years, and some fraction of those patients will actually cross the threshold into what is defined as AML. That dividing line is 20% blasts in the bone marrow or the blood.3,4 Whether you call this high-risk/very high-risk MDS or an evolving acute leukemia, the latter term frankly emphasizes both the severity of the problem as well as the shortened survival that most of these patients will experience. When talking about therapy in these patients, clinicians are more often using drugs and treatment interventions that are either approved or have been validated in patients with AML, particularly allogeneic stem cell transplantation (ASCT).1,5 This is a very challenging disease for community hematologists and oncologists to treat, in part because of the need for transfusions and supportive care. From the time of diagnosis, it probably should be managed in conjunction with a referral center where ASCT is at least one of the options to consider.

Are there any particular risk factors associated with high- or very high-risk MDS?

Older age is likely the predominant risk factor for MDS across the board and all risk levels. There are some environmental exposures that had been associated with MDS, including cigarette smoking, radiation exposures, solvent exposures (eg, benzene), and prior chemotherapy. These exposures are often associated with unfavorable cytogenetic features.6 Patients who have been previously treated with chemotherapy or radiation therapy are at risk of developing MDS between 2 to 10 years after such therapy. This form of MDS is often associated with more complex chromosomal abnormalities.7 Secondary or therapy-related MDS/AML is a common identified complication of standard chemotherapy use for a variety of solid and hematologic malignancies. The incidence of secondary MDS/AML following conventional cancer therapy has been found to range from 0.8% to 6.3% at 20 years, and the median time to development ranges from 3 to 5 years.8

What are the main goals for therapy in these patients?

The only curative therapy that is available for this patient population is ASCT, which is more limited in terms of applicability in older patients. Treatment is also dependent on their fitness or frailty. The possibility of ASCT should be considered from the time of initial diagnosis because survival is limited at this level of disease risk. If a patient is not a candidate for ASCT, then palliation of symptoms with medical therapy is the appropriate pathway, namely trying to get the disease under control and cytoreducing the malignant clone. This is usually done with hypomethylating agents (HMAs). As for the medically unwell or frail patient, supportive care remains the focus of management, including the use of prophylactic antibiotics when patients are neutropenic to protect against infection. Patients who are experiencing bleeding may also need platelet transfusions as part of supportive management.5

How do you determine fitness for therapy in patients with high- or very high-risk MDS?

Many factors can impact therapy in elderly patients with malignant blood diseases, including MDS. A comprehensive geriatric assessment (CGA) has been shown to assist in assessing the elderly prior to therapy. The ELCAPA study by Caillet, et al., identified several critical factors independently associated with a need to alter cancer therapy protocols in patients with various cancers. These included functional impairment as assessed by Eastern Cooperative Oncology Group performance status (ECOG-PS), walking problems/risk of falls, malnutrition, cognitive impairment, depressive disorders, use of multiple medications, urinary or fecal incontinence, concomitant comorbidities, and a decrease in activities of daily living.9 Measurements of fitness will usually include the timed up-and-go test (TUG), namely the time it takes a patient to rise from a standard armchair, walk a distance of approximately 3 meters, turn around and walk back to the chair. Other tests used include handgrip strength and the 6-minute walk test.10-12

