[Clinical efficacy and safety of venetoclax combined with multidrug chemotherapy in the treatment of 15 patients with relapsed or refractory early T-cell precursor acute lymphoblastic leukemia].

Objective: To explore the efficacy and safety of Venetoclax combined with multidrug chemotherapy in patients with relapsed or refractory early T-cell precursor acute lymphoblastic leukemia (R/R ETP-ALL) . Methods: This study retrospectively analyzed 15 patients with R/R ETP-ALL who received Venetoclax combined with multidrug chemotherapy from December 2018 to February 2022. Among them, eight cases were combined with demethylated drugs, four cases were combined with demethylated drugs and HAAG chemotherapy regimen, two cases were combined with demethylated drugs and CAG regimen, and one case was combined with Cladribine. Specific usage and dosage of Venetoclax: 100 mg on day 1, 200 mg on day 2, 400 mg on day 3-28, orally; when combined with azole antifungal drugs, dosage was reduced to 100 mg/d. Results: Fifteen patients (10 males and 5 females) with R/R ETP-ALL were treated with Venetoclax and multidrug chemotherapy with a median age of 35 (12-42) years old. Of 4 refractory and 11 relapsed patients, the efficacy was evaluated on the 21th day following combined chemotherapy: the overall response rate, the complete response (CR) rate, and the CR with incomplete hematological recovery (CRi) rate were 67.7% (10/15), 60.0% (9/15), and 6.7% (1/15), respectively. For the overall study population, the 12-month overall survival (OS) rate was 60.0%, and the median OS was 17.7 months. The disease-free survival (DFS) rate of all CR patients at 12 months was 60.0%, and the median DFS did not reach. About 14 patients had Ⅲ-Ⅳ hematological toxicity, but these adverse reactions were all controllable. No adverse reaction in the nervous system and tumor lysis syndrome occurred in this study, and no adverse reaction of organs above grade Ⅲ occurred. Conclusion: Venetoclax combined with multidrug chemotherapy may be a safe and promising treatment option for patients with R/R ETP-ALL.

[Clinical analysis of amphotericin B cholesteryl sulfate complex for injection in the treatment of invasive fungal disease for patients with hematological malignancies in 30 cases].

Objective: To assess the safety and effectiveness of amphotericin B cholesteryl sulfate complex for injection in the context of empirical and diagnostic antifungal therapy for patients with hematological malignancies in addition to invasive fungal illness. Methods: This single-arm clinical study enrolled 30 patients who received empirical and diagnostic-driven antifungal therapy for hematological malignancies combined with invasive fungal disease. The primary endpoint was safety. Response rate, fever duration, and treatment completion rate were all considered secondary objectives. Results: 30 participants were eventually enrolled in the study, and the treatment completion rate was 80.0% . Most adverse events were in grades 1-2. Infusion response was the most frequent adverse event (24/30, 80% ) . The overall response rate was 80.0% (24/30) . In 24 patients (80.0% ) , the fever persisted for 1 day. Conclusions: Treatment of invasive fungal illness in conjunction with hematological malignancies showed good efficacy and safety with amphotericin B cholesteryl sulfate complex for injection.

[Prognostic value of KIT and other clonal genetic mutations in core-binding factor acute myeloid leukemia].

