Platelet Doubling After First Decitabine Cycle Predicts Response and Survival of Myelodysplastic Syndrome Patients

Abstract

Objective

Although the effect of decitabine on myelodysplastic syndrome (MDS) has been demonstrated, merely a proportion of patients respond to therapy, and no well-recognized predictors have been identified. This study was conducted to investigate the effectiveness of decitabine in real-world clinical practice, and determine the predictive factors of response and overall survival (OS) in MDS patients.

Methods

Clinical and pathological data were collected from 94 patients and analyzed. These patients were reclassified according to the 2016 World Health Organization classification criteria, and restratified by International Prognostic Scoring System prognostic scores. The response evaluation was performed according to the 2006 modified International Working Group response criteria.

Results

In this study, 62% of patients responded to decitabine. Among these patients, 15 patients (16%) obtained complete remission (CR), 15 patients (16%) obtained marrow CR with hematologic improvement (HI), 20 patients (21%) obtained marrow CR without HI, and 8 patients (9%) only obtained HI, and no patient botained partial remission. The OS of the responders was significantly longer than that of non-responders (67 months vs. 7 months, P<0.001). The OS in patients with and without platelet doubling was significantly different in both the low/intermediate and high/very high risk groups (P=0.0398 and P=0.0330). The multivariate analysis revealed that platelet doubling after the first decitabine cycle is an independent predictor of response and OS in MDS patients (P=0.002 and P=0.008).

Conclusion

Decitabine is effective for treating MDS patients in real-world clinical practice. Furthermore, platelet doubling after the first decitabine cycle can be used as a predictor of response and survival in MDS patients.

Keywords

platelet doubling / decitabine / response / survival / myelodysplastic syndrome

References

[1] Gil-PerezA, Montalban-BravoG. Management of myelodysplastic syndromes after failure of response to hypomethylating agents. Ther Adv Hematol, 2019, 10: 2040620719847059

[2] KantarjianH, IssaJPJ, RosenfeldCS, et al.. Decitabine improves patient outcomes in myelodysplastic syndromes—Results of a Phase III randomized study. Cancer, 2006, 106(8): 1794-1803

[3] FenauxP, MuftiGJ, Hellstrom-LindbergE, et al.. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol, 2009, 10(3): 223-232

[4] ScottLJ. Azacitidine: A Review in Myelodysplastic Syndromes and Acute Myeloid Leukaemia. Drugs, 2016, 76(8): 889-900

[5] JabbourE, ShortNJ, Montalban-BravoG, et al.. Randomized phase 2 study of low-dose decitabine vs low-dose azacitidine in lower-risk MDS and MDS/MPN. Blood, 2017, 130(13): 1514-1522

[6] NazhaA, SekeresMA, BejarR, et al.. Genomic Biomarkers to Predict Resistance to Hypomethylating Agents in Patients With Myelodysplastic Syndromes Using Artificial Intelligence. JCO Precis Oncol, 2019, 3: 1-11

[7] JungKS, KimYJ, KimYK, et al.. Clinical Outcomes of Decitabine Treatment for Patients With Lower-Risk Myelodysplastic Syndrome on the Basis of the International Prognostic Scoring System. Clin Lymphoma Myeloma Leuk, 2019, 19(10): 656-664

[8] WangH, LiY, LvN, et al.. Predictors of clinical responses to hypomethylating agents in acute myeloid leukemia or myelodysplastic syndromes. Ann Hematol, 2018, 97(11): 2025-2038

[9] BejarR, LordA, StevensonK, et al.. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood, 2014, 124(17): 2705-2712

[10] SollyF, KoeringC, MohamedAM, et al.. An miRNA-DNMT1 Axis Is Involved in Azacitidine Resistance and Predicts Survival in Higher-Risk Myelodysplastic Syndrome and Low Blast Count Acute Myeloid Leukemia. Clin Cancer Res, 2017, 23(12): 3025-3034

[11] van der HelmLH, AlhanC, WijermansPW, et al.. Platelet doubling after the first azacitidine cycle is a promising predictor for response in myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia (AML) patients in the Dutch azacitidine compassionate named patient programme. Br J Haematol, 2011, 155(5): 599-606