The first question that must be answered for patients with high- and very high-risk MDS is whether or not the patient is an appropriate candidate for ASCT.5 Experienced physicians may tell you that they can distinguish whether someone is an appropriate candidate for an intensive chemotherapy program “from the foot of the bed.” But in my institution, we actually have a special Transplant Optimization Program clinic where anyone who is being considered for ASCT who is over 60 years of age is evaluated.13 This is a clinic that is staffed by a geriatrician, physical therapist, nutritionist, pharmacist, and a transplant nurse practitioner in addition to oncology specialists. The basis for this is that a multidisciplinary and interprofessional team approach may be a little more objective than just the patient’s personal physician in terms of being able to identify patients who should not proceed with a transplant and those who are borderline. These latter patients might be able to improve their performance status or their nutrition for a potentially more successful transplant outcome. The challenge with any intensive intervention in older patients is that they can look pretty fit walking through the door, but the first time they have a serious complication, they can rapidly spiral downward and require intensive care, which is a situation to avoid. So, we are trying to come up with more objective criteria than just older age. We certainly look closely at organ function and comorbidities, including diabetes and heart or kidney failure. Data have shown that comorbidities can markedly impact patients with MDS in terms of survival. Daver, et al., used the Adult Comorbidity Evaluation-27 (ACE-27) to assess the severity of comorbid conditions in patients at all risk levels of MDS. The most common comorbid conditions in the population studied included cardiovascular disorders, other concurrent malignancies, and endocrine disorders. Results demonstrated that the ACE-27 comorbidity score significantly impacted the medial survival of patients in the intermediate-, high-, and very high-risk IPSS-R MDS groups.14 Referral to a center of expertise, both in the use of chemotherapy and transplantation, is especially helpful early in the process. People with high- and very high-risk MDS tend to go downhill fairly quickly as bone marrow failure becomes increasingly severe. If there were a window of time when you could intervene with a curative therapy or give a patient the best chance of having a beneficial response to treatment, you would like to implement that fairly soon.

Can you please provide a brief review on the use of ASCT and intensive chemotherapy in high- and very high-risk MDS?

As mentioned earlier, this subset of MDS is much more like AML in terms of excess blasts in the bone marrow, which signals the lack of differentiation. There are usually also unfavorable cytogenetic features and unfavorable mutations identified by next-generation sequencing (NGS).3-5 These are more common in older patients, but occasionally you will identify the same features in a 40- or 50-year-old, and in these cases the term ‘evolving AML’ seems to fit the pattern better. Most people assume that patients with MDS are always older, but sometimes you see the same degree of myelodysplasia with abnormal features and other high-risk features in younger adults. Our current treatment algorithm states that patients with higher-risk MDS who are transplant candidates should undergo an early ASCT or undergo treatment with HMAs as a bridge to transplant. In contrast, the patient who is ineligible for transplantation should receive HMA therapy until the disease progresses or they become intolerant to therapy.5 Having at least 20% blasts in the bone marrow is usually the requirement for a diagnosis of AML.15,16 However, if someone has 18% blasts in the bone marrow and therefore are below that AML threshold, the question remains whether they should be treated with an HMA (eg, azacitidine or decitabine, alone or together with venetoclax) or whether they should be treated with cytarabine and an anthracycline, as done with AML, before moving fairly rapidly to a transplant? Some data have shown that treating patients ≤60 years of age with MDS/AML with intensive AML chemotherapy resulted in similar outcomes regardless of blast percentage, including patients with blasts at 10% to 19%, 20% to 29% and ≥30%.16 This more intensive therapy is usually our preferred approach in a younger adult. We would start thinking about AML-type treatment in patients who are under 65 or 70 years of age with high- or very high-risk MDS. That would be inpatient-administered cytarabine for 7 days and an anthracycline, either daunorubicin, idarubicin, or less commonly mitoxantrone, for 3 days, with the goal of trying to achieve a complete remission and then moving fairly quickly to ASCT.

