Emerging Therapies in Clinical Trials for MDS

Newsletters published on September 16, 2019
Mikkael A. Sekeres, MD, MS
Professor of Medicine
Chief of the Division of Hematology
Sylvester Comprehensive Cancer Center
University of Miami Miller School of Medicine
Miami, Florida
David P. Steensma, MD, FACP
Associate Professor of Medicine
Harvard Medical School
Senior Physician
Dana-Farber Cancer Institute
Boston, Massachusetts

While hypomethylating agents (HMAs) represent standard treatment for myelodysplastic syndromes (MDS), only about half of patients respond to treatment, duration of response is variable, and treatment is ultimately not curative.1 There are no approved alternatives to HMAs, and when HMA failure occurs, there are no accepted standards of care.2 Novel agents with different mechanisms of action are now being evaluated in this setting. In this newsletter, we review recent data for these agents as presented at the most recent annual meeting of the American Society of Hematology (ASH) and as reported subsequent to that conference. We also include details of potentially impactful ongoing or recently completed clinical trials for which data are awaited.


Guadecitabine (SGI-110) is a dinucleotide derivative of decitabine that is resistant to cytidine deaminase degradation, and therefore may more potently inhibit DNA methyltransferase activity. This second-generation HMA has been evaluated in both the front-line and second-line MDS settings.3 At the most recent ASH annual meeting, Garcia-Manero and colleagues presented the final report from a single-arm phase 2 study of this novel agent in patients with previously untreated intermediate-2 or high-risk MDS.4 The treatment was well tolerated in previously untreated MDS, with an overall response rate (ORR) that was better than what could be expected with the first-generation HMAs azacitidine or decitabine, according to the investigators. Of 87 patients evaluable for response, the ORR was 61% (53 patients), including a 22% rate of complete response (CR) (19 patients) and 3% CR with incomplete platelet recovery (3 patients). The median overall survival was 15 months, and median event-free survival was 14 months (median follow-up, 15 months).

In a separate report at ASH, investigators reported long-term results of a randomized, phase 2 study of guadecitabine in 102 patients with intermediate- or high-risk MDS or chronic myelomonocytic leukemia (CMML).5 They found the novel HMA to be well tolerated in both treatment-naïve and relapsed/refractory MDS. In the treatment-naïve MDS patients, the CR rate of 22% and median OS of 23.4 months compared favorably to what was reported for first-generation HMAs, investigators said. In MDS patients who failed prior HMAs, the rate of CR + marrow CR (mCR) was 32% and median OS was 12 months. Investigators say longer follow-up and randomized trials will be needed to better characterize the effect of guadecitabine on survival; one such study is ASTRAL-3, a randomized phase 3 trial comparing guadecitabine to physicians’ treatment choice after azacitidine or decitabine failure in patients with MDS or CMML.6 This agent has also recently been evaluated in combination with atezolizumab, an immune checkpoint inhibitor, in patients with relapsed/refractory MDS or CMML.7


ASTX727 is a fixed-dose combination of oral decitabine with cedazuridine (E7727), a cytidine deaminase inhibitor. The addition of cedazuridine in this combination approach may improve the bioavailability of the hypomethylating agent.8 A phase 2 dose-confirmation study in adult patients with intermediate- or high-risk MDS or CMML was presented at the 2017 ASH annual meeting. In that study, ASTX727 had a safety profile similar to that reported for intravenous decitabine, with no increase in gastrointestinal side effects. Response rates were as expected based on previous reports, with a clinical benefit seen in 31 patients (62%), including 8 CRs (16%), 14 (28%) mCRs, and hematologic improvement in 9 (18%). Having an oral version of decitabine could provide substantial patient convenience and could also improve treatment adherence, according to investigators.9 The phase 3 ASCERTAIN study is evaluating the role of this fixed-dose combination versus intravenous decitabine in patients with MDS or CMML.10 A recent report on ASCERTAIN indicated that oral decitabine demonstrated exposure equivalence versus intravenous decitabine and that a New Drug Application (NDA) would be filed with the US Food and Drug Administration (FDA) by the end of 2019.11


