Hypomethylating agents (HMAs), such as azacitidine and decitabine, are the main treatment options for myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Azacitidine and decitabine are cytotoxic at high doses, while at lower doses they work by inhibiting DNA methyltransferase, irreversibly incorporating into RNA and/or DNA to block this enzyme. This results in decreased methylation of genomic material and alters gene expression, which then leads to apoptosis or enhanced differentiation.
In an article published in Future Oncology, Swapna Thota and colleagues review the current HMAs for MDS and CMML, including a new cedazuridine–decitabine combination, and discuss future treatment options.1
Goals of therapy in MDS and CMML are dependent on whether a patient is classified as high or low risk. For low-risk patients, the focus is on alleviating symptoms. Higher-risk patients look to chemotherapy to reduce the burden of disease alongside allogeneic stem cell transplants.
Traditional therapies and their limitations
Azacitidine and decitabine are the current standard-of-care treatments for MDS. The pivotal trial that showed the value of azacitidine for the treatment of MDS was AZA-001 (NCT00071799), which compared this HMA against the best supportive care (low-dose cytarabine, induction chemotherapy, or supportive care). Increased overall survival (OS) was demonstrated with azacitidine, from 15 months with best supportive treatment to 24.4 months on azacitidine (HR, 0.58; 95% CI, 0.43–0.77).1 Decitabine has shown similar response rates and is used in a similar fashion.
While the survival benefit of HMA treatment is notable, therapy with these agents is not without risk. Responses can be variable and are often short-lived. Cytopenias frequently become worse in the first 1–4 months of treatment and the time to response may be long. In addition, HMAs do not appear to affect the founder clone, and therefore genomic changes remain and drive continued disease evolution.
Currently, azacitidine and decitabine are administered parenterally, which can lead to non-compliance or treatment cessation. For elderly patients and those with mobility issues, getting to the clinic daily for 5−7 days of infusion can be very burdensome, indicating a need for an oral therapy.
Efforts to develop an oral form of decitabine have been slowed, due to problems in bioavailability caused by the enzyme CDA, which metabolizes HMAs into inactive forms. CDA itself can be inhibited by an agent called tetrahydrouridine. While this agent is poorly soluble in water at low pH, such as that of the stomach, a 2’ fluorinated analog, cedazuridine, is stable in gastric acid conditions. An oral formulation with decitabine combined with cedazuridine (c-Dec) has been approved for the treatment of patients with newly diagnosed MDS.
Preclinical studies of c-Dec showed that increased and more consistent decitabine exposure was achieved when using the cedazuridine combination compared to decitabine alone in animal models. With respect to the timing of doses, a strong pharmacokinetic interaction was present even with concomitant dosing, and therefore the fixed dose c-Dec formulation was chosen and produced. Cedazuridine was found to have no notable antiproliferative effect on its own and caused no off-target toxicity. As a result of these preclinical data, c-Dec was advanced for clinical testing in patients.
The phase I/II study found a combination of 100 mg cedazuridine + 30 mg decitabine achieved exposure similar to intravenous (IV) decitabine at 20 mg/m2. The phase III trial included 138 patients with International Prognostic Scoring System intermediate- or high-risk CMML or MDS and achieved the primary endpoint of demonstrating oral vs IV c-Dec pharmacokinetic equivalency.1
Across all trials, 54.4% of patients (N = 248) experienced a severe adverse event, with 11.3% being treatment related. The most frequent life-threatening events were sepsis and febrile neutropenia, and most Grade ≥3 events were hematologic in nature. Cedazuridine contributed minimally to toxicity.
An overall response rate of 62−64% was recorded for c-Dec in the phase II/III studies. A marrow complete remission (CR) was seen in 5−45% and 11−16% reached CR. The median duration of remission was 13.3 months in the phase II trial (95% CI, 6.5–13.8).
Other novel HMAs
Unmodified oral azacitidine
Unmodified oral azacitidine (CC-486) is another therapeutic option, providing more variable exposure at a lower level but for a greater duration (14−21 days). Compared with a single dose of IV azacitidine at 60 or 80 mg, CC-486 delivers 17% bioavailability. In the phase III QUAZAR AML-001 trial (NCT01566695), patients with de novo or secondary acute myeloid leukemia in first remission were treated with maintenance CC-486 for 14 days of a 28 day cycle. An increase in overall survival was seen with CC-486 vs placebo (24.7 months vs 14.8 months; p = 0.0009). In addition to hematologic toxicity, the most frequent adverse events of all grades recorded with CC-486 were nausea (65%), vomiting (60%), and diarrhea (50%).1
SGI-110 has been modified to make it resistant to deamination by the CDA enzyme. SGI-110 comprises decitabine linked to deoxyguanosine via a phosphodiester bond, which results in slower release of decitabine. A phase II study showed that 22% of patients with MDS achieved CR with a median OS of 23.4 months.1 A phase III trial is currently underway (NCT02907359).
With the approval of c-Dec, the stagnation of the therapeutic field for the treatment of MDS has ended. This oral agent shows many benefits over IV therapy in terms of patient compliance, and the efficacy results are promising. In addition, a few novel agents such as SGI-110 and CC-486 have encouraging results but more therapies are still required to treat MDS. Treatment strategies that are able to impact the founder clone are still needed.