Unravelling the potential of TIM-3 gene polymorphism in allogeneic hematopoietic stem cell transplantation - a preliminary study.

BACKGROUND: T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) molecule is a key regulator of the immune response by exerting an inhibitory effect on various types of immune cells. Understanding the role of TIM-3 in hematopoietic stem cell transplantation (HSCT) may improve transplant outcomes. Our study evaluated the potential association between TIM-3 polymorphisms, namely rs1036199 (A > C) or rs10515746 (C > A), changes which are located in exon 3 and the promoter region of the TIM-3 gene, and post-HSCT outcomes. METHODS: One-hundred and twenty allogeneic HSCT patients and their respective donors were enrolled and genotyped for TIM-3 single nucleotide polymorphisms (SNPs) using real-time PCR with TaqMan assays. RESULTS: We found that the presence of the rare alleles and heterozygous genotypes of studied SNP in recipients tended to protect against or increase the risk for acute graft-versus-host disease (aGvHD). For the rs1036199 polymorphism, recipients with the AC heterozygous genotype (p = 0.0287) or carrying the rarer C allele (p = 0.0334) showed a lower frequency of aGvHD development along all I-IV grades. A similar association was detected for the rs10515746 polymorphism as recipients with the CA genotype (p = 0.0095) or the recessive A allele (p = 0.0117) less frequently developed aGvHD. Furthermore, the rarer A allele of rs10515746 SNP was also associated with a prolonged aGvHD-free survival (p = 0.0424). Cytomegalovirus (CMV) infection was more common in patients transplanted with TIM-3 rs10515746 mismatched donors (p = 0.0229) and this association was also found to be independent of HLA incompatibility and pre-transplant CMV-IgG status. Multivariate analyses confirmed the role of these recessive alleles and TIM-3 incompatibility as an independent factor in aGvHD and CMV development. CONCLUSIONS: Polymorphism of TIM-3 molecule may affect the immune response in HSCT patients. The recessive alleles of rs1036199 and rs10515746 SNPs decreased the risk of developing aGvHD. TIM-3 donor-recipient genetic matching may also affect the risk of post-transplant CMV infection, indicating the potential value of genetic profiling in optimizing transplant strategies.

Retrospective analysis of the effects of impacted third molar on hematologic patients undergoing hematopoietic stem cell transplantation.

Objective: This study aimed to investigate the incidence, treatment status, and impact position of impacted third molars (ITM) and their effects on patients undergoing hematopoietic stem cell transplantation (HSCT). Methods: A retrospective analysis was conducted on the medical records of 454 patients who underwent HSCT, out of which 188 patients had ITM. The presence of ITM and its association with transplant-related infections and complications were recorded and analyzed. Results: Patients with ITM were significantly younger. The number of mandibular ITM was notably higher than maxillary ones, and the risk of pericoronitis in mandibular ITM was significantly higher than in maxillary ones. Out of 311 ITM in 188 patients, 25 were extracted before transplantation. The proportion of extraction and treatment for ITM with pericoronitis or caries was significantly higher than that for ITM without such problems. Moreover, patients with a history of pre-transplant pericoronitis had a significantly higher probability of developing tooth-related complications during transplantation, caused by pericoronitis in ITM compared to patients without a history of pericoronitis. Conclusion: Pre-transplant examination and treatment of ITM are essential, especially in cases with a history of pericoronitis. Oral intervention can significantly reduce the occurrence of tooth-related complications related to ITM during transplantation.

Reactivation of cytomegalovirus and bloodstream infection and its impact on early survival after allogeneic haematopoietic stem cell transplantation: a multicentre retrospective study.