Transplantation itself may not be done as initial therapy for the high-risk or very high-risk patients. That is because if the disease is not under some degree of control, patients who undergo ASCT with excess blasts have poorer outcomes than those who undergo transplant with lower blast percentages. If a patient appears to be a candidate for ASCT, the initial goal is to get control of their disease by sufficient cytoreduction of the malignant clone to eliminate circulating blasts and ideally restore some normal hematopoiesis. Data have shown that patients with more than 10% blasts should receive cytoreductive therapy before ASCT, especially if reduced intensity conditioning is part of the plan. Patients with <10% blasts have the best chance of surviving ASCT without an early relapse.17 In a younger patient, we might opt for an AML-type of combination chemotherapy/intensive chemotherapy regimen, and some data have recommended this as a treatment algorithm for younger patients with higher blast percentages and good-risk cytogenetics prior to transplant. For older patients, especially those with lower blast percentages and intermediate- or poor-risk cytogenetics, use of HMAs (azacitidine or decitabine) would be recommended, but there are some new combinations with new drugs such as venetoclax that might improve the likelihood of having a better transplant response.5,18 Now, these drugs are in clinical trials trying to validate the added benefit of adding a novel agent to an HMA. If there were a clinical trial available for patients, we would generally encourage them to participate.19 Again, I want to emphasize the need for early referral to a center of expertise to discuss how best to control an individual patient’s disease to make transplantation a possibility, including potential patient inclusion in a clinical trial.

What do you consider the role of HMAs in patients at this MDS risk level?

According to current recommendations, HMA therapy is most appropriate in higher-risk patients who are not candidates for transplant.5 In one randomized trial of higher-risk patients, azacitidine was found to provide a median survival of 24 months vs 15 months with standard chemotherapy, low-dose cytarabine, or supportive care.5,20 Trials of decitabine did not show similar survival improvements, but these trials tended toward higher-risk patient populations over a shorter time period, which complicates any true comparison. Overall, clinicians consider both of these HMAs comparable for use with drug choice left up to clinician and patient discretion.5

What do you consider key genetic mutations that should be addressed in high- or very high-risk MDS?

Mutations in isocitrate dehydrogenase 1 or 2 (IDH1 and IDH2) are important to identify at the time of diagnosis of high- or very high-risk MDS. These particular mutations lead to abnormal leukemogenesis.21 Mutated IDH1 or IDH2 are not common and are only found in approximately 4% to 12% of patients with MDS. However, two IDH inhibitors, specifically ivosidenib targeting IDH1 and enasidenib for IDH2, are approved by the United States Food and Drug Administration (FDA) for use in AML, but not in MDS. That said, they are in off-label use by some clinicians.21,22 Both agents are undergoing investigation in combination with azacitidine or with induction chemotherapy in patients with IDH-mutant MDS.19

In terms of genetics, TP53 is an area of major challenge in MDS. TP53 mutations have been associated with higher blast percentages and lower platelet counts which are poor risk factors for this disease.23 APR-246 is a prodrug that binds to cysteines in mutant p53, reactivating the beneficial actions of TP53, namely its pro-apoptotic and cell cycle arrest functions. Data from a study combining APR-246 with azacitidine in patients with TP53-mutated MDS or AML has shown an overall response rate (ORR) of approximately 75% in the evaluable population per protocol, with a 63% response rate in the intent-to-treat (ITT) population.24 Data in patients with TP53-mutated MDS from another study demonstrated complete response (CR) in 61% of patients with MDS, with 41% of patients with MDS or AML achieving either complete or partial cytogenetic response.25 In January 2020, the FDA granted a breakthrough designation to this drug combination for the treatment of TP53-mutated MDS.26

What other emerging agents are of potential interest for future use in patients with high- and very high-risk MDS?

