CEAC (oral semustine, etoposide, cytarabine and cyclophosphamide) vs BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning regimen of autologous stem cell transplantation for diffuse large B-cell lymphoma: a post-hoc, propensity score-matched, cohort study in Chinese patients.

Autologous stem cell transplantation (ASCT) is a salvage therapy for relapsed or refractory diffuse large B-cell lymphoma (DLBCL). We have developed a novel conditioning regimen called CEAC (oral semustine 250 mg/m2 d-6, etoposide 300 mg/m2 d-5 ~ d-2, cytarabine 500 mg/m2 d-5 ~ d-2, and cyclophosphamide 1200 mg/m2 d-5 ~ d-2) In lymphoma patients in China. Here, we conducted a study to compare the conventional BEAM regimen with the CEAC regimen in 110 DLBCL patients. Propensity-score matching was performed in a 1:4 ratio (22 patients received BEAM and 88 received CEAC). Our results showed no significant difference in the overall response rate (95% vs 97%, P = 1.000) and complete response rate (66% vs 73%, P = 0.580) between the two cohorts. The 5-year progression-free survival (PFS), 5-year overall survival (OS), and 5-year cumulative incidence of relapse (CIR) for all patients were 72% (95% CI 62%-82%), 92% (95% CI 86%-97%), and 29% (95% CI 17%-38%), respectively. There was no significant difference in the 5-year PFS (80% vs 70%, P = 0.637), 5-year OS (95% vs 91%, P = 0.496), and 5-year CIR (20% vs 30%, P = 0.733) between cohorts. In terms of safety, the CEAC cohort had a lower incidence rate of grade 1-2 gastrointestinal hemorrhage (P = 0.023) and severe nausea (P = 0.007) compared with the BEAM cohort. In conclusion, the CEAC regimen seems to be a suitable alternative to the BEAM regimen for ASCT in DLBCL patients.

Comparison of Stem Cell Transplantation Using Unrelated, Haploidentical, and Sibling Donors for Patients with Acquired Severe Aplastic Anemia: A Single-Center Retrospective Cohort Study.

The preferred donor (haploidentical donor [HID] versus matched unrelated donor [URD]) choice in patients with acquired severe aplastic anemia (SAA) who lack an HLA-matched sibling donor (MSD) and fail upfront immunosuppressive treatment (IST) therapy is unknown. We retrospectively investigated SAA patients (n = 58) who underwent allogeneic stem cell transplantation (allo-SCT) between January 2012 and October 2022. The 5-year overall survival (OS) and 5-year failure-free survival (FFS) were comparable among the URD (n = 8), HID (n = 25), and MSD (n = 25) cohorts (OS: mean, 87.5 ± 11.7% versus 98.0 ± 6.5% versus 83.3 ± 7.6% [P = .926]; FFS: mean, 60.0 ± 18.2% versus 87.0 ± 7.0% versus 78.3 ± 8.6% [P = .222]). Multivariate analysis revealed that primary engraftment failure independently predicted OS and secondary graft failure predicted FFS among SAA patients who underwent allo-SCT, but donor type and age were not predictive of these outcomes. An urgent second SCT for patients with engraftment failure may be an effective salvage treatment. Our findings show that an alternative donor SCT is indicated for eligible SAA patients without an MSD even if age ≥40 years.

Nanostructure Effect on Magnetization Processes in FePt Polytwin Crystals.

In FePt polytwin crystals with large magnetocrystalline anisotropy, the boundaries may play a crucial role in the magnetization processes occurring under an external magnetic field. In this study, we employed phase-field modeling and computer simulations to systematically investigate the effect of three types of polytwin boundaries-namely, symmetric (Type I), asymmetric (Type II), and mixed (Type III) boundaries-on magnetization processes as well as coercive fields under an external magnetic field along various directions. Because of the large anisotropy of FePt, the domain wall motion mechanism is usually dominant in the domain switching processes, while the magnetization rotation mechanism only becomes important at the late magnetization stage under a high external magnetic field. Among these three types of polytwin boundaries, the low coercivity is mainly due to the domain wall motion process, which starts from the intersection point at the polytwin boundary. The coercive field for the mixed polytwin boundary (Type III) is always in between the values of Type I and II.

Chimeric antigen receptor T-cell therapy combined with autologous stem cell transplantation improved progression-free survival of relapsed or refractory diffuse large B-cell lymphoma patients: A single-center, retrospective, cohort study.

