4,802 results on '"Allogeneic hematopoietic stem cell transplantation"'
Search Results
2. Risk-ADAPTed Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation (ADAPT)
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Stefan Octavian Ciurea, Professor of Clinical Medicine
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- 2024
3. Antigen Specific Adoptive T Cell Therapy for Adenovirus Infection After Hematopoietic Stem Cell Transplantation
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Mari Dallas, Principal Investigator
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- 2024
4. Post-transplant lymphoproliferative disorders after allogeneic hematopoietic stem cell transplantation: a case report, meta-analysis, and systematic review.
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Su, You-yuan, Yu, Ya-fei, Yan, Zhen-yu, Zhao, Ya-jing, Lou, Jian-wei, Xue, Feng, Xu, Miao, Feng, Qi, Ji, Xue-bin, Dong, Xiao-yuan, Wang, Wen, Liu, Chuan-fang, Peng, Jun, and Liu, Xin-guang
- Abstract
Background: Post-transplant lymphoproliferative disorders (PTLD) are rare but severe complications that occur after solid organ or allogeneic hematopoietic stem cell transplantations (allo-HSCT), with rapid progression and high mortality. Primary central nervous system (CNS)-PTLD are rarely recognized histo-pathologically. In addition, the diagnostic value of the Epstein–Barr virus (EBV) DNA copies in CNS-PTLD remains poorly understood. Objectives: We herein report a case of monomorphic EBV-associated CNS-PTLD (diffuse large B-cell lymphoma, DLBCL) after allo-HSCT and perform a meta-analysis to assess the efficacy of PTLD treatment strategies in recent years. Methods: We present the case report covering clinical manifestations, diagnosis, treatment, and outcomes of a patient with primary CNS-PTLD. Additionally, we include a systematic review and meta-analysis of the clinical characteristics of 431 patients with PTLD after allo-HSCT. We evaluate the main treatment options and outcomes of PTLD management, including rituximab, chemotherapies, and autologous or human leukocyte antigen (HLA)-matched EBV-specific cytotoxic T lymphocyte infusion (EBV-CTLs)/donor lymphocyte infusion (DLI). Results: The meta-analysis revealed an overall response rate of 69.0% for rituximab alone (95% CI: 0.47–0.84), 45.0% for rituximab plus chemotherapies (95% CI: 0.15–0.80), and 91.0% for rituximab plus EBV-CTLs/DLI (95% CI: 0.83–0.96). The complete response (CR) rate after treatments for PTLD was 67.0% (95% CI: 0.56–0.77). Moreover, the 6-month and 1-year overall survival (OS) rate was 64.0% (95% CI: 0.31–0.87) and 49.0% (95% CI: 0.31–0.68), respectively. Conclusions: This case highlighted the urgent need for effective, low-toxic treatment regimens for CNS-PTLD. Our meta-analysis suggested that rituximab combined with EBV-CTLs/DLI could be a favorable strategy for the management of PTLD after allo-HSCT. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Association of the pre-transplant CD4/CD8 ratio with the prognosis following allogeneic hematopoietic stem cell transplantation.
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Nagayama, Takashi, Fujiwara, Shin-ichiro, Tominaga, Ryutaro, Yokoyama, Daizo, Noguchi, Atsuto, Furuki, Shuka, Oyama, Takashi, Koyama, Shunsuke, Murahashi, Rui, Nakashima, Hirotomo, Ikeda, Takashi, Hyodo, Kazuki, Kawaguchi, Shin-ichiro, Toda, Yumiko, Umino, Kento, Minakata, Daisuke, Morita, Kaoru, Ashizawa, Masahiro, Yamamoto, Chihiro, and Hatano, Kaoru
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HEMATOPOIETIC stem cell transplantation , *OVERALL survival , *HEMATOLOGIC malignancies , *MULTIVARIATE analysis , *TUMOR microenvironment - Abstract
The tumor microenvironment's cells can promote or inhibit tumor formation, and there are no reports on the CD4/CD8 ratio's association with outcomes post allogeneic hematopoietic stem cell transplantation (allo-HSCT). We retrospectively evaluated the pre-transplant peripheral blood CD4/CD8 ratio in 168 patients who underwent their first allo-HSCT for hematological malignancies at our institution. When patients were divided into two groups according to the median CD4/CD8 ratio 1.35 (range, 0.09–19.89), the high CD4/CD8 ratio group had a higher incidence of relapse, equivalent non-relapse mortality and worse overall survival (OS) than the low CD4/CD8 ratio group. In a multivariate analysis, the CD4/CD8 ratio was significantly associated with an increased risk of relapse, although there was a marginally significant difference in OS. The pre-transplant peripheral blood CD4/CD8 ratio could be a novel biomarker for predicting the prognosis of allo-HSCT. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Efficacy and safety of ruxolitinib in the treatment of chronic graft-versus-host disease: a retrospective analysis.
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Denk, Alexander, Mittermaier, Cornelia, Weber, Daniela, Fante, Matthias, Güneş, Sibel, Edinger, Matthias, Herr, Wolfgang, and Wolff, Daniel
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GRAFT versus host disease , *HEMATOPOIETIC stem cell transplantation , *RUXOLITINIB , *PATIENTS' attitudes , *DRUG approval - Abstract
Steroid-refractory chronic graft-versus-host disease (cGvHD) is associated with significant morbidity and mortality, with ruxolitinib being the first drug approved for its treatment. We retrospectively analyzed the safety and efficacy of ruxolitinib for treatment of cGvHD at our center between 07/2015 and 12/2022 and identified 48 patients receiving ruxolitinib as second (18/48) or advanced (30/48) treatment line. Ruxolitinib was started on median day 340 (range 119–595) after cGvHD onset; median duration of administration was 176 (range, 79–294) days with 16/48 patients continuing treatment at last follow-up. National Institutes of Health organ grading and the intensity of immunosuppression were assessed at the start of ruxolitinib treatment and repeated after 1, 3, 6, and 12 months. Response assessment was terminated at the start of any additional new immunosuppressant treatment. The median time of follow-up was 582 (range, 104–1161) days. At the primary analysis after six months on ruxolitinib treatment, the overall response rate was 33%, and failure-free survival was 58%. Infectious adverse events ≥ CTCAE grade III were observed in 10/48 patients. The response rate was not associated with the severity of cGvHD, number of previous treatment lines, or number of additional agents combined with ruxolitinib applying a univariate regression model. At the time of the 12-month follow-up, four patients experienced recurrence of the underlying malignancy and two patients had experienced non-relapse-related mortality. Overall, ruxolitinib was relatively well-tolerated and showed outcomes comparable to the REACH3 trial in a heavily pretreated patient population. [ABSTRACT FROM AUTHOR]
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- 2024
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7. The application of JAK inhibitors in the peri-transplantation period of hematopoietic stem cell transplantation for myelofibrosis.
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Wang, Zerong, Jin, Xuelian, Zeng, Jiajia, Xiong, Zilin, and Chen, Xinchuan
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HEMATOPOIETIC stem cell transplantation , *MYELOPROLIFERATIVE neoplasms , *GRAFT versus host disease , *OVERALL survival , *RUXOLITINIB , *MYELOFIBROSIS - Abstract
Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) with a poor prognosis, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment with curative potential. Ruxolitinib, a JAK1/2 inhibitor, has shown promising results in improving patients' symptoms, overall survival, and quality of life, and can be used as a bridging therapy to HSCT that increases the proportion of transplantable patients. However, the effect of this and similar drugs on HSCT outcomes is unknown, and the reports on their efficacy and safety in the peri-transplantation period vary widely in the published literature. This paper reviews clinical data related to the use of JAK inhibitors in the peri-implantation phase of hematopoietic stem cell transplantation for primary myelofibrosis and discusses their efficacy and safety. [ABSTRACT FROM AUTHOR]
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- 2024
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8. Disability Associated with Chronic Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation: Analysis of a Cross-Sectional US Patient Survey.
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Hamilton, Betty K., Williams, Paul, Galvin, John, Turnbull, James, and Yu, Jingbo
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HEMATOPOIETIC stem cell transplantation ,GRAFT versus host disease ,DISABILITIES ,SELF-evaluation ,CROSS-sectional method ,STATISTICAL correlation ,COGNITIVE testing ,WORK capacity evaluation ,RESEARCH funding ,TRANSPLANTATION of organs, tissues, etc. ,SEX distribution ,LOGISTIC regression analysis ,INDEPENDENT variables ,HOMOGRAFTS ,SYMPTOM burden ,MULTIVARIATE analysis ,CHI-squared test ,DESCRIPTIVE statistics ,CHRONIC diseases ,RACE ,RESEARCH methodology ,RESEARCH ,STATISTICS ,SOCIAL support ,CELLS ,LABOR supply ,ACTIVITIES of daily living ,NUTRITION ,REGRESSION analysis ,DISEASE complications - Abstract
Introduction: Chronic graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation (HSCT) is associated with poor health-related quality of life (HRQoL) and functional status. However, few studies have evaluated chronic GVHD–related disability and specific activity limitations from a patient perspective. The objective of this analysis was to assess physical, cognitive, and work disability, and describe factors predictive of disability in patients with chronic GVHD in the potentially employable general workforce. Methods: The cross-sectional, online, Living With Chronic GVHD Patient Survey was administered in 2020 to adult US patients who reported an active chronic GVHD diagnosis (i.e., within the previous 5 years) following HSCT. Data included demographics, diagnosis, work status, chronic GVHD symptoms per the Lee Symptom Scale (LSS), and effects on daily living activities. Descriptive and correlational analyses informed composite disability definitions: (1) severe cognitive disability, (2) severe physical disability, and (3) work disability. Results: Of 137 respondents with GVHD included in this analysis, 47.0% reported severe cognitive disability, and approximately two-thirds each reported severe physical disability (67.4%) and work disability (62.8%). Chronic GVHD severity/duration, symptoms (Lee Symptom Scale), and number of transplant specialists consulted were associated with all types of disability (univariable analyses). Severe cognitive disability was associated with the number of transplant specialists consulted, severe physical disability with female sex, and work disability with nonwhite race. Conclusions: In this analysis, we found that the presence of specific symptoms and the number of transplant specialists consulted were associated with all types of severe disability; female sex was predictive of severe physical disability and nonwhite race of work disability. These findings add to the understanding of chronic GVHD-associated disability, suggest a need for improved social support for patients, and highlight potential indicators for those most in need. Plain Language Summary: Chronic graft-versus-host disease (GVHD) is a possible serious complication that can occur after someone has received a bone marrow or stem cell transplant from another person. Symptoms of chronic GVHD can be severe and can affect quality of life. To better understand exactly how chronic GVHD affects quality of life, we asked adults in the USA with chronic GVHD to fill out a survey. The objective of this research was to find out how chronic GVHD affects daily activities and work. The survey asked about physical activities including personal hygiene, eating, shopping, and ability to use the restroom, and the survey asked about mental tasks including managing personal finances and interactions with other people. The survey also asked questions about work, such as the need to take disability leave or to leave a job due to chronic GVHD. Many people with chronic GVHD who completed the survey said they had severe difficulty with mental and/or physical tasks, and many had work-related disability. People with more severe chronic GVHD who had met with many transplant specialists were more likely to have difficulty with mental and physical tasks and also to have work disability. Women who completed the survey were more likely to report severe physical disability than men, and nonwhite participants were more likely to report work disability. The results of this survey highlight a need for improved social support for patients with chronic GVHD. [ABSTRACT FROM AUTHOR]
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- 2024
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9. Anti-PD-1 combined with hypomethylating agent and CAG regimen bridging to allogeneic hematopoietic stem cell transplantation: a novel strategy for relapsed/refractory acute myeloid leukemia.
