Oral HMAs May Provide Safer and More Effective Treatment Options for MDS


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Guillermo Garcia-Manero, MD, spotlights the evolution of oral azacitidine- and decitabine-based regimens for MDS.

Guillermo Garcia-Manero, MD

Guillermo Garcia-Manero, MD

The FDA-approved oral formulation of decitabine/cedazuridine (Inqovi), as well as the investigational oral azacitidine/cedazuridine combination (ASTX030), are expanding the myelodysplastic syndrome (MDS) treatment armamentarium as more tolerable combinations compared with intravenous (IV) or subcutaneous hypomethylating agents (HMAs) and may also provide efficacy and logistics benefits vs non-oral formulations.

In an OncLive® Insights video series, Guillermo Garcia-Manero, MD, spotlighted the current roles for IV and subcutaneous HMAs for patients with MDS; the evolution of oral azacitidine- and decitabine-based regimens for both low-risk and high-risk disease; and the importance of monitoring patients for cytopenias and other adverse effects (AEs) associated with these treatment regimens.

Garcia-Manero is a professor, chief of the Section of Myelodysplastic Syndromes, deputy chair of Translational Research, and the fellowship program director in the Department of Leukemia in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, where he is also the chair of the Faculty Senate.

MDS Risk Stratification

Garcia-Manero began the discussion by explaining the traditional parameters through which patients with MDS are categorized as having lower-risk or higher-risk disease: the percentage of blasts, the degree of cytopenias, and the presence of chromosomal or cytogenetic alterations. He noted that current MDS risk stratification methods also consider the molecular profile of the disease. The Revised International Prognostic Scoring System (IPSS-R) refined the cytogenetic classification of MDS by organizing patients as having very low–, low-, intermediate-, high-, or very high-risk disease. “That created a little bit of confusion because the division between lower- and higher-risk disease was not that straightforward,” Garcia-Manero said.

A new classification system, the Molecular IPSS (IPSS-M), stratifies patient risk based on molecular data from commonly mutated genes, such as TP53. “We are starting to say that patients with lower-risk disease will be those with very low-, moderate-, or low-[risk disease], and the rest will [have] high-risk disease,” Garcia-Manero noted.

Importantly, he explained that many patients’ diseases are upstaged when classified using the IPSS-M vs the IPSS-R. “[In] patients who were intermediate- or low-risk when you put the molecular data in their profile, meaning when you calculate [their disease risk] by the IPSS-M, now they [seem to have] high- or very high-risk disease,” Garcia-Manero said.

Expanding the Role of HMAs

Two HMAs, azacitidine and decitabine, are FDA approved for the treatment of patients with MDS. Garcia-Manero delved into the benefits and drawbacks of these standard agents, citing their favorable safety profiles, which stand at odds with their low response rates. “These are our workhorses in terms of how we treat [patients with] intermediate- and high-risk MDS, and they’ve been important to us…but their activity is modest,” he explained.

Garcia-Manero noted that the phase 3 AZA-001 trial (NCT00071799) produced encouraging data with azacitidine vs standard of care (SOC) in patients with higher-risk MDS, with a median overall survival (OS) of 24.5 months (95% CI, 9.9-not reached) vs 15.0 months (95% CI, 5.6-24.1), respectively (HR, 0.58; 95% CI, 0.43-0.77; stratified log-rank P = .0001).1 “In the real world, the survival with single-agent HMAs…is probably below 20 months,” he postulated. Additionally, most patients with MDS who receive HMAs will relapse or progress and have a poor prognosis, he said. Furthermore, decitabine and azacitidine are “chronic drugs,” which patients must receive for the first 3 to 52 or 7 days,2,3 respectively, of each cycle, until they become ineffective or induce intolerable toxicities.

“From the beginning, we wanted to have an oral approach for these compounds,” Garcia-Manero said. In the AML armamentarium, CC-486, an oral azacitidine compound, was approved by the FDA in 2020.4 That same year, the combination of oral decitabine and the cytidine deaminase inhibitor cedazuridine was approved by the FDA for patients with MDS, based on findings from the ASTX727-01-B trial (NCT02103478) and the ASCERTAIN trial (NCT03306264), in which decitabine/cedazuridine elicited respective complete response (CR) rates of 18% (95% CI, 10%-28%) and 21% (95% CI, 15%-29%).5 “We believe this is transformative for patients because now [they] don’t have to take a shot 5 or 7 days a month,” Garcia-Manero explained.