Autologous hematopoietic stem cell transplantation (ASCT) and chimeric antigen receptor T-cell therapy (CART) are salvage therapies that are utilised for treatment of relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). However, whether the combination therapy of ASCT and CART (ASCT-CART) can improve the survival of R/R DLBCL remains unknown. Overall, 67 R/R DLBCL patients were included, among which 21 patients underwent ASCT-CART therapy and 46 patients underwent ASCT therapy. The median number of mononuclear cells numbers that were infused in the ASCT-CART and ASCT groups was 4.71 × 108 /kg and 5.36 × 108 /kg, respectively (p = 0.469). The median number of CD34+ cell numbers that were infused in the ASCT-CART and ASCT groups was 2.41 × 106 /kg and 3.05 × 106 /kg, respectively (p = 0.663). The median number of CART cells that were infused was 2.63 × 106 /kg with a median transduction rate of 59.83%. The objective response rates to ASCT-CART and ASCT therapy were 90% and 89%, respectively (p = 1.000). However, the ASCT-CART group showed higher complete remission (CR) rates than the ASCT group (71% vs. 33%; p = 0.003). The ASCT-CART group demonstrated superior 3 year progression-free survival (PFS) (80% vs. 44%; p = 0.036) and lower 3 year relapse/progression rate (15% vs. 56%; p = 0.015) compared to the ASCT group. However, the 3 year overall survival results indicated that there were no differences between the two groups (80% vs. 69%; p = 0.545). For R/R DLBCL patients, ASCT-CART therapy is associated with higher CR rate, better PFS, and lower relapse/progression rate. These data support that ASCT-CART therapy can be used as a salvage therapy for R/R DLBCL patients.

SAMHD1 Mutations and Expression in Mantle Cell Lymphoma Patients.

SAMHD1 (sterile alpha motif domain and histidine-aspartate domain-containing protein 1) is a deoxynucleoside triphosphate triphosphohydrolase regulating innate immune and modulating DNA damage signaling. It plays an important role in the development of some tumors. SAMHD1 was also reported as a barrier to cytarabine, a common chemotherapy drug for mantle cell lymphoma (MCL), and as a biomarker of grim prognosis for acute myelocytic leukemia (AML) patients. However, SAMHD1 expression and function in MCL have not been well-defined. In the present study, we evaluated SAMHD1 expression by immunohistochemistry and its gene structure by Sanger sequencing in MCL. Our results showed that SAMHD1 was positive in 36 (62.1%) patients. Importantly, SAMHD1-positive patients were associated with lower chemotherapy response rate (p = 0.023) and shorter overall survival (p = 0.039) than SAMHD1-negative cases. These results suggest that SAMHD1 is an adverse biomarker for MCL patients, which is due to the high expression of SAMHD1 and rapid cell proliferation. These findings were confirmed in an in vitro study using the siRNA technique. Silencing the SAMHD1 gene in the MCL cell line Jeko-1 significantly decreased cell proliferation and increased cell apoptosis. The MCL cell line with SAMHD1 knockdown showed lower Ki-67 proliferation index, higher caspase-3, and higher sensitivity to cytarabine. Furthermore, for the first time, four previously unreported missense mutations (S302Y, Y432C, E449G, and R451H) in exon 8 and exon 12 of the SAMHD1 gene were discovered by sequencing. The mutations had not been found to corelate with SAMHD1 protein expression detected by immunohistochemistry. The biological functions of this mutated SAMHD1 remain to be investigated.

Hematopoietic stem cell transplantation and chimeric antigen receptor T cell for relapsed or refractory diffuse large B-cell lymphoma.

Aim: Autologous hematopoietic stem cell transplantation (ASCT) is the standard-of-care curative treatment for relapsed or refractory diffuse large B-cell lymphoma (RR-DLBCL), but the relapse rate is usually high. Materials & methods: In this study, we treated 14 RR-DLBCL patients by combining ASCT and anti-CD19 chimeric antigen receptor T-cell therapy. Results: Eleven (78.57%) patients achieved complete or partial remission. Median duration of progression-free survival was 14.82 months (95% CI: 0.00-31.20 months) with 6-month progression-free survival rate of 64.29% (95% CI: 39.18-89.40%). Median overall survival was not achieved, with 1-year overall survival rate of 65.48% (95% CI: 36.00-94.96%). No neurotoxicity was observed. Conclusion: Our study demonstrated safety and feasibility of ASCT and anti-CD19 chimeric antigen receptor T-cell treatment for RR-DLBCL patients.

The pretreatment albumin to globulin ratio as a significant predictor in patients with diffuse large B cell lymphoma.

BACKGROUND: The pretreatment albumin to globulin ratio (AGR) has been used to predict survival in several types of tumors. However, whether AGR can predict outcomes in patients with diffuse large B-cell lymphoma (DLBCL) remains unclear. We evaluated the prognosis value of AGR in DLBCL patients. METHODS: We retrospectively analyzed the available serum biochemical results of 335 patients with newly diagnosed DLBCL before treatment. The AGR was calculated as: albumin (g/L)/globulin. X-tile program was used to generate an optimal cut-off value of 1.3 for AGR. And all patients were respectively divided into the low AGR and high AGR groups according to the cut-off value. RESULTS: The low AGR group displayed more adverse clinical chacteristics, including old age, sex (female), increased ß2-microglobulinpoor (ß2-MG), increased lactate dehydrogenase (LDH), B symptoms, poor performance status (PS), advanced stage, number of extranodal sites ≥ 2 and higher International Prognostic Index (IPI). AGR was negatively correlated with age, IPI score, ECOG score, Ann Arbor stage, B symptoms, ß2-MG, LDH, and extranodal involvement, while positively correlated with gender. Patients with a low AGR presented with significantly poorer overall survival (OS, P = .001). Multivariate analysis further demonstrated that a low AGR was an independent adverse predictor for OS (HR = 0.613; 95% CI = 0.412-0.910, P = .015). In addition, AGR distinguished patients with different prognosis in stage III-IV and the non-germinal center B cell-like lymphoma (non-GCB) groups, a low AGR was also significantly associated with poor OS in 2 groups. CONCLUSION: Pretreatment AGR was a simple and effective clinical marker of survival in patients with DLBCL, and may had an additional prognostic value based on Ann Arbor stage and cell of origin for DLBCL.

