Prophylactic therapy using epigenetic agents for RUNX1::RUNXT1-positive high-risk AML after Allo-HSCT.

Disease recurrence is the leading cause of treatment failure in patients with RUNX1::RUNXT1-positive acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Post-transplant maintenance therapy, guided by monitoring minimal residual disease (MRD), is commonly administered; however, relapse rates remain high. This prospective study aimed to assess the effectiveness and safety of epigenetic agents as prophylactic therapy in patients with RUNX1::RUNXT1-positive AML. Thirty high-risk patients received prophylactic therapy (n = 17 and n = 13 in the chidamide and AZA groups, respectively) between January 2019 and July 2023. 34 high-risk patients who received preemptive treatment due to molecular relapse were included in the analysis. The two-year relapse-free survival (RFS) and overall survival (OS) were significantly higher in the prophylactic group compared to the preemptive group (82.82% vs. 51.38%, P = 0.014; 86.42% vs. 56.16%, P = 0.025, respectively); 2-year cumulative incidence of relapse rates were 13.8% and 36.40%, respectively (P = 0.037). In conclusion, prophylactic therapy with epigenetic agents may improve long-term prognosis and is well-tolerated in patients with RUNX1::RUNXT1-positive high-risk AML. Timely post-transplant prophylactic therapy may be more effective than preemptive therapy based on positive MRD results.

Ursodeoxycholic acid does not reduce SARS-CoV-2 infection in newly allogeneic hematopoietic stem cell transplantation recipients: a prospective NICHE cohort.

Introduction: Retrospective studies have suggested that Ursodeoxycholic Acid (UDCA) provide a protective effect against SARS-CoV-2 infection, particularly in patients with liver disease. However, it is uncertain whether this finding can be extended to the allogeneic hematopoietic stem cell transplantation (allo-HSCT) cohort. Therefore, we aim to examine the protective potential of UDCA against SARS-CoV-2 infection in recently received allo-HSCT patients. Methods: During the initial Omicron variant wave in China (December 2022 to February 2023), we conducted a prospective observational study involving 91 hospitalized patients who had undergone allo-HSCT within the previous 6 months as part of the National Longitudinal Cohort of Hematological Diseases (NICHE). Throughout hospitalization, we continuously monitored the status of COVID-19 using SARS-CoV-2 PCR kits or SARS-CoV-2 Antigen Rapid Tests. Results: Among these patients, 67.0% (n = 61) were confirmed to have contracted SARS-CoV-2 infection. For the 52 patients evaluated, 23.1% experienced a severe or critical clinical course. There was no difference in the infection rate or severity of COVID-19 between the UDCA group and the non-UDCA group. We found that only patients transplanted between 3 and 6 months ago demonstrated a higher risk of SARS-CoV-2 infection compared to those who received allo-HSCT within 3 months (Odds Ratio [OR]: 3.241, 95% Confidence Interval [CI]: 1.287-8.814, P = 0.016). But other clinical factors, such as administration of UDCA, showed no difference. Notably, only age ≥38 years old remained as an independent risk factor for a severe clinical course of SARS-CoV-2 infection (OR: 3.664, 95% CI: 1.129-13.007, P = 0.035). Conclusion: The effectiveness of UDCA in protecting newly allo-HSCT recipients against SARS-CoV-2 infection remains unconfirmed. Presently, the most effective strategy appears to be minimizing exposure to SARS-CoV-2. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT04645199, identifier NCT04645199.

Efficacy of venetoclax combined with decitabine conditioning regimen for allogeneic hematopoietic stem cell transplantation in high-risk and elderly patients with myeloid neoplasms.

