Therapy for AML with Myelodysplasia-Related Changes (AML-MRC)

Introduction

Patients with AML-MRC are almost older and highly resistant to chemotherapy, so that they are thought to be not eligible for intensive chemotherapy (IC) compared with de novo AML. Reduced intensity chemotherapy, such as low-dose cytarabine and azacitidine (AZA), are used for AML-MRC therapy, but their overall survival (OS) is not satisfactory. Although chemotherapies for AML (except for M3) have not improved for 30 years, several supportive cares for IC have shown a great progress. In this background, we have used IC as induction, consolidation, and maintenance therapies, including AZA, for elderly AML-MRC to avoid relapses and obtain longer survivals. For patients, whose age are under 65 years, hematopoietic stem cell transplantations (HSCT) were mainly considered after IC treatments.

Methods

Between March 2012 and April 2015, 62 newly diagnosed AML-MRC were treated with idarubicin (IDR) 12 mg/m² on days 1, 3, 5, 8, and enocitabine (BH-AC) 350mg/m² on days 1-10 as an induction chemotherapy (IDR+BH-AC). Over 70 years patients, IDR and BH-AC were reduced to 10 mg/m² and 300 mg/m², respectively. On day 15, if bone marrow blasts were over 5%, etoposide 100 mg/m² was additionally treated on days 16-19. Some fit patients, who reached complete remission (CR), were received cytarabine (Ara-C) 1 g/m² on days 1-5 (bid) and mitoxantrone (MIT) 7 mg/m² on days 2-4, as a consolidation therapy (Ara-C+MIT). As a maintenance therapy, AZA 75mg/m² days 1-5 (i.v.) and IDR day1 + BH-AC days 1-4 (or aclarubicine 14 mg/m² days 1-6 + BH-AC days 1-4) were sequentially treated for one year. If a relapse was observed, mainly AZA was treated to keep a good quality of life.

Results

Total number of patients was 62 (44 were male) and median age at diagnosis was 71 years (range 36-86). Median WBC was 3,800 x 10⁹/L (600-129,200), median peripheral blast count was 16% (0-96), and median bone marrow blast count was 57% (22-95). Thirty-five patients had intermediate cytogenetics and 27 adverse. Twenty-nine patients, who had >5% bone marrow blasts on day 15, were additionally treated with etoposide. Median follow-up time was 25 months.

After the induction therapy, 54 patients (87%) achieved CR, 5 (8%) partial remission, 2 (3%) were refractory, and 1 (2%) died. The CR rate of male was 82% (36/44) and female 100% (18/18). The CR rate of patients with intermediate cytogenetics was 86% (30/35), adverse 89% (24/27), <70 years 83% (20/24), and ≥70 years 89% (34/38). There were no significant differences between CR rates and gender, cytogenetics, or age, respectively.

The CR rate of patients treated with etoposide after IDR+BH-AC was 83% (24/29) and without etoposide 91% (30/33). There was no significant difference between the two groups. Among patients with adverse cytogenetics, 67% (18/27) patients treated with etoposide, and intermediate 31% (11/35) (p=0.00983), so that patients with adverse cytogenetics tended to be resistant to IDR+BH-AC and needed the additional etoposide treatment.

By Kaplan-Meier method, two year survival of 62 patients was 50.1% (95% CI, 33.9-64.3) and 53.2% (95%CI, 35.0-68.4) in patients achieving CR (n=53, excluding one withdrawn patient). The rate of CR duration for 2 years was 48.2% (95% CI, 30.7-63.7). The median survival with adverse cytogenetics in CR was 18 months (95% CI, 11-25) and that of intermediate was not reached (95% CI, 18-NA). There was a significant difference between OS with adverse cytogenetics in CR and intermediate (p=0.00463).

Thirty-two patients in CR received the consolidation therapy, median age was 70 years (range 36-82), 2 patients died due to fungal infection. On the other hand, 21 patients in CR, median age was 77 years (range 59-86), did not have the consolidation, but the maintenance therapy. The survival rate of two groups were almost the same.

Ten patients underwent HSCT, 8 in CR and 2 in refractory or relapse, and 2 patients died due to HSCT-related events. HSCT did not influence on OS and CR duration.

Conclusions

Our intensive chemotherapy for AML-MRC showed a great efficacy and a good tolerability. The additional treatment with etoposide after IDR+BH-AC was especially effective for patients with adverse cytogenetics. Although the 2-years survival rate of elderly AML-MRC was 50% in our study, further efforts are needed to obtain a longer survival, especially for patients with adverse cytogenetics.