Oncogenic activation of RAS occurs in about one-third of human cancers, including hematopoietic malignancies such as MDS and acute myeloid leukemia (AML). Rigosertib, a synthetic benzyl styryl sulfone, blocks signaling of RAS signaling by acting as a small molecule Ras mimetic that binds to the Ras-binding domains of Ras effector proteins.12 The combination of rigosertib and azacitidine is being evaluated in a phase 1/2, multi-center, dose-escalating study in patients with MDS or AML.14 In an initial report of data from the most recent ASH annual meeting, investigators said this combination had encouraging results compared to single-agent azacitidine.15 The ORR was 68% for 31 patients evaluable for response, including 79% for 14 patients who were HMA-naïve, and 59% for 17 who were relapsed or refractory. In previous studies of rigosertib in MDS patients, substantial genitourinary adverse events were reported.16 However, with the use of risk mitigation strategies, investigators have been able to markedly reduce the incidence of those genitourinary adverse events.17 In the phase 3 INSPIRE trial, rigosertib is being compared to physician’s choice of treatment in patients with MDS following failure of a hypomethylating agent; the primary endpoint of INSPIRE is OS in the overall study population as well as in a subgroup of patients with very high risk disease according to the Revised International Prognostic Scoring System (IPSS-R).13


Pevonedistat, described as a “new partner” for azacitidine, is an inhibitor of the NEDD8-activating enzyme that exerts effects on the ubiquitination pathway.18 This agent has demonstrated synergistic antileukemic activity with azacitidine in preclinical models of AML, and in a phase 1b study, those results were confirmed with an intent-to-treat ORR of 50% in treatment-naïve older patients with AML, with no alteration in the azacitidine toxicity profile and dose-limiting toxicities that included transiently elevated AST/ALT.19 In a phase 3 randomized clinical trial, the combination of pevonedistat plus azacitidine is being compared to single-agent azacitidine in patients with higher-risk MDS, CMML, or low-blast AML.20


Adding a histone deacetylase inhibitor (HDAC) to an HMA has been shown to synergistically induce re-expression of silenced genes in myeloid malignancies; however, some clinical studies of these agents in combination have been disappointing due to increased toxicity, which has led to early treatment discontinuations. Pracinostat, a potent oral HDAC inhibitor, was studied in combination with standard dose azacitidine in a randomized phase 2 study including patients with untreated higher-risk MDS; however, the addition of this HDAC inhibitor did not improve outcomes versus azacitidine alone, possibly due to higher rates of treatment discontinuation, indicating that alternative dosing and schedules may improve tolerability.21 In a follow-up study described at the most recent ASH annual meeting, a 25% lower dose of pracinostat combined with azacitidine produced encouraging results in patients with high- to very high-risk MDS previously untreated with an HMA, suggesting that a reduced dose may allow patients to stay on treatment longer and increase likelihood of response. At a planned interim analysis including 20 evaluable patients, 2 (10%) had discontinued treatment due to adverse events, triggering expansion of the study to enroll 60 evaluable patients.22 Pracinostat has orphan drug status in Europe and is being evaluated in a randomized phase 3 AML study.23


Venetoclax, a small molecule selective BCL-2 inhibitor, is approved by the FDA for use in combination with an HMA or low-dose cytarabine for treatment of newly diagnosed AML in older adults not suited for intensive induction chemotherapy. A phase 2 trial of venetoclax with 10 days of decitabine in patients with AML (and some high-risk MDS) was described at the most recent ASH annual meeting.24