Prognostic value of pretreatment plasma D-dimer levels in patients with diffuse large B cell lymphoma (DLBCL).

BACKGROUND: We assessed the prognostic significance of D-dimer in patients of diffuse large B cell lymphoma (DLBCL). METHODS: We performed a retrospective study including 254 patients who were newly diagnosed DLBCL. X-tile was used to generate a cutoff value for D-dimer. Both univariate screen by Cox proportional hazard model and multivariable analysis by Cox regression model were used to assess the impact of pretreatment D-dimer levels on the overall survival (OS). RESULT: According to X-tile, the optimal cut-off value of D-dimer for prediction of survival was set as 1.6 µg/mL, and a D-dimer level ≥ 1.6 µg/mL was significantly associated with poor overall survival (OS) (OS: 31.7 vs. 79.1%, P < 0.001). In multivariable analysis, it was found that a higher D-dimer level was an independent predictor for worse OS (Hazard ratio (HR): 3.594 95% Confidence interval (CI): 2.296-5.267, P < 0.001). In subgroup analysis of International Prognostic Index (IPI), survival of low-risk and intermediate-risk group with a D-dimer level ≥ 1.6 µg/mL were both similar to that of the high-risk group (OS: 31.6 vs. 36.5%, P = 0.957; OS: 38.0 vs. 36.5%, P = 0.758). In addition, among patients treated with surgery, those with higher D-dimer had substantially worse survival than that with lower D-dimer (OS: 27.0 vs. 84.5%, P < 0.001). CONCLUSION: Pretreatment D-dimer is a simple but effective predictor of survival among patients with DLBCL.

HBV infection potentiates resistance to S-phase arrest-inducing chemotherapeutics by inhibiting CHK2 pathway in diffuse large B-cell lymphoma.

A considerable number of diffuse large B-cell lymphoma (DLBCL) patients are infected with hepatitis B virus (HBV), which is correlated with their poor outcomes. However, the role of HBV infection in DLBCL treatment failure remains poorly understood. Here, our data demonstrated that HBV infection was closely associated with poorer clinical prognosis independent of its hepatic dysfunction in germinal center B-cell type (GCB type) DLBCL patients. Interestingly, we found that DLBCL cells expressing hepatitis B virus X protein (HBX) did not exhibit enhanced cell growth but did show reduced sensitivity to methotrexate (MTX) and cytarabine (Ara-C), which induced S-phase arrest. Mechanism studies showed that HBX specifically inhibited the phosphorylation of checkpoint kinase 2 (CHK2, a key DNA damage response protein). CHK2 depletion similarly conferred resistance to the S-phase arrest-inducing chemotherapeutics, consistent with HBX overexpression in DLBCL cells. Moreover, overexpression of wild-type CHK2 rather than its unphosphorylated mutant (T68A) significantly restored the reduced chemosensitivity in HBX-expressing cells, suggesting that HBV infection conferred resistance to chemotherapeutics that induced S-phase arrest by specifically inhibiting the activation of CHK2 response signaling in DLBCL.

Artemether suppresses cell proliferation and induces apoptosis in diffuse large B cell lymphoma cells.

Artemether (ART), a derivative of the well-known anti-malaria drug artemisinin, demonstrates potent anti-cancer activity in various cancer cells, however its effects on lymphoma remain unknown. The present study demonstrated that ART significantly inhibited proliferation of diffuse large B cell lymphoma (DLBCL) in vivo and in vitro, and led to G0/G1 phase arrest. Mechanistic studies demonstrated that ART suppressed the expression of the cell cycle proteins cyclin dependent kinase (CDK) 2, 4, and Cyclin D1, and specifically repressed the proto-oncogene c-Myc, rather than regulating the extracellular signal-regulated kinase or protein kinase B signaling pathways (two key pathways involved in regulating cell proliferation). In addition, high-concentration ART treatment significantly induced the apoptosis of DLBCL cells by promoting the cleavage of Caspase-3 and Poly (ADP-ribose) polymerase (PARP) 1. Overall, the data indicated that ART exhibited anti-cancer activity by inhibiting the expression of cell cycle genes and c-Myc, and promoting Caspase-3 and PARP1 cleavage, which suggested that ART may serve as a dual pharmaceutical for the treatment DLBCL.