Objective: To evaluate the prognostic significance of clonal gene mutations using next-generation sequencing in patients with core-binding factor acute myeloid leukemia (CBF-AML) who achieved first complete remission after induction chemotherapy. Methods: The study, which was conducted from July 2011 to August 2017 in First Affiliated Hospital of Soochow University, comprised 195 newly diagnosed patients with CBF-AML, including 190 patients who achieved first complete remission after induction chemotherapy. The cohort included 134 patients with RUNX1-RUNXIT1(+) AML and 56 patients with CBFß-MYH11(+) AML. The cohort age ranged from 15 to 64 years, with a median follow-up of 43.6 months. Overall survival (OS) and disease-free survival (DFS) were assessed by the log-rank test, and the Cox proportional hazards regression model was used to determine the effects of clinical factors and genetic mutations on prognosis. Results: The most common genetic mutations were in KIT (47.6% ) , followed by NRAS (20.0% ) , FLT3 (18.4% ) , ASXL2 (14.3% ) , KRAS (10.7% ) , and ASXL1 (9.7% ) . The most common mutations involved genes affecting tyrosine kinase signaling (76.4% ) , followed by chromatin modifiers (29.7% ) . Among the patients receiving intensive consolidation therapy, the OS tended to be better in patients with CBFß-MYH11(+) AML than in those with RUNX1-RUNXIT1 (+) AML (P=0.062) . Gene mutations related to chromatin modification, which were detected only in patients with RUNX1-RUNXIT1(+) AML, did not affect DFS (P=0.557) . The patients with mutations in genes regulating chromatin conformation who received allo-hematopoietic stem cell transplantation (allo-HSCT) achieved the best prognosis. Multivariate analysis identified KIT exon 17 mutations as an independent predictor of inferior DFS in patients with RUNX1-RUNXIT1(+) AML (P<0.001) , and allo-HSCT significantly prolonged DFS in these patients (P=0.010) . Conclusions: KIT exon 17 mutations might indicate poor prognosis in patients with RUNX1-RUNXIT1(+) AML. Allo-HSCT may improve prognosis in these patients, whereas allo-HSCT might also improve prognosis in patients with mutations in genes related to chromatin modifications.

[CAR T-cell bridging to allo-HSCT for relapsed/refractory B-cell acute lymphoblastic leukemia: the follow-up outcomes].

Objective: This study aims to investigate the efficacy and safety of chimeric antigen receptor (CAR) T-cell bridging allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of recurrent and refractory acute B-lymphocytic leukemia (R/R B-ALL) . Methods: A total of 50 R/R B-ALL patients who underwent CAR T-scell therapy to bridge allo-HSCT in the First Affiliated Hospital of Soochow University from January 2017 to May 2019 were retrospectively analyzed. The overall survival (OS) rate, event-free survival (EFS) rate, cumulative recurrence rate (CIR) , and transplant-related mortality (TRM) of patients with different bone marrow minimal residual disease (MRD) levels were analyzed before and after CAR T-cell infusion and before allo-HSCT. Results: The response rate of CAR T-cell therapy and the incidence rate of severe cytokine release syndrome were 92% and 28% , respectively. During 55 infusions, no treatment-related deaths occurred in any of the patients. The median time of CAR T-cell infusion to allo-HSCT was 54 (26-232) days, the median follow-up time after CAR T-cell infusion was 637 (117-1097) days, and the 1-year OS and EFS rates were (80.0±5.7) % and (60.0±6.9) % . The 1-year CIR and TRM after allo-HSCT were (28.0±0.4) % and (8.0±0.2) % . After CAR T-cell infusion and before allo-HSCT, patients with bone marrow MRD<0.01% had a significantly longer EFS [ (70.0±7.2) % vs (20.0±12.6) % , P<0.001; (66.7±7.5) % vs (36.4±14.5) % , P=0.008]and lower CIR [ (25.0±0.5) % vs (70.0±2.6) % , P<0.001; (23.08±0.47) % vs (45.45±2.60) % , P=0.038]. Conclusion: CAR T-cell therapy bridging allo-HSCT is safe and effective for recurrent and refractory B-ALL.

[The prognostic value of cloned genetic mutations detected by second-generation sequencing in RUNX1-RUNX1T1 positive acute myeloid leukemia patients receiving intensive consolidation therapy].