Cytomegalovirus reactivation (CMVr) and bloodstream infections (BSI) are the most common infectious complications in patients after allogeneic haematopoietic stem cell transplantation (allo-HSCT). Both are associated with great high morbidity whilst the BSI is the leading cause of mortality. This retrospective study evaluated the incidence of CMVr and BSI, identified associated risk factors, assessed their impact on survival in allo-HSCT recipients during the first 100 days after transplantation. The study comprised 500 allo-HSCT recipients who were CMV DNA-negative and CMV IgG-positive before allo-HSCT. Amongst them, 400 developed CMVr and 75 experienced BSI within 100 days after allo-HSCT. Multivariate regression revealed that graft failure and acute graft-versus-host disease were significant risk factors for poor prognosis, whereas CMVr or BSI alone were not. Amongst all 500 patients, 56 (14%) developed both CMVr and BSI in the 100 days after HSCT, showing significantly reduced 6-month overall survival (p = 0.003) and long-term survival (p = 0.002). Specifically, in the initial post-transplant phase (within 60 days), BSI significantly elevate mortality risk, However, patients who survive BSI during this critical period subsequently experience a lower mortality risk. Nevertheless, the presence of CMVr in patients with BSI considerably diminishes their long-term survival prospects. This study provides real-world data on the impact of CMVr and BSI following transplantation on survival, particularly in regions such as China, where the prevalence of CMV IgG-positivity is high. The findings underscore the necessity for devising and executing focused prevention and early management strategies for CMVr and BSI to enhance outcomes for allo-HSCT recipients.

Disseminated Cryptococcosis With Prostate Involvement in a Patient With T-cell Prolymphocytic Leukemia and Prostate Cancer.

T-cell prolymphocytic leukemia (T-PLL) presents unique treatment challenges because of its rarity and aggressiveness. Allogeneic hematopoietic stem cell transplantation offers a potentially curative option, but its safety in patients with concurrent invasive fungal infections and solid malignancies remains uncertain. We present a case of a 68-year-old male with T-PLL who developed disseminated cryptococcal disease with prostate involvement and concurrent prostate cancer (PCa). Despite the challenges, successful control of the infection and radical prostatectomy enabled the patient to proceed safely to allogeneic transplantation. The case highlights the importance of vigilance for unusual infections, such as Cryptococcus, in immunocompromised patients presenting with lower urinary tract symptoms. Clinicians should consider the possibility of PCa in this population, particularly in the context of chronic leukemia. Concurrently, the potential association between fungal prostate infections and PCa warrants further investigation.

[The prognostic value of colonoscopy grading for acute graft-versus-host disease in patients with malignant hematological disorders after unrelated cord blood transplantation].

Objective: To investigate the prognostic value of enteroscopic grading for the prognostic assessment of patients with malignant hematological diseases who developed intestinal acute graft-versus-host disease (IT-aGVHD) after unrelated cord blood transplantation (UCBT) . Methods: Fifty patients with IT-aGVHD who developed hormone resistance after UCBT from June 2016 to June 2023 at Anhui Provincial Hospital were collected to compare the effective and survival rates of IT-aGVHD treatment in the group with milder enteroscopic mucosal injury (27 cases, enteroscopic grading of Ⅰ and Ⅱ) and the group with more severe injury (23 cases, enteroscopic grading of Ⅲ and Ⅳ) and to retrospectively analyze the factors affecting patients' prognosis. Results: Patients in the mild and severe groups had an effective rate of 92.6% and 47.8% at 28 days after colonoscopy (P<0.001), 81.5% and 39.1% at 56 days after colonoscopy (P=0.002), with optimal effective rate of 92.6% and 65.2% (P=0.040), respectively, and the differences were statistically significant. The multifactorial analysis found that enteroscopic grading was an independent risk factor affecting the effective rate of IT-aGVHD treatment. The overall survival rate at 2 years after colonoscopy was 70.4% (95% CI 52.0% -88.8% ) and 34.8% (95% CI 14.8% -54.8% ) for patients in the mild and severe groups, respectively, and the difference was statistically significant (P=0.003). Multifactorial analysis revealed that enteroscopic grading, cytomegalovirus infection status, second-line treatment regimen, and patients' age were independent risk factors for survival. Conclusion: The treatment efficacy and prognosis of patients in the group with less severe enteroscopic injury (grades Ⅰ and Ⅱ) were better than those in the group with more severe injury (grades Ⅲ and Ⅳ) .

