Emerging Approaches for Myelodysplastic Syndromes

Supplements And Featured PublicationsExploring Therapeutic Strategies in Myelodysplastic Syndromes
Volume 2020
Issue 1

Oncologists who specialize in the treatment of hematologic malignancies participated in a virtual workshop to discuss the emerging treatment landscape in myelodysplastic syndromes.

Dan DeAngelo, MD, PhD

On June 7, 2020, a select group of oncologists who specialize in the treatment of hematologic malignancies participated in a virtual workshop to discuss the emerging treatment landscape in myelodysplastic syndromes (MDS). In an expert discussion led by Dan DeAngelo, MD, PhD, perspectives and insights on novel agents in MDS were exchanged. Experts aimed to describe and discuss pertinent issues they face as physicians when treating patients with MDS, discuss the limitations of currently available therapeutic agents, review novel treatment approaches and new treatment strategies for patients with MDS, and gain insight into how the potential approval of newer therapies may impact the treatment landscape in MDS.

MDS Treatment Landscape and Unmet Needs

Approximately 10,000 people in the United States are diagnosed with MDS per year, although the number of cases of MDS is thought to be higher because of underreporting. MDS is uncommon in people aged younger than 50 years; in individuals aged older than 70 years, the incidence is at least 20 cases per 100,000. Of all patients with MDS, about one-third will go onto develop acute myeloid leukemia (AML).1,2

In the current treatment landscape for MDS, transplantation remains the standard curative modality. Selecting candidates for transplantation is based on risk stratification; high-risk patients may receive transplants at the time of their diagnosis while those with lower-risk disease may delay transplant. Nevertheless, survival outcomes are limited, even in low-risk cases.3 Among high-risk MDS cases, life expectancy is 3.2 years for immediate transplant compared with 6.5 years for low-risk cases.3 Beyond transplantation, therapeutic options in the current landscape are lacking. The hypomethylating agent (HMA) azacitidine is the only agent that has shown improvement in overall survival (OS) among patients with higher-risk MDS. Findings from the AZA- 001 trial showed that patients who received azacitidine had a median survival of 24.4 months compared with 15.0 months for patients who received conventional care regimens, a 9.4-month median survival benefit. Two-year survival rates were 50.8% for patients receiving azacitidine and 26.2% for patients who received conventional care regimens.4

Stakeholder Insights. With no other agents yielding OS results comparable to those of azacitidine, stakeholders agreed that the lack of compelling data and approved options in the treatment landscape of MDS represents a great unmet need. Because life expectancy is often less than 2 years, the stakeholders agreed that new therapeutic strategies that yield increased response rates and depth of response, as well as better durability and tolerability, are needed.

Another unmet need, according to stakeholders, pertains to the limited use of HMAs as monotherapies, as patients could potentially benefit from combination approaches using other HMAs. In other hematologic malignancies and diseases, different combinations of therapies are routine, whereas MDS is among the few diseases that continues to rely on monotherapy. As the treatment landscape moves forward, new combinations with more durable response or higher rates of response may be able to challenge the timing of the transplant. Additionally, stakeholders noted that patients should not be prematurely discontinued from therapy.

Emerging Therapies


Rigosertib inhibits cellular signaling as a Ras mimetic by targeting the Ras-binding domain, thus blocking multiple cancer targets in the downstream pathways, such as PI3K/ AKT and Raf/PLK.5

At the 24th European Hematology Association Congress in 2019, investigators shared findings from a trial showing that sequential exposure with rigosertib followed by azacitidine achieved maximum synergy with clinically achievable concentrations. In the trial, 55 patients were treated with rigosertib at a dose greater than 840 milligrams per day; 29 were HMA-naïve, and 26 had received previous HMA therapy. Findings showed that 34% of patients in the HMA-naïve group achieved complete remission (CR), with a median duration of response of 12.2 months and a median duration of treatment of 7.8 months. Among patients who failed HMA therapy, 4% experienced complete remissions and 4% experienced partial remission (PR) with a median duration of response of 10.8 months and a median duration of treatment of 4.9 months.5

Stakeholder Insights. The stakeholders noted that the 12-month response duration rate in the combination treatment was low; however, the treatment-naïve patients had CR and PR rates similar to those achieved with azacitidine. Thus, the utility of rigosertib may depend on the results of a randomized HMA failure trial in very high-risk patients. If the results of this study are positive, rigosertib may play an important role in MDS care, with potential for combinations in the future. The data were disappointing and stakeholders questioned the role of rigosertib in MDS care, pending the readouts of additional trials.