Objective: To investigate the prognostic value of clonal gene mutations detected by second-generation sequencing in patients with positive RUNX1-RUNX1T1 acute myeloid leukemia (AML) who received high-dose chemotherapy or autologous transplantation (intensive consolidation therapy) in the first complete remission (CR(1)) state. Methods: 79 AML patients with positive RUNX1-RUNX1T1 who received intensive consolidation therapy in CR(1) state from July 2011 to August 2017 were analyzed retrospectively. Kaplan-Meier curve and Cox regression model were used to figure out the effect of leukocyte counts at onset and gene mutations for prognosis. Results: C-KIT, FLT3, CEBPA and DNMT3A gene mutations were found in 25 (31.6%) , 6 (7.6%) , 7 (8.9%) and 1 (1.3%) patient among the population. Mutations in C-KIT exon17 and C-KIT exon8 were detected in 19 (24.1%) and 5 (6.3%) cases, respectively, and mutations of FLT3-ITD were confirmed in 5 (6.3%) cases. The higher leukocyte counts presented at onset of leukemia, the shorter overall survival (OS) was seen in these patients (P=0.03) . Patients with C-KIT exon17 mutation had significantly shorter OS (P=0.01) and disease free survival (DFS) (P=0.006) compared with those without gene mutations, and patients with FLT3-ITD gene mutation got the inferior OS (P=0.048) and DFS (P=0.071) . Conclusion: In AML patients with positive RUNX1-RUNX1T1 receiving intensive consolidation therapy, the white blood cell counts at onset of leukemia, C-KIT mutations in exon 17, and FLT3-ITD gene mutations suggest poor prognosis, which would contribute to elaborate risk stratification, personalized treatment and predict prognosis for these patients.

[Clinical analysis of bronchiolitis obliterans syndrome after haplo- hematopoietic stem cell transplantation].

Objective: To investigate the incidence, risk factors and survival of bronchiolitis obliterans syndrome (BOS) in patients who had undergone haplo-hematopoietic stem cell transplantation (haplo-HSCT) . Methods: This study retrospectively analyzed clinical data of 444 consecutive patients who underwent haplo-HSCT and survived at least 100 days after transplantation in the First Affiliated Hospital of Soochow University between January 2013 and December 2015. Results: By the end of follow-up on January 1, 2018, 25 patients (5.63%) had BOS (BOS group) . The median onset time of BOS was 448 (165-845) d post transplantation, the 1-year, 2-year and 3-year cumulative incidence of BOS was 1.6% (95%CI 1.5%-1.6%) , 4.8% (95%CI 4.7%-4.8%) and 5.8% (95%CI 5.7%-5.8%) , respectively. Among patients with chronic graft-versus-host disease (cGVHD) , the cumulative incidence at the same intervals was 2.8% (95%CI 2.7%-2.8%) , 9.5% (95%CI 9.4%-9.5%) and 11.5% (95%CI 11.4%-11.6%) , respectively. In the multivariate analysis, the risk factors for BOS were high-risk primary disease, Ⅱ-Ⅳ aGVHD and preceding cGVHD with other organs. The 3-year overall survival (OS) was lower among patients with than those without BOS, but the difference was not significant [71.8% (95%CI 53.9%-89.6%) vs 72.4% (95%CI 68.1%-76.7%) , P=0.400]. Overall 1-year, 3-year survival of patients with BOS from the time of diagnosis was 78.4% (95%CI 61.5%-95.3%) and 37.0% (95%CI 2.5%-71.5%) , respectively, significantly less than those without (93.9% and 89.3%, from day 448 after transplantation, respectively, P<0.001) . Furthermore, we found a significantly higher incidence of transplantation-related mortality (TRM) in patients with compared with patients without BOS (28.2% vs 10.9%, P<0.001) . The main risk factor for OS of BOS patients was the severity of pulmonary impairment at the time of diagnosis. Patients who developed severe BOS had a worse OS than those with moderate and mild BOS (P=0.049) . Conclusion: BOS is a severe pulmonary complication of haplo-HSCT. High-risk primary disease, Ⅱ-Ⅳ aGVHD and preceding cGVHD were independent risk factors for BOS. Patients who developed BOS had a worse OS than those without BOS. The main risk factor for OS of BOS patients was the severity of pulmonary impairment.

[Comparison of efficacy of first-line administration of generic dasatinib or imatinib in patients with Philadelphia chromosome positive acute lymphoblastic leukemia treated by hematopoietic stem cell transplantation].

