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•The rATG-targeted dosing strategy results in more patients falling within the optimal total AUC range of active rATG.•The distribution of rATG-AUC with the targeted dosing strategy gathered more concentrated around the optimal range.•Even patients beyond this range in the targeted dosing group can still benefit from this strategy.

Hitherto, the optimal timing of rabbit anti-thymocyte globulin (rATG) in matched sibling donor peripheral blood stem cell transplantation (MSD-PBSCT) remains to be elucidated. We wanted to evaluate the effect of a new timing strategy of rATG in MSD-PBSCT patients on transplantation outcomes. In this prospective single-arm phase 2 clinical trial, 45 consecutive MSD-PBSCT patients were enrolled from February 1, 2019, to January 31, 2021. The rATG was administered intravenously at a total dose of 5 mg/kg from day −5 to day −2 before graft infusion (4d-ATG group). Thirty-seven MSD-PBSCT patients receiving rATG at the same total dose of 5 mg/kg from day −5 to day −4 before graft infusion from December 1, 2014, to January 31, 2019 served as historical control (2d-ATG group). No graft failure occurred in either group. In the 4d-ATG group, median timing to neutrophil and platelet engraftment was 12 days. The cumulative incidences (CI) of grade 2-4 and grade 3-4 acute graft-versus-host disease (GVHD) at day 100 were 37.8% and 4.4%. The 2-year CIs of severe chronic GVHD and extensive chronic GVHD were 2.2% and 9.6%. The rates of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation at day 180 were 24.4% and 37.8%, respectively. No patients died of non-relapse causes. Twenty-one patients relapsed at a median of 203 days after transplantation, and the 2-year cumulative incidence of relapse (CIR) was 51.4%. The 2-year probabilities of overall survival (OS), disease-free survival (DFS), and GVHD-free and relapse-free survival (GRFS) were 72.4%, 48.6%, and 40.8%, respectively. There were no significant differences between the 4d-ATG group and 2d-ATG group with regard to timing of neutrophil and platelet engraftment, incidences of CMV reactivation, EBV reactivation, acute GVHD, chronic GVHD, probabilities of OS, and GRFS. The 2-year CIR was significantly increased, and the 2-year DFS was significantly reduced in 4d-ATG group compared with the control group (CIR: 51.4% versus 13.5%, P< .001; DFS: 48.6% versus 75.7%, P = .014). High CIR and worse DFS were noted in MSD-PBSCT receiving 4d-ATG regimen compared with historical control (2d-ATG regimen). Inappropriate rATG timing may increase the risk of relapse after MSD-PBSCT in patients with hematologic malignancies.

•The optimal active ATG exposure in adult haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) is unclear.•This study shows total AUC of active ATG is the best predictor for virus reactivation and aGVHD.•Higher total AUC is associated with higher risk of virus reactivation and lower risk of aGVHD.•The optimal total AUC range with the minimum virus reactivation and comparable II–IV aGVHD was 110–148.5 UE/mL/day.

•We evaluated ruxolitinib combined with methylprednisolone as first-line therapy for acute graft-versus-host disease.•We found a high response rate to ruxolitinib combined with 1 mg/kg/day methylprednisolone.•Ruxolitinib spared steroid exposure and allied toxicity.

•We evaluated ruxolitinib combined with methylprednisolone as first-line therapy for acute graft-versus-host disease.•We found a high response rate to ruxolitinib combined with 1 mg/kg/day methylprednisolone.•Ruxolitinib spared steroid exposure and allied toxicity.

Introduction:

Background: CMV reactivation after unmanipulated haploidentical stem cell transplantation (SCT) frequently occurs, causing life-threatening morbidities and transplantation failure. Preemptive therapy upon the detection of CMV viremia using antiviral agents is currently the standard of care but its efficacy is quite limited and associated with significant toxicity. The CMV antigen-specific cytotoxic T lymphocytes (CTLs) therapy was limited by the time-consuming manufacture process and relatively low success rate. More effective and safer approaches for the treatment of CMV reactivation after haploidentical SCT are in urgent need.

t(8;21) is one of the most frequent chromosomal translocations occurring in acute myeloid leukemia (AML) and is considered the leukemia-initiating event. The biologic and clinical significance of microRNA dysregulation associated with AML1/ETO expressed in t(8;21) AML is unknown. Here, we show that AML1/ETO triggers the heterochromatic silencing of microRNA-193a(miR-193a) by binding at AML1-binding sites and recruiting chromatin-remodeling enzymes. Suppression of miR-193aexpands the oncogenic activity of the fusion protein AML-ETO, because miR-193arepresses the expression of multiple target genes, such as AML1/ETO, DNMT3a, HDAC3, KIT, CCND1, and MDM2directly, and increases PTENindirectly. Enhanced miR-193alevels induce G1arrest, apoptosis, and restore leukemic cell differentiation. Our study identifies miR-193aand PTENas targets for AML1/ETO and provides evidence that links the epigenetic silencing of tumor suppressor genes miR-193aand PTENto differentiation block of myeloid precursors. Our results indicated a feedback circuitry involving miR-193aand AML1/ETO/DNMTs/HDACs, cooperating with the PTEN/PI3K signaling pathway and contributing to leukemogenesis in vitro and in vivo, which can be successfully targeted by pharmacologic disruption of the AML1/ETO/DNMTs/HDACscomplex or enhancement of miR-193ain t(8;21)–leukemias.

