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Background: Real-world data on outcomes of upfront allogeneic hematopoietic stem cell transplantation (allo-HCT) for adult T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) patients in first complete remission (CR1) is still lacking. Methods: A single center retrospective study was conducted from 94 consecutive patients received their first allo-HCT between 2010 and 2021, which include 76 patients received upfront allo-HCT and 18 patients received allo-HCT in non-upfront settings. Results: There were no significant differences in most variables. In the upfront allo-HCT group, 52 (68%) patients achieved CR1 with one cycle of induction regimen. 24 (32%) patients achieved CR1 with more than one cycle. In the non-upfront group, there were 14 patients with active disease and 4 patients in second CR before transplant. The majority of patients received antithymocyte globulin-based graft-versus-host disease prophylaxis. Median follow-up time was 51 months for both groups. 5-year overall survival (OS) was 54% in the upfront allo-HCT group. While, in the non-upfront group, 5-year OS were 19% (P = 0.013). 5-year progression free survival in the upfront group was higher than that in the non-upfront group (50% versus 20%, P = 0.02). 5-year cumulative incidence relapse rate was significantly higher in non-upfront group (64% vs. 32%, P = 0.006). While, there was no difference in the 5-year non-relapse mortality (NRM) rate (19% versus 16%, P = 0.56). The most common cause of death was disease progression. In multivariable analysis, non-upfront allo-HCT (hazard ratios (HR) 2.14, P = 0.03) and HCT-CI (≥ 2) (HR 6.07, P = 0.002) were identified to be associated with worse OS. Non-upfront allo-HCT and HCT-CI (≥ 2) were also found to be independent risk factors for higher relapse rate. While, haploidentical-HCT was found to be associated with increased NRM. Conclusions: Our study indicated that allo-HCT remains an important curative treatment for adult patients with T-ALL, especially when it was performed in the upfront setting. [ABSTRACT FROM AUTHOR]

Chemotherapy followed by donor lymphocyte infusion (DLI) is a promising treatment for relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the best strategy for administering this therapy is still unclear. This study sought to explore the efficacy and safety of chidamide and CAG (cytarabine, aclarubicin, and granulocyte colony-stimulating factor) (CCAG) regimen followed by DLI in relapsed AML/MDS after allo-HSCT. This was a single-arm, phase II trial in patients with relapsed AML/MDS after allo-HSCT. CCAG regimen followed by DLI was given according to the inclusion and exclusion criteria. Twenty adult patients were enrolled. The median follow-up time was 12 months. The complete remission (CR) rate was 45% and the partial remission (PR) rate was 5%. The 1-year overall survival (OS) was 56.7% (95% confidence interval (95% CI), 31.6–75.6%), and the median OS was 19 months. The 1-year relapse-free survival (RFS) was 83.3% (95% CI, 27.3–97.5%). Patients relapsing more than 6 months after HSCT and achieving CR/PR after CCAG plus DLI regimen attained significantly higher survival rates. The cumulative incidence of grade III–IV acute graft-versus-host disease (aGVHD) was 9.4%. There was no treatment-related mortality (TRM). These data suggest that CCAG plus DLI regimen is safe and induces durable remission and superior survival in patients with relapsed AML/MDS after allo-HSCT. Trial registration number: ChiCTR.org identifier: ChiCTR1800017740 and date of registration: August 12, 2018. [ABSTRACT FROM AUTHOR]

We started a single-arm, phase II, open-label, prospective clinical trial using steroids-ruxolitinib as the first-line therapy for intermediate- to high-risk aGVHD (NCT04397367). Here, we report the association of a biomarker panel (sST2, REG3α, sTNFR1, IL-6 and IL-8) with responses to GVHD therapy. The novel first-line therapy for 39 patients with newly diagnosed aGVHD consisted of 1 mg/kg methylprednisolone and 5 mg/day ruxolitinib. The serum concentrations of the biomarkers were prospectively detected at planned time points. Of the 39 patients, the complete response rate at day 28 was 82.05%. In patients who achieved CR, the concentrations of REG3α (P14 = 0.01; P28 = 0.10) and sTNFR1 (P14 = 0.42; P28 = 0.04) declined at day 14 and day 28 compared with the pre-enrolment levels. In refractory patients, the levels of REG3α at day 14 were higher than those pre-enrolment (P = 0.04). REG3α (P = 0.02) was elevated in the refractory patients compared with the patients achieving CR at day 14 after enrolment, while there was no significant difference in the levels of sST2, sTNFR1 or IL-6. Elevated REG3α levels may predict refractory aGVHD after novel first-line therapy with steroids-ruxolitinib. [ABSTRACT FROM AUTHOR]