[12] JungHA, MaengCH, KimM, et al.. Platelet response during the second cycle of decitabine treatment predicts response and survival for myelodysplastic syndrome patients. Oncotarget, 2015, 6(18): 16653-16662

[13] TangY, ZhangX, HanS, et al.. Prognostic Significance of Platelet Recovery in Myelodysplastic Syndromes With Severe Thrombocytopenia. Clin Appl Thromb Hemost, 2018, 24(9_suppl): 217S-222S

[14] ArberDA, OraziA, HasserjianR, et al.. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood, 2016, 127(20): 2391-2405

[15] GreenbergPL, TuechlerH, SchanzJ, et al.. Revised international prognostic scoring system for myelodysplastic syndromes. Blood, 2012, 120(12): 2454-2465

[16] ChesonBD, GreenbergPL, BennettJM, et al.. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood, 2006, 108(2): 419-425

[17] JeongSH, KimYJ, LeeJH, et al.. A prospective, multicenter, observational study of long-term decitabine treatment in patients with myelodysplastic syndrome. Oncotarget, 2015, 6(42): 44985-44994

[18] SalimO, ToptasT, AvsarE, et al.. Azacitidine versus decitabine in patients with refractory anemia with excess blast-Results of multicenter study. Leuk Res, 2016, 45: 82-89

[19] LeeJH, JangJH, ParkJ, et al.. A prospective multicenter observational study of decitabine treatment in Korean patients with myelodysplastic syndrome. Haematologica, 2011, 96(10): 1441-1447

[20] YeL, RenY, ZhouX, et al.. Decitabine improves overall survival inmyelodysplastic syndromes-RAEB patients aged ≥60 years and has lower toxicities: Comparison with low-dose chemotherapy. Blood Cells Mol Dis, 2019, 77: 88-94

[21] KantarjianHM, O’BrienS, HuangX, et al.. Survival advantage with decitabine versus intensive chemotherapy in patients with higher risk myelodysplastic syndrome: comparison with historical experience. Cancer, 2007, 109(6): 1133-1137

[22] WangM, HanHH, GuoR, et al.. Clinical Efficacy of Low-dose Decitabine Combined with CAG Regimen in Patients with Myelodysplastic Syndrome-refractory Anemia with Excess Blasts(MDS-RAEB). Zhongguo Shi Yan Xue Ye Xue Za Zhi, 2017, 25(5): 1482-1486(Chinese)

[23] ZhangJL, CaoYP, LiJG. Efficacy and Safety of Decitabine Combined with CAG (Cytarabine, Aclarubicin, G-CSF) for Patients with Intermediate or High Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia: a Meta-Analysis. Zhongguo Shi Yan Xue Ye Xue Za Zhi, 2019, 27(2): 494-503(Chinese)

[24] ItzyksonR, ThepotS, QuesnelB, et al.. Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine. Blood, 2011, 117(2): 403-411

[25] TrainaF, VisconteV, ElsonP, et al.. Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms. Leukemia, 2014, 28(1): 78-87

[26] DiNardoCD, PatelKP, Garcia-ManeroG, et al.. Lack of association of IDH1, IDH2 and DNMT3A mutations with outcome in older patients with acute myeloid leukemia treated with hypomethylating agents. Leuk Lymphoma, 2014, 55(8): 1925-1929

[27] WelchJS, PettiAA, MillerCA, et al.. TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. N Engl J Med, 2016, 375(21): 2023-2036

[28] BallyC, AdesL, RennevilleA, et al.. Prognostic value of TP53 gene mutations in myelodysplastic syndromes and acute myeloid leukemia treated with azacitidine. Leuk Res, 2014, 38(7): 751-755

[29] WangJ, YiZ, WangS, et al.. The effect of decitabine on megakaryocyte maturation and platelet release. Thromb Haemost, 2011, 106(2): 337-343

[30] DingK, FuR, LiuH, et al.. Effects of decitabine on megakaryocyte maturation in patients with myelodysplastic syndromes. Oncol Lett, 2016, 11(4): 2347-2352

[31] ZhangW, LiuC, WuD, et al.. Decitabine improves platelet recovery by down-regulating IL-8 level in MDS/AML patients with thrombocytopenia. Blood Cells Mol Dis, 2019, 76: 66-71