This prospective clinical investigation focused on the addition of venetoclax and decitabine to myeloablative conditioning regimens, targeting high-risk and elderly individuals undergoing allogeneic hematopoietic stem cell transplantation. In total, 19 patients were enrolled in the trial between December 2021 and February 2023, and their progress was monitored for a median follow-up period of 258 days, ranging from 35 to 544 days. In the initial regimen (n=11), venetoclax was administered at a dosage of 400 mg per day from day -14 to day -1, while in the modified regimen (n=8), it was administered from day -14 to day -5. Decitabine was orally administered at a dosage of 20mg/m2/day from day -7 to day -3. Grade 3/4 adverse events observed included hematological events, hypertension, infections, allergy, and increased amylase. In the entire cohort, the overall survival (OS) and relapse-free survival (RFS) rates at 6 months were 63% (95% CI, 45-89) and 63% (95% CI, 45-89), respectively. The non-relapse mortality (NRM) rate at 6 months was 37% (95% CI, 16-58), while the cumulative incidence of relapse (CIR) was 0. However, the incidence of grade II-IV acute graft-versus-host disease (aGVHD) and grade III-IV aGVHD within 100 days was found to be 31% (95% CI, 12-53) and 26% (95% CI, 9-47), respectively. These rates indicate a relatively high occurrence, making it less suitable to administer the regimen to elderly patients. Therefore, further high-quality studies are required to enhance the conditioning regimen specifically for high-risk and elderly patients diagnosed with myeloid neoplasms. Clinical trial registration: ChiCTR2100050272.

Different situations of identifying second primary malignant tumors in lymphoma patients with synchronous solid tumors.

BACKGROUND: To our knowledge, the different situations of identifying second primary malignant tumors (SPMTs) in lymphoma patients with synchronous solid tumors remain to be comprehensively investigated. METHODS: We retrospectively collected information pertaining to lymphoma patients with synchronous solid tumors (diagnosed within 6 months) at Peking University Cancer Hospital & Institute between 2009 and 2019. The non-parametric Aalen-Johansen estimator was applied to calculate cumulative incidence function in the competing risk model. Furthermore, propensity score-matched analysis was performed to compare survival differences in lymphoma patients with or without synchronous solid tumors. RESULTS: Thirty-eight patients were enrolled. There were three situations of identifying SPMTs. First, in 15 patients (39.5%), SPMTs were identified before the initiation of any treatment. Among them, priority was given to anti-lymphoma treatment in case of only three patients. Second, in 17 patients (44.7%), SPMTs were unexpectedly detected on surgical specimen assessment; of them, 13 received anti-lymphoma treatment after surgery. Third, in six patients (15.8%), SPMTs were identified after the outset of treatment for the primary tumor; in this population, three of four patients with lymphoma switched toward the treatment plan for SPMTs. The 5-year overall survival was 58.7%. The cumulative incidence function within 5 years was 26.6% for lymphoma and 14.7% for other solid tumors. The early identification of SPMTs was associated with better outcomes (p = 0.048). After balancing the baseline characteristics, no differences in survival were observed between lymphoma patients with and without synchronous solid tumors (p = 0.664). CONCLUSIONS: This is the first study to present the different situations of identifying SPMTs in lymphoma patients with synchronous solid tumors. In only <50% patients, SPMTs were identifiable at baseline. SPMT identification at different situations may make it difficult to choose the optimal therapeutic option, which may consequently impact patient survival.

Effect of autologous hematopoietic stem cell transplantation for patients with peripheral T-cell lymphoma in China: A propensity score-matched analysis.

Background: The role of consolidation therapy with autologous stem cell transplantation (ASCT) in patients with peripheral T-cell lymphoma (PTCL) in first complete remission (CR1) or partial remission (PR1) remains controversial. The existing data from China are limited. Therefore, we aimed to investigate the effect of ASCT on the survival of Chinese patients with PTCL showing response to induction chemotherapy at our hospital. Methods: We retrospectively reviewed the data of patients with PTCL (excluding Natural killer/T cell lymphoma) in CR1 or PR1 treated at Peking University Hospital &Institute from 1996 to 2020. Propensity score matching (PSM) was used to balance clinical characteristics between the ASCT and non-ASCT groups. The primary endpoints were event-free survival (EFS) and overall survival (OS). Results: Of the 414 selected patients, 73 received ASCT consolidation and 341 did not. Over a median follow-up of 5.7 years, survival was significantly better in the ASCT group than in the non-ASCT group (median EFS, 8.1 years vs. 2.8 years, P = 0.002; median OS, 14.9 years vs. 10.2 years, P = 0.007). The 5-year EFS and OS rates were 68.4% and 77.0% in ASCT group, and 43.2% and 57.6% in non-ASCT group, respectively. The survival benefit was confirmed in the propensity score matched cohort (46 patients who received ASCT and 84 patients who did not receive ASCT): P = 0.007 for median EFS and P = 0.022 for the median OS. Cox regression analysis showed that ASCT was independently associated with better survival: hazard ratio (HR) for EFS, 0.46 (95% CI: 0.28-0.76); HR for OS, 0.50 (95% CI: 0.31-0.84). Subgroup analysis showed that ASCT was more likely to benefit higher-risk patients and those with advanced disease. Among the subtypes of PTCL, the benefit was significant in angioimmunoblastic T-cell lymphoma (HR = 0.26 [95% CI: 0.10-0.66] for EFS and 0.29 [95% CI: 0.12-0.74] for OS), but not in the other subtypes. Conclusion: ASCT may improve the long-term survival of patients with PTCL in first CR or PR, especially for patients with angioimmunoblastic T-cell lymphoma. The specific groups most likely to benefit from upfront ASCT need to be clearly identified.

