In this interview, Olatoyosi Odenike, MD, speaks with i3 Health about the approval of oral decitabine/cedazuridine (Inqovi®, Astex Pharmaceuticals, Inc.) for adult patients with myelodysplastic syndromes (MDS). Dr. Odenike, Director of the Leukemia Program at the University of Chicago and an investigator of one of the clinical trials on which the approval was based, discusses the challenges of treating patients with MDS and the significance of the approval of oral decitabine/cedazuridine.
What are some of the most challenging aspects of treating patients with MDS?
Olatoyosi Odenike, MD: Myelodysplastic syndromes are a heterogenous group of hematopoietic stem cell disorders characterized by bone marrow failure and a variable propensity towards evolution to acute myeloid leukemia (AML). Current standard approaches are not curative. Approximately 40% to 50% of patients will not respond to azanucleoside therapy, and for those who respond, disease progression inevitably occurs after a variable period of time. Infections, bleeding complications, red blood cell and/or platelet transfusion dependency, and transformation to AML all have a significant impact on quality of life and survival. Allogeneic stem cell transplant is the only known cure, but since MDS is generally a disease of older adults, many patients may not be eligible for transplant due to multiple associated comorbid conditions and diminished performance status or fitness level.
Therefore, clinical and translational investigation focused on promising new approaches for the treatment of our patients with MDS is of the utmost importance. Basic science investigation to understand the fundamental drivers of this disease, which may then lead to more effective therapies for our patients, is also of paramount importance.
What questions do you commonly encounter from patients with MDS, and how do you counsel them?
Dr. Odenike: Patients frequently want to know what caused this disease and what its manifestations are. MDS is a clonal stem cell disorder/blood cancer that is characterized by gene mutations, chromosomal abnormalities, and the possibility of evolving to a more aggressive blood cancer. In general, it's a disease of older adults, though specific causal factors are not well understood at this time. In a proportion of patients, especially in those with a family history of blood or bone marrow malignancies or other malignancies, there could be an inherited predisposition that merits further investigation. Prior exposure to chemotherapy and/or radiation for another cancer can also predispose to MDS. Exposure to certain environmental toxins or chemicals has been implicated, as well. For many of our patients, however, a specific cause is often not evident.
Manifestations of the disease include low blood counts and other symptoms attributable to bone marrow failure, such as fatigue, infections, and bleeding. To address these issues, we focus on obtaining a comprehensive assessment of the patients and the disease at the time of presentation, in order to get a more nuanced sense of what the approach to therapy should be.
Patients also want to know whether their disease is treatable and curable, as well as how much time they may have. In general, MDS is treatable, as therapy is directed towards improved hematopoiesis or bone marrow function and preventing transformation to a more aggressive state. The disease can be curable with an allogeneic hematopoietic stem cell transplant, which may be of benefit in certain patients after factoring in their comorbidities, level of fitness, and disease characteristics. Risk stratification of the disease is important in order to determine if a transplant recommendation is likely to be of benefit to the individual.
Counseling patients on how much time they have is variable, as it is impossible to predict perfectly. We have imperfect prognostic models, and as oncologists, we go through the parameters with patients to determine the risk and aggressiveness of their disease. Most importantly, we do our best to tailor our treatment recommendations to improve the odds of prolonging survival. This may include offering a clinical trial that may provide an opportunity to access novel approaches focused on improving upon standard outcomes and expectations.
Can you comment on the significance of the approval of oral decitabine/cedazuridine for patients with MDS?
Dr. Odenike: For patients with MDS, especially those with higher-risk disease, treatment with azanucleosides—namely, azacitidine or decitabine, both of which are commercially available only as parenteral formulations—is the standard of care. Treatment with these agents is generally ongoing for as long as the patient is deriving benefit, and treatment cycles are given roughly one week on and three weeks off. For parenteral decitabine, this implies that patients have to come into their oncologist's office daily for intravenous (IV) injections five days in a row. Some patients are on therapy for one to two years, and this works out to a lot of back and forth to the office.
Having an oral formulation adds significant convenience for patients in regard to cutting down on visits, and it also eliminates the need for repeated IV injections. Compared with the IV treatment, oral decitabine/cedazuridine performed similarly in regard to drug levels, pharmacokinetic profile, efficacy, and safety. From a clinical investigation standpoint, having an oral formulation may lend itself more easily to combinatorial therapy with other investigational oral agents that are showing promise in clinical trials in MDS. There may also be an opportunity to more easily investigate other schedules of oral administration in the clinical trial setting in order to further optimize activity beyond the current conventional schedule, Days 1-5 of every 28-day cycle.
Are there any particular adverse events that physicians and nurses should monitor for in patients with MDS receiving oral decitabine/cedazuridine?
Dr. Odenike: Myelosuppression occurs with the oral formulation to a similar degree as seen with the IV formulation. Therefore, despite the fact that this treatment is given orally, it is essential for patients to have blood counts monitored frequently, especially early on. Appropriate supportive care, including transfusion support as necessary, also needs to be employed.
About Dr. Odenike
Olatoyosi Odenike, MD, is a Professor of Hematology/Oncology and Director of the Leukemia Program at the University of Chicago Medicine. She is also Vice Chairman of the Medical Advisory Board for the Aplastic Anemia and MDS (AAMDS) International Foundation. Dr. Odenike specializes in the treatment of acute and chronic leukemias, chronic myeloproliferative diseases, and MDS. Her research focuses on the development of novel therapies to improve treatment options and outcomes in patients with myeloproliferative disorders and leukemia, with a particular focus on molecularly targeted agents. She serves on the editorial board of Frontiers in Hematology-Oncology and the Blood Cancer Journal and serves as a reviewer of several other medical journals.
For More Information
Savona MR, Odenike O, Amrein PC, et al (2019). An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicenter, open-label, dose-escalation, phase 1 study. Lancet Haematol, 6(4):e194-e203. DOI:10.1016/S2352-3026(19)30030-4
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of i3 Health.