t(8;21) is one of the most frequent chromosomal translocations occurring in acute myeloid leukemia (AML) and is considered the leukemia-initiating event. The biologic and clinical significance of microRNA dysregulation associated with AML1/ETO expressed in t(8;21) AML is unknown. Here, we show that AML1/ETO triggers the heterochromatic silencing of microRNA-193a (miR-193a) by binding at AML1-binding sites and recruiting chromatin-remodeling enzymes. Suppression of miR-193a expands the oncogenic activity of the fusion protein AML-ETO, because miR-193a represses the expression of multiple target genes, such as AML1/ETO, DNMT3a, HDAC3, KIT, CCND1, and MDM2 directly, and increases PTEN indirectly. Enhanced miR-193a levels induce G1 arrest, apoptosis, and restore leukemic cell differentiation. Our study identifies miR-193a and PTEN as targets for AML1/ETO and provides evidence that links the epigenetic silencing of tumor suppressor genes miR-193a and PTEN to differentiation block of myeloid precursors. Our results indicated a feedback circuitry involving miR-193a and AML1/ETO/DNMTs/HDACs, cooperating with the PTEN/PI3K signaling pathway and contributing to leukemogenesis in vitro and in vivo, which can be successfully targeted by pharmacologic disruption of the AML1/ETO/DNMTs/HDACs complex or enhancement of miR-193a in t(8;21)–leukemias.

Reprograming the N6-methyladenosine (m6A) landscape is a promising therapeutic strategy against recalcitrant leukemia. In this study, we synthesized gold nanorods (GNRs) of different aspect ratios using a binary surfactant mixture of hexadecyltrimethylammonium bromide and sodium oleate. Following surface functionalization with chitosan and a 12-mer peptide, GNRa-CSP12 measuring 130 × 21 nm2was selectively taken up by leukemia cells via targeted endocytosis. Low doses of GNRa-CSP12 inhibited the growth of leukemia cells by disrupting the redox balance and inducing ferroptosis. Mechanistically, GNRa-CSP12 abrogated endogenous Fe2+-dependent m6A demethylase activity, which led to global m6A hypomethylation and post-transcriptional regulation of downstream genes that are involved in glycolysis, hypoxia, and immune checkpoint pathways. In addition, combination treatment with GNRa-CSP12 and tyrosine kinases inhibitors (TKIs) synergistically obviated the m6A-mediated TKI resistance phenotype. Finally, GNRa-CSP12 as a potential immunotherapeutic agent could enhance immunotherapy outcome in leukemia. Our preclinical findings provide the proof-of-concept for targeting m6A-methylation-based epitranscriptomics using nanoparticle as an “epigenetic drug” for cancer therapy.

IntroductionThe prognosis of patients with very high-risk hematologic malignancies who have relapsed/refractory diseases or carrying very poor-risk gene mutations were dismal even after allogeneic hematopoietic stem cell transplantation. Donor lymphocyte infusion (DLI) is a promising prophylactic strategy for reducing relapse after transplant. However, DLI-associated graft-versus-host disease (GVHD) and non-relapse mortality (NRM) were still concerned, especially after allogeneic peripheral blood stem cell transplantation (allo-PBSCT). Therefore, prophylactic DLI should be safe with tolerable DLI-associated GVHD and NRM except for its anti-leukemia effect. To evaluate the safety and efficacy of prophylactic DLI for the very high-risk hematologic malignancies after allo-PBSCT, we performed a cohort study in 160 consecutive patients with hematological malignancies who received unmanipulated allo-PBSCT. DLI procedure was modified to use G-CSF mobilized peripheral progenitors instead of steady state lymphocytes and 4 to 6 weeks of immunosuppressant for prevention of DLI-associated GVHD. The outcomes of those very high-risk patients (group A: DLI group; group B: non-DLI group) and the patients without the very high-risk features (group C) who were not planned for prophylactic DLI were compared.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is an effective, even curative, treatment for patients with high-risk hematologic malignancies. Transplantation from haploidentical donors (haplo-HCT) has been applied for the treatment of hematologic malignancies within the past 2 decades. Bone marrow (BM), G-CSF-primed peripheral blood stem cells (PBSCs), G-CSF-primed BM (G-BM) or the combination of PBSCs and G-BM can serve as stem cell sources for allo-HCT. The optimal source of stem cells in cases of haplo-HCT without ex vivo TCD under myeloablative conditioning is not yet clear. Therefore, we initiated a study of unmanipulated haplo-HCT from PBSCs (haplo-PBSCT) for the treatment of high-risk hematologic malignancies. In this report, we analyzed 89 adult patients who received consecutive haplo-PBSCT to evaluate the efficacy and safety of this transplantation procedure.

No relevant conflicts of interest to declare.

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the only effective, even curative treatment for refractory/relapsed AML patients. Unmanipulated haploidentical HCT (haplo-HCT) resulted in encouraging outcomes for treatment of hematologic malignancies and become an alternative option in case of lacking HLA matched sibling donor (MSD). Unmanipulated haplo-HCT from G-CSF mobilized bone marrow and peripheral blood stem cell (PBSC) has shown similar results as that from MSD-HCT in leukemia. Here, we report the results of a cohort study on the efficacy and toxicity of haplo-PBSCT compared with MSD-PBSCT for treatment of refractory/relapsed AML.