A Comparison of Clinical Prognostic Indices in Elderly Patients with Diffuse Large B-Cell Lymphoma Treated with a Pegylated Liposomal Doxorubicin Combination Regimen in China.

Background: There is no consensus regarding the risk stratification scores for elderly patients with diffuse large B-cell lymphoma (DLBCL). We aimed to compare the prognostic predictive ability of the current clinical scoring indices in DLBCL elderly patients treated with the R-CODP regimen (rituximab, cyclophosphamide, pegylated liposomal doxorubicin, vincristine, and prednisone). Methods: We retrospectively collected the data of elderly DLBCL patients who received the R-CODP regimen as the first-line treatment. The efficacy of the regimen was evaluated. The Akaike information criteria (AIC), concordance index (C-index), and integrated discrimination improvement (IDI) were used to assess the fitness and prognostic performance of the current clinical prognostic indices. Results: In the total of 158 patients enrolled, the median follow-up time was 6.7 years (95% CI: 6.3-7.9), and the 5-year OS was 52.8% (95% CI: 45.5%-61.2%). The International Prognostic Index (IPI), National Comprehensive Cancer Network-IPI (NCCN-IPI), and Elderly International Prognostic Index (E-IPI) were all significantly associated with OS (P < 0.001 for all). However, no significance was observed in 5-year OS in the low- vs low-intermediate-risk groups for IPI (P = 0.377), NCCN-IPI (P = 0.238), and E-IPI (P = 0.080). Compared with the IPI and NCCN-IPI, the E-IPI had the lowest AIC value of 747.5 and the highest C-index of 0.692. For predicting 5-year mortality, the E-IPI showed better performance (AUC: 0.715 for E-IPI vs 0.676 for IPI, P = 0.036), with the IDI of 6.29% (95% CI: 3.71%-8.88%, P < 0.001) and 4.80% (95% CI: 1.32%-8.28%, P = 0.007) compared to the IPI and NCCN-IPI, respectively. Conclusion: The E-IPI might be a better prognostic prediction model in Chinese DLBCL generics treated with R-CODP for predicting 5-year mortality. However, the IPI, NCCN-IPI, and E-IPI did not seem to be able to distinguish patients with a favorable prognosis well.

Impact of relative dose intensity of R-CCOP regimen in elderly patients with diffuse large B-cell lymphoma in China.