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Yu-Xin Wang, An Wang, Yong-Feng Su, Jun Wang, Yu-Hang Li, Fei Li, Yu Jing, Lei Xu, Yi-Zhi Wang, Xuan Zheng, Liang-Ding Hu, Xiao-Ning Gao, and Dai-Hong Liu
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HEMATOPOIETIC stem cell transplantation ,STEM cell transplantation ,ACUTE myeloid leukemia ,GRANULOCYTE-colony stimulating factor ,HEMATOPOIETIC stem cells - Abstract
Introduction: The prognosis of relapsed/refractory acute myeloid leukemia (r/ rAML) is dismal, and allogeneic hematopoietic stem cell transplant (allo-HSCT) is a potential cure. Combining anti-PD-1, hypomethylating agent (HMA), and CAG (cytarabine, aclarubicin/idarubicin, granulocyte colony-stimulating factor) regimen has showed primary efficacy in r/rAML. However, pre-transplant exposure to anti-PD-1 may lead to severe graft-versus-host disease (GVHD). This preliminary study aimed to evaluate the safety and efficacy of allo-HSCT in r/ rAML patients receiving the anti-PD-1+HMA+CAG regimen. Methods: Fifteen r/rAML patients (12 related haploidentical donors [HIDs], 2 matched siblings, 1 unrelated donor) received this regimen and subsequent peripheral blood HSCT. Results: Four patients with HIDs received a GVHD prophylaxis regimen consisted of Anti-thymocyte globulin and a reduced-dose of post-transplant cyclophosphamide. The median follow-up was 20.9 months (range, 1.2-34.2). The cumulative incidences of acute GVHD grade 2-4 and grade 3-4 were 40% and 13.3%, respectively. The 2-year incidence of moderate-to-severe chronic GVHD, nonrelapse mortality, and relapse were 10%, 22.3%, and 22.5%, respectively. The 2-year overall survival and GVHD-free/relapse-free survival rates were 54% and 48.6%, respectively. No death or relapse was observed in the PTCy group. Conclusion: The anti-PD-1+HMA+CAG regimen bridging to allo-HSCT for r/r AML was tolerable with promising efficacy. GVHD prophylaxis with PTCy for HIDHSCT showed preliminary survival advantage. [ABSTRACT FROM AUTHOR]
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- 2024
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10. Post‐transplant‐cyclophosphamide and short‐term Everolimus as graft‐versus‐host‐prophylaxis in patients with relapsed/refractory lymphoma and myeloma—Final results of the phase II OCTET‐EVER trial.
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Richardson, Tim, Scheid, Christof, Herling, Marco, Frenzel, Lukas P., Herling, Carmen, Aguilar, Marta Rebecca Cruz, Theurich, Sebastian, Hallek, Michael, and Holtick, Udo
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STEM cell transplantation , *GRAFT versus host disease , *HEMATOPOIETIC stem cell transplantation , *EVEROLIMUS , *MULTIPLE myeloma - Abstract
Background: Conditioning regimens and the choice of immunosuppression have substantial impact on immune reconstitution after allogeneic hematopoietic stem cell transplantation (aHSCT). The pivotal mechanism to maintain remission is the induction of the graft‐versus‐tumor effect. Relapse as well as graft versus host disease remain common. Classic immunosuppressive strategies implementing calcineurin inhibitors (CNI) have significant toxicities, hamper the immune recovery, and reduce the anti‐cancer immune response. Methods: We designed a phase II clinical trial for patients with relapsed and refractory lymphoid malignancies undergoing aHSCT using a CNI‐free approach consisting of post‐transplant cyclophosphamide (PTCy) and short‐term Everolimus after reduced‐intensity conditioning and matched peripheral blood stem cell transplantation. The results of the 19 planned patients are presented. Primary endpoint is the cumulative incidence and severity of acute GvHD. Results: Overall incidence of acute GvHD was 53% with no grade III or IV. Cumulative incidence of NRM at 1, 2, and 4 years was 11%, 11%, and 16%, respectively, with a median follow‐up of 43 months. Cumulative incidence of relapse was 32%, 32%, and 42% at 1, 2, and 4 years after transplant, respectively. Four out of six early relapses were multiple myeloma patients. Overall survival was 79%, 74%, and 62% at 1, 2, and 4 years. GvHD‐relapse‐free‐survival was 47% after 3 years. Conclusions: Using PTCy and short‐term Everolimus is safe with low rates of aGvHD and no severe aGvHD or cGvHD translating into a low rate of non‐relapse mortality. Our results in this difficult to treat patient population are encouraging and warrant further studies. [ABSTRACT FROM AUTHOR]
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- 2024
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11. Production of donor-derived cytotoxic T lymphocytes with potent anti-leukemia activity for adoptive immunotherapy in high-risk pediatric patients given haploidentical hematopoietic stem cell transplantation.
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Tanzi, Matteo, Montini, Enrica, Rumolo, Agnese, Moretta, Antonia, Comoli, Patrizia, Acquafredda, Gloria, Rotella, Jessica, Taurino, Gloria, Compagno, Francesca, Cave, Francesco Delle, Perotti, Cesare, Marseglia, Gian Luigi, Zecca, Marco, and Montagna, Daniela
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T cells , *HEMATOPOIETIC stem cell transplantation , *CYTOTOXIC T cells , *CHILD patients , *ENDOTOXINS , *SOMATIC cells , *DEAD , *ACUTE leukemia , *CURRENT good manufacturing practices - Abstract
Somatic cell therapy based on the infusion of donor-derived cytotoxic T lymphocytes (CTL) able to recognize patients' leukemia blasts (LB) is a promising approach to control leukemia relapse after allogeneic HSCT. The success of this approach strongly depends on the ex vivo generation of high-quality donor-derived anti-leukemia CTL in compliance with Good Manufacturing Practices (GMP). We previously described a procedure for generating large numbers of donor-derived anti-leukemia CTL through stimulation of CD8-enriched lymphocytes with dendritic cells (DCs) pulsed with apoptotic LB in the presence of interleukin (IL)-12, IL-7 and IL-15. Here we report that the use of IFN-DC and the addition of IFNα2b during the priming phase significantly improve the generation of an efficient anti-leukemia T cells response in vitro. Using this approach, 20 high-risk pediatric patients given haploidentical HSCT for high-risk acute leukemia were enrolled and 51 batches of advanced therapy medical products (ATMP), anti-leukemia CTL, were produced. Quality controls demonstrated that all batches were sterile, free of mycoplasma and conformed to acceptable endotoxin levels. Genotype analysis confirmed the molecular identity of the ATMP based on the starting biological material used for their production. The majority of ATMP were CD3+/CD8+ cells, with a memory/terminal activated phenotype, including T-central memory populations. ATMP were viable after thawing, and most ATMP batches displayed efficient capacity to lyse patients' LB and to secrete interferon-γ and tumor necrosis factor-α. These results demonstrated that our protocol is highly reproducible and allows the generation of large numbers of immunologically safe and functional anti-leukemia CTL with a high level of standardization. [ABSTRACT FROM AUTHOR]
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- 2024
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12. WT1 gene mutations impact post-transplant relapse in myelodysplastic syndrome with excess blasts 2 patients.
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Guo, Wenwen, Zhang, Haixiao, Wang, Mingyang, Zheng, Yawei, Cao, Yigeng, Zhang, Xiaoyu, Zhai, Weihua, Zhang, Rongli, Yang, Donglin, Wei, Jialin, He, Yi, Ma, Qiaoling, Xia, Yonghui, Pang, Aiming, Feng, Sizhou, Han, Mingzhe, and Jiang, Erlie
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MYELODYSPLASTIC syndromes , *HEMATOPOIETIC stem cell transplantation , *GENETIC mutation , *BLAST injuries , *ACUTE myeloid leukemia , *NEPHROBLASTOMA - Abstract
Wilms tumor 1 (WT1) gene mutations are infrequent in myelodysplastic syndrome (MDS), but MDS with WT1 mutations (WT1mut) is considered high risk for acute myeloid leukemia (AML) transformation. The influence of WT1 mutations in patients with MDS after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is unclear. We performed a retrospective analysis of 136 MDS with excess blasts 2 (MDS-EB2) patients with available WT1 status who underwent their first allo-HSCT between 2017 and 2022 in our center. There were 20 (20/136, 15%) cases in the WT1mut group and 116 (116/136, 85%) cases in the WT1 wild-type (WT1wt) group. WT1mut patients had a higher 2-year cumulative incidence of relapse (CIR) than WT1wt cases (26.2% vs. 9.4%, p = 0.037) after allo-HSCT. Multivariate analysis of relapse showed that WT1 mutations (HR, 6.0; p = 0.002), TP53 mutations (HR, 4.2; p = 0.021), and ≥ 5% blasts in bone marrow (BM) at transplantation (HR, 6.6; p = 0.004) were independent risk factors for relapse. Patients were stratified into three groups according to the risk factors. Two-year CIR differed significantly in high-, intermediate-, and low-risk groups (31.8%, 11.6%, and 0%, respectively). Hence, WT1 mutations may be related to post-transplant relapse in patients with MDS-EB2, which warrants further study. [ABSTRACT FROM AUTHOR]
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- 2024
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13. Significance of absolute neutrophil count before allogeneic hematopoietic stem cell transplantation in adult patients with aplastic anemia.
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Nakamura, Yukinori, Zaimoku, Yoshitaka, Yamaguchi, Hiroki, Yamazaki, Hirohito, Kanaya, Minoru, Uchida, Naoyuki, Doki, Noriko, Sakurai, Masatoshi, Hiramoto, Nobuhiro, Kako, Shinichi, Onizuka, Makoto, Onodera, Koichi, Maruyama, Yumiko, Ohigashi, Hiroyuki, Nishida, Tetsuya, Yoshihara, Satoshi, Matsuoka, Ken-ichi, Eto, Tetsuya, Kanda, Yoshinobu, and Fukuda, Takahiro
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STEM cell transplantation , *HEMATOPOIETIC stem cell transplantation , *APLASTIC anemia , *STEM cell donors , *ADULTS , *NEUTROPHILS - Abstract
The impact of absolute neutrophil count (ANC) before allogenic hematopoietic stem cell transplantation (HSCT) on the outcomes for patients with aplastic anemia (AA) remains unclear. We retrospectively evaluated the relationship between ANC before transplantation and patient outcomes, involving 883 adult Japanese patients with AA who underwent allogeneic HSCT as their first transplantation between 2008 and 2020. Patients were divided into three groups based on ANC: 0/µL (n = 116); 1–199 (n = 210); and ≥ 200 (n = 557). In the low ANC groups (ANC < 200), patient age was higher, previous anti-thymocyte globulin (ATG) treatments were infrequent, duration from diagnosis to transplantation was shorter, hematopoietic cell transplantation-comorbidity index (HCT-CI) was higher, ATG-based conditioning was used infrequently, and peripheral blood stem cell from related donor and cord blood were used frequently. In multivariate analysis, patient age, previous ATG treatment, HCT-CI, stem cell source, and ANC before transplantation were significantly associated with 5-year overall survival (OS) ("ANC ≥ 200": 80.3% vs. "ANC 1–199": 71.7% vs. "ANC 0": 64.4%). The cumulative incidence of bacterial infection, invasive fungal disease, and early death before engraftment were significantly higher in the low ANC groups. Among patients with ANC of zero before transplantation, younger patient age, shorter duration from diagnosis to transplantation, HCT-CI of 0, and bone marrow from related donor as stem cell source were significantly associated with better OS. Consequently, ANC before allogeneic HSCT was found to be a significant prognostic factor in adult patients with AA. Physicians should pay attention to ANC before transplantation. [ABSTRACT FROM AUTHOR]
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- 2024
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14. Ruxolitinib for the treatment of acute graft-versus-host disease: a retrospective analysis.
