Low-dose decitabine for refractory prolonged isolated thrombocytopenia after HCT: a randomized multicenter trial

Abstract

Refractory prolonged isolated thrombocytopenia (RPIT) is an intractable complication after allogeneic hematopoietic cell transplantation (HCT), which often leads to poor prognosis. A clinical study was designed to validate the efficacy and safety of low-dose decitabine for RPIT after HCT and explore the related underlying mechanisms. Eligible patients were randomly allocated to receive 1 of 3 interventions: arm A, low-dose decitabine (15 mg/m2 daily IV for 3 consecutive days [days 1-3]) plus recombinant human thrombopoietin (300 U/kg daily); arm B, decitabine alone; or arm C, conventional treatment. The primary end point was the response rate of platelet recovery at day 28 after treatment. Secondary end points included megakaryocyte count 28 days after treatment and survival during additional follow-up of 24 weeks. Among the 91 evaluable patients, response rates were 66.7%, 73.3%, and 19.4% for the 3 arms, respectively (P < .001). One-year survival rates in arms A (64.4% ± 9.1%) and B (73.4% ± 8.8%) were similar (P = .662), and both were superior to that in arm C (41.0% ± 9.8%; P = .025). Megakaryocytes, endothelial cells (ECs), and cytokines relating to megakaryocyte migration and EC damage were improved in patients responding to decitabine. This study showed low-dose decitabine improved platelet recovery as well as overall survival in RPIT patients after transplantation. This trial was registered at www.clinicaltrials.gov as #NCT02487563.

Conditioning therapy with N‐acetyl‐L‐cysteine, decitabine and modified BUCY regimen for myeloid malignancies patients prior to allogeneic hematopoietic stem cell transplantation

“…Of the multilineage reconstitution, platelet delayed recovery is the main concern, which accounts for 20%-37% of HSCT recipients. 30 Our data showed a platelet reconstitution advantage in decitabine and NAC treated cohort, with more patients in Arm A achieving a platelet count above 50 Â 10 9 /L. The improved hematopoietic reconstitution after NAC treatment was considered to be associated with repaired bone marrow microenvironment (i.e., endothelial cells and mesenchymal stem cells function) in previous studies.…”

“…In this study, we included NAC in the traditional mBUCY regimen. Of the multilineage reconstitution, platelet delayed recovery is the main concern, which accounts for 20%–37% of HSCT recipients 30 . Our data showed a platelet reconstitution advantage in decitabine and NAC treated cohort, with more patients in Arm A achieving a platelet count above 50 × 10 9 /L.…”

“…In addition to anti-leukemic activity, we previously reported decitabine could promote platelet recovery after allo-HSCT in multicenter randomized trial, probably by immunomodulatory effect. 30,35 Another hypomethylating agent, azacytidine, has been found to be able to enhance the activity of regulatory T cells and cytotoxic T cells, both of which play an important role in regulating GVHD while maintaining the beneficial GVL effect. 36,37 While the effect of decitabine on GVHD remain controversial.…”

Avatrombopag for the treatment of thrombocytopenia post hematopoietic stem-cell transplantation

“…This outcome indicated that patients with sufficient MKs in the BM were more likely to benefit from avatrombopag, and for those with decreased MKs in the BM, or refractory to other therapies, low-dose DAC would be recommended. 31,32…”

Expansion of human megakaryocyte-biased hematopoietic stem cells by biomimetic Microniche

“…On the other hand, the problem of lineage recovery failure in HSC-based therapy, especially the Mk lineage, have called the demand for the study of HSCs function maintenance 6 . Patients who fail in Mk lineage reconstitution after transplantation need to rely on platelet transfusion, which is a heavy financial and physiological burden 7 – 9 . However, the strategy of “high-fidelity” expansion of HSCs with self-renewal and Mk-lineage reconstruction ability has yet to be optimized.…”