By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

The Food and Drug Administration has approved an oral fixed-combination medication for the treatment of adults with myelodysplastic syndromes (MDS). The combination is comprised of decitabine, a nucleoside metabolic inhibitor/hypomethylating agent, and cedazuridine, a cytidine deaminase (CDA) inhibitor. Inhibition of CDA reduces the degradation of decitabine in the gastrointestinal tract and liver-preserving oral bioavailability. Before this combination, decitabine was given by intravenous (IV) infusion over three or five days, which required a visit to a healthcare facility. Decitabine and cedazuridine (DEC/CED) received priority review and fast-track breakthrough therapy designations. It is distributed as Inqovi.

INDICATIONS

DEC/CED should be prescribed to treat adult patients with MDS. This includes previously untreated and treated de novo and secondary MDS with the following French-American-British subtypes: chronic myelomonocytic leukemia (CMML); intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups; and refractory anemia, refractory anemia with excess blasts, and refractory anemia with ringed sideroblasts.1

DOSAGE

The recommended dose is one tablet orally once daily on days 1 through 5 of each 28-day cycle at the same time each day on an empty stomach.1 Food should not be ingested two hours before or two hours after each dose. Dose reduction/modification is recommended for myelosuppression, elevation of serum creatinine, serum bilirubin, liver enzymes, or active or uncontrolled infections.1 Each tablet contains 35 mg of DEC and 100 mg of CED.

POTENTIAL ADVANTAGES

This oral formulation provides a much more convenient administration compared to the IV infusion that necessitated a visit to a healthcare facility for administration. The systemic exposure of DEC/CED after five consecutive once-daily dosing days is comparable to that of IV DEC, with a cumulative mean ratio of area under the plasma time curve of 99% (90% confidence interval, 93-106).1

POTENTIAL DISADVANTAGES

The frequencies of adverse reactions generally were similar between DEC/CED and IV DEC.1 In clinical trials, 5% of subjects permanently discontinued the drug because of adverse reactions, 41% reported dose interruptions, and 19% experienced dose reduction.1 Serious and fatal adverse reactions with DEC/CED are related to myelosuppression, such as Grade 3 and 4 thrombocytopenia (76%), neutropenia (73%), and anemia (71%).1

COMMENTS

Aberrant DNA methylation is a possible mechanism of pathogenesis in MDS. DEC is a hypomethylating agent because it inhibits DNA methyltransferase.1 DEC/CED was compared to IV DEC in two open-label, randomized, two-cycle, two-sequence, crossover studies.1,2 In both studies, subjects with MDS or CMML (n = 80; n = 133) were randomized to DEC/CED or IV DEC (20 mg/m2) in cycle 1 and the reverse for cycle 2 for days 1 through 5 of each 28-day cycle. Starting with cycle 3, all subjects took DEC/CED until disease progression or unacceptable toxicity. Pharmacokinetics and pharmacodynamic assessments were observed in the intrasubject crossover cycles 1 and 2. The two formulations showed comparable systemic exposure and in percent change in demethylation from baseline. Clinical response was based on complete response (CR) and the rate of conversion from transfusion dependence to transfusion independence, starting with cycle 3.

In the first study, after a median duration of treatment of 6.6 months and median follow-up time of 24 months, CR rate was 18%, with a median duration of 8.7 months and median time to CR of 4.8 months. Twenty of 41 subjects who were red blood cell- and/or platelet transfusion-dependent were transfusion-independent in any 56-day post-baseline period. Sixty-four percent of those who were transfusion-independent remained transfusion-independent.

In the second study, the CR rate was 21%, with a median duration of CR of 7.5 months and median time to CR of 4.3 months. Thirty of 57 transfusion-dependent subjects became transfusion-independent, and 48 of 76 remained transfusion-independent. CR rates were similar to those reported for the IV formulation.3,4

CLINICAL IMPLICATIONS

MDS is a group of blood and bone marrow disorders that is considered a form of cancer.5,6 It is characterized by stem cells not maturing properly, resulting in immature and abnormally developed cells in the circulation, with fewer normal healthy red cells, white cells, and/or platelets. There are seven subtypes, with some subtypes progressing to acute myeloid leukemia. The National Comprehensive Cancer Network recommends azacitidine or DEC for most patients with clinically relevant thrombocytopenia or neutropenia or increased marrow blasts. Both require parenteral administration with DEC, which requires IV infusion over one to three hours with monthly, multiple-day administrations.

DEC/CED provides an oral option for a drug that requires long-term administration with comparable pharmacokinetic and pharmacodynamic assessments and with clinical responses consistent with IV DEC. Hypomethylating agents, such as DEC, result in a 40% to 50% response rate, with 10% to 20% complete response.4 The responders also tend to experience disease progression with loss of response over time.4 Therefore, new treatment options still are needed. The cost for DEC/CED was unavailable at the time of this review.

REFERENCES

  1. Taiho Oncology, Inc. Inqovi prescribing information. July 2020.
  2. Garcia-Manero G, Griffiths EA, Steensma DP, et al. Oral cedazuridine/decitabine for MDS and CMML: A phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Blood 2020;136:674-683.
  3. BluePoint Laboratories. Decitabine.
  4. Uy N, Singh A, Gore SD, Prebet T. Hypomethylating agents (HMA) treatment for myelodysplastic syndromes: Alternatives in the frontline and relapse settings. Expert Opin Pharmacother 2017;18:1213-1224.
  5. American Society of Clinical Oncology. Myelodysplastic syndromes — MDS: Introduction. December 2017.
  6. American Cancer Society. About myelodysplastic syndromes.