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Denk, Alexander, Edinger, Matthias, Weber, Daniela, Holler, Ernst, Fante, Matthias, Meedt, Elisabeth, Gunes, Sibel, Poeck, Hendrik, Mittermaier, Cornelia, Herr, Wolfgang, and Wolff, Daniel
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ACUTE diseases , *GRAFT versus host disease , *RUXOLITINIB , *HEMATOPOIETIC stem cell transplantation , *RETROSPECTIVE studies - Abstract
Steroid-refractory acute graft-versus-host disease (aGvHD) is a serious complication after allogeneic hematopoietic stem cell transplantation, associated with significant mortality. Ruxolitinib was the first drug approved for aGvHD, based on results of the REACH2 trial; however, real-world data are limited. We retrospectively analyzed the safety and efficacy of ruxolitinib for treatment of aGvHD at our center from March 2016 to August 2022 and assessed biomarkers of risk. We identified 49 patients receiving ruxolitinib as second- (33/49), third- (11/49), fourth- (3/49), or fifth-line (2/49) treatment. Ruxolitinib was started on median day 11 (range, 7–21) after aGvHD onset; median duration of administration was 37 days (range, 20–86), with 10 patients continuing treatment at last follow-up. Median follow-up period was 501 days (range, 95–905). In the primary analysis at the 1-month assessment, overall response rate was 65%, and failure-free survival was 78%. Infectious complications ≥ CTCAE Grade III were observed in 10/49 patients within 1-month followup. Patients responding to ruxolitinib therapy required fewer steroids and exhibited lower levels of the serum biomarkers regenerating islet-derived protein 3-alpha, suppression of tumorigenicity 2, and the Mount Sinai Acute GVHD International Consortium algorithm probability. A univariate regression model revealed steroid-dependent aGvHD as a significant predictor of better response to ruxolitinib. Within 6-months follow-up, four patients experienced recurrence of underlying malignancy, and eight died due to treatment-related mortality. Overall, ruxolitinib was welltolerated and showed response in heavily pretreated patients, with results comparable to those of the REACH2 trial. Biomarkers may be useful predictors of response to ruxolitinib. [ABSTRACT FROM AUTHOR]
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- 2024
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15. Acute mixed-lineage leukemia treated with desensitization therapy prior to HLA–haploidentical transplantation with high donor-specific antibodies.
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Katsuki, Kengo, Tachibana, Takayoshi, Izumi, Akihiko, Kim, Kumryo, Suzuki, Taisei, Tanaka, Masatsugu, and Nakajima, Hideaki
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A 43-year-old woman was referred to our department for hematopoietic stem cell transplantation for acute myeloid leukemia, as she failed to achieve remission following induction therapy. Umbilical cord blood transplantation was initially planned; however, multiple anti-human leukocyte antigen (HLA) antibodies with a mean fluorescence intensity of over 10,000 were detected, and optimal umbilical cord blood could not be obtained. The plan was then switched to peripheral blood stem cell transplantation (PBSCT) from the patient's son, who had a 5/8 HLA haploidentical match. However, the patient had donor-specific antibodies against the donor's HLA-B 0702 and HLA-C 0702. To address this issue, after rituximab therapy, the patient was given platelet transfusions from B0702- and C0702-positive donors on day − 1 and day 0, and immunoglobulin on day 0, followed by PBSCT. Donor-specific antibodies decreased by over 90%, and engraftment was confirmed on day 13. Since then, the patient has remained relapse-free and healthy. This case suggests that appropriate management of donor-specific antibodies can enable safe transplantation, even in donors who test positive for these antibodies. [ABSTRACT FROM AUTHOR]
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- 2024
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16. The impact of the donors' COVID-19 status on the outcomes of allogeneic hematopoietic stem cell transplantation: a multi-center retrospective study.
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Yifei Huang, Zhiping Fan, Yingying Hu, Sizhou Feng, Shunqing Wang, Shanyu Zhang, Fen Huang, Li Xuan, Na Xu, Hui Liu, Zhixiang Wang, Jing Sun, Qifa Liu, and Ren Lin
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HEMATOPOIETIC stem cell transplantation ,STEM cell transplantation ,HEPATIC veno-occlusive disease ,PROGRESSION-free survival ,VIRUS diseases - Abstract
Introduction: To explore the impact of donors' COVID-19 status on allogeneic stem cell transplantation (allo-HSCT), we compared the transplant outcomes of 74 participants. Methods: This multi-center retrospective study included nine participants receiving grafts from COVID-19 positive donors (CPD), 45 from COVID-19 experienced donors (CED), and 20 from COVID-19 naive donors (CND). We evaluated engraftment, complications, and survival rates among the three groups. Results: All apheresis procedures were successful with no significant differences in CD34+ cells or lymphocytes in grafts among the three groups. All patients achieved engraftment by day 30 post-HSCT. The incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 55.6%, 20%, and 10% in the CPD, CED, and CND groups, respectively (p = 0.024). Multivariate analysis indicated that COVID-19 positivity in donors at the time of apheresis was an independent risk factor for II-IV aGVHD (p = 0.020, OR = 12.159, 95% CI 1.783-135.760). No differences were observed among the groups in terms of chronic GVHD, viral infection, or sinusoidal obstruction syndrome. The 6-month overall survival and disease-free survival rates were also similar among the three groups. Discussion: Our results suggest that the COVID-19-positive status of donors might not impact graft collection, engraftment, or short-term survival of allo-HSCT recipients but might increase the risk of aGVHD. Further research is needed to explore the influence of donors' COVID-19 status on long-term complications and survival in allo-HSCT recipients. [ABSTRACT FROM AUTHOR]
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- 2024
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17. Application of CD25 and CTLA4 gene transcription levels in early prediction of acute graftversus-host disease.
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Ken Huang, Mengxin Yang, Yuhang Zhou, Yaxuan Cao, Guanxiu Pang, Jie Zhao, Yang Liu, and Jianming Luo
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ACUTE diseases ,GENETIC transcription ,CD25 antigen ,HEMATOPOIETIC stem cell transplantation ,ALLOIMMUNITY ,RECEIVER operating characteristic curves ,GRAFT versus host disease - Abstract
Introduction: Our study investigated the potential of peripheral blood T cell CD25, CD28, and CTLA-4 gene transcription levels as predictive biomarkers for acute graft-versus-host disease (aGVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: Real-time reverse transcription fluorescent quantitative PCR (RTqPCR) analysis was conducted on day +7, +14, and +21 post-transplantation in patients undergoing allo-HSCT. Results: Elevated levels of CD25 and CTLA-4 mRNA were found to be associated with the occurrence of aGVHD, as well as severe and gastrointestinal aGVHD. Receiver operating characteristic (ROC) curve analysis was utilized to assess the predictive value of each biomarker. Combined analysis of CD25 and CTLA-4 mRNA levels demonstrated promising predictive potential for aGVHD. Conclusion: Our results confirmed that the transcription levels of CD25 and CTLA-4 genes could be used as early predictive biomarkers for aGVHD post-allo-HSCT. [ABSTRACT FROM AUTHOR]
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- 2024
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18. Reduced Dose of Post-Transplant Cyclophosphamide with Tacrolimus for the Prevention of Graft-versus-Host Disease in HLA-Matched Donor Peripheral Blood Stem Cell Transplants: A Prospective Pilot Study.
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Juárez, Alex, Salas, María Queralt, Pedraza, Alexandra, Suárez-Lledó, María, Rodríguez-Lobato, Luís Gerardo, Solano, María Teresa, Serrahima, Anna, Nomdedeu, Meritxell, Cid, Joan, Lozano, Miquel, Charry, Paola, Arcarons, Jordi, Llobet, Noemí, Rosiñol, Laura, Fernández-Avilés, Francesc, Rovira, Montserrat, and Martínez, Carmen
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THERAPEUTIC use of antineoplastic agents , *GRAFT versus host disease , *HEMATOPOIETIC stem cell transplantation , *DRUG toxicity , *MYCOSES , *TRANSPLANTATION of organs, tissues, etc. , *DRUG therapy , *PILOT projects , *NEUTROPHILS , *BLOODBORNE infections , *CATHETER-related infections , *CYSTITIS , *CYTOMEGALOVIRUS diseases , *MAJOR adverse cardiovascular events , *BLOOD transfusion reaction , *HEMORRHAGIC diseases , *DESCRIPTIVE statistics , *DOSE-effect relationship in pharmacology , *LONGITUDINAL method , *BLOOD platelets , *TACROLIMUS , *DRUG efficacy , *HERPESVIRUS diseases , *PROGRESSION-free survival , *CYCLOPHOSPHAMIDE , *HLA-B27 antigen , *OVERALL survival , *IMMUNOSUPPRESSION , *EVALUATION , *DISEASE risk factors - Abstract
Simple Summary: High-dose post-transplant cyclophosphamide is effective in preventing graft-versus-host disease (GVHD) but is associated with adverse outcomes such as delayed engraftment, infections, and cardiac issues. This pilot study evaluated the efficacy and toxicity of reduced-dose PTCY (40 mg/kg/day) in patients undergoing HLA-matched allogeneic hematopoietic stem cell transplantation (alloHSCT). Neutrophil and platelet engraftment occurred at medians of 15 and 16 days, respectively. At day 100, the incidences of grade II–IV and III–IV acute GVHD were 18.2% and 4.5%, respectively, with no cases of grade IV acute GVHD or steroid-refractory disease. One-year incidence of moderate-severe chronic GVHD was 6.4%. Both incidences, acute GVHD and chronic GVHD, are similar to our previous experience with higher doses of PTCY. Two-year overall survival and relapse-free survival were 77.1% and 58.3%. There were low incidences of infections and only one early cardiac event. These results suggest that reduced-dose PTCY provides adequate immunosuppression with a low toxicity profile. PTCY 50 mg/kg/day on days +3/+4 is an excellent strategy to prevent GVHD. However, its use is associated with adverse outcomes such as delayed engraftment, increased risk of infection, and cardiac complications. This pilot study evaluates the efficacy and toxicity of a reduced dose of PTCY (40 mg/kg/day) combined with tacrolimus in 22 peripheral blood HLA-matched alloHSCT patients. At day +100, the cumulative incidences of grade II–IV and III–IV acute GVHD were 18.2% and 4.5%, respectively. No grade IV acute GVHD or steroid-refractory disease was observed. The cumulative incidences of all-grade and moderate-severe chronic GVHD at 1-year were 11.4% and 6.4%, respectively. No patient died from transplant-related complications. Two-year OS and RFS were 77.1% and 58.3%, respectively. All patients engrafted, with neutrophil and platelet recovery occurring at a median of 15 (IQR 14–16) and 16 days (IQR 12–23), respectively. The cumulative incidences of bloodstream bacterial infections, polyomavirus BK hemorrhagic cystitis, HHV6 reactivation, CMV reactivation, and fungal infections were 13.6%, 9.1%, 9.1%, 4.6%, and 6%, respectively. Only one early cardiac event was observed. These results suggest that PTCY 40 mg/kg/day on a +3/+4 schedule provides adequate immunosuppression to allow for engraftment and prevent clinically significant GVHD with a low toxicity profile. [ABSTRACT FROM AUTHOR]
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- 2024
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19. Minimal important difference of the 6-minute walk test after allogenic hematopoietic stem cell transplantation.
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Murao, Masanobu, Kondo, Tadakazu, Hamada, Ryota, Miyasaka, Junsuke, Matsushita, Michiko, Otagaki, Ayumi, Kajimoto, Taishi, Arai, Yasuyuki, Kanda, Junya, Nankaku, Manabu, Ikeguchi, Ryosuke, Takaori-Kondo, Akifumi, and Matsuda, Shuichi
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HEMATOPOIETIC stem cell transplantation , *EXERCISE physiology , *PHYSICAL therapy , *RECEIVER operating characteristic curves , *RESEARCH funding , *HOSPITAL care , *MULTIPLE regression analysis , *QUESTIONNAIRES , *HOMOGRAFTS , *TREATMENT effectiveness , *DESCRIPTIVE statistics , *WALKING , *EXERCISE tests , *DATA analysis software , *REGRESSION analysis , *EVALUATION , *REHABILITATION - Abstract
The 6-min walk test (6MWT) of allogenic hematopoietic stem cell transplantation (allo-HSCT) recipients has been gaining attention; however, minimal differences have not been reported. This study aimed to determine the minimal important difference (MID) in the 6MWT among hospitalized patients with allo-HSCT. The MID of the 6MWT was calculated using three different methodologies based on an anchor-based method; basic anchor-based methods, linear regression analysis, and receiver operating characteristic (ROC) curve analysis. The decrease in the score of Question 2 of the European Organization for Research and Treatment of Cancer Quality of life questionnaire core-30 was included as an anchor question for calculating the MID. Both actual and percentage changes in 6MWT values from baseline and at discharge were used in the MID calculations. In the actual and percentage change of the 6MWT, the one with the larger the area under the curve in the ROC curve was recommended as the MID. Among the three methods using actual values, the largest MID of the 6MWT was −37.5 m (sensitivity: 54%, specificity: 88%). More careful follow-up after discharge is necessary for allo-HSCT patients who show a reduction of 37.5 m or more in the acute illness phase. Advancements in allogeneic hematopoietic stem cell transplantation have improved the survival rates of individuals with malignant hematological disorders, and efforts should now be focused on enhancing their physical function and quality of life. There is a problem that the physical performance of the patients is reduced by the side effects of treatment. More careful follow-up after discharge is necessary for allo-HSCT patients who show a reduction of 37.5 m or more in the acute illness phase. [ABSTRACT FROM AUTHOR]
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- 2024
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20. 异基因造血干细胞移植术对急性白血病患者甲状腺 功能影响的危险因素研究.
