Clinical outcomes of decitabine treatment for patients with lower-risk myelodysplastic syndrome based on the International Prognostic Scoring System
Ki Sun Jung, Yoo-Jin Kim, Yeo-Kyeoung Kim, Sung Kyu Park, Hoon Gu Kim, Soo Jeong Kim, Jinny Park, Chul Won Choi, Young Rok Do, Inho Kim, Seonyang Park, Yeung-Chul Mun, Seong Hyun Jeong, Min-Kyoung Kim, Hyeon Gyu Yi, Myung Hee Chang, Su Youn Kim, Je-Hwan Lee, Jun Ho Jang
a Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
b Division of Hematology-Oncology, Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Korea
c Acute Leukemia Center, Seoul St. Mary’s Hematology Hospital, College of Medicine, Catholic University of Korea, Seoul, Korea
d Department of Hematology, Chonnam National University Hwasun Hospital, Jeollanam-do, Korea
e Department of Internal Medicine, Soonchunhyang University Hospital, Bucheon, Korea
f Division of Hematology and Oncology, Department of Internal Medicine, Gyeongnam Regional Cancer Center, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea
g Division of Hematology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
h Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Korea
i Division of Oncology and Hematology, Department of Internal Medicine, Korea University Medical Center, Seoul Korea
j Division of Hematology-Oncology, School of Medicine, Keimyung University, Daegu, Korea
k Department of Internal Medicine, Seoul National University, Seoul, Korea
l Department of Hematology and Oncology, School of Medicine, Ewha Womans University, Seoul, Korea
m Department of Hematology-Oncology, Ajou University School of Medicine, Suwon, Korea
n Division of Oncology-Hematology, Department of Medicine, Yeungnam University College of Medicine, Daegu, Korea
o Department of Internal Medicine, Inha University College of Medicine, Incheon, Korea
p Department of Hematology-Oncology, National Health Insurance Service Ilsan Hospital, Ilsan, Korea
q Medical Affairs, Janssen Korea, Seoul, Korea
r Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
Abstract
Decitabine showed a survival benefit in the higher-risk group (Lower-Risk Prognostic Scoring System [LR-PSS] category 3) of the International Prognostic Scoring System (IPSS) lower-risk (IPSS low or intermediate [INT]-1) MDS patients who responded to decitabine. Therefore, classification using the LR-PSS category was helpful for this subgroup, indicating that decitabine treatment may alter the natural course of disease in these patients.
Introduction: Decitabine has shown clinical benefits in patients with INT-2 or high-risk myelodysplastic syndrome (MDS), as determined by IPSS, but the benefits have not been well demonstrated in patients with lower-risk (IPSS low or INT-1) disease. Recently, it was proposed that the prognosis for patients with IPSS lower-risk disease is heterogeneous, with a substantial proportion of these patients having poor survival.
Materials and Methods: This study included patients with IPSS lower-risk MDS from the DRAMA (NCT01400633) and DIVA (NCT01041846) studies, which were prospective observational studies evaluating the efficacy and safety of decitabine treatment in patients with MDS. Using LR-PSS, we classified IPSS lower-risk MDS. Patients in each LR-PSS category were divided by overall response (OR) to decitabine treatment, and survival outcomes were compared.
Results: One hundred sixteen patients were enrolled: LR-PSS category 1 (n = 12, 10.3%), category 2 (n = 56, 48.3%) and category 3 (n = 48, 41.4%). Survival outcomes differed among the 3 categories (P = 0.046). The overall survival (OS) by OR showed a significant difference in total patients (P = 0.008) and category 3 patients (P = 0.003). We analyzed predictive factors for OR, but no variable was found to significantly affect OR.
Conclusion: Decitabine treatment showed a survival benefit in the higher-risk group of IPSS lower-risk MDS patients who responded to treatment, and classification using the LR-PSS category was helpful for this subgroup, indicating that decitabine treatment may alter the natural course of disease in these patients.