Pevonedistat is a first-in-class small molecule NAE inhibitor. Ubiquitination and degradation of select NAE-active regulatory proteins are important for cancer cell growth; therefore, inhibition of these proteins can induce apoptosis and cell death. Findings from a phase 2 trial (NCT02610777) evaluating pevonedistat in combination with azacitidine versus azacitidine alone were presented at the American Society of Clinical Oncology 2020 Virtual Scientific Program. The primary end point was OS; the secondary end points were event- free survival (EFS), defined as time to death or transformation to AML in higher-risk MDS/chronic myelomonocytic leukemia (CMML), and overall response rate (ORR). Notably, the study was powered on EFS as the original primary end point, with OS originally being a secondary end point, but this was changed based on regulatory feedback after enrollment. Patients had either higher-risk MDS (nearly half of patients), higher-risk CMML, or oligoblastic or low-cast-count AML, and they had not received previous HMA therapy. They were randomized into the pevonedistat/azacitidine arm (n = 60) or the azacitidine-alone arm (n = 60).

Findings showed that the safety profile of pevonedistat/ azacitidine was comparable with that of azacitidine alone. The median number of azacitidine treatment cycles was 13.0 in the combination group and 8.5 in the azacitidine group. Median OS was 21.8 months in the combination group and 19.0 months in the azacitidine group (HR, 0.802; 95% CI, 0.512-1.256; P = .334). Median EFS was 21.0 months in the combination arm and 16.6 months in azacitidine arm (HR, 0.665; 95% CI, 0.423-1.047; P = .076). Among patients with higher-risk MDS, median EFS was 20.2 and 14.8 months in the pevonedistat/azacitidine and azacitidine-alone groups, respectively (HR, 0.539; 95% CI, 0.292-0.995; P = .045). Thus, although the clinical difference in EFS between the regimens was not statistically significant among the overall population, those with higher-risk MDS did have a statistically significant benefit from the pevonedistat/azacitidine combination. In the overall response-evaluable population, ORR was 70.9% in patients receiving the pevonedistat combination regimen and 60.4% in the azacitidine-alone group. Additionally, 40.0% of patients in the pevonedistat combination group had a CR, compared with 30.2% of patients in the azacitidine-alone group.6

Stakeholder Insights. Assessing the value of the phase 2 trial results, stakeholders noted that pevonedistat was well tolerated and that the lower response rates among those in the smaller CMML patient population was an important contributor to the EFS findings that failed to reach statistical significance in the overall intent-to-treat population. Patients with higher-risk MDS appeared to respond best to pevonedistat, which, coupled with pevonedistat’s unique mechanism of action, warrant further study for this agent. To avoid dilution of the data, stakeholders suggested that future studies evaluate a more focused patient population of patients with higher-risk MDS.


Magrolimab is an anti-CD47 antibody, leading to phagocytosis of cancer cells. It contains a antiphagocytic signal that enables macrophage immune evasion. The 5F9005 study evaluated magrolimab either alone or in combination with azacitidine in patients with AML and MDS.7 Patients received a dose ramp-up from 1 mg/kg to 30 mg/kg by week 2, then 30 mg/kg maintenance dosing. The primary end points were safety of magrolimab alone or with azacitidine, and the efficacy of magrolimab plus azacitidine in untreated AML/ MDS. Secondary end points were the pharmacokinetics, pharmacodynamics, and immunogenicity of 5F9 and addi- tional measures of efficacy (DOR, PFS, OS). Patients were eligible for the study if they had untreated AML or untreated high-risk MDS.