Persistent thrombocytopenia (PT) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with an increased risk of bleeding and poor survival. The exact pathogenesis underlying PT remains unclear, and its management is difficult. Here we conducted a retrospective study to evaluate the efficacy and safety of eltrombopag (EPAG) in 34 patients with PT after allo-HSCT. Seven patients suffered from prolonged isolated thrombocytopenia (PIT), and 27 had secondary failure of platelet recovery (SFPR). For most patients, the initial dose was 25 mg or 50 mg daily, then adjusted to the maximum dose of 50–100 mg per day according to the response of platelet recovery and toleration of patients. The cumulative incidence (CI) of platelet recovery to at least 20 × 109/L and 50 × 109/L without transfusion support for at least 7 days was 72.1% and 60.7%, respectively. Nineteen (86.4%) of 22 responders were able to taper off the medication; furthermore, the platelet counts remained stable 1 month after withdrawal of EPAG. Although two patients discontinued EPAG during treatment due to headache and nausea, no patients developed grade 3 or 4 toxicities. Hypoplasia of bone marrow and decreased megakaryocytes (MKs) were found to be risk factors for overall response (OR) and complete response (CR) in multivariate analysis, respectively. Overall, our results indicated that EPAG can be used in the treatment of PT and that continuous exposure to EPAG may not be necessary. [ABSTRACT FROM AUTHOR]

The optimal rabbit anti-thymocyte globulin (rATG) graft-versus-host disease (GVHD) prophylaxis regimen in matched sibling donor peripheral blood stem cell transplantation (MSD-PBSCT) remains to be elucidated. In this prospective study, we used low-dose rATG for GVHD prophylaxis in patients or donors aged ≥ 40 years with hematological malignancies receiving MSD-PBSCT. rATG was administered to 40 patients at an intravenous dose of 5 mg/kg divided over day 5 and day 4 before graft infusion. No graft failure occurred. Median times to leukocyte engraftment and platelet engraftment were 11.0 days and 13.9 days. The cumulative incidence of grades 2-4 and grades 3-4 acute GVHD at day +100 was 30.0% and 2.6%. The 2-year cumulative incidence of extensive chronic GVHD and severe chronic GVHD was 11.4% and 14.7%. 93.5% (29/31) of patients had discontinued immunosuppressive medication within 3 years after transplantation. The 2-year cumulative incidence of transplant-related mortality (TRM) and relapse was 14.0% and 22.6%. The cumulative incidence of cytomegalovirus reactivation, Epstein-Barr virus reactivation, and fungal infection was 22.3%, 12.9%, and 12.5%. Kaplan-Meier estimates for overall survival, disease-free survival, and GVHD-free and relapse-free survival 3 years after transplantation were 68.9%, 68.9%, and 54.0%. rATG for GVHD prophylaxis is tolerable and efficacious at a 5 mg/kg total dose administered over 2 days (days -5 to -4) in patients receiving allogeneic MSD-PBSCT. [ABSTRACT FROM AUTHOR]