In an interim analysis, the venetoclax-decitabine regimen had a safety profile that was acceptable, according to investigators, with a rate of CR/CR with incomplete blood count recovery (CRi) of 92% in newly diagnosed AML, and similarly “impressive” response rates in the relapsed/refractory setting, according to investigators. Currently recruiting is a phase 1 study looking at the combination of venetoclax with azacitidine in high-risk MDS.25


  1. Zeidan AM, Stahl M, Hu X, et al. Long-term survival of older patients with MDS treated with HMA therapy without subsequent stem cell transplantation. Blood. 2018;131(7):818-821. doi:10.1182/blood-2017-10-811729
  2. Santini V. How I treat MDS after hypomethylating agent failure. Blood. 2019;133(6):521-529. doi:10.1182/blood-2018-03-785915
  3. Garcia-Manero G, Roboz G, Walsh K, et al. Guadecitabine (SGI-110) in patients with intermediate or high-risk myelodysplastic syndromes: phase 2 results from a multicentre, open-label, randomised, phase 1/2 trial. Lancet Haematol. 2019;6(6):e317-e327. doi:10.1016/S2352-3026(19)30029-8
  4. Garcia-Manero G, Sasaki K, Montalban-Bravo G, et al. Final Report of a Phase II Study of Guadecitabine (SGI-110) in Patients (pts) with Previously Untreated Myelodysplastic Syndrome (MDS). Blood. 2018;132(Suppl 1):232-232. doi:10.1182/blood-2018-99-116838
  5. Garcia-Manero G, Ritchie EK, Walsh KJ, et al. Long Term Results of a Randomized Phase 2 Dose-Response Study of Guadecitabine, a Novel Subcutaneous (SC) Hypomethylating Agent (HMA), in 102 Patients with Intermediate or High Risk Myelodysplastic Syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML). Blood. 2018;132(Suppl 1):231-231. doi:10.1182/blood-2018-99-110465
  6. Guadecitabine (SGI-110) vs Treatment Choice in Adults With MDS or CMML Previously Treated With HMAs. https://clinicaltrials.gov/ct2/show/NCT02907359. Accessed July 1, 2019.
  7. O’Connell CL, Kropf PL, Punwani N, et al. Phase I Results of a Multicenter Clinical Trial Combining Guadecitabine, a DNA Methyltransferase Inhibitor, with Atezolizumab, an Immune Checkpoint Inhibitor, in Patients with Relapsed or Refractory Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia. Blood. 2018;132(Suppl 1):1811-1811. doi:10.1182/blood-2018-99-117658
  8. Odenike O. Incorporating novel approaches in the management of MDS beyond conventional hypomethylating agents. ASH Educ Program Book. 2017;2017(1):460-469. doi:10.1182/asheducation-2017.1.460
  9. Garcia-Manero G, Griffiths EA, Roboz GJ, et al. A 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(Suppl 1):4274-4274.
  10. Study of ASTX727 vs IV Decitabine in MDS and CMML. https://clinicaltrials.gov/ct2/show/NCT03306264. Accessed July 1, 2019.
  11. Columbus G. Novel Cedazuridine/Decitabine Combo Meets Primary Endpoint in Phase III MDS/CMML Trial. OncLive. https://www.onclive.com/web-exclusives/novel-cedazuridinedecitabine-combo-meets-primary-endpoint-in-phase-iii-mdscmml-trial. Accessed July 1, 2019.
  12. Reddy EP, Divakar SK, Carpio RV-D, et al. Rigosertib Blocks RAS Signaling By Acting As a Small Molecule RAS Mimetic That Binds to the RAS-Binding Domains of RAS Effector Proteins. Blood. 2014;124(21):5616-5616.
  13. Controlled Study of Rigosertib Versus Physician’s Choice of Treatment in MDS Patients After Failure of an HMA. https://clinicaltrials.gov/ct2/show/NCT02562443. Accessed July 1, 2019.