BACKGROUND: The actual relative dose intensity (RDI) of the attenuated R-CCOP regimen (rituximab, cytoxan, pegylated liposomal doxorubicin [PLD], vincristine, and prednisone) has not been fully investigated in Chinese geriatric patients with diffuse large B-cell lymphoma (DLBCL). In particular, the optimum dose for PLD remains unclear. METHODS: We retrospectively collected clinical data from patients with untreated DLBCL aged 65-80 years subsequently treated with the R-CCOP. The restricted cubic spline model (RCS) was used to test the non-linear relationship between the predictors and outcomes. RESULTS: Eighty-four patients were enrolled, with a median age of 73.5 years. More than half of the patients (54.8%) received at least 6 cycles. The median dose per cycle of cytoxan and PLD were 605.5 and 19.9 mg/m2. The 5-year progression-free survival (PFS), overall survival rate, and disease-specific survival rates were 38.7%, 44.8%, and 57.2%, respectively. The RDI of PLD (PLD-RDI, <70% vs ≥ 70%) was only significant in the univariate analysis (P = 0.002) but not in the multivariate analysis. The RCS model showed a decreasing trend of hazards with an increasing PLD dose per cycle after adjustment. No significant difference was observed between the low- and high-risk groups with PLD-RDI ≥ 70% (P = 0.548). However, patients in the high-risk group had unfavorable PFS with PLD-RDI < 70% (P = 0.006). CONCLUSION: The optimal dose of PLD for elderly patients with DLBCL in China remains to be determined. Evaluating the tolerance and identifying risk categories are critical for clinical decision-making in this population.

Successful treatment of a case with synchronous follicular lymphoma and gastric adenocarcinoma with CD19 CAR T cells and literature review.

WHAT IS KNOWN AND OBJECTIVE: Anti-CD19 CAR-T cell therapy is effective in B-cell lymphoma. However, it is rarely used in lymphoma combined with other malignant tumours. CASE DESCRIPTION: A relapsed/refractory follicular lymphoma (r/r FL) patient underwent anti-CD19 CAR-T cell therapy and achieved complete response to lymphoma. However, gastric adenocarcinoma (GAC) was diagnosed during the cellular therapy. After infusion of CAR-T cells, he received curative treatment for GAC, and maitained complete response in both r/r FL and GAC after the treatment. WHAT IS NEW AND CONCLUSION: Anti-CD19 CAR-T therapy is an effective treatment for r/r FL, also provided opportunity for the sequential therapy of GAC, and remained significant quality of life afterwards.

Conditional survival and hazards of death for peripheral T-cell lymphomas.

Typically, peripheral T-cell lymphoma (PTCLs) prognosis is estimated using overall survival before treatment. However, these estimates cannot show how prognosis evolves with the changing hazard rate over time. Patients (n = 650) with newly diagnosed PTCLs were enrolled retrospectively. After a median follow-up of 5.4 years, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) and NK/T cell lymphoma had initially lower 3-year conditional overall survival (COS3; i.e., the 3-year conditional overall survival was defined as the probability of surviving an additional 3 years) and higher hazards of death (26-44.3%). However, after 2 years, the COS3 increased and the death risk decreased over time, whereas anaplastic lymphoma kinase-positive anaplastic large-cell lymphoma constantly had a lower risk over time (0-19.5%). For patients with complete remission after initial treatment, prognosis varied by histological subtypes, with PTCL, NOS having a negative impact. Our data suggested that the risk stratification using the International Prognostic Index might not accurately predict the COS3 for survivors of PTCLs. The COS3 provided time-dependent prognostic information for PTCLs, representing a possible surrogate prognosis indicator for long-term survivors after systemic chemotherapy.

Combination of cyclophosphamide and cytarabine as induction regimen for newly diagnosed adult acute myeloid leukemia.

Optimizing the induction therapy of acute myeloid leukemia (AML) may improve the remission rate and reduce the risk of relapse, thereby extend survival. Cyclophosphamide (CTX) shows benefit in treating relapsed and refractory AML patients, but it has not been reported in first-line induction regimens. To assess the efficacy and safety of CTX and moderate-dosage cytarabine (Ara-C) as induction chemotherapy in newly diagnosed adult AML, 40 patients were enrolled to receive CTX (20 mg/kg/d) for 4 consecutive days and Ara-C for 3 (1 g/m2 q12h, CA4+3) or 5 (1 g/m2 qd, CA4+5) days. With one course of induction chemotherapy, the overall response rate and the complete remission rate (CR) was 82.5% (33/40) and 77.5% (31/40), respectively. The expected 5 years overall survival and relapse-free survival was 64% in patients experienced CR and fulfilled consolidation therapy. The neutrophil and platelet recovery time were 17 (range, 10-20) days and 16.5 (range, 12-30) days in the CA4+3 group, faster than that of 20 (16-36) days and 20 (14-36) days in the CA4+5 group (P = .006 and P = .006). The cyclophosphamide and cytarabine (CA) regimen was generally safe and had reversible adverse effects. The patients who failed to respond to the CA regimen did not benefit from a second course of other traditional induction chemotherapy either. In conclusion, the combined regimen of CTX and Ara-C represents a promising therapeutic approach to induce the first CR of newly diagnosed adult AML.

