Treatment with Oral Azacitidine in Elderly Patients with Higher Risk Myelodysplastic Syndromes after Response to Subcutaneous Azacitidine

Background Hypomethylating agents (HMAs) are the standard of care for (elderly) IPSS-R higher risk MDS (HR-MDS) patients, but HMA treatment for those patients who are not eligible for hematopoietic stem cell transplant has to be continued for very long time to maintain efficacy. This prolonged continuous treatment renders patients dependent on hospital and on caregivers, and as a result, decreases QoL and too often provokes premature interruption of therapy. Oral azacitidine is approved for maintenance therapy of acute myeloid leukemia patients in complete remission after intensive chemotherapy, and it has shown activity in lower risk MDS. Oral decitabine has been recently approved by FDA for treatment of MDS. There are no data regarding maintenance of response achieved by sc azacitidine in HR MDS by switching to the oral formulation. Aim The primary objective of the study is to explore the feasibility of replacing subcutaneous (sc) azacitidine by the oral formulation, in patients with HR-MDS and responding to sc azacitidine as well as the maintenance or improvement of the achieved hematological response (time to relapse/progression).Methods A monocentric, pilot phase 2 study (ClinicalTrials.gov: NCT04806906) was planned to enroll 10 subjects with confirmed diagnosis of MDS or dysplastic non proliferative CMML, IPSS-R higher risks, aged ≥ 65 years, in CR/CRi, PR or SD with HI stable for additional 2 cycles after response at 4-6 cycles of azacitidine therapy, hence a total of at minimum 6 to 8 cycles of sc azacitidine. At screening, morphological MDS diagnosis, cytogenetic analysis, IWG response assessment, bone marrow and peripheral blood sampling for flow cytometric analysis, NGS evaluation of somatic mutations, DNA methylation analysis and HRQoL are performed. During treatment, subjects are assessed for safety, tolerability and efficacy of oral azacitidine. Assessments during treatment include monitoring for AEs, monitoring for loss of response and SPMs, physical examination, vital signs and weight measurement, ECOG performance status, hematology and serum chemistry, serum ferritin level, concomitant medications, therapies and procedures, review of bone marrow aspirate or biopsy. Patients receive 300 mg oral azacitidine for the first 14 days of each 28-day treatment cycle until no longer receiving the benefit or until progression. Dose of oral azacitidine can be de-escalated based on toxicity. Besides feasibility of treatment with oral azacitidine, we evaluate safety/tolerability, time to treatment discontinuation, and patient-reported outcomes, utilizing the EQ-5D, and measures of healthcare resource utilization. DNA methylation pattern of bone marrow CD34 positive cells at diagnosis, after response to sc azacitidine, and after 2 and 4 cycles of oral azacitidine is also determined by ERRBS for all patients. Results As per August 1, 2022, with a follow up ranging from 1-10 months, 5 HR MDS patients have been enrolled in the study. Median age is 81 yrs (79-86). Male/female ratio: 4/1. At start of therapy with sc azacitidine IPSS-R risk was high 3/5, very high 2/5. Median number of cycles of sc azacitidine is 25 (7-56), median number of cycles of oral azacitidine is 4 (1-9). The dose of 300mg/day was maintained for all patients. Pattern of DNA methylation determined by ERRBS is available for all treated patients and confirms the activity of oral azacitidine. Two patients evolved to AML after 9 and 4 cycles of oral azacitidine, with progression free survival (PFS) from onset of therapy of 17 and 12 months respectively. None of those 2 patients had adverse events during therapy. Treatment was interrupted after 2 cycles in 1 patient following a GI event grade 3 and following patient decision; 2 patients are still ongoing without report of hematological or non-hematological toxicity. At present 1/5 patients died with AML. Conclusions. The patients included in this study were HR MDS, particularly frail, not eligible to investigational studies because of poor compliance and very old median age. The administration of oral azacitidine in patients who responded to sc azacitidine is feasible, the treatment is very well tolerated with no AEs different from those observed in sc azacitidine treatment. Two of five treated patients experienced progressive disease after >12 months of HMA therapy from diagnosis. Oral azacitidine may allow prolonged and continuous treatment in frail HR MDS, optimizing outcome.

Santini:AbbVie: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Sanna:Janssen: Consultancy, Honoraria, Other: travel, Speakers Bureau; Abbvie: Honoraria, Other: travel, Speakers Bureau; Astra Zeneca: Honoraria, Speakers Bureau.

oral azacitidine in higher risk myelodysplastic syndromes