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胡 瑾, 牛 奔, 李 梦, and 马燕琳
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Objective To investigate the incidence and identify risk factors associated with thyroid disease (TD) in patients diagnosed with acute leukemia (AL) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods Clinical data of 98 AL patients who underwent allo-HSCT for the first time in the Department of Hematology of the First People's Hospital of Yunnan Province from January 2018 to June 2023 were collected and retrospectively analyzed. All AL patients were treated with anti-tumor drugs (excluding immune checkpoint inhibitors) and allo-HSCT, divided into non-TD group (n = 55) and TD group (n = 43) based on whether TD occurred. We collected the patients' general information and laboratory data, analyzed whether there were statistical differences between the two groups, and explored the related risk factors for TD after allo-HSCT treatment. Results Among the 98 AL patients who underwent allo-HSCT, 43 (43.8%) exhibited abnormal thyroid function, including 22 cases of hypothyroidism (comprising clinical and subclinical hypothyroidism), 9 cases of hyperthyroidism (including clinical and subclinical hyperthyroidism), and 12 cases of elevated thyroid antibodies. Univariate analysis of the non-TD group and TD group showed no statistical significance in age, gender, donorrecipient relationship, HLA matching, donor and recipient blood type, neutrophil implantation time and PLT implantation time (P > 0.05). However, there were statistically significant differences in disease type and the presence of concurrent aGVHD (P < 0.05). The binary logistic regression analysis revealed that aGVHD was identified as a significant risk factor for the development of thyroid disorders after transplantation (OR=3.693, 95%CI=1.166~11.699, P < 0.05). Furthermore, when compared to the underlying disease ALL, AML and other AL exhibited a significantly higher susceptibility to thyroid disorders (P < 0.05). Conclusion Hypothyroidism is the most common type of TD caused by allo-HSCT treatment in AL patients, and TD is more likely to occur in acute non-lymphocytic post-transplantation, and patients with aGVHD is a risk factor for TD. [ABSTRACT FROM AUTHOR]
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- 2024
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21. Risk factors and survival outcomes in children with early cardiotoxicity after allogeneic hematopoietic stem cell transplantation.
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Tong, Ke, Meng, Yan, Zhang, Luying, Lei, Xiaoying, Liu, Qihui, Guan, Xianmin, Yu, Jie, and Dou, Ying
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HEMATOPOIETIC stem cell transplantation , *STEM cell transplantation , *SURVIVAL rate , *CARDIOTOXICITY , *HEART valve diseases , *DISEASE risk factors , *CHILDREN'S hospitals , *PERICARDIAL effusion , *ARRHYTHMIA - Abstract
Cardiotoxicity in children is a potentially fatal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT); therefore, early identification of risk factors can improve patient prognosis. However, there are few data on the clinical characteristics of early-stage cardiotoxicity in children after allo-HSCT. We conducted a retrospective single-center study of pediatric patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) between January 2016 and December 2022 at the Children's Hospital Affiliated with Chongqing Medical University to evaluate the clinical characteristics of early cardiac events (ECEs) after allo-HSCT and their impact on survival outcomes. We enrolled 444 patients who underwent allo-HSCT—304 males (68%) and 140 females (32%)—with a median age of 3.3 years (1.8–6.5 years) at transplantation. We found that 73 patients (16.4%) had ECEs after allo-HSCT. The ECEs included valvular disease (n = 46), pericardial effusion (n = 38), arrhythmia (n = 9), heart failure (n = 16), and dilated cardiomyopathy (n = 1). Female sex, age ≥ 6 years, body mass index (BMI) < 16 kg/m2 and HLA-type mismatches were risk factors for ECEs. We designed a stratified cardiac risk score that included these risk factors, and the higher the score was, the greater the cumulative incidence of ECEs. The occurrence of an ECE was closely associated with a lower overall survival (OS) rate and greater nonrelapse mortality (NRM). In addition, stratified analysis based on the number of combined ECEs showed that the greater the number of combined ECEs was, the more significant the negative impact on OS rates. [ABSTRACT FROM AUTHOR]
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- 2024
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22. Impact of cladribine, cytarabine, and G-CSF (CLAG) as a bridging therapy prior to allogeneic hematopoietic stem cell transplantation in relapsed or refractory acute myeloid leukemia.
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Cui, Tong, Li, Huiyu, Zhou, Shiyuan, Li, Jing, Zhu, Qian, Zhu, Wenjuan, Tang, Zaixiang, Ma, Xiao, Qiu, Huiying, Wu, Depei, and Wu, Xiaojin
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HEMATOPOIETIC stem cell transplantation , *ACUTE myeloid leukemia , *CYTARABINE - Abstract
The combination of cladribine, cytarabine, and G-CSF (CLAG) has exhibited robust synergistic anti-leukemia activity as an induction therapy (IT) in acute myeloid leukemia (AML). However, the impact of CLAG as a bridging therapy (BT) administered between IT and allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with relapsed or refractory (R/R) AML remains uncertain. In this retrospective study, we examined the efficacy of CLAG as a transitional strategy prior to allo-HSCT in R/R AML. We included 234 patients with R/R AML who received the modified busulfan plus cyclophosphamide conditioning regimen for allo-HSCT in our center during the past 6 years, performed a propensity-score matching analysis, partitioned them into four distinct cohorts, and further integrated them into the CLAG group and non-CLAG group based on response to IT and utilization of CLAG. Our cohorts encompassed 12 patients in Cohort A (modified composite complete remission (mCRc) after IT, CLAG), 31 in Cohort B (mCRc after IT, non-CLAG), 35 in Cohort C (non-complete remission (non-CR) after IT, CLAG), and 80 in Cohort D (non-CR after IT, non-CLAG). Intriguingly, among patients with non-CR status, the administration of CLAG correlated with a notably statistically diminished risk of relapse and improved survival at 2-year follow-up (Cohort C vs. Cohort D). Employing CLAG as a BT prior to allo-HSCT demonstrates substantial effectiveness, a relative degree of safety, and manageable toxicity in selected R/R AML cases. [ABSTRACT FROM AUTHOR]
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- 2024
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23. Reconstitution of Natural Killer cells after allogeneic hematopoietic stem cell transplantation is facilitated by Huiyang-Guben decoction through activating the Smad7/Stat3 signal pathway.
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Gao, Xiaoli, Wang, Qi, He, Haitao, Yang, Tonghua, Zhang, Haixi, Zhao, Jie, and Yao, Xiangmei
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Natural Killer (NK) cell is the first batch of re-constructed cell populations after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and its delayed reconstitution inevitably causes poor outcome. The traditional Chinese medicine Huiyang-Guben decoction (HYGB) has been clinically used in patients undergoing allo-HSCT, but its effect on NK cell reconstruction is still unclear. 40 patients with allo-HSCT therapy were randomly divided into the control group and the HYGB group, and were given oral administration of normal saline or HYGB for 4 weeks before allo-HSCT, respectively. NK cells were cultured and treated with transforming growth factor β (TGF-β) and HYGB in vitro, and cell viability, cell apoptosis, and the function of NK cells were evaluated. Functional verification experiments were performed by knocking down signal transduction molecule 7 (Smad7) in NK cells before TGF-β and HYGB treatment. Clinical data suggested that HYGB intervention decreased the incidence of acute graft-versus-host disease after allo-HSCT, and increased the proportion of NK cell population. Meanwhile, HYGB improved cell viability, restrained apoptotic cell death, and enhanced cell killing activity of NK cells in patients with allo-HSCT. Notably, we found that HYGB significantly increased the expression level of Smad7 and the phosphorylation level of signal transducer and activator of transcription 3 (Stat3) in NK cells from patients with allo-HSCT. Moreover, HYGB alleviated TGF-β-induced NK cell impairment and re-activated the Smad7/Stat3 signaling in vitro, while silencing Smad7 reversed the protective effect of HYGB on TGF-β-treated NK cells. HYGB promotes NK cell reconstruction and improves NK cell function after allo-HSCT through activating the Smad7/Stat3 signaling pathway. [ABSTRACT FROM AUTHOR]
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- 2024
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24. Impact of Inflammatory Burden on Voriconazole Exposure in Oncohematological Pediatric Patients Receiving Antifungal Prophylaxis after Allogeneic HCT.
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Gatti, Milo, Campoli, Caterina, Muratore, Edoardo, Belotti, Tamara, Masetti, Riccardo, Lanari, Marcello, Viale, Pierluigi, and Pea, Federico
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HEMATOPOIETIC stem cell transplantation ,DRUG monitoring ,DRUG dosage ,BLOOD proteins ,CHILD patients - Abstract
(1) Background: The impact of inflammation on voriconazole exposure in oncohematological pediatric patients represents a debated issue. We aimed to investigate the impact of serum C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6) levels on voriconazole exposure in oncohematological pediatric patients requiring allogeneic hematopoietic stem cell transplantation (HCT). (2) Methods: Pediatric patients undergoing allogeneic HCT and receiving therapeutic drug monitoring (TDM)-guided voriconazole as primary antifungal prophylaxis between January 2021 and December 2023 were included. The ratio between concentration and dose (C/D) of voriconazole was used as a surrogate marker of total clearance. A receiving operating characteristic curve analysis was performed by using CRP, PCT, or IL-6 values as the test variable and voriconazole C/D ratio > 0.188 or >0.375 (corresponding to a trough concentration value [C
min ] of 3 mg/L normalized to the maintenance dose of 16 mg/kg/day in patients of age < 12 years and of 8 mg/kg/day in those ≥12 years, respectively) as the state variable. Area under the curve (AUC) and 95% confidence interval (CI) were calculated. (3) Results: Overall, 39 patients were included. The median (IQR) voriconazole Cmin was 1.7 (0.7–3.0) mg/L. A CRP value > 8.49 mg/dL (AUC = 0.72; 95%CI 0.68–0.76; p < 0.0001), a PCT value > 2.6 ng/mL (AUC = 0.71; 95%CI 0.63–0.77; p < 0.0001), and an IL-6 value > 27.9 pg/mL (AUC = 0.80; 95%CI 0.71–0.88; p < 0.0001) were significantly associated with voriconazole overexposure. Consistent results were found in patients aged <12 and ≥12 years. (4) Conclusions: A single specific threshold of inflammatory biomarkers may be linked to a significantly higher risk of voriconazole exposure in oncohematological pediatric patients after HCT, irrespective of age. Adopting a TDM-guided strategy could be useful for minimizing the risk of voriconazole overexposure. [ABSTRACT FROM AUTHOR]- Published
- 2024
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25. Post-transplant lymphoproliferative disorders after allogeneic hematopoietic stem cell transplantation: a case report, meta-analysis, and systematic review
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You-yuan Su, Ya-fei Yu, Zhen-yu Yan, Ya-jing Zhao, Jian-wei Lou, Feng Xue, Miao Xu, Qi Feng, Xue-bin Ji, Xiao-yuan Dong, Wen Wang, Chuan-fang Liu, Jun Peng, and Xin-guang Liu
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Post-transplant lymphoproliferative disorders ,Allogeneic hematopoietic stem cell transplantation ,Central nervous system ,Rituximab ,Meta-analysis ,Pathology ,RB1-214 - Abstract
Abstract Background Post-transplant lymphoproliferative disorders (PTLD) are rare but severe complications that occur after solid organ or allogeneic hematopoietic stem cell transplantations (allo-HSCT), with rapid progression and high mortality. Primary central nervous system (CNS)-PTLD are rarely recognized histo-pathologically. In addition, the diagnostic value of the Epstein–Barr virus (EBV) DNA copies in CNS-PTLD remains poorly understood. Objectives We herein report a case of monomorphic EBV-associated CNS-PTLD (diffuse large B-cell lymphoma, DLBCL) after allo-HSCT and perform a meta-analysis to assess the efficacy of PTLD treatment strategies in recent years. Methods We present the case report covering clinical manifestations, diagnosis, treatment, and outcomes of a patient with primary CNS-PTLD. Additionally, we include a systematic review and meta-analysis of the clinical characteristics of 431 patients with PTLD after allo-HSCT. We evaluate the main treatment options and outcomes of PTLD management, including rituximab, chemotherapies, and autologous or human leukocyte antigen (HLA)-matched EBV-specific cytotoxic T lymphocyte infusion (EBV-CTLs)/donor lymphocyte infusion (DLI). Results The meta-analysis revealed an overall response rate of 69.0% for rituximab alone (95% CI: 0.47–0.84), 45.0% for rituximab plus chemotherapies (95% CI: 0.15–0.80), and 91.0% for rituximab plus EBV-CTLs/DLI (95% CI: 0.83–0.96). The complete response (CR) rate after treatments for PTLD was 67.0% (95% CI: 0.56–0.77). Moreover, the 6-month and 1-year overall survival (OS) rate was 64.0% (95% CI: 0.31–0.87) and 49.0% (95% CI: 0.31–0.68), respectively. Conclusions This case highlighted the urgent need for effective, low-toxic treatment regimens for CNS-PTLD. Our meta-analysis suggested that rituximab combined with EBV-CTLs/DLI could be a favorable strategy for the management of PTLD after allo-HSCT.
