Haploidentical hematopoietic cell transplantation with or without an unrelated cord blood unit for adult acute myeloid leukemia: a multicenter, randomized, open-label, phase 3 trial.

Coinfusion of unrelated cord blood (UCB) units in haploidentical hematopoietic cell transplantation (haplo-HCT) (haplo-cord HCT) for hematopoietic malignancies showed promising results in previous reports, but the efficiency of haplo-cord HCT in acute myeloid leukemia (AML) still lacks sufficient evidence. This multicenter, randomized, phase 3 trial (ClinicalTrials.gov NCT03719534) aimed to assess the efficacy and safety of haplo-cord HCT in AML patients. A total of 268 eligible patients aged 18-60 years, diagnosed with measurable residual disease in AML (excluding acute promyelocytic leukemia), with available haploidentical donors and suitable for allotransplantation, were randomly allocated (1:1) to receive haplo-cord HCT (n = 134) or haplo-HCT (n = 134). The 3-year overall survival (OS) was the primary endpoint in this study. Overall median follow-up was 36.50 months (IQR 24.75-46.50). The 3-year OS of Haplo-cord HCT group was better than haplo-HCT group (80.5%, 95% confidence interval [CI]: 73.7-87.9 vs. 67.8% 95% CI 60.0-76.5, p = 0.013). Favorable progression-free survival (70.3%, 95% CI 62.6-78.8 vs. 57.6%, 95% CI 49.6-67.0, p = 0.012) and cumulative incidence of relapse (12.1%, 95% CI 12.0-12.2 vs. 30.3%, 95% CI 30.1-30.4, p = 0.024) were observed in haplo-cord HCT group. Grade 3-4 adverse events (AEs) within two years posttransplantation in the two groups were similar. Haplo-cord HCT patients exhibited a faster cumulative incidence of neutrophil recovery (p = 0.026) and increased T-cell reconstitution in the early period posttransplantation. Haplo-cord HCT can improve OS in AML patients without excessive AEs, which may exert additional benefits for recipients of haplo-HCT.

Comparison of valganciclovir versus foscarnet for the treatment of cytomegalovirus viremia in adult acute leukemia patients after allogeneic hematopoietic cell transplantation.

Cytomegalovirus (CMV) reactivation increases treatment-related mortality (TRM) after allogeneic hematopoietic cell transplantation (allo-HCT). We analyzed 141 adult acute leukemia (AL) patients suffered allo-HCT between 2017 and 2021, who developed CMV viremia post-HCT and treated with valganciclovir or foscarnet, to evaluate effectiveness and safety of both drugs. Viremia clearance rates (14 and 21 d post treatment) and toxicities were similar in two groups. However, valganciclovir was associated with a lower cumulative incidence of CMV recurrence within 180 days (16.7% vs. 35.7%, p=0.029) post CMV clearance. Finally, 2-year TRM was lower in valganciclovir group (9.7% ± 0.2% vs. 26.2% ± 0.3%, p = 0.026), result a superior 2-year overall survival (OS; 88.1% ± 5.2% vs. 64.4% ± 5.5%, p = 0.005) and leukemia-free survival (LFS; 82.0% ± 5.9% vs. 58.9% ± 5.6%, p = 0.009). Valganciclovir might decrease CMV viremia recurrence and led to better long-term outcome than foscarnet in adult AL patients developed CMV viremia post-HCT. Considering the inherent biases of retrospective study, well-designed trials are warranted to validate our conclusion.

Insufficiency of collagenases in establishment of primary chondrocyte culture from cartilage of elderly patients receiving total joint replacement.