Transcriptome profiling reveals the crucial biological pathways involved in cold response in Moso bamboo (Phyllostachys edulis).

Most bamboo species including Moso bamboo (Phyllostachys edulis) are tropical or subtropical plants that greatly contribute to human well-being. Low temperature is one of the main environmental factors restricting bamboo growth and geographic distribution. Our knowledge of the molecular changes during bamboo adaption to cold stress remains limited. Here, we provided a general overview of the cold-responsive transcriptional profiles in Moso bamboo by systematically analyzing its transcriptomic response under cold stress. Our results showed that low temperature induced strong morphological and biochemical alternations in Moso bamboo. To examine the global gene expression changes in response to cold, 12 libraries (non-treated, cold-treated 0.5, 1 and 24 h at -2 °C) were sequenced using an Illumina sequencing platform. Only a few differentially expressed genes (DEGs) were identified at early stage, while a large number of DEGs were identified at late stage in this study, suggesting that the majority of cold response genes in bamboo are late-responsive genes. A total of 222 transcription factors from 24 different families were differentially expressed during 24-h cold treatment, and the expressions of several well-known C-repeat/dehydration responsive element-binding factor negative regulators were significantly upregulated in response to cold, indicating the existence of special cold response networks. Our data also revealed that the expression of genes related to cell wall and the biosynthesis of fatty acids were altered in response to cold stress, indicating their potential roles in the acquisition of bamboo cold tolerance. In summary, our studies showed that both plant kingdom-conserved and species-specific cold response pathways exist in Moso bamboo, which lays the foundation for studying the regulatory mechanisms underlying bamboo cold stress response and provides useful gene resources for the construction of cold-tolerant bamboo through genetic engineering in the future.

Effectiveness of umbilical cord mesenchymal stem cells in patients with critical limb ischemia / Efectividad de las células madre mesenquimales del cordón umbilical en pacientes con isquemia crítica de extremidades

Introduction and objective: Transplantation of umbilical cord mesenchymal stem cells (UC-MSCs) has been shown to be effective in treating critical limb ischemia (CLI). However, the mechanism of MSCs-mediated improvements, especially on the immune-inflammatory aspects of this disease, is still unknown. In this study, we investigated the changes in T-lymphocyte subpopulations and inflammatory mediators (such as IL-6, IL-10 and TNF-alpha) in PBMCs from CLI patients after UC-MSCs treatment and correlation between inflammatory mediators and EPCs. Patients and methods: 8 patients received UC-MSCs transplantation. Before the treatment, at 24h and 1 month thereafter, peripheral blood samples were collected from 8 patients and 8 healthy volunteers. Patients were evaluated for changes in IL-6, IL-10, TNF-alpha and levels of circulating EPCs. Results: TNF-alpha and IL-6 serum levels increased at 24h (p=0.017, p=0.099) after treatment and then decreased at 1 month (p=0.031, p=0.072) compared with those before treatment. The percentages of CD3+T, CD3+CD4+T-lymphocytes and NK cells decreased significantly after UC-MSCs treatment (p=0.002, p=0.012 and p=0.029, respectively). TNF-alpha (r=−0.602, p=0.038) was shown to be inversely correlated with the number of circulating EPCs. Conclusions: This study demonstrates that UC-MSCs have anti-inflammatory and immunomodulation properties in CLI and suggests that UC-MSCs promote healing of non-healing wounds