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- 2024
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26. Fludarabine, busulfan, and melphalan conditioning regimen in allogeneic hematopoietic stem cell transplantation for adult patients with myeloid malignancies: A multicenter retrospective study
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Jieling Jiang, Xiaofan Li, Dong Wu, Quanyi Lu, Kourong Miao, Houcai Wang, Xiaoping Li, Yingnian Chen, Shiyuan Zhou, Yali Zhou, Guiping Liao, Chuanhe Jiang, Xiaohong Yuan, Youshan Zhao, Chunkang Chang, Jie Chen, Han Zhu, Ruye Ma, Nainong Li, Xiaolin Yin, Xiaojin Wu, Sanbin Wang, Chun Wang, and Jiong Hu
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allogeneic hematopoietic stem cell transplantation ,busulfan ,melphalan ,myeloid malignancies ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract Relapse remains the main cause of treatment failure in patients with myeloid malignancies even after allogeneic hematopoietic stem cell transplantation (allo‐HSCT). We observed a particularly low incidence of relapse in patients prepared with fludarabine, busulfan and melphalan in our previous study and this multicenter retrospective analysis aimed to confirm the feasibility of the regimen and to identify the potential prognostic factors. This study was performed using registry data from adults patients with myeloid malignancies who underwent their first allo‐HSCT following fludarabine(≥100 mg/m2), busulfan (≥3.2 mg/kg) and melphalan (≥100 mg/m2) based conditioning at nine transplantation centers in China between Jan. 2020 and Mar. 2022. A total of 221 consecutive patients (AML n = 171, MDS‐IB‐1 or 2 n = 44, CMML n = 6) with median age of 46 were enrolled in this study. The median follow‐up was 507 days for survivors. The 2‐year NRM, CIR, OS and DFS were 10.6% ± 2.2%, 14.8% ± 3.3%, 79.4% ± 3.7% and 74.6% ± 3.7%, respectively. In multivariate analyses, high HCT‐CI (≥3) was the only independent factor for higher NRM [hazard ratio (HR), 2.96; 95% confidence interval (CI), 1.11 to 7.90; p = 0.030] and ECOG score ≥2 was the only independent factor for inferior OS (HR, 2.43; 95%CI, 1.15 to 5.16; p = 0.020) and DFS (HR, 2.12; 95%CI, 1.13 to 4.02; p = 0.020). AML diagnosis and positive measurable residual disease (MRD) at transplantation were predictors for higher CIR (HR = 7.92, 95%CI 1.05‐60.03, p = 0.045; HR = 3.64, 95%CI 1.40‐9.44, p = 0.008; respectively), while post‐transplantation cyclophosphamide based graft‐versus‐host disease prophylaxis was associated with lower CIR (HR = 0.24 95%CI 0.11‐0.54, p = 0.001). The intensity of conditioning regimen did not impact CIR, NRM, DFS and OS. These results supported that double alkylating agents of busulfan and melphalan based conditioning regimens were associated with low relapse rate and acceptable NRM in adult patients with myeloid malignancies. The optimal dose remained to be confirmed by further prospective studies.
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- 2024
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27. Polyomic Biomarker Verification in Adult Chronic Graft-Versus-Host Disease (ABLE3.0/CTTC2201)
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Kirk Schultz, Principal Investigator
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- 2023
28. Biomarker Verification in Pediatric Chronic GvHD: ABLE 2.0 / PTCTC GVH 1901 Study
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Kirk Schultz, Professor of Pediatrics
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- 2023
29. Disability Associated with Chronic Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation: Analysis of a Cross-Sectional US Patient Survey
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Betty K. Hamilton, Paul Williams, John Galvin, James Turnbull, and Jingbo Yu
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Allogeneic hematopoietic stem cell transplantation ,Chronic graft-versus-host disease ,Cross-sectional survey ,Disability ,Long-term survivors ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Introduction Chronic graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation (HSCT) is associated with poor health-related quality of life (HRQoL) and functional status. However, few studies have evaluated chronic GVHD–related disability and specific activity limitations from a patient perspective. The objective of this analysis was to assess physical, cognitive, and work disability, and describe factors predictive of disability in patients with chronic GVHD in the potentially employable general workforce. Methods The cross-sectional, online, Living With Chronic GVHD Patient Survey was administered in 2020 to adult US patients who reported an active chronic GVHD diagnosis (i.e., within the previous 5 years) following HSCT. Data included demographics, diagnosis, work status, chronic GVHD symptoms per the Lee Symptom Scale (LSS), and effects on daily living activities. Descriptive and correlational analyses informed composite disability definitions: (1) severe cognitive disability, (2) severe physical disability, and (3) work disability. Results Of 137 respondents with GVHD included in this analysis, 47.0% reported severe cognitive disability, and approximately two-thirds each reported severe physical disability (67.4%) and work disability (62.8%). Chronic GVHD severity/duration, symptoms (Lee Symptom Scale), and number of transplant specialists consulted were associated with all types of disability (univariable analyses). Severe cognitive disability was associated with the number of transplant specialists consulted, severe physical disability with female sex, and work disability with nonwhite race. Conclusions In this analysis, we found that the presence of specific symptoms and the number of transplant specialists consulted were associated with all types of severe disability; female sex was predictive of severe physical disability and nonwhite race of work disability. These findings add to the understanding of chronic GVHD-associated disability, suggest a need for improved social support for patients, and highlight potential indicators for those most in need.
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- 2024
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30. Suppression of P53 Pathway is an Important Factor Inducing Acute Graft-versus-Host Disease Through T Cell Activation Based on Bioinformatics Analysis
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Wang S, Qin W, Cheng T, Zeng C, Chen X, and Xu Y
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allogeneic hematopoietic stem cell transplantation ,agvhd ,p53 pathway ,t cells ,activation. ,Pathology ,RB1-214 ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Shiyu Wang,1– 4 Wei Qin,1– 4 Tingting Cheng,1– 4 Cong Zeng,1– 4 Xu Chen,1– 4 Yajing Xu1– 4 1Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2National Clinical Research Center for Geriatric Diseases (Xiangya Hospital), Changsha, Hunan, People’s Republic of China; 3Hunan Hematologic Neoplasms Clinical Medical Research Center, Changsha, Hunan, People’s Republic of China; 4National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Soochow, Jiangsu, People’s Republic of ChinaCorrespondence: Yajing Xu, Department of Hematology, Xiangya Hospital, Central South University, #87 Xiangya Road, Changsha, Hunan, People’s Republic of China, Email xyyajingxu@csu.edu.cnPurpose: Acute graft-versus-host disease (aGVHD) poses a significant impediment to achieving a more favourable therapeutic outcome in allogeneic hematopoietic stem cell transplantation (allo-HSCT). The tumour suppressor p53 plays a pivotal role in preventing aGVHD development. However, whether P53 pathway which contains p53 family members and other related genes participates in aGVHD development remains an unsolved question.Patients and Methods: Transcriptomic data was obtained from Gene Expression Omnibus (GEO) database. Gene set enrichment analysis was applied to determine the enrichment degree of signaling pathways. CIBERSORT and ssGSVA were used to evaluate immune cell compositions. Univariate and multivariate logistic regression analysis were performed to examine the independent diagnostic variables. qRT-PCR was utilized to validate the genes expression levels in our cohort.Results: A total number of 102 patients (42 aGVHD patients vs 60 non-aGVHD patients) were obtained after integrating two datasets in GEO database (GSE73809 and GSE4624). P53 pathway was remarkably suppressed in T cells from aGVHD patients and negatively associated with activated T cells as well as T cells activation related signaling pathways, including T-cell receptor (TCR), mTORC1, MYC and E2F target pathways. A risk model for aGVHD built by four genes (DDIT3, FBXW7, TPRKB and TOB1) in P53 pathway, exhibiting high differentiate and predictive value. DDIT3 and FBXW7 mRNA expression levels significantly decreased in peripheral blood mononuclear cells (PBMCs) from aGVHD patients compared with non-aGVHD group in our patient cohort, consisting with bioinformatics analysis.Conclusion: P53 pathway plays a potential role in impeding T cell activation through suppressing its related signaling pathways, thereby preventing aGVHD development. P53 pathway may emerge as a promising therapeutic target in aGVHD treatment.Keywords: allogeneic hematopoietic stem cell transplantation, aGVHD, P53 pathway, T cells, activation
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- 2024
31. Efficacy of rituximab for the treatment and prevention of autoimmunity in patients with Wiskott-Aldrich syndrome and X-linked thrombocytopenia
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Saori Katayama, Tomohiro Nakano, Tasuku Suzuki, Masahiro Irie, Hidetaka Niizuma, Atsuo Kikuchi, and Yoji Sasahara
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Allogeneic hematopoietic stem cell transplantation ,Autoimmunity ,Reduced-intensity conditioning ,Rituximab ,Wiskott-Aldrich syndrome ,X-linked thrombocytopenia ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Immunological dysfunction in multiple lineages of hematopoietic cells and mixed chimerism after allogeneic hematopoietic stem cell transplantation (HSCT) are associated with an increased risk of autoimmunity in patients with Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT). Here, we report the efficacy of rituximab against autoimmunity in five patients with WAS and XLT. One patient with systemic arthritis and vasculitis, and two patients with immune thrombocytopenia were successfully treated with rituximab before initiating reduced-intensity conditioning. Rituximab was also used in combination with conditioning to prevent autoimmunity by depleting the recipient B cells in the other two patients with XLT. None of the patients developed autoimmunity without delay in donor B cell reconstitution, even though two patients had stable mixed chimerism after HSCT. These results suggest that aberrant B cell-intrinsic mechanisms are a central cause of autoimmunity, and rituximab is an effective therapeutic option for autoimmunity in patients with WAS and XLT.
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- 2024
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32. Research progress in the treatment of severe aplastic anemia
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FU Chen, LI Ping
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severe aplastic anemia ,immunosuppressive therapy ,platelet receptor agonists ,androgen ,allogeneic hematopoietic stem cell transplantation ,Medicine - Abstract
Severe aplastic anemia(SAA)is a critically ill disease of the blood system that progresses rapidly, has a high mortality rate, and a very poor prognosis. The application of drugs like androgens and Eltrombopag has significantly increased the survival rate of those with aplastic anemia (AA), compared with horse antithymocyte globulin(H-ATG) and cyclosporine, which was once the standard treatment. Patients who do not respond well to immunotherapy or experience a recurrence of symptoms post-treatment have the option to undergo hematopoietic stem cell transplantation (HSCT). The advancement of pre-treatment techniques for HSCT and the utilization of diverse medications following the transplantation procedure have contributed to reduced incidence of graft versus-host disease (GVHD) and improved transplant success. Allogeneic hematopoietic stem cell transplantation has become a hot topic in clinical research. This study summarizes the transplant and non transplant treatments of SAA in recent years, and analyzes its efficacy and related advantages and disadvantages.