Introduction
Myelodysplastic syndrome (MDS) is a disease characterized by peripheral cytopenia due to ineffective hematopoiesis and possible evolution to acute myeloid leukemia (AML).1,2 Therapeutic options for this disease have generally been selected based on the International Prognostic Scoring System (IPSS).3 Specifically, for the treatment of lower-risk patients (IPSS low or intermediate-1), the options include supportive care or low- to high-intensity therapy based on symptoms, severity of cytopenia, chromosomal abnormalities such as deletion (5q), or increased marrow blasts; however, the optimal treatment of this subgroup remains unclear.4,5
The Lower-Risk Prognostic Scoring System (LR-PSS) was developed by the MD Anderson Cancer Center to identify patients with IPSS lower-risk MDS who have a poorer prognosis.6 According to this system, the median survival of each subgroup (categories 1, 2 and 3) is 80.3, 26.6 and 14.2 months, respectively. These results were also validated in two studies7,8 the prognosis of patients with LR-PSS category 3 appears to be similar to that of MDS patients classified as IPSS intermediate-2 or high risk. Therefore, this subgroup may require early treatment, but the clinical benefit for these patients has not yet been evaluated.
Decitabine is a DNA methyl transferase inhibitor hypomethylating agent and a relatively low-intensity chemotherapeutic agent.9 Several phase II and III clinical trials have shown the efficacy of decitabine in patients with MDS, but this agent has a clinical benefit in only intermediate-2 or high-risk MDS patients.10-12 In Korea, two observational studies (DIVA13 and DRAMA14) investigating the efficacy of decitabine treatment in MDS patients also demonstrated that the survival benefit of patients who achieved hematologic improvement (HI) was significant in the intermediate-2 and high-risk groups but not in the lower-risk group. Therefore, we classified the IPSS lower-risk MDS patients from the DIVA and DRAMA studies using the LR- PSS and then analyzed the clinical outcomes following decitabine treatment in each subgroup.
Materials and Methods
This study included patients with lower-risk MDS, as determined by the IPSS, from the DRAMA (NCT01400633) and DIVA (NCT01041846) studies, which were prospective observational studies evaluating the efficacy and safety of decitabine treatment in patients with MDS. There were no low-risk category patients in these studies. Therefore, we classified patients in the intermediate-1 group by the LR-PSS categories and divided the patients into two groups depending on the treatment response in each LR-PSS category (categories 1, 2 and 3). The overall response (OR) included complete response (CR), partial response (PR), molecular CR with or without HI and HI only using the modified IWG 2006 response criteria.15 We also searched for predictors for OR and overall survival (OS) by using baseline patient and disease characteristics.
Descriptive statistics for continuous variables are presented as the median and range (minimum-maximum), and categorical variables are presented as frequencies with percentages in parentheses. We plotted Kaplan-Meier survival curves by OR group (responder/nonresponder) and compared the curves using a log-rank test for each LR-PSS subgroup. We estimated odds ratios and 95% Wald confidence intervals (CIs) to identify predictors of OR by using multivariate logistic regression, and we estimated hazard ratios and 95% CIs to identify predictors of OS by using multivariate Cox proportional hazards regression models with the same variables. All statistical analyses were performed using the statistical software package SAS 9.4 (Statistical Analysis System, SAS-Institute, Cary, NC, USA), and P values less than 0.05 were considered statistically significant.
Results
Patient and disease characteristics
A total of 116 patients were analyzed. Based on the LR-PSS, 12 patients (10.3%) were classified as category 1; 56 patients (48.3%), as category 2; and 48 patients (41.4%), as category 3. The baseline characteristics for all patients are presented in Table 1. Patients who were classified as LR-PSS category 3 were older and predominantly male and had more comorbidities. Refractory cytopenia with multilineage dysplasia (RCMD) was the most common WHO subtype (54/116, 46.6%). Transfusion dependency at baseline was more common in LR-PSS category 3.