Background Collagenases are frequently used in chondrocyte isolation from articular cartilage. However, the sufficiency of this enzyme in establishing primary human chondrocyte culture remains unknown. Methods Cartilage slices shaved from femoral head or tibial plateau of patients receiving total joint replacement surgery (16 hips, 8 knees) were subjected to 0.02% collagenase IA digestion for 16 h with (N = 19) or without (N = 5) the pre-treatment of 0.4% pronase E for 1.5 h. Chondrocyte yield and viability were compared between two groups. Chondrocyte phenotype was determined by the expression ratio of collagen type II to I. The morphology of cultured chondrocytes was monitored with a light microscope.Results Cartilage with pronase E pre-treatment yielded significantly higher chondrocytes than that without the pre-treatment (3,399 ± 1,637 cells/mg wet cartilage vs. 1,895 ± 688 cells/mg wet cartilage; P = 0.0067). Cell viability in the former group was also significantly higher than that in the latter (94% ± 2% vs. 86% ± 6%; P = 0.03). When cultured in monolayers, cells from cartilage with pronase E pre-treatment grew in a single plane showing rounded shape while cells from the other group grew in multi-planes and exhibited irregular shape. The mRNA expression ratio of collagen type II to I was 13.2 ± 7.5 in cells isolated from cartilage pre-treated with pronase E, indicating a typical chondrocyte phenotype. Conclusions Collagenase IA was not sufficient in establishing primary human chondrocyte culture. Cartilage must be treated with pronase E prior to collagenase IA application.

Fucosylation Promotes Cytolytic Function and Accumulation of NK Cells in B Cell Lymphoma.

Natural killer (NK) cells have been demonstrated as a promising cellular therapy as they exert potent anti-tumor immune responses. However, applications of NK cells to tumor immunotherapy, especially in the treatment of advanced hematopoietic and solid malignancies, are still limited due to the compromised survival and short persistence of the transferred NK cells in vivo. Here, we observed that fucosyltransferase (FUT) 7 and 8 were highly expressed on NK cells, and the expression of CLA was positively correlated with the accumulation of NK cells in clinical B cell lymphoma development. Via enzyme-mediated ex vivo cell-surface fucosylation, the cytolytic effect of NK cells against B cell lymphoma was significantly augmented. Fucosylation also promoted NK cell accumulation in B cell lymphoma-targeted tissues by enhancing their binding to E-selectin. Moreover, fucosylation of NK cells also facilitated stronger T cell anti-tumor immune responses. These findings suggest that ex vivo fucosylation contributes to enhancing the effector functions of NK cells and may serve as a novel strategy for tumor immunotherapy.

Features of Epstein-Barr Virus and Cytomegalovirus Reactivation in Acute Leukemia Patients After Haplo-HCT With Myeloablative ATG-Containing Conditioning Regimen.

Background: Haploidentical donor hematopoietic cell transplantation (haplo-HCT) has become a preferred option for patients without HLA-matched donors, but it increases the risk of viral reactivations. Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are common viruses post-HCT, but limited data have been reported in the setting of haplo-HCT. Methods: We conducted a retrospective study enrolling acute leukemia patients who received haplo-HCT with myeloablative conditioning regimen employing ATG in our center from July 2014 to July 2017. All the patients enrolled were EBV-IgM and EBV-DNA negative but EBV-IgG positive, and so were their donors. The same went for CMV as well. Results: In total, 602 patients were recruited consisting of 331 with acute myeloid leukemia (AML) and 271 with acute lymphoblastic leukemia (ALL). One-year cumulative incidences of EBV (22.9% ± 2.4% vs. 27.4% ± 2.8%, P = 0.169) and CMV (24.7% ± 2.4% vs. 29.4% ± 2.8%, P = 0.190) reactivation were comparable between AML and ALL. EBV and CMV were independent risk factors for each other. In the AML group, male recipients [HR = 1.275, 95% CI (1.001-1.624), P = 0.049] and acute graft-versus-host disease [HR = 1.592, 95% CI (1.001-2.533), P = 0.049] were independent risk factors for EBV reactivation and CMV reactivation, respectively. CMV rather than EBV reactivation was related to a trend of worsened treatment-related mortality (TRM) (15.6% ± 0.1% vs. 10.2% ± 0.0%, P = 0.067) and progression-free survival (PFS) (60.6% ± 4.1% vs. 70.3% ± 2.3%, P = 0.073), while significant impacts were revealed only in the subgroup analysis. CMV reactivation resulted in a remarkable inferior 2-year overall survival (OS) (64.2% ± 5.7% vs. 77.6% ± 3.2%, P = 0.038) and PFS (55.0% ± 5.9% vs. 71.9% ± 3.4%, P = 0.042) in ALL patients. On the other hand, in the EBV+/CMV- subgroup, relapse was lower in ALL patients (8.2% ± 0.2% vs. 32.4% ± 0.8%, P = 0.010) compared with AML patients, which led to a superior 2-year OS (82.0% ± 6.2% vs. 60.3% ± 8.8%, P = 0.016) and PFS (74.5% ± 7.0% vs. 57.5% ± 8.4%, P = 0.036). Conclusion: We concluded that EBV and CMV reactivations were frequent in acute leukemia patients after haplo-HCT, with possibly distinctive risk factors from HLA-matched HCT. There could be a potential interaction between EBV and CMV, but impacts on transplant outcomes remained complex.