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- 2024
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33. Meta-analysis on the efficacy of allogeneic hematopoietic stem cell transplantation to treat malignant lymphoma
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Zhao Jin, Guo Xiaojing, Zheng Meijing, and Su Liping
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autologous hematopoietic stem cell transplantation ,allogeneic hematopoietic stem cell transplantation ,malignant lymphoma ,meta-analysis ,Biology (General) ,QH301-705.5 - Abstract
The goal of the study involved the comparison of clinical efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and autologous hematopoietic stem cell transplantation (auto-HSCT) in the treatment of malignant lymphoma (ML). The effectiveness of allo-HSCT versus auto-HSCT in the treatment of ML was compared by searching EMBASE, PubMed, Web of Science, and the Cochrane Library for relevant studies. The confidence intervals (CI) and odds ratio (OR) of the article’s outcomes were described by a forest plot. Finally, 972 patients in seven articles were included. Overall survival (OS) did not differ significantly between allo-HSCT and auto-HSCT groups (OR = 0.87, 95% CI: 0.66–1.14, P = 0.31). Furthermore, there was no significant difference in adverse reactions (AR) between the two groups (OR = 1.35, 95% CI: 0.81–2.24, P = 0.25). We observed a significant difference in progression-free survival (PFS) between the two groups (OR = 4.14, 95% CI: 2.93–5.35, P < 0.01). There was no evidence of publication bias in this meta-analysis. The incidence of OS and AR differ significantly between allo-HSCT and auto-HSCT, but the PFS was longer in ML patients who received allo-HSCT.
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- 2024
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34. Clinical manifestations, prognostic factors, and outcomes of adenovirus pneumonia after allogeneic hematopoietic stem cell transplantation
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Yuewen Wang, Xiaohui Zhang, Lanping Xu, Yu Wang, Chenhua Yan, Huan Chen, Yuhong Chen, Fangfang Wei, Wei Han, Fengrong Wang, Jingzhi Wang, Xiaojun Huang, and Xiaodong Mo
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Adenovirus pneumonia ,Posttransplantation ,Allogeneic hematopoietic stem cell transplantation ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background Severe pneumonia is one of the most important causes of mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Adenovirus (ADV) is a significant cause of severe viral pneumonia after allo-HSCT, and we aimed to identify the clinical manifestations, prognostic factors, and outcomes of ADV pneumonia after allo-HSCT. Methods Twenty-nine patients who underwent allo-HSCT at the Peking University Institute of Hematology and who experienced ADV pneumonia after allo-HSCT were enrolled in this study. The Kaplan–Meier method was used to estimate the probability of overall survival (OS). Potential prognostic factors for 100-day OS after ADV pneumonia were evaluated through univariate and multivariate Cox regression analyses. Results The incidence rate of ADV pneumonia after allo-HSCT was approximately 0.71%. The median time from allo-HSCT to the occurrence of ADV pneumonia was 99 days (range 17–609 days). The most common clinical manifestations were fever (86.2%), cough (34.5%) and dyspnea (31.0%). The 100-day probabilities of ADV-related mortality and OS were 40.4% (95% CI 21.1%-59.7%) and 40.5% (95% CI 25.2%-64.9%), respectively. Patients with low-level ADV DNAemia had lower ADV-related mortality and better OS than did those with high-level (≥ 106 copies/ml in plasma) ADV DNAemia. According to the multivariate analysis, high-level ADV DNAemia was the only risk factor for intensive care unit admission, invasive mechanical ventilation, ADV-related mortality, and OS after ADV pneumonia. Conclusions We first reported the prognostic factors and confirmed the poor outcomes of patients with ADV pneumonia after allo-HSCT. Patients with high-level ADV DNAemia should receive immediate and intensive therapy.
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- 2024
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35. Epidemiology, Microbiology, and Risk Factors of Bacterial Bloodstream Infections in Patients After Allogeneic Hematopoietic Stem Cell Transplantation
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Zhang R, Xiong Y, Zhang L, and Liu L
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allogeneic hematopoietic stem cell transplantation ,bloodstream infection ,pathogenic bacteria ,antibiotic resistance patterns ,risk factors ,Infectious and parasitic diseases ,RC109-216 - Abstract
Ruonan Zhang, Yiying Xiong, Linyi Zhang, Lin Liu Department of Hematology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Lin Liu, Email liulin@cqmu.edu.cnPurpose: To investigate the clinical characteristics, etiology, and risk factors of bacterial bloodstream infection (BSI) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. This study also aimed to provide a clinical basis for early identification of high-risk patients and optimization of empirical antimicrobial treatment.Patients and Methods: This is a retrospective study of clinical data during agranulocytosis from 331 patients with hematological malignancies who underwent allo-HSCT at our institute between January 2016 and December 2022. The incidence, distribution and drug resistance patterns, and the risk factors of BSI were analyzed.Results: Among the 331 HSCT patients, 250 had febrile neutropenia and 45 cases were found to have BSI. The incidence of BSI in patients with agranulocytosis fever was 18% (45/250). A total of 48 pathogens were isolated during BSI episodes, gram-negative bacteria (GNB) accounted for 70.8% (34/48), gram-positive bacteria (GPB) for 29.2% (14/48). Multivariate analysis revealed that ≥grade 2 acute graft-versus-host disease (aGVHD) and previous BSI within 6 months before HSCT were independently associated with an increased occurrence of BSI. Coagulase-negative staphylococci (CoNS) and Escherichia coli were the most commonly isolated GPB and GNB, respectively. A total of 32 GNB were tested for drug susceptibility, the detection rate of carbapenem-resistant Enterobacteriaceae (CRE) was 12.5% (4/32), and extended-spectrum β-lactamase (ESBL) accounted for 56.3% (18/32).Conclusion: BSIs are still a common and severe complication after allo-HSCT. In our center, BSIs in allo-HSCT patients are dominated by gram-negative bacteria and the resistance rate to carbapenem drugs is high. Risk factors for BSI during agranulocytosis were previous BSI within 6 months before HSCT and ≥grade 2 aGVHD.Keywords: allogeneic hematopoietic stem cell transplantation, bloodstream infection, pathogenic bacteria, antibiotic resistance patterns, risk factors
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- 2024
36. True Donor Cell Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation: Diagnostic and Therapeutic Considerations—Brief Report
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Michèle Hoffmann, Yara Banz, Jörg Halter, Jacqueline Schoumans, Joëlle Tchinda, Ulrike Bacher, and Thomas Pabst
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donor cell leukemia ,allogeneic hematopoietic stem cell transplantation ,mixed-phenotype acute leukemia ,chimerism ,leukemogenesis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Donor cell leukemia (DCL) is a rare complication after allogeneic hematopoietic stem cell transplantation (HSCT) accounting for 0.1% of relapses and presenting as secondary leukemia of donor origin. Distinct in phenotype and cytogenetics from the original leukemia, DCL’s clinical challenge lies in its late onset. Its origin is affected by donor cell anomalies, transplant environment, and additional mutations. A 43-year-old woman, treated for early stage triple-negative breast cancer, developed mixed-phenotype acute leukemia (MPAL), 12 years later. Following induction chemotherapy, myeloablative conditioning, and allo-HSCT from her fully HLA-matched brother, she exhibited multiple cutaneous relapses of the original leukemia, subsequently evolving into DCL of the bone marrow. Cytogenetic analysis revealed a complex male karyotype in 20 out of 21 metaphases, however, still showing the MPAL phenotype. DCL diagnosis was confirmed by 90.5% XY in FISH analysis and the male karyotype. Declining further intensive chemotherapy including a second allo-HSCT, she was subsequently treated with repeated radiotherapy, palliative systemic therapies, and finally venetoclax and navitoclax but died seven months post-DCL diagnosis. This case underlines DCL’s complexity, characterized by unique genetics, further complicating diagnosis. It highlights the need for advanced diagnostic techniques for DCL identification and underscores the urgency for early detection and better prevention and treatment strategies.
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- 2024
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37. 异基因造血干细胞移植治疗地中海贫血 54 例临床分析并文献复习.
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聂伟业 and 覃春捷
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Objective To explore the clinical efficacy and related complications of allogeneic hematopoietic stem cell transplantation in the treatment of thalassemia. Methods A retrospective analysis of the efficacy and related complications of 54 patients with thalassemia who underwent allogeneic hematopoietic stem cell transplantation in the Department of Hematology of the hospital from November 2018 to September 2021. Results The implantation rate was 100.0%, the thalassemia-free survival rate was 98.1%, and there were 8 cases of acute graft-versus-host disease (aGVHD), the incidence rate was 14.8%. Further analysis of the related risk factors for aGVHD showed that there were statistical differences among different donor sources (P< 0.05). Among other related complications of transplantation, there was a statistical difference between age and CMV(P<0.05), and there was a statistical difference between donor source and hemorrhagic cystitis(HC) (P <0.05). Conclusion Allogeneic hematopoietic stem cell transplantation can effectively treat thalassemia, and donor source and age may be risk factors for complications after transplantation. [ABSTRACT FROM AUTHOR]
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- 2024
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38. Role of Uric Acid Levels as a Prognostic Indicator in Allogeneic Hematopoietic Stem Cell Transplantation: Insights from a Single-Center Study.
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Şanlı, Neslihan Mandacı, Keklik, Muzaffer, and Ünal, Ali
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HEMATOPOIETIC stem cell transplantation , *URIC acid , *OVERALL survival , *PROGRESSION-free survival , *BLOOD diseases - Abstract
Uric acid (UA) acts as a richly available water-soluble antioxidant, contributing to approximately two-thirds of the overall free-radical-scavenging activity in human serum. It is discharged from damaged cells during the preparation for allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study assessed how pretransplantation uric acid levels influence survival and mortality in allo-HSCT patients. In a retrospective analysis of 267 patients with hematologic diseases who underwent allo-HSCT, uric acid levels were documented on the day of allo-HSCT (day 0). Patients were divided into two cohorts based on their pretransplant uric acid levels: those at or below 4.4 mg/dL and those above 4.4 mg/dL. Among them, 153 (57.3%) were male, and 114 (42.7%) were female, with a median age of 31 years (ranging from 13 to 66). Those with serum uric acid levels of 4.4 mg/dL or lower exhibited notably poorer overall survival (OS) and disease-free survival (DFS) compared to those surpassing 4.4 mg/dL (p=0.032 and p=0.045, respectively). Our findings indicate an interrelation between low pretransplant serum uric acid levels and reduced survival rates in allo-HSCT patients. Further exploration into potential mechanisms, such as compromised antioxidative capacity in hypouricemia, may establish uric acid as a promising prognostic marker in allo-HSCT. [ABSTRACT FROM AUTHOR]
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- 2024
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39. Systemic inflammatory autoimmune disease before allogeneic hematopoietic stem cell transplantation is a risk factor for death in patients with myelodysplastic syndrome or chronic myelomonocytic leukemia.
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Tazoe, Kumiyo, Harada, Naonori, Makuuchi, Yosuke, Kuno, Masatomo, Takakuwa, Teruhito, Okamura, Hiroshi, Hirose, Asao, Nakamae, Mika, Nishimoto, Mitsutaka, Nakashima, Yasuhiro, Koh, Hideo, Hino, Masayuki, and Nakamae, Hirohisa
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CHRONIC leukemia , *HEMATOPOIETIC stem cell transplantation , *MYELODYSPLASTIC syndromes , *GRAFT versus host disease , *DISEASE risk factors , *AUTOIMMUNE diseases - Abstract
Myelodysplastic syndrome (MDS) is well known to be complicated by systemic inflammatory autoimmune disease (SIADs). However, it remains unclear how the prognosis after allogenic hematopoietic stem cell transplantation (allo-HSCT) in patients with MDS is impacted by SIADs that occur before allo-HSCT. Therefore, we hypothesized that SIADs before allo-HSCT may be a risk factor for negative outcomes after allo-HSCT in patients with MDS. We conducted a single-center, retrospective, observational study of sixty-nine patients with MDS or chronic myelomonocytic leukemia who underwent their first allo-HCT. Fourteen of the patients had SIADs before allo-HSCT. In multivariate analysis, the presence of SIADs before allo-HSCT was an independent risk factor for overall survival (HR, 3.36, 95% confidence interval: 1.34–8.42, p = 0.009). Endothelial dysfunction syndrome was identified in five of 14 patients with SIADs who required immunosuppressive therapy or intensive chemotherapy, and notably, all patients with uncontrollable SIADs at allo-HSCT developed serious endothelial dysfunction syndrome and died in the early phase after allo-HSCT. The development of SIADs in the context of MDS is thought to reflect the degree of dysfunction of hematopoietic cells in MDS and suggests a higher risk of disease progression. In addition, MDS patients with SIADs before allo-HSCT are considered to be at higher risk of endothelial dysfunction syndrome because of preexisting vascular endothelial dysfunction due to SIADs. In conclusion, SIADs before allo-HSCT constitute an independent risk factor for death in MDS patients undergoing allo-HSCT. [ABSTRACT FROM AUTHOR]
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- 2024
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40. Thiotepa-busulfan-fludarabine-based conditioning as a promising approach prior to allogeneic hematopoietic stem cell transplantation in patients with blastic plasmacytoid dendritic cell neoplasm.
