Outcome after allogeneic hematopoietic stem cell transplantation following Venetoclax-based therapy among AML and MDS patients.

The use of Bcl-2 inhibitor Venetoclax (VEN) combined with hypomethylating agents or chemotherapy has shown efficacy in treating acute myeloid leukemia (AML) as frontline treatment and for relapse, allowing more patients to bridge to allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the influence of VEN-based therapy on the prognosis of subsequent allogeneic HSCT remains unknown. We retrospectively collected data from patients who proceeded to allo-HSCT between November 2018 and November 2020 after VEN-based therapy at five transplant centers in Zhejiang Province, China. A total of 39 patients were analyzed. Thirty-one patients were diagnosed with AML (28 de novo, 3 secondary to MDS), 6 with MDS, and 2 with CMML. The majority (74.4%) of patients received VEN-based therapy for the treatment of relapse (38.5%) or refractory disease (35.9%); 5 (12.8%) received it as an initial treatment, and 5 (12.8%) patients who were already in complete remission (CR) received VEN for further consolidation or deep remission before HSCT. Twenty-seven (69.2%) patients were in CR at the time of HSCT. Day + 100 cumulative incidences of grade I-IV acute graft-versus-host disease (aGVHD) and grade II-IV aGVHD were 43.6% and 15.4%, respectively. Of 34 evaluable patients, 6.4% and 25.6% developed chronic GVHD at 1 year and 2 years. The 100-day cytomegalovirus (CMV) reactivation occurred in 76.3% of patients and Epstein-Barr virus (EBV) reactivation occurred in 29.7% of patients. With a median follow-up of 14.7 months, overall survival, progression-free survival, relapse, and non-relapse mortality incidence at 1 year were 75.5%, 61.6%, 16.7%, and 21.7%, respectively. Both univariate and multivariate analysis revealed that relapsed/refractory (R/R) disease was associated with inferior PFS (HR 4.849, 95% CI 1.009-23.30; p = 0.049). Prior poor response to VEN was found to be a significant factor predicting higher risk of relapse (HR 4.37, 95% CI 1.130-16.9; p = 0.033). Our results showed that VEN-based regimen therapy followed by allo-HSCT in AML patients is feasible and does not increase the risk of transplant-related mortality and toxicity.

Allogeneic Bone Marrow-Derived Mesenchymal Stromal Cells Expanded In Vitro for Treatment of Aplastic Anemia: A Multicenter Phase II Trial.

We conducted a phase II, noncomparative, multicenter study to assess the efficacy and safety of allogeneic bone marrow-derived mesenchymal stromal cells (BM-MSCs) expanded in vitro for patients with aplastic anemia (AA) refractory to immunosuppressive therapy. Seventy-four patients from seven centers received allogeneic BM-MSCs at a dose of 1-2 × 106 cells/kg per week for 4 weeks. Responses were assessed at 0.5, 1, 2, 3, 6, 9, and 12 months after the first cells infusion. Patients with response at 1 month continued to receive four infusions. All patients were evaluable. The overall response rate was 28.4% (95% confidence interval, 19%-40%), with 6.8% complete response and 21.6% partial response. The median times to response of leukocytic, erythrocytic, and megakaryocytic linages were 19 (range, 11-29), 17 (range, 12-25), and 31 (range, 26-84) days, respectively. After median follow-up of 17 months, overall survival was 87.8%. Seven patients developed transitory and mild headache and fever, but no other adverse events were observed. Antithymocyte globulin used in previous treatment and no activated infection throughout treatment were predictors for response. Allogeneic BM-MSCs infusion is a feasible and effective treatment option for refractory AA. The trial was registered at www.clinicaltrials.gov as NCT00195624. Stem Cells Translational Medicine 2017;6:1569-1575.

TNF-α enhances vascular cell adhesion molecule-1 expression in human bone marrow mesenchymal stem cells via the NF-κB, ERK and JNK signaling pathways.

The migration of circulating mesenchymal stem cells (MSCs) to injured tissue is an important step in tissue regeneration and requires adhesion to the microvascular endothelium. The current study investigated the underlying mechanism of MSC adhesion to endothelial cells during inflammation. In in vitro MSC culture, tumor necrosis factor­α (TNF­α) increased the level of vascular cell adhesion molecule­1 (VCAM­1) expression in a dose­dependent manner. The nuclear factor-κB (NF-κB), extracellular signal­regulated kinase (ERK) and c­Jun N­terminal kinase (JNK) signaling pathway inhibitors, pyrrolidine dithiocarbamate (PDTC), U0126 and SP600125, respectively, suppressed VCAM­1 expression induced by TNF­α at the mRNA and protein levels (P<0.05). TNF­α augmented the activation of NF­κB, ERK and JNK, and promoted MSC adhesion to human umbilical vein endothelial cells; however, the inhibitors of NF­κB, ERK and JNK did not affect this process in these cells. The results of the current study indicate that adhesion of circulating MSCs to the endothelium is regulated by TNF-α-induced VCAM-1 expression, which is potentially mediated by the NF­κB, ERK and JNK signaling pathways.

[Relation of MBL ExonI 54 and NFκB1-94ins/del ATTG Polymorphism with Fever during Neutropenia in Patients with Acute Leukaemia after Chemotherapy].