The efficacy of the oral decitabine-based combination may also be more robust than that of IV decitabine, although head-to-head data have yet to be generated, Garcia-Manero noted. Oral decitabine/cedazuridine is also under investigation in combination with venetoclax (Venclexta), IDH1/2 inhibitors, menin inhibitors, and FLT3 inhibitors. Garcia-Manero and colleagues conducted a study of oral decitabine/cedazuridine plus venetoclax in patients with MDS and chronic myelomonocytic leukemia (CMML), in which the oral combination elicited an overall response rate of 94.5% and a CR rate of 35.1%.6 “It’s going to be interesting to see how these kinds of oral approaches…are going to impact the real-world [use] of these HMAs,” he said.

Furthermore, as ASCERTAIN used the IPSS-M to risk-stratify patients, many patients enrolled in the trial were found to have higher-risk disease than they would had they been classified through other stratification systems, which “makes the clinical activity of [decitabine/cedazuridine] more significant,” he said. A retrospective analysis of ASCERTAIN also revealed that 44 of 125 of patients enrolled in the trial had TP53 mutations.7 “That’s the…worst prognostic feature that we have right now in MDS,” Garcia-Manero stated, sharing that patients with TP53 mutations have an expected OS of less than 1 year. However, the analysis showed prolonged OS and leukemia-free survival with oral decitabine/cedazuridine vs IV decitabine in patients with TP53 mutations. “We’re now performing more advanced studies trying to see if this kind of signature with TP53-mutated disease holds, because that could be important for patients and for our understanding of clinical trial design,” Garcia-Manero said.

Following the favorable outcomes with oral decitabine/cedazuridine in ASCERTAIN, Garcia-Manero and colleagues developed an oral regimen of azacitidine plus cedazuridine. Preliminary phase 1 data were presented at the 2023 ASH Annual Meeting and demonstrated that the 20 mg dose of cedazuridine resulted in approximately 100% bioavailability of azacitidine.8 “We believe that we have achieved the proper ratio of azacitidine vs cedazuridine that could allow us to develop a completely identical pharmacological form of oral azacitidine/cedazuridine compared with IV or subcutaneous azacitidine,” Garcia-Manero said. “This…could be transformative because the most commonly used HMA is azacitidine, and by using a drug that is virtually pharmacokinetically and pharmacodynamically identical, we could [provide] total oral programs for our patients.”

Oral HMA regimens may contribute to deeper and more robust responses in patients with MDS because prolonged, uninterrupted exposure to these agents is associated with improved treatment outcomes, according to Garcia-Manero. Although receiving an all-oral HMA-based regimen may require initial use of prophylactic antibiotics or periodical transfusional support throughout follow-up, “once these patients are responding to therapy, this [regimen] becomes quite easy and straightforward with proper clinical follow-up,” Garcia-Manero said. Moreover, many patients with MDS, particularly those who are older, are undertreated because of issues including barriers to transportation to infusion sites. “An oral approach could expand the treatment of this population in need,” Garcia-Manero emphasized.

Monitoring Oral HMA Administration

“Physicians and patients should not assume that because these drugs are oral, [patients] don’t need to see the clinician or have lab work because at the end of the day, yes, these are oral compounds, but they are the same drugs [as] azacitidine or decitabine,” Garcia-Manero explained. “They are forms of chemotherapy and are indeed cytotoxic, so [patients] require the same amount of support.” Garcia-Manero recommended patients see a physician on the first day of each month they receive the agent and continue to receive appropriate laboratory work to monitor the incidence of cytopenias. “You should support the patients the same way you [would] support patients [receiving] IV or subcutaneous [HMAs],” he noted.

HMAs in Lower-Risk MDS and CMML

Garcia-Manero also emphasized the potential use of azacitidine and decitabine in patients with lower-risk MDS. “We have been working on different formulations of…decitabine/cedazuridine…that could be a safer way to treat patients with lower-risk disease,” Garcia-Manero added. Since the oral HMA formulation of decitabine/cedazuridine is currently approved as a fixed-dose combination, he recommended using a 3-day dosing schedule of this regimen in patients with lower-risk MDS.