Venetoclax is a drug of particular interest. This agent is a potent and selective BCL2 inhibitor that has high oral bioavailability. Data from a study of patients with relapsed/refractory (R/R) MDS and AML where most of them were treated with venetoclax in combination with azacitidine or decitabine demonstrated an ORR of 21% with a median overall survival (OS) of 3 months.21,27,28 This drug is also being studied in combination with agents other than HMAs in several clinical trials for treatment of MDS and AML.19 CPX-351 is an agent that has been approved for use in patients with secondary AML and newly-diagnosed therapy-related AML. This drug is a liposomal formulation of cytarabine and daunorubicin. It is currently undergoing investigation in patients with higher-risk MDS who have experienced HMA failure and also potentially as first-line therapy for patients with higher-risk disease.19,21 CC-486 is an oral form of azacitidine. Recent data showed that this drug extended the OS and relapse-free survival (RFS) in patients over 60 years of age with AML in first remission when used as a maintenance treatment. It is administered daily for 14 days every four weeks.29 There is also an oral combination agent called ASTX727, which is oral decitabine combined with a drug called cedazuridine which inhibits the enzyme that metabolizes or degrades decitabine in the gastrointestinal tract. It has been studied in MDS with phase I data, including 47% of patients with relapsed disease. Results demonstrated an ORR of 32% in patients who received ASTX727.21,30 More recent phase III data have shown that this combination provided a decitabine exposure equivalent to intravenous decitabine in patients with high-risk MDS or chronic myelomonocytic leukemia (CMML).31 Finally, a first-in-class agent, Hu5F9-G4 (magrolimab), is undergoing early development for treatment of MDS and AML. This antibody targets CD47, a macrophage immune checkpoint that functions as a “don’t eat me” signal in malignant tumors. Early results with this agent used as monotherapy or with azacitidine demonstrated a CR or CR with incomplete platelet recovery (CRi) of 60% in patients with MDS.32

What do you consider the most critical treatment factors in decisions to use new or emerging drugs for your patients with high- or very-high risk MDS or to place them in a clinical trial?

As soon as the safety of a new drug has been established, the agent needs to be moved into frontline treatment in previously untreated patients, particularly those in the high- and very high-risk groups. These patients are often sick at the time of diagnosis or have fairly severe bone marrow failure, and if they are still well when first diagnosed, they decline fairly quickly and their disease progresses. Testing new drugs in second- or third-line relapsed/refractory patients is not very productive. The initial intervention will tend to select for more resistant subclones, so it is a bigger challenge for a new drug to show its effectiveness when it is used in patients who are sicker, more transfusion dependent, and potentially more drug-resistant. I think a new drug should be moved fairly quickly into use in the newly-diagnosed patients. Apart from transplantation, these patients are not being cured, and many of them are older or not good candidates for a transplant. There is clearly room to improve on the currently available treatments with new and emerging agents.