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Huang, Xianbo, Wang, Shasha, Xu, Yu, Mei, Chen, Han, Qingmei, Wu, Xianhui, Du, Fengwei, Ren, Yanling, Jin, Jie, Tong, Hongyan, and Qian, Jiejing
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HEMATOPOIETIC stem cell transplantation , *DENDRITIC cells , *TUMORS - Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive myeloid malignancy associated with a poor prognosis. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) has emerged as a potential treatment strategy for BPDCN, standardized conditioning regimens remain lacking. In this manuscript, we present two cases of BPDCN that were treated with a thiotepa-busulfan-fludarabine (TBF)-based conditioning regimen prior to allo-HSCT. Both cases demonstrated complete remission post-transplantation, sustained donor chimerism, and remission maintenance, suggesting the potential efficacy of the TBF conditioning regimen for BPDCN transplantation. Given the small sample size in our study, we emphasize caution and advocate for larger studies to confirm the efficacy of TBF in the treatment of BPDCN. [ABSTRACT FROM AUTHOR]
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- 2024
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41. Case report: Donor-derived CLL-1 chimeric antigen receptor T-cell therapy for relapsed/ refractory acute myeloid leukemia bridging to allogeneic hematopoietic stem cell transplantation after remission.
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Xiaojuan Miao, Yanrong Shuai, Ying Han, Nan Zhang, Yilan Liu, Hao Yao, Xiao Wang, Guangcui He, Dan Chen, Fangyi Fan, Chang, Alex H., Yi Su, and Hai Yi
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HEMATOPOIETIC stem cell transplantation ,ACUTE myeloid leukemia ,CHIMERIC antigen receptors ,EXTRAMEDULLARY diseases ,CYTOKINE release syndrome - Abstract
Background: Explore the efficacy and safety of donor-derived CLL-1 chimeric antigen receptor T-cell therapy (CAR-T) for relapsed/refractory acute myeloid leukemia (R/R AML) bridging to allogeneic hematopoietic stem cell transplantation (allo-HSCT) after remission. Case presentation: An adult R/R AML patient received an infusion of donorderived CLL-1 CAR-T cells, and the conditioning regimen bridging to allo-HSCT was started immediately after remission on day 11 after CAR-T therapy upon transplantation. Then, routine post-HSCT monitoring of blood counts, bone marrow (BM) morphology, flow cytometry, graft-versus-host disease (GVHD) manifestations, and chimerism status were performed. Result: After CAR-T therapy, cytokine release syndrome was grade 1. On day 11 after CAR-T therapy, the BM morphology reached complete remission (CR), and the conditioning regimen bridging to allo-HSCT started. Leukocyte engraftment, complete donor chimerism, and platelet engraftment were observed on days +18, +23, and +26 post-allo-HSCT, respectively. The BM morphology showed CR and flow cytometry turned negative on day +23. The patient is currently at 4 months post-allo-HSCT with BM morphology CR, negative flow cytometry, complete donor chimerism, and no extramedullary relapse/GVHD. Conclusion: Donor-derived CLL-1 CAR-T is an effective and safe therapy for R/R AML, and immediate bridging to allo-HSCT after remission may better improve the long-term prognosis of R/R AML. [ABSTRACT FROM AUTHOR]
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- 2024
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42. Case report: Donor-derived CLL-1 chimeric antigen receptor T-cell therapy for relapsed/refractory acute myeloid leukemia bridging to allogeneic hematopoietic stem cell transplantation after remission.
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Xiaojuan Miao, Yanrong Shuai, Ying Han, Nan Zhang, Yilan Liu, Hao Yao, Xiao Wang, Guangcui He, Dan Chen, Fangyi Fan, Chang, Alex H., Yi Su, and Hai Yi
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HEMATOPOIETIC stem cell transplantation ,ACUTE myeloid leukemia ,CHIMERIC antigen receptors ,EXTRAMEDULLARY diseases ,CYTOKINE release syndrome - Abstract
Background: Explore the efficacy and safety of donor-derived CLL-1 chimeric antigen receptor T-cell therapy (CAR-T) for relapsed/refractory acute myeloid leukemia (R/R AML) bridging to allogeneic hematopoietic stem cell transplantation (allo-HSCT) after remission. Case presentation: An adult R/R AML patient received an infusion of donor-derived CLL-1 CAR-T cells, and the conditioning regimen bridging to allo-HSCT was started immediately after remission on day 11 after CAR-T therapy upon transplantation. Then, routine post-HSCT monitoring of blood counts, bone marrow (BM) morphology, flow cytometry, graft-versus-host disease (GVHD) manifestations, and chimerism status were performed. Result: After CAR-T therapy, cytokine release syndrome was grade 1. On day 11 after CAR-T therapy, the BM morphology reached complete remission (CR), and the conditioning regimen bridging to allo-HSCT started. Leukocyte engraftment, complete donor chimerism, and platelet engraftment were observed on days +18, +23, and +26 post-allo-HSCT, respectively. The BM morphology showed CR and flow cytometry turned negative on day +23. The patient is currently at 4 months post-allo-HSCT with BM morphology CR, negative flow cytometry, complete donor chimerism, and no extramedullary relapse/GVHD. Conclusion: Donor-derived CLL-1 CAR-T is an effective and safe therapy for R/R AML, and immediate bridging to allo-HSCT after remission may better improve the long-term prognosis of R/R AML. [ABSTRACT FROM AUTHOR]
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- 2024
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43. Clinical manifestations, prognostic factors, and outcomes of adenovirus pneumonia after allogeneic hematopoietic stem cell transplantation.
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Wang, Yuewen, Zhang, Xiaohui, Xu, Lanping, Wang, Yu, Yan, Chenhua, Chen, Huan, Chen, Yuhong, Wei, Fangfang, Han, Wei, Wang, Fengrong, Wang, Jingzhi, Huang, Xiaojun, and Mo, Xiaodong
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HEMATOPOIETIC stem cell transplantation , *PROGNOSIS , *SYMPTOMS , *PNEUMONIA , *ADENOVIRUSES - Abstract
Background: Severe pneumonia is one of the most important causes of mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Adenovirus (ADV) is a significant cause of severe viral pneumonia after allo-HSCT, and we aimed to identify the clinical manifestations, prognostic factors, and outcomes of ADV pneumonia after allo-HSCT. Methods: Twenty-nine patients who underwent allo-HSCT at the Peking University Institute of Hematology and who experienced ADV pneumonia after allo-HSCT were enrolled in this study. The Kaplan–Meier method was used to estimate the probability of overall survival (OS). Potential prognostic factors for 100-day OS after ADV pneumonia were evaluated through univariate and multivariate Cox regression analyses. Results: The incidence rate of ADV pneumonia after allo-HSCT was approximately 0.71%. The median time from allo-HSCT to the occurrence of ADV pneumonia was 99 days (range 17–609 days). The most common clinical manifestations were fever (86.2%), cough (34.5%) and dyspnea (31.0%). The 100-day probabilities of ADV-related mortality and OS were 40.4% (95% CI 21.1%-59.7%) and 40.5% (95% CI 25.2%-64.9%), respectively. Patients with low-level ADV DNAemia had lower ADV-related mortality and better OS than did those with high-level (≥ 106 copies/ml in plasma) ADV DNAemia. According to the multivariate analysis, high-level ADV DNAemia was the only risk factor for intensive care unit admission, invasive mechanical ventilation, ADV-related mortality, and OS after ADV pneumonia. Conclusions: We first reported the prognostic factors and confirmed the poor outcomes of patients with ADV pneumonia after allo-HSCT. Patients with high-level ADV DNAemia should receive immediate and intensive therapy. [ABSTRACT FROM AUTHOR]
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- 2024
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44. Comparing the Outcomes of Matched and Mismatched Unrelated Allogeneic Hematopoietic Stem Cell Transplantation with Different Anti-Thymocyte Globulin Formulations: A Retrospective, Double-Centre Experience on Behalf of the Polish Adult Leukemia Group.
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Giordano, Ugo, Mordak-Domagała, Monika, Sobczyk-Kruszelnicka, Małgorzata, Giebel, Sebastian, Gil, Lidia, Dudek, Krzysztof D., and Dybko, Jarosław
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HEMATOPOIETIC stem cell transplantation , *GRAFT versus host disease , *HEMATOLOGIC malignancies , *IMMUNOSUPPRESSIVE agents , *CYTOMEGALOVIRUSES , *HOMOGRAFTS , *GLOBULINS , *TREATMENT effectiveness , *RETROSPECTIVE studies , *MULTIVARIATE analysis , *DESCRIPTIVE statistics , *CONFIDENCE intervals , *PROGRESSION-free survival , *OVERALL survival , *EVALUATION - Abstract
Simple Summary: Allogeneic hematopoietic stem cell transplantation (allo-HCT) remains an effective treatment modality in many hematological malignancies. Few studies directly compare rabbit anti-thymocyte globulin (r-ATG) formulations Thymoglobuline (ATG-T) and Grafalon (ATG-G). Our retrospective analysis compared the outcomes in 87 adult allo-HCT patients receiving ATG-T or ATG-G. No significant differences were found in acute graft-versus-host disease (aGvHD) incidence. However, chronic GvHD (cGvHD) was less common with ATG-T (7.5% vs. 38.3%, p = 0.001). ATG-T patients had higher cytomegalovirus (CMV) reactivation rates (70% vs. 31.9%, p < 0.001) and a shorter time to CMV (<61 days, 77.8% vs. 33.3%, p = 0.008), but were mostly asymptomatic (85.7% vs. 43.8%, p = 0.005). Overall survival (OS) and relapse-free survival (RFS) at 5 and 3 years, respectively, showed no significant differences between ATG-T and ATG-G (32.0% vs. 40.3%, p = 0.423; 66.7% vs. 60.4%, p = 0.544). Despite notable advancements in immunotherapy in the past decades, allogeneic hematopoietic stem cell transplantation (allo-HCT) remains a promising, potentially curative treatment modality. Only a limited number of studies have performed a direct comparison of two prevalent rabbit anti-thymocyte globulin (r-ATG) formulations—specifically, Thymoglobuline (ATG-T, formerly Genzyme) and Grafalon (ATG-G, formerly Fresenius). The primary objective of our retrospective analysis was to compare the outcomes of adult patients undergoing matched or mismatched unrelated donor (MUD/MMUD) allo-HCT, with a graft-versus-host disease (GvHD) prophylaxis based on either ATG-T or ATG-G. A total of 87 patients who had undergone allo-HCT between 2012 and 2022 were included. We observed no significant differences between ATG-T and ATG-G concerning the occurrence of acute graft-versus-host disease (aGvHD), regardless of its severity. Conversely, chronic graft-versus-host disease (cGvHD) occurred less frequently in the ATG-T group compared to the ATG-G group (7.5% vs. 38.3%, p = 0.001). The negative impact of ATG-G on cGvHD was confirmed by multivariate analysis (HR 8.12, 95% CI 2.06–32.0, p = 0.003). Patients treated with ATG-T manifested a higher incidence of cytomegalovirus (CMV) reactivations (70% vs. 31.9%, p < 0.001), with a shorter time between transplant and CMV (<61 days, 77.8% vs. 33.3%, p = 0.008) and a higher median CMV copy number (1000 vs. 0, p = 0.004). Notably, despite a higher occurrence of CMV reactivations in the ATG-T cohort, most patients were asymptomatic compared to ATG-G (85.7% vs. 43.8%, p = 0.005). By multivariate analysis, only aGvHD had an influence on CMV reactivations (HR 0.18, 95% CI 0.04–0.75, p = 0.019). Finally, we observed no significant differences in terms of 5-year overall survival (OS) and 3-year relapse-free survival (RFS) while comparing ATG-T and ATG-G (32.0% vs. 40.3%, p = 0.423; 66.7% vs. 60.4%, p = 0.544, respectively). [ABSTRACT FROM AUTHOR]
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- 2024
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45. Effect of sustained measurable residue disease negativity and post‐remission treatment selection on the prognosis of acute lymphoblastic leukemia in adults.
