A Five-Day Schedule of Decitabine May Be Effective Treatment in High Risk MDS or Relapsed AML Presenting as MDS
Authors: Parovichnikova Elena , Kokhno Alina , Kaplanskaya Irina , Domracheva Elena , Samoylova O. , Obidina N. , Mashuk V. , Bocharnikova O. , Pospelova Tatyana , Savchenko Valeryi 
Published: April 2020

INTRODUCTION. Hypomethylating agents have provided a new option in the treatment of the patients with myelodysplastic syndromes (MDS). Developed in the 1970s as antileukemic drugs, azacitidine (AZA) and decitabine (DAC) after dose and schedule modification have proven to be very active in MDS. The overall response rate in intermediate and high risk MDS was reported to be as high as 73%–81% with 34%–36% of CR for decitabine in a 5-day schedule in a single center trial (H.Kantarjian, Blood2007, 109, 52–57; Cancer2007;109:265–273) and 60% with 7% CR for AZA in a CALGB randomized trial (Silverman JCO, 2002; 20: 2429-40). It was also demonstrated that AZA gave a significant OS advantage when compared to conventional supportive care (P.Fenaux, 2007 ASH abstr 817). The major point of these studies is the overall low toxicity of the drugs. This promising data became the basis for the Russian Leukemia Study Group to initiate a multicenter trial testing the efficacy of the 5 day schedule of DAC in high risk MDS and relapsed AML presenting as MDS.

PATIENTS AND METHODS. From Aug 2007 to July 2008 13 patients from 6 hematological centers were enrolled in the study: median age 59y (26–77 yy), RAEB-5pts (IPSS Int-2 – 1pt, high risk-3, 1-no cytogenetics), RCMD-2 pts (IPSS Int-1 - 1pt, Int 2 -1 pt), RARS (IPSS Low – 1 pt), AML – 4 pts (de novo -2, relapsed after MUD -1 pt, relapsed after MDS transformation -1 pt) CMML 1 pt. Half of the patients (7 pts) were pretreated with different therapies. DAC was used in a 5 days schedule: 20 mg/m2 once daily 1-hour i.v. infusion for 5 days, three courses were applied till response evaluation. The treatment was stopped at progression to AML or in the absence of any improvement after 3 courses. Median number of courses was 4 (1–8), median follow-up from treatment start – 8 mo (5–12 mo).

RESULTS. Among 5 RAEB and 2 RCMD pts we observed 2 stable CR (after 2–3 courses), 1 partial CR (after 2 courses), 1 rapid progression to AML after short (4 weeks) hematological response, 3 pts did not respond. So, 3 of 7 advanced MDS pts (43%) achieved hematological remission. DAC was ineffective in the low risk RARS patient with prolonged disease history (2 years). CR was registered in one CMML patient after 3 courses with a disease response of 5 months duration and 10 months overall survival from the start of treatment. In 2 out 4 AML patients marrow CR was obtained, two patients progressed to overt AML and died. One pt continues in CR (+5 mo), the other one relapsed at 9 months of major Cytogenetic Response (mCR). Of note, this was the third mCR in this pt and DAC was applied after MUD allogeneic transplantation. General toxicity of DAC was acceptable, though the majority of the patients experienced prolonged neutropenia with infections and thrombocytopenia transfusion dependent after DAC therapy. All patients were hospitalized at least once.

CONCLUSION. Although the study group is small and heterogeneous we nevertheless may conclude that decitabine induced 6 of 13 (46%) CR+mCR in very high risk MDS and AML patients. Response was usually achieved after the 3rd course. Decitabine may be an option for AML patients relapsing after stem cell transplantation and in AML secondary to MDS, although the AML should not be highly proliferative. The drug should be used in leukemia departments by doctors and clinical staff who are aware of and can manage myelosuppression complications.