Clinical outcomes
The three categories showed similar proportions of patients who achieved OR, while the proportion of CR was higher in LR-PSS category 1 than in the other categories. In contrast, the proportion of mCR without HI tended to increase for the higher-risk categories (Table 2.) With a median follow-up period of 532 days (range, 75-1111 days) for survivors, 40 patients died and the median OS was not reached. The OS was significantly different between the three LR-PSS categories (P = 0.0462) (Figure 1).
The responder group showed a significant difference in OS (P = 0.0078, Figure 2-A).
And the OS classified by OR in each LR-PSS category is also provided in Figure 2-B~D. Unlike the category 1 and 2 patients, the patients in category 3 showed a significant difference in OS between responders and nonresponders (P = 0.0034).
We analyzed patients in LR-PSS categories 1, 2 and 3 to identify predictors at baseline for OR or OS by using a multivariate regression model. However, no significant predictors were identified. The results are presented in Table 3 (OR) and Table 4 (OS).
Discussion
The results of our analysis suggest that decitabine is beneficial in the treatment of patients with lower-risk MDS; approximately 60% of total patients showed a response, which is in agreement with a recent study.16 A subgroup with poor prognosis can be identified among lower-risk MDS patients, and early treatment may improve the outcome in these patients. Thus, in this study, we classified patients with lower-risk MDS according to the LR-PSS and investigated the clinical outcome for decitabine treatment in each subgroup. When lower-risk MDS patients were categorized using the LR-PSS in previous studies, the three risk categories showed significant differences in OS; in particular, category 3 patients had poor prognoses, similar to those of higher-risk MDS patients.6-8 Likewise, our analysis showed significant differences in survival outcomes among the three category groups. We found that OS in patients with LR-PSS categories 1 and 2 was not dependent on response, but for patients with LR-PSS category 3 disease, OS according to OR was significantly associated with decitabine treatment. The clinical outcome of hypomethylating agents in each subgroup is still unknown; however, this analysis demonstrated the survival benefit of decitabine treatment in the lower-risk MDS subgroup, most notably for patients with category 3 disease. In this sense, our study proposes that active decitabine treatment may provide a survival benefit in a subset of patients having poor prognostic features with lower-risk MDS; decitabine responders showed a significant difference in OS compared to nonresponders, indicating that decitabine may influence the natural course of disease in a subset of patients having poor prognostic features of lower-risk MDS.
The IPSS low-risk group was not included in our study because there were no patients in the IPSS low-risk group from the two studies, DIVA and DRAMA. However, it is unlikely that patients from the IPSS low-risk group would belong to LR-PSS category 3; thus, we assume that this group would have little impact on the results of our research.
The IPSS is a typical prognosis-stratifying model for patients with MDS, but there is heterogeneity in the prognosis, especially within the IPSS lower-risk group. Thus, further models such as the revised IPSS (IPSS-R) and LR-PSS were developed to stratify a subgroup that had poor outcomes in the lower risk group. The IPSS-R and LR-PSS may be superior tools for classifying these patients. When the IPSS, IPSS-R and LR-PSS were compared, the discriminatory power was better for the LR-PSS than for the IPSS-R and IPSS.17,18 Although further investigations are needed to identify prognoses in MDS patients, we selected the LR-PSS to stratify lower-risk MDS patients in this study.
We observed a survival benefit in MDS patients with category 3 disease who responded to decitabine treatment. The predictive factors for response in MDS patients treated with hypomethylating agents remain uncertain. When patients with high-risk MDS are treated with azacitidine, predictive factors for low response include previous low-dose cytosine arabinoside treatment (P = 0.009), bone marrow blasts > 15% (P = 0.004) and abnormal karyotype (P = 0.03).19 An analysis from another study found that lower-risk cytogenetics, younger age and lower lactate dehydrogenase levels were significant predictors for OS in MDS patients treated with decitabine therapy.20 In our study, there were no significant predictive factors for survival outcome or OR. It is likely that the small number of enrolled patients and the inclusion of nine independent variables in the regression model affected the results of the analysis. Further investigations are therefore needed to develop more effective models to determine predictive factors for indicating early treatment and predicting treatment response.