Epstein-Barr virus and cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation in patients with non-Hodgkin lymphoma: the prevalence and impacts on outcomes : EBV and CMV reactivation post allo-HCT in NHL.

Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivations are common complications after allogeneic hematopoietic cell transplantation (allo-HCT), but data focusing on non-Hodgkin lymphoma (NHL) are limited. We retrospectively analyzed the prevalence of EBV and CMV reactivation post-allo-HCT and the impacts on transplant outcomes in 160 NHL patients. The 1-year incidences of EBV and CMV reactivation were 22.58% and 25.55%, respectively. Independent impactors for EBV reactivation were more than 6 lines of chemotherapy (P = 0.030), use of rituximab (P = 0.004), and neutrophil recovery within 30 days post-HCT (P = 0.022). For T-cell lymphoblastic lymphoma patients, the International Prognostic Index (IPI) (P = 0.015) and chronic GVHD (P = 0.001) increased the risk of CMV reactivation. CMV reactivation was independently related to a lower risk of relapse (P = 0.027) but higher transplant-related mortality (TRM) (P = 0.038). Although viral reactivation had no significant impact on overall survival (OS) in the whole cohort, it led to an inferior 2-year OS (67.6% versus 92.5%, P = 0.005) and TRM (20.1% versus 4.7%, P = 0.020) in recipients surviving for more than 180 days. We concluded that EBV and CMV reactivation post-allotransplant still deserved concern particularly in NHL patients with high-risk factors, since it is generally related to a deteriorated prognosis. Large-scale studies are warranted to validate our findings.

Epstein-Barr virus reactivation after allogeneic hematopoietic stem cell transplantation: multifactorial impact on transplant outcomes.

Epstein-Barr virus (EBV) reactivation after allogeneic hematopoietic cell transplantation (allo-HCT) is one of the major concerns that may lead to fatal EBV diseases. However, updated data are needed because of the remarkable evolution of the HCT protocol and donor selection. We conducted a retrospective study that enrolled 890 allo-HCT recipients. Independent risk factors for EBV reactivation were use of antithymocyte globulin, haploidentical donor, and the presence of chronic graft-versus-host disease. The cumulative incidence of EBV reactivation was 2.9%, 11.7%, 27.3%, and 41.9% for patients with 0, 1, 2, and 3 risk factors, respectively (P < 0.001). Posttransplant lymphoproliferative disorders (PTLDs) occurred in seven patients. EBV reactivation was associated with inferior survival in recipients who survived more than 2 years post-HCT (P < 0.001) but might time-dependently benefit those patients with malignancies by decreasing relapse incidence (P = 0.046). A decreased relapse incidence was observed 1 year after HCT for recipients at first or second remission (P = 0.042) and in the first year post-HCT for recipients with advanced diseases (P = 0.032). We concluded that with current management, PTLDs were efficiently controlled, but EBV reactivation still had a multifactorial impact on transplant outcomes. Multicenter prospective studies are warranted to validate these findings.