Objective: To investigate the efficacy of first-line administration of generic dasatinib or first-generation TKI (imatinib) in patients with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph(+) ALL) treated by hematopoietic stem cell transplantation (HSCT). Methods: Clinical features and prognoses of 63 newly diagnosed Ph(+) ALL patients from Jan 2014 to June 2017 treated by HSCT combined with first-line administration of generic dasatinib or imatinib were retrospective analyzed. Results: Of 63 Ph(+) ALL patients, 31 cases were administered generic dasatinib, and the other 32 ones imatinib. Complete remission (CR) rates at the fourth week of induction therapy in generic dasatinib and imatinib groups were 96.8% and 93.8% (P=1.000) , respectively. Meanwhile major molecular response (MMR; BCR-ABL/ABL reduce 3log) rates were 41.9% and 43.8% (χ(2)=0.021, P=0.884), respectively. Relapse rates before transplantation were 6.5% and 12.5% (P=0.672), respectively. MMR rates before HSCT were 83.9% and 68.8% (χ(2)=1.985, P=0.159), respectively. The 20-monthes overall survival (OS) rates of generic dasatinib and imatinib groups were 95.5% and 76.5% (χ(2)=0.990, P=0.320) respectively; 20-monthes event-free survival (EFS) rates were 93.5% and 61.4% (χ(2)=5.926, P=0.015), respectively. Statistically significant differences of EFS were reached. Multiple factors analysis showed that generic dasatinib (HR=0.201, 95% CI 0.045-0.896, P=0.035) and MMR before transplantation (HR=0.344, 95% CI 0.124-0.956, CI=0.041) could improve EFS. Conclusions: First-line administration of generic dasatinib could improve EFS for Ph(+)ALL patients treated by HSCT when compered with imatinib.

[Anti-CD(25) monoclonal antibody as a salvage therapy for steroid-refractory acute graft-versus-host disease in 80 patients receiving allogeneic hematopoietic stem cell transplantation].

Objective: To investigate the efficacy of anti-CD(25) monoclonal antibody for steroid-refractory acute graft-versus-host disease (SR-aGVHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Methods: A total of 80 patients with SR-aGVHD from January 1st 2012 to December 31st 20l6 were enrolled in this study. Acute GVHD were classified as classic aGVHD (n=72) and late-onset aGVHD (n=8). Anti-CD(25) monoclonal antibodys (mAb) were administrated on days 1, 4, 8, 15, and 22. The efficacy of anti-CD(25) mAb was evaluated at day 28 after the initial treatment. The associated factors of clinical outcome were analyzed. Results: The overall response (OR) rate of anti-CD(25) mAb was 75% (60/80), with complete response (CR) rate, partial response (PR) rate and no response(NR) rate 52.5% (42/80), 22.5% (18/80), and 25% (20/80), respectively. GVHD-relapse was not observed with a median follow-up time of 394.5 days (range, 12-1 761 days). The 6-month overall survival (OS) rate was 68.4%(95%CI 63.2%-73.6%). The 1-year OS rate was 63.1% (95%CI 57.6%-68.6%), and 2-years OS rate was 50.7% (95%CI 44.3%-57.1%). Non-relapse mortality (NRM) rate of 1 and 3 years was 32.6% (95%CI 27.2%-38%) and 41.7% (95%CI 35.3%-48.1%), respectively. The 1 and 2 years cumulative incidence of chronic graft versus host disease (cGVHD) was 32.9% (95%CI 26.4%-39.4%) and 38.9% (95%CI 31.8%-46.0%). By univariate and multivariate analysis, liver involvement was an independent poor risk factor of SR-aGVHD (OR=4.66, 95%CI 1.145-18.962, P=0.032). Conclusion: Anti-CD(25) mAb serves as an alternative and effective salvage therapy for SR-aGVHD at present. Liver involvement is a predictive factor of poor response in patients with SR-aGVHD.

[An experimental study of CD4 targeted chimeric antigen receptor modified T cell with anti-lymphoma activity].