The mixed-lineage leukemia (MLL)-AF4 fusion protein encoded by the chromosomal translocation t(4;11) predicts a poorer prognosis in acute lymphoblastic leukemia (ALL) than in other MLL-associated leukemias. However, the detailed mechanism underlying regulation of MLL-AF4 expression remains largely unknown. In this study, we showed that microRNA (miR)-142-3p was significantly downregulated in ALL patients expressing MLL-AF4. Upregulation of miR-142-3p decreased MLL-AF4 expression in the RS4;11 leukemic cell line, which suggests that MLL-AF4 is a direct target of miR-142-3p. Ectopic expression of miR-142-3p remarkably suppressed cell proliferation and induced apoptosis in RS4;11 cells expressing the MLL-AF4 fusion protein. We also found that exogenous expression of miR-142-3p strongly reduced the expression of MLL-AF4 target genes such as homeobox A (HOXA)9, HOXA7, and HOXA10 in RS4;11 cells. Taken together, our results indicate that miR-142-3p functions as a growth suppressor in MLL-AF4 + ALL, and its suppressive effects are mediated primarily through repression of MLL-AF4 expression. [ABSTRACT FROM AUTHOR]

The oncogenic fusion protein AML1-ETO retains the ability of AML1 to interact with the enhancer core DNA sequences, but blocks AML1-dependent transcription. Previous studies have shown that post-translational modification of AML1-ETO may play a role in its regulation. Here we report that AML1-ETO-positive patients, with high histone lysine methyltransferase Enhancer of zeste homolog 1 (EZH1) expression, show a worse overall survival than those with lower EZH1 expression. EZH1 knockdown impairs survival and proliferation of AML1-ETO-expressing cells in vitro and in vivo. We find that EZH1 WD domain binds to the AML1-ETO NHR1 domain and methylates AML1-ETO at lysine 43 (Lys43). This requires the EZH1 SET domain, which augments AML1-ETO-dependent repression of tumor suppressor genes. Loss of Lys43 methylation by point mutation or domain deletion impairs AML1-ETO-repressive activity. These findings highlight the role of EZH1 in non-histone lysine methylation, indicating that cooperation between AML1-ETO and EZH1 and AML1-ETO site-specific lysine methylation promote AML1-ETO transcriptional repression in leukemia. The oncogenic fusion protein AML1-ETO has the ability of AML1 to interact with DNA but blocks AML1-dependent transcription. Here the authors report that histone lysine methyltransferase EZH1 interacts with AML1-ETO and methylates AML1-ETO at lysine 43, promoting AML1-ETO transcriptional repression in leukemia. [ABSTRACT FROM AUTHOR]

The prognosis of patients with high-risk acute myeloid leukemia (AML) is dismal even after allogeneic stem cell transplantation (allo-HSCT), with relapse remaining the leading cause of treatment failure. Here, we investigated whether ruxolitinib and decitabine plus modified busulfan-cyclophosphamide (mBu/Cy) conditioning could reduce relapse in high-risk AML after allo-HSCT. This prospective, single-arm, phase II trial enrolled 37 patients who received allo-HSCT between September 2020 and March 2022 at the First Medical Center of Chinese People’s Liberation Army (PLA) General Hospital. Eligible patients (10–62 years) had relapsed/refractory, positive measurable residual disease (MRD) prior to conditioning or adverse genetic abnormalities. Ruxolitinib (35 mg twice daily, days − 15 to − 10) and decitabine (20 mg/m2/day, days − 15 to − 10) were administered followed by mBu/Cy conditioning. All patients achieved engraftment. The cumulative incidences (CIs) of acute graft-versus-host disease (GVHD) grades II–IV and III–IV were 35.0% and 10.5%, respectively. The 1-year cumulative incidence of chronic GVHD was 8.1%. The 1-year CI of relapse was 29.7% among all patients, 0% in patients who achieved the first complete remission (CR1) prior to conditioning, and 0% in those with MRD-negative prior to conditioning. The 1-year non-relapse mortality was 5.4%. The 1-year probabilities of overall survival, disease-free survival, and GVHD-free relapse-free survival were 70.3%, 62.2%, and 54.1%, respectively. In conclusion, the novel conditioning showed primary efficacy in terms of a reduction in relapse in high-risk patients with AML after allo-HSCT, especially in those who achieved CR1 and MRD-negative prior to conditioning. Also, the new conditioning regimen may help reduce the incidence of chronic GVHD. ClinicalTrials.govidentifier: NCT04582604. [ABSTRACT FROM AUTHOR]