  14. Phase II Part 2 Expansion of Oral Rigosertib in Combination With Azacitidine. https://clinicaltrials.gov/ct2/show/NCT01926587. Accessed July 1, 2019.
  15. Navada SC, Garcia-Manero G, Atallah EL, et al. Phase 2 Expansion Study of Oral Rigosertib Combined with Azacitidine (AZA) in Patients (Pts) with Higher-Risk (HR) Myelodysplastic Syndromes (MDS): Efficacy and Safety Results in HMA Treatment Naïve & Relapsed (Rel)/Refractory (Ref) Patients. Blood. 2018;132(Suppl 1):230-230. doi:10.1182/blood-2018-99-119259
  16. Raza A, Al-Kali A, Tibes R, et al. Rigosertib Oral in Transfusion Dependent Lower Risk Myelodysplastic Syndromes (LR-MDS): Optimization of Dose and Rate of Transfusion Independence (TI) or Transfusion Reduction (TR) in a Single-Arm Phase 2 Study. Blood. 2017;130(Suppl 1):1689-1689.
  17. Maniar M, Ren C, Zbyszewski PS, et al. Evaluation of Underlying Cause of Genitourinary (GU) Adverse Events (AEs) in Patients with Myelodysplastic Syndromes upon Oral Administration of Rigosertib: Safety and Pharmacokinetic Analysis of Rigosertib across Three Clinical Trials. Blood. 2018;132(Suppl 1):3106-3106. doi:10.1182/blood-2018-99-116982
  18. Fathi AT. Pevonedistat, a new partner for 5-azacitidine. Blood. 2018;131(13):1391-1392. doi:10.1182/blood-2018-02-829051
  19. Swords RT, Coutre S, Maris MB, et al. Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML. Blood. 2018;131(13):1415-1424. doi:10.1182/blood-2017-09-805895
  20. Sekeres MA, Fram RJ, Hua Z, Ades L. Phase 3 study of first line pevonedistat (PEV) + azacitidine (AZA) versus single-agent AZA in patients with higher-risk myelodysplastic syndromes (HR MDS), chronic myelomonocytic leukemia (CMML) or low-blast acute myelogenous leukemia (AML). J Clin Oncol. 2018;36(15_suppl):TPS7077-TPS7077. doi:10.1200/JCO.2018.36.15_suppl.TPS7077
  21. Garcia-Manero G, Montalban-Bravo G, Berdeja JG, et al. Phase II Randomized Double-Blinded Study of Pracinostat in Combination with Azacitidine in Patients with Untreated Higher-Risk Myelodysplastic Syndromes. Cancer. 2017;123(6):994-1002. doi:10.1002/cncr.30533
  22. Keng MK, Khaled SK, Cooper B, et al. Planned Interim Analysis of a Phase 2 Study Evaluating the Combination of Pracinostat, a Histone Deacetylase Inhibitor (HDACi), and Azacitidine in Patients with High/Very High-Risk Myelodysplastic Syndrome (MDS). Blood. 2018;132(Suppl 1):4362-4362. doi:10.1182/blood-2018-99-112741
  23. An Efficacy and Safety Study Of Pracinostat In Combination With Azacitidine In Adults With Acute Myeloid Leukemia. https://clinicaltrials.gov/ct2/show/NCT03151408. Accessed July 1, 2019.
  24. Maiti A, DiNardo CD, Cortes JE, et al. Interim Analysis of Phase II Study of Venetoclax with 10-Day Decitabine (DEC10-VEN) in Acute Myeloid Leukemia and Myelodysplastic Syndrome. Blood. 2018;132(Suppl 1):286-286. doi:10.1182/blood-2018-99-113749
  25. A Study Evaluating Venetoclax Alone and in Combination With Azacitidine in Subjects With Relapsed/Refractory Myelodysplastic Syndromes (MDS). https://clinicaltrials.gov/ct2/show/NCT02966782. Accessed July 1, 2019.

For more information on managing your patients with MDS, please view the CE Education activity here.

Last modified: September 16, 2019