Garcia-Manero also discussed the possibility of using HMAs in patients with CMML. “Traditionally, we have considered patients with CMML as part of the spectrum of MDS, but the reality is that we understand [CMML] as a different biology, a different disease entity,” he noted. A subgroup analysis of ASCERTAIN showed that oral decitabine/cedazuridine is a reasonable treatment option for patients with CMML.9 Using an oral HMA formulation in the CMML population would be advantageous for several patients with CMML who also receive oral hydroxyurea, Garcia-Manero explained.

Managing HMA-Associated AEs

Although azacitidine and decitabine are relatively well tolerated, they are associated with myelosuppression, including neutropenia, anemia, and thrombocytopenia, which most frequently occur during the first 1 to 2 months of therapy, Garcia-Manero explained. The use of prophylactic antibiotics, antifungals, and clinical follow-up with potential complete blood cell [monitoring] and transfusions are all mandatory aspects of safely prescribing these agents, he emphasized. Additionally, routine bone marrow assessments can help oncology care teams monitor patient responses and determine how to proceed with the next treatment cycle.

Garcia-Manero also emphasized the importance of educating patients about the AEs they might experience while receiving HMAs. Patients should be aware of the possibility of a temporary increase in the incidence of cytopenias during the first months of therapy. “It’s fundamental to explain to the patient in detail what’s going to happen over the next few months and give some instructions in terms of when to come to the emergency room, how to take the antibiotics, and the expectations in terms of their [white blood cell (WBC)] counts,” he said.

The decision to reduce or adjust HMA dosing depends on baseline characteristics, including WBC counts, blast percentages, and bone marrow cellularity, as well as the time it takes for patients to recover from AEs, Garcia-Manero noted. Patients whose WBC counts return to normal levels by day 28 of their current cycle do not need dose adjustments. However, dose reductions or treatment delays may be necessary in patients with progressive myelosuppression, significant cytopenias, or hypocellular marrow counts. In these circumstances, a 5-day regimen of decitabine/cedazuridine may need to be reduced to 4 or 3 days, he said.

Overall, Garcia-Manero emphasized that the emerging era of oral HMA-based regimens in MDS “is going to be transformative for our patients…The field is moving toward the incorporation of these active oral approaches with a backbone of these oral HMAs.”


  1. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, 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. doi:10.1016/S1470-2045(09)70003-8
  2. Decitabine. Prescribing information. FDA; 2018. Accessed January 22, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021790s021lbl.pdf
  3. Azacitidine. Prescribing information. FDA; 2022. Accessed January 22, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/050974s034lbl.pdf
  4. FDA approves Onureg (azacitidine tablets) for acute myeloid leukemia. FDA. September 1, 2020. Accessed January 22, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-onureg-azacitidine-tablets-acute-myeloid-leukemia
  5. FDA approves oral combination of decitabine and cedazuridine for myelodysplastic syndromes. FDA. July 7, 2020. Accessed January 18, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-oral-combination-decitabine-and-cedazuridine-myelodysplastic-syndromes
  6. Bataller A, Bazinet A, Venugopal S, et al. Phase 1/2 study of oral decitabine/cedazuridine in combination with venetoclax in treatment-naïve higher-risk myelodysplastic syndromes or chronic myelomonocytic leukemia. Hemasphere. Published online August 8, 2023. doi:10.1097/01.HS9.0000967600.18588.ff
  7. Savona MR, McCloskey JK, Griffiths EA, et al. Prolonged survival in bi-allelic TP53-mutated (TP53mut) MDS subjects treated with oral decitabine/cedazuridine in the ascertain trial (ASTX727-02). Blood. 2022;140(suppl 1):2066-2069. doi:10.1182/blood-2022-163841
  8. Garcia-Manero G, McCloskey J, Scott BL, et al. Development of oral azacitidine with cedazuridine for myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPN) including CMML (chronic myelomonocytic leukemia) by targeting pharmacokinetic AUC equivalence vs subcutaneous azacitidine. Blood. 2023;142(suppl 1):3245. doi:10.1182/blood-2023-178024
  9. Savona MR, McCloskey JK, Griffiths EA, et al. Efficacy of oral decitabine/cedazuridine (ASTX727) in the CMML subgroup from the Ascertain phase 3 study. Blood. 2021;138(suppl 1):3682. doi:10.1182/blood-2021-154179
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