OBJECTIVE: To explore the correlation between MBL ExonI 54 and NFκB1-94ins/del ATTG polymorphism and fever during neutropenia in patients with acute leukaemia (AL) (except M3) after first chemotherapy in Chinese Han population. METHODS: Blood samples obtained from 76 fever patients with AL during neutropenia episodes were detected to analyse single nucleotide polymorphism (SNP) in the MBL ExonI 54 and NFκB1-94ins/del ATTG gene, and analyse the correlation between above-mentioned 2 polymorphisms and fever during neutropenia of AL patients after chemotherapy. RESULTS: In 76 patients, no correlation were found between MBL ExonI 54 and NFκB1-94ins/del ATTG polymorphism and fever during neutropenia in patients with acute leukaemia after chemotherapy (P > 0.05). No significant relation were found in sex, age, underlying disease, disease status or degrees of neutropenia in febrile neutropenia between MBL ExonI 54 and NFκB1-94ins/del ATTG polymorphism (P > 0.05). However, patients with MBL ExonI 54 mutation presented longer febrile duration with a median of 5 days compared to 3 days of patients with wildtype MBL ExonI 54 genotype (P < 0.05). CONCLUSIONS: There is no clear correlation between MBL ExonI 54 and NFκB1-94ins/del ATTG polymorphism and fever during neutropenia in patients with acute leukaemia after chemotherapy. However, the patients with MBL ExonI 54 mutation have been observed to present a longer febrile duration.

Efficacy and safety of mesenchymal stromal cell treatment from related donors for patients with refractory aplastic anemia.

BACKGROUND AIMS: This study evaluated the feasibility, safety and immunological effects of the intravenous administration of mesenchymal stromal cells (MSCs) from a related donor in patients with refractory aplastic anemia (AA). METHODS: A mean of 6 × 10(5)/kg (range, 5.0-7.1 × 10(5)) MSCs were injected intravenously to 18 patients, including 14 patients with nonsevere AA and four patients with severe AA who were refractory to prior immunosuppressive treatment. The outcomes of patients treated with MSCs were evaluated and compared with a historic control cohort, including 18 patients with refractory AA. RESULTS: Two patients had injection-related adverse events, including transient fever and headache. No major adverse events were reported during the follow-up period. An immunological analysis revealed an increased proportion of CD4(+)CD25(+) FOXP3(+)regulatory T cells in peripheral mononuclear cells. Following up for 1 year, six of 18 patients (33.3%) achieved a complete response or a partial response to MSC treatment. In six patients, two achieved a complete response including a recovery of three hematopoietic cell lines after MSCs therapy at days 88 and 92, two patients achieved only a red cell recovery with hemoglobin levels >100 g/L at days 30 and 48 and two patients had only a platelet recovery with a platelet count of >60 × 10(9)/L at days 54 and 81. In the control cohort, only one patient (5.56%) achieved a partial response during the follow-up period. CONCLUSIONS: The data from the present study suggest that treatment with MSCs from a related donor may be a promising therapeutic strategy for patients with refractory AA. The trial has been registered at ClinicalTrials.gov: identifier NCT01305694.

[Roles of CEBPA mutation and expression abnormality in acute myeloid leukemia - review].

CCAAT enhancer binding protein A (CEBPA) and its product transcription factor CCAAT enhancer binding protein α (C/EBPα) play pivotal roles in early granulocyte development. C/EBPα induces the transition and keeps the balance of differentiation and proliferation of myeloid progenitors. The mutation and dysregulation of CEBPA at transcription, translation or post-translation level lead to differentiation block and over proliferation of immature hematopoietic cells, which are important mechanisms of acute myeloid leukemia (AML). The mutation and dysregulation of CEBPA also provide clues for evaluating the outcome of AML patients and potential targets for differentiation-inducing therapies. This review focus on CEBPA mutation and AML, dysregulation of C/EBPα protein expression and AML, as well as C/EBPα protein and targeting therapy.

[Relationship of tumor necrosis factor gene polymorphism and acute graft-versus-host disease after unrelated allogeneic hematopoietic stem cell transplantation].

OBJECTIVE: To explore the relationship between tumor necrosis factor (TNF) gene polymorphisms in donors and recipients and the incidence and severity of acute graft-versus-host diseases (aGVHD) after unrelated allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: Single nucleotide polymorphisms (SNPs) of TNFalpha-238 (G/A), TNFalpha-857 (C/T), TNFalpha-863 (C/A), TNFalpha-1031 (T/C), TNFbeta + 252(A/G) were analyzed by Multiplex SNaPshot analysis in 76 pairs of donors and recipients. RESULTS: Transplantation involving donors with TNFalpha-857 CC genotype resulted in a higher incidence of grade II-IV aGVHD than donors with CT genotype (91.3% vs 8.7%, P = 0.039). In the 23 patients with grade II-IV aGVHD, no patients had TNFbeta + 252 AA genotype, 19 (82.6%) had GA genotype and 4 (17.4%) had GG genotype. There was a significant difference in the distribution pattern of the TNFbeta + 252 (AA, GA and GG) genotypes in these patients (P = 0.03). There was no significant association of TNFalpha-238 (G/A), TNFalpha-863 (C/A) and TNFalpha-1031(T/C) polymorphisms with the risk of aGVHD. CONCLUSION: These results suggest donor TNFalpha-857 CC genotype is related to a higher incidence of grade II-IV aGVHD, and patients with TNFbeta + 252 AA genotype have protection against the risk of grade II-IV aGVHD.