Magrolimab plus azacitidine induced a 92% ORR (50% CR) in MDS, which compares favorably with azacitidine monotherapy. The median time to response was 1.9 months among the entire patient population, which is more rapid than the time with azacitidine alone. Even in patients who did not have a transplant, some of the responses were durable and appeared to have relatively long duration of response. The median duration of response and survival has not been reached, which compares favorably with current therapies.7

Stakeholder Insights. The faculty concluded that magrolimab looks to be more active in the up-front setting and questioned why it is inactive in the relapsed setting. It is possible that macrophages get exhausted or there is some immune phenomenon in which they’re not responsive. A major challenge identified is the question of whether blood banks would be able to handle the complexity of the typing and screening. This issue is further complicated amid the coronavirus disease 2019 pandemic.


APR-246 is a methylated derivative and structural analogue that reactivates p53 and induces apoptosis. A study of the frontline combination therapy with APR-246 included patients with treatment-naïve, high-risk MDS, as well as oligoblastic AML.8 APR-246 plus azacitidine was studied in patients with TP53-mutant myeloid neoplasms. The phase 1b part of the study treated patients with APR-246 4500 mg/day on days 1 to 4 plus azacitidine (75 mg/m2) on a classic 7-day schedule. The primary end point was CR rate and secondary end points were ORR, duration of response, and OS in the phase 2 portion of the study.

The most common adverse effects (AEs) related to APR-246 were mostly gastrointestinal (nausea/vomiting) and neurologic, which were transient and reversible in all cases. Three patients (5%) discontinued because of secondary AEs. The hematologic toxicities appeared to be similar to what is seen with a single agent. The ORR for patients who received the APR-246 regimen was 87% among evaluable patients. Additionally, approximately half of the evaluable patients had a CR. Time to remission was about 3 months for this combination. Of the patients included in the study, 66 TP53 mutations were sequenced in 45 evaluable patients; 53 (80%) were missense and 62 (94%) were in the DNA-binding domain. All patients had at least 1 TP53 mutation in the DNA-binding domain.7,9

Stakeholder Insights. The faculty agreed that although these data will not lead to an imminent approval, APR-246 could allow physicians to transplant patients more frequently than with other therapies, given the lack of significant myelosuppression-related toxicities. Inducing patients with a doublet, giving them a transplant, and then continuing with posttransplant maintenance therapy will be very important. The high efficacy data ultimately warrant further consideration in clinical trials.


ASTX-727, a combination of oral decitabine and cedazuridine, was evaluated in a phase 3 study (ASCERTAIN, NCT03306264) in which patients with MDS/CMML received either oral decitabine alone or oral ASTX-727 in combination with intravenous decitabine. Among the 101 evaluable patients who were treated with ASTX-727, 64.4% of patients experienced some response, with 11.9% achieving CR, 45.5% experiencing marrow CR, and 11.9% of patients achieving marrow CR with some hematologic improvement.10,11

Stakeholder Insights. A major advantage of this therapy is that it would allow for an all-oral regimen, which could prove to be valuable in the community. Generally, in the first 2 cycles of treatment, the patient needs transfusion support if there is no remission. If the patient goes into remission, however, this agent could be a game-changer and result in quality-of-life improvements. Cost and the financial impact to the patient may also be a concern with ASTX-727 if it is approved.


BCL-2 overexpression allows cancer cells to evade apoptosis. Venetoclax, which has been approved for other indications, frees proapoptotic proteins that initiate programmed cell death. A phase 1b study included 57 eligible patients with untreated, de novo, intermediate-2 risk or high-risk MDS, with 60% of patients being high risk. Findings showed that almost 40% of patients had a CR and another 40% had a CR/ marrow. The time to response was about 2 months, and 70% of patients maintained response at 12 months.12-15

Stakeholder Insights. Stakeholders agree that venetoclax may be an important therapy in MDS, particularly in combination with other agents such as azacitidine. A trial evaluating this combination is in development now. AEs included myelosuppression and gastrointestinal- predominant toxicity, but generally venetoclax was very well managed.


Significant unmet needs and barriers to effective treatment remain in the MDS therapeutic landscape. Despite a historic lack of approvals in MDS, compelling data for several potential treatment options in the pipeline offer the promise of improved outcomes. If the agents discussed in this article earn FDA approval, the new challenge for clinicians will be selecting an optimal treatment regimen.