  1. Atallah E, Bylow K, Troy J. Saber W. Treatment of older patients with high-risk myelodysplastic syndromes (MDS): The emerging role of allogeneic hematopoietic stem cell transplantation (allo HSCT). Curr Hematol Malig Rep. 2014;9(1):57-65.
  2. Greenberg P, Cox C, LeBeau MM, et al. International Scoring System for Evaluating Prognosis in Myelodysplastic Syndromes. Blood. 1997;89(6):2079-2088.
  3. Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndrome. Blood. 2012;120(12):2454-2465.
  4. Park J. How likely is it for patients with MDS to transform to AML? (November 7, 2018). Available at:
  5. Steensma DP. Myelodysplastic syndromes current treatment algorithm 2018. Blood Cancer J. 2018;8(5):47.
  6. American Society of Clinical Oncology: Cancer.Net. Myelodysplastic syndromes - MDS: Risk factors. (December 2017). Available at:
  7. American Society of Clinical Oncology: Cancer.Net. Myelodysplastic syndromes – MDS: Subtypes and classification. (December 2017). Available at:
  8. Bhatia S. Therapy-related myelodysplasia and acute myeloid leukemia. Semin Oncol. 2013;40(6):666.675.
  9. Caillet P, Canoui-Poitrine F, Vouriot J, et al. Comprehensive geriatric assessment in the decision-making process in elderly patients with cancer: ELCAPA Study. J Clin Oncol. 2011;29(27):3636-3642.
  10. Åhlund K, Bäck M, Öberg B, Ekerstad N. Effects of comprehensive geriatric assessment on physical fitness in an acute medical setting for frail elderly patients. Clin Interv Aging. 2017;12:1929-1939.
  11. Klepin HD, Geiger AM, Tooze JA, et al. Geriatric assessment predicts survival for older adults receiving induction chemotherapy for acute myelogenous leukemia. Blood. 2013;121(21):4287-4294.
  12. Klepin HD, Ritchie E, Major-Elechi B, et al. Geriatric assessment among older adults receiving intensive therapy for acute myeloid leukemia: Report of CALGB 361006 (Alliance). J Geriatr Oncol. 2020;11(1):107-113.
  13. Derman BA, Kordas K, Ridgeway J, et al. Results from a multidisciplinary clinic guided by geriatric assessment before stem cell transplantation in older adults. Blood Adv. 2019;3(22):3488-3498.
  14. Daver N, Naqvi K, Jabbour E, et al. Impact of comorbidities by ACE-27 in the revised-IPSS for patients with myelodysplastic syndromes. Am J Hematol. 2014;89(5):509-516.
  15. Leukemia and Lymphoma Society. Acute myeloid leukemia: Diagnosis. (2019). Available at:
  16. DiNardo CD, Garcia-Manero G, Pierce S, et al. Interactions and relevance of blast percentage and treatment strategy among younger and older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome. Am J Hematol. 2016;91(2):227-232.
  17. Brierley CK, Steensma DP. Allogeneic stem cell transplantation in myelodysplastic syndromes: Does pretransplant clonal burden matter? Curr Opin Hematol. 2016;23:167-174.
  18. Sekeres MA, Cutler C. How we treat higher-risk myelodysplastic syndromes. Blood. 2014;123(6):829-836.
  19. (2020). Available at
  20. Fenaux P. et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: A randomised, open-label, phase III study. Lancet Oncol. 2009;10(3)223-232.
  21. Gil-Perez A, Montalban-Bravo G. Management of myelodysplastic syndromes after failure or response to hypomethylating agents. Ther Adv Hematol. 2019;10:2040620719847059.
  22. DiNardo CD, Jabbour E, Ravandi F, et al. IDH1 and IDH2 mutations in myelodysplastic syndromes and role in disease progression. Leukemia. 2016;30(4):980-984.
  23. Haase D, Stevenson KE, Neuberg D, et al. TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups. Leukemia. 2019;33(7):1747-1758.
  24. Cluzeau T, Sebert M, Rahmé R, et al. APR-246 Combined with Azacitidine (AZA) in TP53 Mutated Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML). a Phase 2 Study By the Groupe Francophone Des Myélodysplasies (GFM). Blood. 2019;134 (Supplement_1):677.
  25. Sallman DA, DeZerm AE, Garcia-Manero G, et al. Phase 2 results of APR-246 and azacitidine (AZA) in patients with TP53 mutant myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia (AML). Blood. 2019;134 (Supplement_1):676.
  26. Healio. FDA grants breakthrough therapy designation to APR-246, azacitidine combination for myelodysplastic syndrome. (January 30, 2020). Available at:
  27. DiNardo CD, Rausch CR, Benton C, et al. Clinical experience with the BCL2-inhibitor venetoclax in combination therapy for relapsed and refractory acute myeloid leukemia and related myeloid malignancies. Am J Hematol. 2018;93(3):401-407.
  28. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naïve, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7-17.
  29. ASH Clinical News. QUAZAR: Oral azacitidine maintenance improves survival in transplant-ineligible AML. (January 1, 2020). Available at:
  30. Garcia-Manero G, Griffiths EA, Roboz GJ, et al. Phase 2 dose-confirmation study of oral ASTX727, a combination of oral decitabine with a cytidine deaminase inhibitor (CDAi) cedazuridine (E7727), in subjects with myelodysplastic syndromes (MDS). Blood. 2017;130(Supplement 1):4274.
  31. Columbus G. Phase III Ascertain trial meets endpoint in topline results for cedazuridine and decitabine in MDS/CMML. (June 11, 2019). Available at:
  32. Sallman DA, Donnellan WB, Asch AS, et al. The first-in-class anti-CD47 antibody Hu5F9-G4 is active and well tolerated alone or with azacitidine in AML and MDS patients: Initial phase 1b results. J Clin Oncol. 2019;37(15_Suppl):7009-7009.