In conclusion, approximately 60% of the patients with lower-risk MDS responded to decitabine treatment, and a survival benefit was shown for a subset of lower-risk MDS patients having poor prognostic features who responded to treatment, indicating that decitabine treatment may alter the natural course of disease in this group. Based on these findings, a prospective study with a larger sample size may be required to prove the clinical outcome of hypomethylating agents for the subgroup of lower-risk MDS patients. Moreover, further studies are warranted to ascertain prognostic factors to select patients in the lower-risk group who might benefit from early intervention.
References
1. Cazzola M, Malcovati L. Myelodysplastic syndromes—coping with ineffective hematopoiesis. N Engl J Med. 2005;352:536–538.
2. Leone G, Teofili L, Voso MT, et al. DNA methylation and demethylating drugs in myelodysplastic syndromes and secondary leukemias. Haematologica. 2002;87:1324– 1341.
3. Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079–2088.
4. Malcovati L, Hellström-Lindberg E, Bowen D, et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood. 2013;122:2943–2964.
5. Garcia- Manero G. Myelodysplastic syndromes: 2015 update on diagnosis, risk-stratification and management. Am J Hematol. 2015;90:831–841.
6. Garcia-Manero G, Shan J, Faderl S, et al. A prognostic score for patients with lower risk myelodysplastic syndrome. Leukemia. 2008;22:538–543.
7. Bejar R, Stevenson KE, Caughey BA, et al. Validation of a prognostic model and the impact of mutations in patients with lower-risk myelodysplastic syndromes. J Clin Oncol. 2012;30:3376–3382.
8. Komrokji RS, Corrales- Yepez M, Al Ali N, et al. Validation of the MD Anderson Prognostic Risk Model for patients with myelodysplastic syndrome. Cancer. 2012;118:2659–2664.
9. Jones PA, Taylor SM. Cellular differentiation, cytidine analogs and DNA methylation. Cell. 1980;20:85–93.
10. Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106:1794–1803.
11. Wijermans P, Lübbert M, Verhoef G, et al. Low-dose 5-aza-2′-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients. J Clin Oncol. 2000;18:956–962.
12. Kantarjian H, Oki Y, Garcia-Manero G, et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood. 2007;109:52–57.
13. Lee JH, Jang JH, Park J, et al. A prospective multicenter observational study of decitabine treatment in Korean patients with myelodysplastic syndrome. Haematologica. 2011;96:1441–1447.
14. Jeong SH, Kim YJ, Lee JH, et al. A prospective, multicenter, observational study of long- term decitabine treatment in patients with myelodysplastic syndrome. Oncotarget. 2015;6:44985–44994.
15. Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006;108:419–425.
16. Lee JH, Kim YJ, Sohn SK, et al.; AML MDS Working Party of the Korean Society of Hematology. Benefits of hypomethylating therapy in IPSS lower-risk myelodysplastic syndrome patients: a retrospective multicenter case series study. Leuk Res. 2017;60:135–144.
17. Komrokji RS, Wang XF, Al Ali NH, et al. Comparing the prognostic value of risk stratifying models for patients with lower-risk myelodysplastic syndromes (MDS): is one model better? A report on the behalf of the MDS Clinical Research Consortium. Blood. 2013;122:1505.
18. Zeidan AM, Sekeres MA, Wang XF, et al.; MDS Clinical Research Consortium (Funded by Edward P. Evans Foundation). Comparing the prognostic value of risk stratifying models for patients with lower-risk myelodysplastic syndromes: is one model better? Am J Hematol. 2015;90:1036–1040.
19. Itzykson R, Thépot S, Quesnel B, et al.; Groupe Francophone des Myelodysplasies (GFM). Prognostic factors for response and overall survival in 282 patients with higher- risk myelodysplastic syndromes treated with azacitidine. Blood. 2011;117:403–411.
20. Wijermans PW, Lübbert M, Verhoef G, et al. An epigenetic approach to the treatment of advanced MDS; the experience with the DNA demethylating agent 5-aza-2′- 5-Azacytidine (decitabine) in 177 patients. Ann Hematol. 2005;84:9–17.