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  2. Aster JC, Stone RM. Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS). UpToDate. Updated May 28, 2020. Accessed August 12, 2020. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-myelodysplastic-syndromes-mds#:~:text=CLIN- ICAL%20PRESENTATION%20Clinical%20manifestations%20of,complete%- 20blood%20count%20(CBC)
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  4. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al; International Vidaza High- Risk MDS Survival Study Group. 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. doi:10.1016/S1470-2045(09)70003-8
  5. Navada SC, Garcia-Manero G, Atallah E, et al. Phase II study of oral rigosertib combined with azacitidine in patients with higher-risk myelodysplastic syndromes (MDS). Presented at: 24th European Hematology Association Congress; June 13-16, 2019; Amsterdam, the Netherlands. Abstract S839. https://library.ehaweb.org/eha/2019/24th/267422/mi- chael.e.petrone.phase.ii.study.of.oral.rigosertib.combined.with.azacitidine. html?f=listing%3D3%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D1
  6. Ades L, Watts JM, Radinoff A, et al. Phase II study of pevonedistat (P) + azacitidine (A) versus A in patients (pts) with higher-risk myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML), or low-blast acute myelogenous leukemia (LB AML) (NCT02610777). J Clin Oncol. 2020;38(15 suppl; abstr 7506).
  7. Sallman DA, Asch AA, Al Malki MM, et al. The first-in-class anti-CD47 antibody magrolimab (5F9) in combination with azacitidine is effective in MDS and AML patients: ongoing phase 1b results. Blood. 2019;134(Suppl 1):569. doi:10.1182/blood-2019-126271
  8. Bykov VJ, Zhang Q, Zhang M, et al. Targeting of mutant p53 and the cellular redox balance by APR-246 as a strategy for efficient cancer therapy. Front Oncol. 2016;6:21. doi:10.3389/fonc.2016.00021
  9. Cluzeau T, Sebert M, Rahmé R, et al. APR-246 combined with azacitidine (AZA) in TP53 mutated myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). a phase 2 study by the Groupe Francophone Des Myélodysplasies (GFM). Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual. Abstract S181. https://library. ehaweb.org/eha/2020/eha25th/295001/thomas.cluzeau.apr-246. combined.with.azacitidine.in.tp53.mutated.html?f=menu%3D6%2Abrowse- by%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D1766%2Aot_ id%3D23227%2Afeatured%3D16775
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    and safety from a randomized cross-over phase 3 study (ASCERTAIN study) of an oral hypomethylating agent ASTX727 (cedazuridine/decitabine) compared to IV decitabine. Presented at: 2019 61st American Society of Hematology Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL. Abstract 846. https://astx.com/wp-content/up- loads/2019/12/2019_ASTX727_Oral_ASH-abst-846_Garcia-Manero.pdf
  11. Duchmann M, Itzykson R. Clinical update on hypomethylating agents. Int J Hematol. 2019;110(2):161-169. doi:10.1007/s12185-019-02651-9
  12. Mewar R. Venclexta – new data in CLL, NHL, AML, MM. Roche. Accessed August 12, 2020. https://www.roche.com/dam/jcr:cd8b9047-a812- 4bc5-9473-ed74fccc46bb/en/ASH_2016_Reema_Mewar_FINAL.pdf
  13. DiNardo CD, Pratz KW, Letai A, et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018;19(2):216-228. doi:10.1016/S1470- 2045(18)30010-X
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  15. Zeidan AM, Garcia-Manero G, DeZern AE, et al. Clinical benefit of luspatercept in patients with lower-risk myelodysplastic syndromes (LR-MDS) and high transfusion burden (HTB) in the phase 3 MEDALIST study. Presented at: 25th Congress of the European Hematology Association; June 11-21, 2020; virtual. Abstract EP798. https://library.ehaweb.org/eha/2020/ eha25th/294715/amer.zeidan.clinical.benefit.of.luspatercept.in.patients. with.lower-risk.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2A- search%3Dep798
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