A Nationwide Survey of Lower Risk Myelodysplastic Syndromes in Japan

Introduction: There are some treatment options for lower risk myelodysplastic syndromes (MDS) such as erythropoiesis-stimulating agents (ESAs), anabolic steroids, hypomethylating agents, and immunosuppressants. The object of this multicenter retrospective study was to survey the current situation about treatment selection and the prognosis of the lower risk MDS cases in Japan. We also evaluated the prognosis of the cases with paroxysmal nocturnal hemoglobinuria (PNH) type cells and therapeutic effects of cyclosporine.

Methods: We investigated the clinical information in the form of a questionnaire for joint research facilities as to each case of newly diagnosed MDS between 2013 and 2018 corresponding to the lower risk of International Prognostic Scoring System (IPSS) or revised IPSS (IPSS-R). The diagnosis of MDS was based on WHO 2008 or WHO 2016 classification. Survival analysis was conducted using Kaplan-Meier method and log-rank test. Multivariate analysis was performed using Cox proportional hazard regression model. This study was approved by the institutional review board of the University of Tokyo and other research facilities. This work was supported by the Research Program of Intractable Disease (the Japanese National Research Group on Idiopathic Bone Marrow Failure Syndromes) provided by the Ministry of Health, Labor, and Welfare of Japan.

Results: 1,304 cases at thirty facilities nationwide were enrolled. Median age was 76 years [IQR, 68 - 83], and male and female ratio was 61.3% and 38.7%. At diagnosis, 19.0% and 4.4% of the cases were dependent on red blood cells and platelets transfusion, respectively. The risk classification of enrolled cases was as follows: very low, 217 (16.6%); low, 652 (50.0%); intermediate, 360 (27.6%); high, 56 (4.3%); very high, 4 (0.3%); not determined, 14 (1.1%). 1,230 cases of the very low, low and intermediate risk groups were included in subsequent analyzes. Serum erythropoietin levels were measured in 466 cases (37.9%) with a median of 61.8 IU/l, and 74.2% and 85.7% cases showed less than 200 IU/l and 500 IU/l, respectively. PNH type cells in the peripheral blood were evaluated in 231 cases and were positive in 33 cases (14.3%). Median follow-up period was 22 months.

As an initial therapy, 26.4% and 11.6% of transfusion-dependent and independent cases started to receive ESAs, respectively. 16.6% and 11.5% took oral anabolic hormones, and azacytidine were administered to 17.0% and 7.2% of each group. 55.4% of transfusion-independent cases were just followed up at first. Median overall and acute myeloid leukemia (AML)-free survival was 70.0 months [95% CI, 61.0 - not reached] and 62.0 months [95% CI, 54.0 - 74.0], respectively. Log-rank analysis revealed significant differences among IPSS-R risk groups about overall and AML-free survival (p<0.01 and p<0.01, respectively). Multivariate analysis confirmed that initiating azacytidine at the time of diagnosis conferred an independent significant poor prognostic factor with respect to overall survival (hazard ratio for death, 1.74; p<0.01) and AML-free survival (hazard ratio for death or onset of AML, 1.86; p<0.01) in addition to sex, age, IPSS-R classification, and transfusion-dependency.

Comparing thirty-three positive cases of PNH type cells with 198 negative cases, overall and AML-free survival was significantly better in the former group (p<0.01 and p<0.01, respectively). Median overall and AML-free survival were not reached in the positive group and 51.0 months [95% CI, 47.0 - 79.0] and 49.1 months [95% CI, 40.0 - 57.1] in the negative group, respectively. Interestingly, focused on the positive cases, 14 cases receiving cyclosporine revealed better AML-free survival than the others (p=0.033). Overall survival was tended to be better (p=0.052). On the other hand, cyclosporine did not improve the prognosis of the PNH type cells negative cases. It is thought to be consistent with the effectiveness of immunosuppressive therapy in aplastic anemia with PNH type cells.

Conclusion: ESAs, anabolic steroids, and azacytidine were frequently selected as an initial treatment for lower risk MDS cases in Japan, however, when to start azacytidine is an issue for consideration. Good response to cyclosporine may be obtained in cases with PNH type cells.