Introducción y objetivo: El trasplante de células madre mesenquimales del cordón umbilical (CMM-CU) ha demostrado eficacia en el tratamiento de la isquemia crítica de las extremidades (ICE). Sin embargo, se desconoce el mecanismo de las mejoras mediadas por las CMM, especialmente en los aspectos inmune-inflamatorios de esta enfermedad. Este estudio analiza los cambios en las subpoblaciones de linfocitos T y en los mediadores inflamatorios (como IL-6, IL-10 y TNF-alpha) en CMSP de pacientes con ICE después del tratamiento con CMM-CU y estudia la correlación entre mediadores inflamatorios y células progenitoras endoteliales (CPE). Pacientes y métodos: Ocho pacientes recibieron trasplante de CMM-CU. Se recogieron muestras de sangre periférica de 8 pacientes y 8 voluntarios sanos, antes del tratamiento, a las 24h y un mes después. Los pacientes fueron evaluados para detectar cambios en IL-6, IL-10, TNF-alpha y niveles de CPE circulantes. Resultados: Los niveles séricos de TNF-alpha e IL-6 aumentaron 24h después del tratamiento (p=0,017, p=0,099) y luego disminuyeron al mes (p=0,031, p=0,072) en comparación con los niveles antes del tratamiento. Los porcentajes de CD3+T, CD3+CD4+ linfocitos T y células NK disminuyeron significativamente después del tratamiento con CMM-CU (p=0,002, p=0,012 y p=0,029, respectivamente). TNF-alpha (r=−0,602, p=0,038) demostró estar correlacionada inversamente con el número de CPE circulantes. Conclusiones: Este estudio demuestra que las CMM-CU tienen propiedades antiinflamatorias e inmunomoduladoras en la ICE y sugieren que las CMM-CU promueven la curación de heridas que no cicatrizan

Effectiveness of umbilical cord mesenchymal stem cells in patients with critical limb ischemia.

INTRODUCTION AND OBJECTIVE: Transplantation of umbilical cord mesenchymal stem cells (UC-MSCs) has been shown to be effective in treating critical limb ischemia (CLI). However, the mechanism of MSCs-mediated improvements, especially on the immune-inflammatory aspects of this disease, is still unknown. In this study, we investigated the changes in T-lymphocyte subpopulations and inflammatory mediators (such as IL-6, IL-10 and TNF-α) in PBMCs from CLI patients after UC-MSCs treatment and correlation between inflammatory mediators and EPCs. PATIENTS AND METHODS: 8 patients received UC-MSCs transplantation. Before the treatment, at 24h and 1 month thereafter, peripheral blood samples were collected from 8 patients and 8 healthy volunteers. Patients were evaluated for changes in IL-6, IL-10, TNF-α and levels of circulating EPCs. RESULTS: TNF-α and IL-6 serum levels increased at 24h (p=0.017, p=0.099) after treatment and then decreased at 1 month (p=0.031, p=0.072) compared with those before treatment. The percentages of CD3+T, CD3+CD4+T-lymphocytes and NK cells decreased significantly after UC-MSCs treatment (p=0.002, p=0.012 and p=0.029, respectively). TNF-α (r=-0.602, p=0.038) was shown to be inversely correlated with the number of circulating EPCs. CONCLUSIONS: This study demonstrates that UC-MSCs have anti-inflammatory and immunomodulation properties in CLI and suggests that UC-MSCs promote healing of non-healing wounds.

Pharmacokinetics of an oral drug (acetaminophen) administered at various times in relation to subcutaneous injection of exenatide (exendin-4) in healthy subjects.

Exenatide is an incretin mimetic with potential glucoregulatory activity in type 2 diabetes. This randomized, single-blind, placebo-controlled 6-way crossover study assessed exenatide's effect on acetaminophen pharmacokinetics. Of 40 randomized healthy subjects, 39 completed the study. On the placebo day, acetaminophen (1000 mg) was ingested and placebo injected subcutaneously at 0 hours. On exenatide days, acetaminophen was ingested at -1, 0, +1, +2, and +4 hours, relative to the 10 mug exenatide injected subcutaneously at 0 hours. With exenatide injection, mean plasma acetaminophen AUC(0-12 h) values were reduced by 11% to 24% (vs placebo). Peak plasma acetaminophen concentrations were similar for the -1-hour and placebo groups and reduced by 37% to 56% at other times. The most frequent adverse events were generally mild to moderate nausea and vomiting. Exenatide treatment concurrent with or preceding acetaminophen ingestion slowed acetaminophen absorption but had minimal effect on the extent of absorption.