Objective: To study the specific killing effect of CD4 membrane protein targeted chimeric antigen receptor modified T (CAR-T) cell. Methods: The second generation CD4 targeted chimeric antigen receptor containing 4-1BB costimulation domain was insert into lentiviral vector through recombinant DNA technology. Lentivirus was prepared and packaged by 293T cells with four plasmids. Beads activated T cells were transduced with lentivirus and the transduction efficiency was checked with Protein L and flow cytometry. T cell subsets and IFN-γ concentrations were detected with probe-tagged antibody and cytometric bead assay. Results: ①The transduction efficiency of activated T cells with prepared lentivirus were 50.0%-70.0%. A subset of CD8+ T cell acquired dim expression of CD4 membrane protein after activation. CD4+T cell and CD8+CD4dim T cell were gradually killed by CD4 targeted CAR-T post lentivirus transduction. ②The kill efficacy of CD4 targeted CAR-T cell and control T cell toward KARPAS 299 T cell at an E∶T ratio of 8∶1 for 24 h was (96.9±2.1)% and (11.2±3.1)%, CAR-T cell has a higher killing efficacy than control T cell (t=7.137, P=0.028). The IFN-γ concentrations in culture supernatant of CAR-T cell with K562-CD4 cell, CAR-T cell with K562 cell and CAR-T cell alone were (15 648±2 168), (1 978±354) and (1 785±268) pg/ml, CAR-T cell cocultured with K562-CD4 cell produced more IFN-γ than the other two controls (P<0.01). Conclusions: CD4 targeted CAR-T has an immunophenotype of CD8+CD4-T cell. CD4 targeted CAR-T cell has killing efficacy toward normal CD4+T cell and CD4+T lymphoma cell. CD4 targeted CAR-T cell also has a killing efficacy toward CD4dim target cell.

Myeloablative conditioning regimens with combined of haploidentical and cord blood transplantation for myelodysplastic syndrome patients.

The purpose of this study was to evaluate the strategy of haploidentical (HID) stem cell combined with a small doses of umbilical cord blood (UCB) from a third-party donor transplantation (haplo-cord transplant) for treatment of myelodysplastic syndromes (MDS), by comparing with identical-sibling donor (ISD) transplantation. Eighty-five patients were included between January 2012 and December 2015, with a median 40 years old. Forty-eight patients received haplo-cord transplant and 37 patients received ISD transplant. Haplograft engraftment succeeded in all haplo-cord patients. For haplo-cord and ISD transplantation, adjusted cumulative incidences of grades 2-4 acute GvHD at 100 days were 27 and 11% (P=0.059); adjusted cumulative incidences of chronic GvHD at 2 years were 22 and 34% (P=0.215). The 2-year adjusted probabilities of overall survival were 64 and 70% (P=0.518), and of relapse-free survival were 56 and 66% (P=0.306). The 2-year adjusted cumulative incidences of relapse were 12 and 14% (P=0.743), and of non-relapse mortality were 33 and 23% (P=0.291). In conclusion, haplo-cord-HSCT achieves outcomes similar to those of ISD-HSCT for MDS and the haplo-cord-HSCT may potentially improve the outcome of HID- and UCB-HSCT alone. Thus, the haplo-cord transplantation may be a better valid alternative for MDS when an ISD is not available.

[Clinical analysis of 7 patients with Epstein-Barr virus encephalitis after allogeneic hematopoietic stem cell transplantation].

Objective: To summarize the clinical features, treatment and prognosis of patients with Epstein Barr virus (EBV) encephalitis after allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Methods: The clinical data of 7 patients with EBV encephalitis who had undergone allo-HSCT in the First Affiliated Hospital of Soochow University from January 2012 to December 2015 were reviewed. Results: The incidence of EBV encephalitis was 0.70% (7/998) , and the median time was 63 (10-136) d after allo-HSCT. Seven patients had fever and mental disorder, of whom 4 cases of brain MRI were positive. Two patients received HLA-matched unrelated transplantation, while other 5 ones received haploidentical allo-HSCT. In conditioning regimen process, 7 patients were combined with anti-thymocyte globulin (ATG) to prevent graft versus host disease (GVHD) , of whom 6 patients had grade Ⅱ-Ⅳ acute GVHD. All patients of EBV-DNA were negative in CSF after taking anti-virus agent Rituximab. Until the last follow-up, a total of 3 patients died, 2 died of leukemia recurrence, 1 EBV encephalitis progression. Conclusion: Once suspected EBV encephalitis after allo-HSCT, brain MRI and EBV-DNA in CSF should be detected, which could improve early diagnosis of EBV encephalitis. The usage of Rituximab was effective and well tolerated.