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Yu, Jiechen, Luo, Yanrong, Wang, Libing, Wang, Tao, Ye, Mingyu, Chen, Jie, Ni, Xiong, Chen, Li, Gao, Lei, and Yang, Jianmin
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LYMPHOBLASTIC leukemia , *ACUTE leukemia , *HEMATOPOIETIC stem cell transplantation , *PROGNOSIS , *ADULTS - Abstract
Background: To explore the effects of monitoring measurable residual disease and post‐remission treatment selection on the clinical outcomes of B‐cell acute lymphoblastic leukemia (B‐ALL) in adults. Methods: Between September 2010 and January 2022, adult patients with B‐ALL who received combination chemotherapy, with or without allogeneic hematopoietic stem cell transplantation (allo‐HSCT), were included in the retrospective study, which was approved by the Ethics Committee and the observation of Declaration of Helsinki conditions. Results: One hundred and forty‐three B‐ALL patients achieved complete remission (CR) were included in the study, of whom 94 patients (65.7%) received allo‐HSCT in first complete remission (CR1). Multivariate analysis showed that the most powerful factors affecting OS were transplantation (hazard ratio [HR] = 0.540, p = 0.037) and sustained measurable residue disease (MRD) negativity (HR = 0.508, p = 0.037). The subgroup analysis showed that the prognosis of the allo‐HSCT group was better than that of the chemotherapy group, regardless of whether MRD was negative or positive after two courses of consolidation therapy. After consolidation therapy, the prognosis of patients with positive MRD remained significantly better in the allo‐HSCT group than in the chemotherapy group. However, no significant difference was observed in the prognosis between the allo‐HSCT and chemotherapy groups with negative MRD after consolidation therapy. Conclusions: B‐ALL patients who achieve sustained MRD negativity during consolidation therapy have excellent long‐term outcomes even without allo‐HSCT. Allo‐HSCT is associated with a significant benefit in terms of OS and DFS for patients who were with positive MRD during consolidation therapy. [ABSTRACT FROM AUTHOR]
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- 2024
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46. 异基因造血干细胞移植后短期内死亡的危险因素分析.
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高思雨, 姚莉红, 边志磊, 张素平, 李 丽, 范金鹏, 秦 菁, 彭英楠, and 万鼎铭
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HEMATOPOIETIC stem cell transplantation , *STEM cell transplantation , *BLOOD diseases , *GRAFT versus host disease , *HEMATOPOIETIC stem cells - Abstract
BACKGROUND: Allogeneic hematopoietic stem cell transplantation is an effective and even the only way to cure various hematological diseases, but the shortterm mortality rate is relatively high after transplantation. OBJECTIVE: To investigate the risk factors affecting the overall survival of patients with hematological diseases in the short term (within 100 days) after allogeneic hematopoietic stem cell transplantation, so as to reduce mortality and effectively prevent related risks in the short term (within 100 days) after allogeneic hematopoietic stem cell transplantation. METHODS: Clinical data of 585 patients with hematological diseases who underwent allogeneic hematopoietic stem cell transplantation at the Hematopoietic Stem Cell Transplantation Center of First Affiliated Hospital of Zhengzhou University from January 1, 2018 to June 30, 2021 were retrospectively analyzed. The risk factors that affected overall survival within 100 days after allogeneic hematopoietic stem cell transplantation were explored. RESULTS AND CONCLUSION: A total of 585 patients with hematologic diseases underwent allogeneic hematopoietic stem cell transplantation. 92 patients died within 100 days after transplantation, with a mortality rate of 15.7% (92/585). The median age of death cases was 26.5 years old (1-56 years), and the median survival time of death cases was 48 days (0-97 days). Univariate analysis exhibited that age ≥14 years old, acute graft-versus-host disease, grade IV acute graftversus-host disease, bacterial bloodstream infection, as well as carbapenem-resistant organism bloodstream infection, were risk factors for overall survival within 100 days after allogeneic hematopoietic stem cell transplantation (P < 0.05). Multivariate regression analysis showed that age ≥14 years old, grades III-IV acute graft-versus-host disease, bacterial bloodstream infection, and carbapenem-resistant organism bloodstream infections were independent risk factors for overall survival (within 100 days) in patients after allogeneic hematopoietic stem cell transplantation. Hazard ratios were 1.77(95%CI 1.047-2.991), 7.926(95%CI 3.763-16.695), 2.039(95%CI 1.117-3.722), and 3.389(95%CI 1.563-7.347), respectively. In conclusion, all-cause mortality rate after allogeneic hematopoietic stem cell transplantation is relatively high in the short term. A timely diagnosis and effective treatment of bacterial bloodstream infection and acute graftversus-host disease are essential to improving allogeneic hematopoietic stem cell transplantation outcomes. [ABSTRACT FROM AUTHOR]
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- 2024
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47. Population pharmacokinetics of cyclosporine A in pediatric patients with thalassemia undergoing allogeneic hematopoietic stem cell transplantation.
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Cai, Rongda, Zhang, Limin, Wu, Tingqing, Huang, Yumei, Lu, Jiejiu, Huang, Tianmin, Wu, Yun, Wu, Dongni, Qi, Jianying, Niu, Lulu, Xiao, Yang, Chen, Xin, Liu, Yongjun, Luo, Yilin, and Liu, Taotao
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HEMATOPOIETIC stem cell transplantation , *FLUCONAZOLE , *GOODNESS-of-fit tests , *STATISTICAL correlation , *PREDICTION models , *ERYTHROCYTES , *CYCLOSPORINE , *SCIENTIFIC observation , *BODY weight , *RETROSPECTIVE studies , *LONGITUDINAL method , *THALASSEMIA , *MEDICAL records , *ACQUISITION of data , *BONE marrow transplantation , *INDIVIDUALIZED medicine , *VORICONAZOLE , *ABSORPTION , *CHILDREN - Abstract
Purpose: To establish the population pharmacokinetics (PPK) model of cyclosporine A(CsA) in pediatric patients with thalassemia undergoing allogeneic hematopoietic stem cell transplantation (HSCT), aiming at providing a reference for clinical dose individualization of CsA. Methods: Children with thalassemia who underwent allogeneic HSCT were enrolled retrospectively. The PPK structural model and the random variable model of CsA were established on NONMEN. And goodness of fit plots (GOFs), visual predictive check (VPC), and bootstrap and normalized prediction distribution errors (NPDE) were used to evaluate the final model. Results: A one-compartment model with first-order absorption was employed to fit the base model. A total of 74 pediatric patients and 600 observations of whole blood concentration were included. The final model included weight (WT) in clearance (CL), alongside post-operative day (POD), fluconazole (FLUC), voriconazole (VORI), posaconazole (POSA), and red blood cell count (RBC) significantly. All the model evaluations were passed. Conclusion: In the PPK model based on the pediatric cohort on CsA with thalassemia undergoing allogeneic HSCT, WT, POD, FLUC, VORI, POSA, and RBC were found to be the significant factors influencing CL of CsA. The reliability and robustness of the final model were excellent. It is expected that the PPK model can assist in individualizing dosing strategy clinically. [ABSTRACT FROM AUTHOR]
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- 2024
- Full Text
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48. 重型再生障碍性贫血治疗的研究进展.
- Author
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傅晨 and 李平
- Abstract
Severe aplastic anemia (SAA) is a critically ill disease of the blood system that progresses rapidly, has a high mortality rate, and a very poor prognosis. The application of drugs like androgens and Eltrombopag has significantly increased the survival rate of those with aplastic anemia (AA), compared with horse antithymocyte globulin (H-ATG) and cyclosporine, which was once the standard treatment. Patients who do not respond well to immunotherapy or experience a recurrence of symptoms post-treatment have the option to undergo hematopoietic stem cell transplantation (HSCT). The advancement of pre-treatment techniques for HSCT and the utilization of diverse medications following the transplantation procedure have contributed to reduced incidence of graft versus-host disease (GVHD) and improved transplant success. Allogeneic hematopoietic stem cell transplantation has become a hot topic in clinical research. This study summarizes the transplant and non transplant treatments of SAA in recent years, and analyzes its efficacy and related advantages and disadvantages. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
49. Effects of CYP3A5 Genotype on Tacrolimus Pharmacokinetics and Graft-versus-Host Disease Incidence in Allogeneic Hematopoietic Stem Cell Transplantation.
- Author
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Marco, Daniel N., Molina, Mònica, Guio, Ana-María, Julian, Judit, Fortuna, Virginia, Fabregat-Zaragoza, Virginia-Lucila, Salas, María-Queralt, Monge-Escartín, Inés, Riu-Viladoms, Gisela, Carcelero, Esther, Roma, Joan Ramón, Llobet, Noemí, Arcarons, Jordi, Suárez-Lledó, María, Rosiñol, Laura, Fernández-Avilés, Francesc, Rovira, Montserrat, Brunet, Mercè, and Martínez, Carmen
- Subjects
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HEMATOPOIETIC stem cell transplantation , *GRAFT versus host disease , *CYTOCHROME P-450 CYP3A , *DISEASE incidence , *PHARMACOGENOMICS , *TACROLIMUS - Abstract
Tacrolimus (Tac) is pivotal in preventing acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT). It has been reported that genetic factors, including CYP3A5*3 and CYP3A4*22 polymorphisms, have an impact on Tac metabolism, dose requirement, and response to Tac. There is limited information regarding this topic in alloHSCT. The CYP3A5 genotype and a low Tac trough concentration/dose ratio (Tac C0/D ratio) can be used to identify fast metabolizers and predict the required Tac dose to achieve target concentrations earlier. We examined 62 Caucasian alloHSCT recipients with a fast metabolizer phenotype (C0/dose ratio ≤ 1.5 ng/mL/mg), assessing CYP3A5 genotypes and acute GVHD incidence. Forty-nine patients (79%) were poor metabolizers (2 copies of the variant *3 allele) and 13 (21%) were CYP3A5 expressers (CYP3A5*1/*1 or CYP3A5*1/*3 genotypes). CYP3A5 expressers had lower C0 at 48 h (3.7 vs. 6.2 ng/mL, p = 0.03) and at 7 days (8.6 vs. 11.4 ng/mL, p = 0.04) after Tac initiation, tended to take longer to reach Tac therapeutic range (11.8 vs. 8.9 days, p = 0.16), and had higher incidence of both global (92.3% vs. 38.8%, p < 0.001) and grade II-IV acute GVHD (61.5% vs. 24.5%, p = 0.008). These results support the adoption of preemptive pharmacogenetic testing to better predict individual Tac initial dose, helping to achieve the therapeutic range and reducing the risk of acute GVHD earlier. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
50. Hematopoietic cell transplantation (HCT) in MDS patients of older age.
- Author
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Niederwieser, Christian and Kröger, Nicolaus
- Subjects
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HEMATOPOIETIC stem cell transplantation , *OLDER patients , *MYELODYSPLASTIC syndromes , *GRAFT versus host disease , *AGE groups - Abstract
Hematopoietic cell transplantation (HCT) has evolved to an essential treatment in younger and more recently in elderly patients with myelodysplastic syndrome (MDS), the age group with the highest incidence. Less intense conditioning regimens and improvements in supportive therapy have reduced considerably transplant related mortality and in the same time increased the access to this curative treatment. Timing of HCT in the course of the disease assumes a crucial role. Detection of disease progression, geriatric assessment, comorbidity evaluation, and identification of transplant-specific risks are becoming increasingly important in this context. Novel statistical methods, molecular biomarkers, and quantification of tumor burden pre- and post-HCT will play an essential role in years to come. More effective and less toxic treatments to reduce the tumor burden before and/or after HCT are expected to improve the outcome. In this review article we discuss the current views and what we can expect. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
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