Guillermo Garcia-Manero, MD from The University of Texas MD Anderson Cancer Center speaks about ASH 2020 Abstract – 1230 Clinical Efficacy and Safety of Oral Decitabine/Cedazuridine in 133 Patients with Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)Clinically Relevant Abstract
Introducing:
The standard of care for the treatment of MDS and CMML is developed with hypomethylating agents (HMAs) or DNA methyltransferase inhibitors (DNMTi) such as decitabine or azacitidine. Because of the rapid degradation of cytidine deaminase (CDA) in the gut and liver, the oral bioavailability of these agents has been reduced, requiring intravenous infusion or subcutaneous injections daily for 5-7 days per month (m). Owing to regular time commitment and travel to treatment facilities, this parenteral administration provision brings major burdens to older cancer patients. It also raises the risk of exposure to SARS-CoV-2 and infection during the COVID-19 pandemic. In a randomized cross-over trial, oral decitabine 35 mg/cedazuridine 100 mg (ASTX727) is an oral fixed-dose combination drug of decitabine and the CDA inhibitor cedazuridine showing 99 percent (90 percent CI 93 to 106 percent) comparable sensitivity to standard IV dose decitabine 20 mg/m2 (Garcia-Manero et al, ASH 2019). The clinical effectiveness and safety findings of oral decitabine/cedazuridine from 133 patient trials of MDS and CMML are presented here (ASTX727-02 ASCERTAIN study).
Methodology:
A randomized crossover design was used in which patients were randomized to either Sequence A: decitabine 35 mg/cedazuridine 100 mg in Cycle 1 followed by IV decitabine 20 mg/m2 in Cycle 2 or Sequence B: IV decitabine in Cycle 1 followed by oral decitabine/cedazuridine in Cycle 2 in order to conduct an intra-patient comparison of decitabine PK (primary PK endpoint: decitabine AUC equivalence over 5 days of dosing). There were repeated cycles every 28 days. In all subsequent cycles from Cycle 3 onwards, all patients received oral decitabine/cedazuridine before disease development or unacceptable toxicity. Patients were eligible for IV decitabine, as per the FDA-approved mark (MDS patients by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk patients). Best response as determined by an independent panel of experts in compliance with the 2006 International Working Group (IWG) response criteria, transfusion independence for at least 8 or 16 consecutive weeks, overall survival, and protection were the clinical endpoints. Adverse effects (AEs) are classified by the Common Adverse Events Terminology Criteria (CTCAE) v 4.03.
Outcomes:
138 participants, 133 of whom were treated in the sample, were randomized. The median age was 71.0 years (range 44-88), 65 percent were male, 88 percent were MDS and 12 percent were CMML, 43 percent were either red blood cells (RBCs) or platelet transfusion-dependent at baseline, 25 percent had cytogenetics of poor risk, and 42 percent had >5 percent baseline bone marrow blasts. The median follow-up length was 12.6 m (range 9.3 to 20.5 m) at the data cutoff for the response study, with a median number of treatment cycles of 8. (range 1 to 18). The best response was complete response (CR) in 28 patients (21%; 95% CI 15-29%), marrow (m)CR with hematological improvement (HI) in 20 patients (15%), mCR without HI in 23 patients (17.3%) and HI in 10 patients (7.5%) for an overall objective response (CR+mCR+HI) in 81 patients among the 133 patients handled (61 percent; 95 percent CI 52-69 percent ). The median CR length was 7.5 m (range 1.6 to 17.5 m), and the median CR time was 4.3 m (range 1.6 to 17.5 m) (range 2.1 to 15.2 m). 27 (20 percent) of the 133 patients treated underwent allogeneic hematopoietic cell transplantation. Of the 57 patients who were either RBCs or transfusion-dependent platelets at baseline, 30 (53 percent) were transfusion independent for at least 8 consecutive weeks for both RBCs and platelets, and 19 (33 percent) became transfusion independent for at least 16 consecutive weeks for both RBCs and platelets. It has not achieved median survival. Neutropenia in 51.5 percent, thrombocytopenia in 50 percent, anemia in 40 percent, febrile neutropenia in 26 percent, leukopenia in 21 percent, pneumonia in 12 percent, and sepsis in 7 percent of patients treated with oral decitabine/cedazuridine were the most common treatment-Emergent AEs of Grade 3 regardless of causality (excluding the IV decitabine cycle).
Overview/Conclusions:
Clinical results for regular IV decitabine 20 mg/m2 daily for 5 days are consistent with the efficacy and protection of oral decitabine 35 mg/ cedazuridine 100 mg daily for 5 days every 28 days. The only oral HMA with systemic exposure comparable to its injectable drug is oral decitabine/cedazuridine. An all-oral combination trial, further study of oral decitabine/cedazuridine is warranted and is underway.