[Correlative factors on prevalence rate of dislipidemia among 1 337 coal miners in Shanxi province].

Objective: To understand the prevalence rate and correlative factors of dislipidemia among Shanxi coal miners and to provide evidence for the development of programs on dislipidemia prevention. Methods: We investigated 1 337 mine workers from a Coal Group in April 2016 and collected data related to their blood biochemistry. We then classified the types in accordance with the diagnostic criteria of " Guidelines for prevention and treatment of dyslipidemia in Chinese adults (2007)" , using χ(2) test and unconditional logistic regression model for analysis. Results: The overall prevalence rate of Dislipidemia was 59.1% (790/1 337), with males as 60.4% (708/1 173) and females as 50.0%(82/164) while males appeared higher (χ(2)=6.386, P<0.05). Among the 20-34, 35-49, 50 and above year-old groups, the rates were 68.8%, 58.7%, 49.5%, respectively. Results from the χ(2) test showed that gender, age and body mass index were the influencing factors on dislipidemia (χ(2)=7.117, P<0.01; χ(2)=37.135, P<0.01; χ(2)=7.009, P<0.05), while logistic regression analysis showed that sex, age, body mass index level, systolic blood pressure were significantly associated with dislipidemia (P<0.05). Male miners appeared 1.501 times (OR=1.501, 95%CI: 1.895-2.516) higher than female miners in suffering from the risk of dyslipidemia. In different age groups, risks of dyslipidemia in the 35-49, 20-34 year-old groups were 1.672 (OR=1.672, 95%CI: 1.501-2.392) and 2.369 times (OR= 2.369, 95% CI: 1.275-3.469) higher than the 50 year-old. Group that with high BMI, the risk of dyslipidemia was 1.443 times (OR=1.443, 95%CI: 1.139-1.828) higher than the normal BMI group. Group with abnormal systolic pressure was 1.829 times (OR=1.829, 95%CI: 1.152-2.906) higher than normal systolic pressure group. However, diastolic blood pressure, blood sugar, uric acid, and electrocardiogram findings did not seem to show statistically significant meanings on dislipidemia. Conclusion: Among the coal mine workers, those who were males, aged from 20 to 34, having high blood pressure (systolic blood pressure abnormalities) or with high BMI (≥24.0 kg/m(2)) need to be taken special attention on care and prevention of dislipidemia.

Effect of body mass index on overall survival of patients with allogeneic hematopoietic stem cell transplantation.

BACKGROUND/OBJECTIVES: The present work was performed to investigate the association between body mass index (BMI) before transplantation and the overall survival (OS) of patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT). SUBJECTS/METHODS: Data from 310 adults who were diagnosed with acute leukemia and underwent allo-HSCT between March 2001 and December 2011 were analyzed. According to the suggested BMI categories for Asian population, patients with BMIs of ⩾23 and ⩾25 kg/m2 were identified as overweight and obese, respectively. Cox proportional hazards models was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: The median follow-up time among the patients was 19.7 months (interquartile range=8.1-37.7). A total of 93 (34.8%) people died within the follow-up period. After adjusting for the potential confounders, normal-weight, overweight and obese patients showed significantly lower HRs than those of underweight patients, with a significant trend of OS improvement upon increasing BMI (P=0.019). Overweight and obese patients survived longer, with a significantly decreased HR by ~40% (HR=0.60; 95% CI: 0.38-0.95) compared with underweight and normal-weight patients. CONCLUSIONS: An increased OS was seen in allo-HSCT patients with BMI⩾23 kg/m2 compared to those with lower BMI. Further work are still needed to investigate of the effects of BMI or body composition on the survival of allo-HSCT patients.