Azacitidine with Oral Cytarabine and Etoposide Induces Immediate Hematological and Cytogenetic Response in Higher Risk Myelodysplastic Syndromes Even in Single Azacitidine Resistance

Background: Although azacitidine (AZA) induces high hematological response and delayed progression to acute myeloid leukemia (AML) in patients with myelodysplastic syndromes (MDSs), its cytotoxic and cytogenetic effects are relatively poor. Moreover, the prognosis of patients at very high risk in the revised international prognostic scoring system (IPSS-R), with poor cytogenetics including complex abnormalities and monosomy 7, and with AZA resistance is extremely poor. Therefore, AZA-based combination therapy with low toxicity is warranted. In the past, effective low-dose etoposide (VP16) and cytarabine ocfosphate (SPAC) combination therapy for refractory MDS and AML was reported. Here, we report 10 higher-risk MDS and AML patients treated with AZA in combination with oral VP16 and SPAC.

Patients and methods: AZA (75 mg/m² daily for 7 days) in combination with SPAC (300 mg daily for 14 days) and VP16 (25 mg daily for 14 days) was administered to 10 patients (median age, 80 years; range, 48 to 90) with newly diagnosed (n=2) and previously AZA-treated (n=8) MDS and AML between December 2013 and April 2015. The diagnoses were RCMD (n=2), RAEB1 (n=2), RAEB2 (n=1), CMML (n=1), and AML-MRC (n=4). IPSS-R categories were low (n=1), intermediate (n=3), high (n=2), and very high (n=4). In 8 AZA-treated patients, its median cycle before this study was 11 (1-30). Results: In the pretreatment period, neutrophil count, platelet count, hemoglobin level, bone marrow blast rate, and WT1 were 805/µl (170-2700), 53.0 (25-222) × 10⁹/l, 8.4 g/dl (7.2-13.5), 6.5% (1.4-30.0), and 1200 (200-31,000) copies/µg RNA, respectively. Five out of 10 had complex karyotype abnormalities. After 1 course of treatment, the overall response rate was 100%. The rate of any hematological improvement (HI) was 90% (9 out of 10) including HI-neutrophil (HI-N) for 67%, HI-platelet (HI-P) for 75%, and HI-erythroid (HI-E) for 0%. Marrow CR (mCR) and cytogenetic response rates were 67% (6 out of 9) and 83% (5 out of 6), respectively. Notably, 3 out of 4 complex abnormalities were also improved. Moreover, WT1 was decreased from 1200 to 60 copies/µg RNA. Interestingly, all (4 out of 4) of the patients with erythroblast hyperplasia or strong erythroid dysplasia exhibited HI-P, HI-N, blast decrease, and at least one log decrease of WT1 copy number. Owing to high marrow suppression including 100% of grade 3 to 4 neutropenia and all patients but 1 with grade 3 to 4 thrombocytopenia, the time to the second course was longer (43 days) than for single AZA. The times to elevation of neutrophils (>500/µl) and platelets (>50×10⁹/L) were 35 and 37.5 days, respectively. Although 70% (7 out of 10) of patients suffered from infection including febrile neutropenia, no other grade 3 to 4 non-hematological adverse events (AEs) resulting in therapy-related death occurred. At present, four of 10 are continuing AZA without disease progression (PD), 2 patients discontinued it due to impaired quality of life (QOL) and the remaining 4 patients had PD (median 6 months). With a median follow-up time of 24 months from starting AZA alone or in combination, median OS was not reached.

Conclusion: Our AZA-based combination therapy induced immediate cytotoxicity of malignant MDS clone with poor cytogenetics and single AZA resistance. SPAC, VP16 and AZA might promote effect of each other. However, prolonged marrow suppression resulted in severe infection, impaired QOL and a delayed treatment schedule. Therefore, response duration appeared to be relatively short, resulting in shorter survival. Appropriate dose setting and treatment duration, effective infection control methods such as G-CSF administration, and prophylactic antibiotics were warranted. However, this method did not require an intravenous drip and had good cost performance. Finally, our cohort is very small, so further experience is needed.