Treatment of AML with Myelodysplasia Related Changes(AML-MRC) By Sequential Therapy of Azacitidine (AZA) and Intensive Chemotherapy
Authors: Kyo Taiichi , Kyo Kouhei , Toishikawa Kayo , Imanaka Ryota , Ochi Tetsuro , Katayama Yuta , Okatani Takeshi , Itagaki Mitsuhiro , Iwato Koji , Asaoku Hideki 
Published: October 2019

Abstract
Background
Azacitidine (AZA) and intensive chemotherapy (IC) are respectively effective for MDS-MRC to some extent. However, their median overall survivals (OS) are within 1 year in the previous reports.
Aims
The remission induction therapy is performed with AZA for patients with the bone marrow (BM) blast of <30% and with IC for patients with the BMblast of >30% to improve CR rate. The patients who reached CR with AZA or IC, maintenance therapy by sequential AZA and IC were performed to prolong the OS.
Patients and methods
Sixty-six patients,who were diagnosed as AML-MRC from December, 2011 to March, 2014 in our institution were included. AZA was administered by drip infusion at a dose of 75 mg/m2 for 5 days every 26 day. As the IC, IBMP (idarubicin,behenoyl-ara-C (enocitabine), mercaptopurine, and prednisolone) was administered for 10 days. The patients ,who reached CR with AZA or IBMP, then sequential therapy of AZA for 5 days and mini-IBMP for 5 days/or BAMP (A; acularubicin) for 6 days were treated by establishing the withdrawal period for 21 to 35 days. When possible, the high-dose ara-C (HDAC) for 5 days was included. Among the patients with the BMblast of >30%, 4 patients underwent allogeneic stem cell transplantation (allo-SCT). OS was evaluated using Kaplan-Meier estimates.
Results
Twenty four patients, whose BM blast<30% (20 - 29%, median23%) treated with AZA as the first treatment. Six secondary AML were included. Fourteen patients were male (58%), the median age was 75-years (51-90), the IPSS cytogenetic risk was good in 5 patients (21%), intermediate in 6 (25%) and poor in 13 (54%). The median cycle of AZA was 12 (3-29). By the IWG criteria, CR was achieved by 10 patients (42%), marrow CR by 2 (8%), PR by 1 (4%), SD by 5 (21%) and PD by 6 (25%). The median number of cycle by CR was 3 (2 -10). Forty two patients, whose BM blast>30% (32-95%, median 56%) treated with the remission induction therapy by IBMP. One secondary AML was included. Thirty patients were male (73%), the median age was 73-years (36-86), the cytogenetic risk was good in 8 patients (19%), intermediate in 14 (33%) and poor in 20 (48%). CR was achieved by 34 patients (81%), PR by 4 (10%) and failure by 4 (10%). The median follow up was 13 M in the BM blast<30% group and 12 M in the BM blast>30% group.
The median OS in the BM blast<30% was 23 M.The median OS in the BM blast>30% group have not reached and 1year survival was 67%, 2 years survival 51% on the basis of Kaplan-Meier estimates. In both groups, there were 51 patients with CR+PR, 9 of which were treated with AZA only after CR, and 42 (82%) of which received sequential AZA treatment and IC. HDAC was included in chemotherapy by 24 patients (57%). Thirty eight patients, other than 4 patients who underwent Allo-SCT, have not reached the median OS, and 2 years survival was 55%. As concerns cytogenetic risk, the median OS in 33 patients with poor risk was 17 M, and 33 patients with good + intermediate risk have not reached the median OS, and 2years survival was 55%.
Summary/Conclusion
There was only one death of chemotherapy and AZA and IC for AML-MRC is very safe and good remission induction therapy. We have not described this time, but the measures for infection by such as fungi have contributed largely. In spite of the interim analysis of small sample size as 66 patients and short observation period, the median OS is approximately 2 years, so that the sequential therapy of AZA and IC is a feasible and useful therapy which realizes prolongation of OS. Particularly, the median OS of 17 M in the cytogenetic poor risk group can be mentioned as great progress. Because before introduction of AZA, when we treated more than 200 patients with AML-MRC only by almost similar chemotherapy, the median OS in the poor risk group was only 6M. Currently, we are following up 6 patients, who stopped the treatment,alive more than 6 M without any treatments. SinceAML-MRC is a disease in elderly people, it is important to devise therapeutic methods to prolong the untreatment period with CR in many patients in the future.

Disclosures
No relevant conflicts of interest to declare.