Myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) comprise a distinct category of hematologic diseases according to the 2008 WHO classification. The treatment of MDS/MPN remains challenging due to lack of large clinical trials evaluating this group of disorders, since they are usually grouped with MDS. Supportive treatment with blood transfusions and erythropoietin are often used due to lack of efficacy of most therapies. Hypomethylating agents have been approved for the treatment of CMML and are widely used in the treatment of the remaining types of MDS/MPN.
This retrospective study aims to analyze the survival, prognostic characteristics, and treatment response to 5-azacytidine in patients with MDS/MPN included in the Hellenic 5-azacytidine registry.
Patients and Methods
Adult patients diagnosed with MDS/MPN treated with 5-azacytidine were included in the study. Demographic, clinical, hematological and treatment data were collected through the Hellenic 5-azacytidine registry and analyzed with IBM SPSS statistics, version 23.0 (IBM Corporation, North Castle, NY, USA).
Ninety-two (92) patients with MDS/MPN were included in the study. The main characteristics of the patients are shown in the table of Figure 1A.
The cytogenetic analysis at diagnosis showed that 56 (69.1%) patients had a normal karyotype, while only 1 (1.1%) had a complex karyotype. The more common isolated chromosomal aberration was trisomy of chromosome 8 (9 patients (11.1%) - 7 patients with CMML and 2 patients with MDS/MP-U), followed by chromosome 7 monosomy (2 patients with CMML1, 2.5%) and loss of the Y chromosome (2 patients (2.5%), 1 with CMML1 and 1 with MDS/MPN-U).
All patients were treated with 5-azacytidine (89.1% with a regimen of 75 mg/m² SC/IV per day for 7 days every 4 weeks and 10.9% with 75 mg/m2 SC/IV per day for 5+2 days every 4 weeks). Twenty-one patients (11 with CMML1, 7 with CMML2, and 3 with MDS/MPN-U) had been previously treated with chemotherapeutic regimens. Response to 5-azacytidine was as follows: Failure, 25 (27.8%) patients; stable disease, 23 (25.6%); partial response, 5 (5.6%); complete response, 16 (17.6%); hematologic improvement, 21 (23.3%).
The median follow-up of the patients was 19.3 months and the overall survival (OS) of the group was 26.0 months (95%CI: 14.4-37.6). OS differed significantly among the different types of MDS/MPN (Figure 1B). IPSS-R was a good predictor of OS (Log Rank (Mantel-Cox), p<0.0001). Patients with high serum ferritin levels at diagnosis (over 375 ng/dL that was the median value for the cohort) had a median OS of 22.0 months, while patients with low ferritin levels had a median overall survival of 58.2 months (Log Rank (Mantel-Cox), 0.002). Higher IPSS-R score, presence of peripheral blood blasts and high serum ferritin levels retained their prognostic significance in multivariate analysis, while hemoglobin below 9.9 g/dL (median value for the group) lost its predictive value in multivariate analysis. The age of the patients at diagnosis and the karyotype risk were not predictive of OS. Moreover, OS of patients with chromosome 8 trisomy did not differ from that of patients with a normal karyotype or other chromosomal abnormalities. None of the above-mentioned factors were predictive of response to 5-azacytidine.
This is, to our knowledge, the largest retrospective series of patients with MDS/MPN treated with 5-azacytidine. The following are the main conclusions derived from the analysis of this cohort's data. Patients with MDS/MPN-U have a significantly lower OS in comparison to patients with CMML1/2; a favorable response to 5-azacytidine (PR, CR, HI) is achieved in about 45% of the patients (about one fourth of them had already been previously treated); high IPSS-R scores, presence of peripheral blood blasts and high serum ferritin levels are independent predictors of a low OS, while in our cohort, age at diagnosis, hemoglobin levels and karyotype risk could not predict prognosis. The median OS of our group is comparable to that of other recent studies. Our study supports the use of 5-azacytidine in patients with MDS/MPN, who can benefit from an effective treatment with less toxicity than classic chemotherapeutic regimens, that in younger patients may serve as a bridge to allogeneic bone marrow transplant. The clinical significance of serum ferritin levels is highlighted and should be further investigated.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.