Low-Dose Decitabine for Patients With Thrombocytopenia Following Allogeneic Hematopoietic Stem Cell Transplantation: A Pilot Therapeutic Study

Isolated thrombocytopenia after hematopoietic stem cell transplantation (HSCT) is defined as consistently low platelet counts after transplantation, with recovery of all other peripheral blood cell lines.¹ It represents a challenging clinical problem because it often leads to an increased risk of life-threatening hemorrhage, frequent requirement of platelet transfusions, and extended hospital stays.² Previous studies have demonstrated that decitabine, a hypomethylating agent, can increase platelet counts by enhancing platelet release and megakaryocyte maturation in mice.³ Herein, we report a pilot study showing efficacy of decitabine in patients with isolated thrombocytopenia post-HSCT.

An open-label study was designed to evaluate decitabine treatment for isolated thrombocytopenia in allogeneic HSCT patients with hematological malignant neoplasms. The inclusion criteria were (1) primary or secondary platelet count of 30 × 10³/μL or less persistently at day 60 post-HSCT or later; (2) recovered neutrophil and hemoglobin; (3) full donor chimerism; and (4) no response to conventional therapies (eg, thrombopoietin, immunoglobulin, rituximab, plasma exchange alone or in combination) for a duration of at least 4 weeks. Patients with relapse of their malignant disease, active infections, uncontrolled graft-vs-host disease (GVHD), severe organ damage, or transplant-related thrombosis were excluded. Enrolled patients were distributed into either the control group to receive the conventional therapies or the treatment group to receive additional decitabine (15 mg/m² daily intravenously for 3 consecutive days) in random. All participants provided written informed consent in accordance with the Declaration of Helsinki, and the study protocol was approved by the ethics committee of The First Affiliated Hospital of Soochow University, Suzhou, China.

Peripheral blood cell counts, virology, antiplatelet antibodies, and T-cell subsets were analyzed routinely. Bone marrow puncture was performed before treatment (week 0) and then repeated at week 4. Platelet responses were evaluated according to an international working group guideline within a 8-week study period.⁴

From July 2013 through February 2014 at our hospital, 251 patients received allogeneic HSCT, and 72 of them developed isolated thrombocytopenia afterward. During this period, 22 patients (Table) were enrolled in this study based on the criteria described herein. The response rate was 100% in the decitabine group vs 27.3% in the control group (P = .001). In the treatment group, platelet counts increased significantly 4 weeks after decitabine injections (Figure), with a median time of 22 days to achieve platelet transfusion-independence, and maintained until the sixth month, except for the patient with minor response.

In bone marrow morphological analysis, patients in both groups revealed low levels of megakaryocytes at week 0. However, the significantly increasing megakaryocyte level, especially the “platelet shedding” megakaryocyte, was observed only in decitabine group at week 4 (Figure). Transplantation-related complications (eg, chronic GVHD), antiplatelet antibodies, and T-cell subsets did not noticeably change after decitabine treatment. No clinically significant myelosuppression, febrile neutropenia, or nonhematologic toxic effects were observed during the study period.

Our study shows a very encouraging result of decitabine in increasing peripheral platelets in HSCT recipients, with remarkably increased megakaryocyte counts. There was no evident change in antiplatelet antibodies and T-cell subtypes after decitabine administration, implying that decitabine functions independent of immune regulation. In mice, decitabine was found to induce megakaryocyte differentiation and promote platelets release.³ This mechanism may have contributed to our results.

Myelosuppression is the main concern of decitabine. Low-dose decitabine could optimize clinical responses with less toxic effects.⁵ Based on previous studies, we used 15 mg/m² for 3 days, which was well tolerated by the participants.

Although the sample size of this study is small, with a relatively short follow-up, the clinically significant platelet recovery following decitabine treatment suggest potentially important clinical benefits and warrant the necessity for a large-scale clinical trial of this promising therapy.

Corresponding Author: Depei Wu, MD, PhD, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, The First Affiliated Hospital of Soochow University, 188 Shizi St, Suzhou, Jiangsu Province, China 215006 (wudepei@medmail.com.cn).

Published Online: February 26, 2015. doi:10.1001/jamaoncol.2014.316.

Author Contributions: Dr Wu had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Han, Wu.

Acquisition, analysis, or interpretation of data: Han, Tang.

Drafting of the manuscript: Han, Tang, Chen.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Han, Tang, Chen.

Administrative, technical, or material support: Liang, Ye.

Study supervision: Ruan, Wu.

Conflict of Interest Disclosures: None reported.

Funding/Support: This work was supported by grants from the Jiangsu Province of China (BK20131167, RC2011105, and ZX201102), National Nature Science Foundation of China (81270591), National Key Basic Research Program of China (2012CB526600), Jiangsu Provincial Special Program of Medical Science (BL2012005) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Role of the Funder/Sponsor: Jiangsu Province of China, National Nature Science Foundation of China, National Key Basic Research Program of China, Jiangsu Provincial Special Program of Medical Science and the Priority Academic Program Development of Jiangsu Higher Education Institutions had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Information: Drs Han and Tang contributed equally to this study and are co–first authors.

Additional Contributions: We thank Dr Lijun Xia at Oklahoma Medical Research Foundation, for his critical reading and comments. He was not compensated for his assistance.