Real‐life experience with azacitidine in myelodysplastic syndromes according to IPSS cytogenetic profile

To the Editor: Before hypomethylating agents became the mainstay of therapy for myelodysplastic syndromes (MDS) patients with bad prognostic features, treatment was usually support for older patients, and chemotherapy followed by transplant procedures for younger patients [1]. Rates of response and overall survival (OS) were low, even though patients were selected to receive intensive chemotherapy. The introduction of azacitidine changed therapeutic strategies and allowed treatment also of elderly patients. The AZA001 trial, an international randomized phase III study of azacitidine (75 mg/m/day for 7 days every 28-day), compared the drug with the three most common conventional regimens (CCR, i.e., best supportive care, low-dose cytarabine, and intensive chemotherapy) in IPSS (International Prognostic Scoring System) intermediate-2-and high-risk MDS [2]. Treatment was chosen according to physician preselection, based on age, comorbidities, performance status, and patient preferences. After a median follow up of 21 months, median OS was significantly longer in the azacitidine arm compared with the combined CCR group (24.5 vs 15 months, respectively) and 2-year OS was also significantly longer for azacitidine (50.8 vs 26.2%). OS was superior with azacitidine independently from IPSS cytogenetic subgroups: in particular, in patients with 27/del (7q), median OS was 13 months compared to 4.6 months for patients included in the CCR cohort [2]. Aim of our study was to assess azacitidine efficacy according to cytogenetic risk at baseline in a large group of intermediate/high-risk MDS patients treated outside clinical trials. One hundred and sixty-six patients with primary or secondary MDS [chronic myelomonocytic leukemia (CMML) were excluded] were diagnosed and treated with azacitidine at six different Italian hematology units. Patients were recruited consecutively, based on physician’s perspective and decision. All patients received azacitidine at the dose of 75 mg/mq with a schedule of 51 21 2 or of 7 consecutive days every 28 days, until disease progression or unacceptable toxicity. For all patients, clinical parameters such as age, sex, WHO classification, IPSS, and baseline cytogenetic evaluation were retrospectively collected. Responses were evaluated according to 2006 IWG criteria in an intention to treat basis [3]. Of 166 patients recruited, 103 were males and 63 females; median age was 69.5 years (range 49–89). A median of eight cycles was performed (range 1–60). According to IPSS stratification, there were 29 patients with intermediate-1 risk, 118 patients with intermediate-2, and 15 with high–risk MDS (seven patients not determined). According to the WHO classification, 37 patients were diagnosed as having RAEB-1, 101 patients as RAEB-2, and 28 patients as RCMD. According to IPSS cytogenetic risk stratification, 88 patients were in the good risk, 22 patients were in the intermediate risk, and 39 in the poor risk. The most frequent cytogenetic aberration, aside normal karyotype (48%), was 27 or del(7q) as isolated aberration in 9.4% of patients, 25/del (5q) in 6%, 18 in 5%, others (such as del(20q), trisomy, or inversion of chromosome 3, 121) in 14.5% of patients. Complex karyotype was observed in 16% of patients, in most of whom involving chromosome 7. According to IPSS cytogenetic stratification, we observed the following responses according to IWG criteria: of 88 patients classified as good risk, overall 15% achieved complete remission (CR), 9% partial remission (PR), and 6% hematological improvement (HI), whereas 11% progressed to acute leukemia or failed to achieve any response. Of 22 patients classified as intermediate cytogenetic risk, overall 10% achieved CR, 15% achieved PR, and 2% HI, none experienced disease progression and 5% failed to achieve any response. Of 39 patients stratified as high cytogenetic risk, 9% achieved CR, 13% achieved PR, and 5% achieved HI, 20% progressed to acute leukemia and 7% failed to achieve any response. Although patients with unfavorable karyotype obtained responses similar to low risk, cytogenetic risk appeared to have a prognostic weight on longterm OS: patients stratified in the low-risk group had a median OS of 27 months compared to patients in the intermediate risk (20 months) and in the high risk (14 months, P5 0.02) (Table I). In particular, high-risk patients with complex karyotype had the shortest OS, with a median of 7 months only. The French group reported prognostic factors in 282 patients who received azacitidine in a compassionate named program. In this group of patients, 31% had a low-risk cytogenetic profile, 17% were in the intermediate and 47% in the poor prognostic category. Ten of 25 (40%) patients with noncomplex 27/del7q, 39 of 103 (38%) patients with complex karyotype, and 4 of 12 (33%) patients with noncomplex del5q/25 presented a clinical response. The multivariate analysis predicted shorter response duration and OS in the presence of a complex karyotype at baseline [4]. Our results are indeed similar to previous data by the MDACC (MD Anderson Cancer Center), who reported that chromosome 5 and 7 abnormalities were associated to shorter survival but not to the achievement of best response [5]. This patient group was similar, in terms of frequency of high-risk cytogenetic abnormalities (26%) and OS (median 20 months) to the series of patients enrolled in the AZA001 trial (high-risk cytogenetic abnormalities: 28% and median OS 24.4 months) [2]. Our results suggest that patients with poor cytogenetic profile at baseline should receive azacitidine, due to the high frequency of responses obtained. However, the short response duration observed in this subset indicates that these patients should be candidate, soon after achievement of response, to a transplant procedure if possible or to investigational treatment combinations aiming at complete eradication of leukemic stem cells.