[Analysis of the efficacy and prognostic factors of allogeneic hematopoietic stem cell transplantation in patients with myelodysplastic syndrome with blastomycosis and survival comparison of different subtypes after the WHO 2022 reclassification].

Objective: To evaluate the efficacy and prognostic factors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with myelodysplastic syndrome accompanied by myelodysplasia (MDS-EB) and to compare the prognosis of different subtypes of patients classified by World Health Organization (WHO) 2022. Methods: A total of 282 patients with MDS-EB who underwent allo-HSCT at the Hematology Hospital of the Chinese Academy of Medical Sciences from October 2006 to December 2022 were included in the study. The WHO 2022 diagnostic criteria reclassified MDS into three groups: myelodysplastic tumors with type 1/2 of primitive cell proliferation (MDS-IB1/IB2, 222 cases), MDS with fibrosis (MDS-f, 41 cases), and MDS with biallelic TP53 mutation (MDS-biTP53, 19 cases). Their clinical data were retrospectively analyzed. Results: ① The median age of 282 patients was 46 (15-66) years, with 191 males and 91 females. Among them, 118 (42% ) and 164 (58% ) had MDS-EB1 and MDS-EB2, respectively. ②Among the 282 patients, 256 (90.8% ) achieved hematopoietic reconstruction after transplantation, with 11 (3.9% ) and 15 (5.3% ) having primary and secondary implantation dysfunctions, respectively. The cumulative incidence of acute graft-versus-host disease (GVHD) 100 days post-transplantation was (42.6±3.0) %, and the cumulative incidence of grade Ⅱ-Ⅳ acute GVHD was (33.0±2.8) %. The cumulative incidence of chronic GVHD 1 year post-transplantation was (31.0±2.9) %. Post-transplantation, 128 (45.4% ), 63 (22.3% ), 35 (12.4% ), and 17 patients (6.0% ) developed cytomegalovirus infection, bacteremia, pulmonary fungal infection, and Epstein-Barr virus infection. ③The median follow-up time post-transplantation was 22.1 (19.2-24.7) months, and the 3-year overall survival (OS) and disease-free survival (DFS) rates were 71.9% (95% CI 65.7% -78.6% ) and 63.6% (95% CI 57.2% -70.7% ), respectively. The 3-year non-recurrent mortality rate (NRM) is 17.9% (95% CI 13.9% -22.9% ), and the 3-year cumulative recurrence rate (CIR) is 9.8% (95% CI 6.7% -13.7% ). The independent risk factors affecting OS post-transplantation include monocyte karyotype (P=0.004, HR=3.26, 95% CI 1.46-7.29), hematopoietic stem cell transplantation complication index (HCI-CI) of ≥3 points (P<0.001, HR=2.86, 95% CI 1.72-4.75), and the occurrence of acute gastrointestinal GVHD of grade Ⅱ-Ⅳ (P<0.001, HR=5.94, 95% CI 3.50-10.10). ④The 3-year OS and DFS rates in the MDS-IB1/IB2 group post-transplantation were better than those in the MDS-biTP53 group [OS: 72.0% (95% CI 63.4% -80.7% ) vs 46.4% (95% CI 26.9% -80.1% ), P=0.020; DFS: 67.4% (95% CI 60.3% -75.3% ) vs 39.7% (95% CI 22.3% -70.8% ), P=0.015]. The 3-year CIR was lower than that of the MDS-biTP53 group [7.3% (95% CI 4.3% -11.4% ) vs 26.9% (95% CI 9.2% -48.5% ), P=0.004]. The NRM at 3 years post-transplantation in the MDS-IB1/IB2, MDS-f, and MDS-biTP53 groups were 16.7% (95% CI 12.1% -22.1% ), 20.5% (95% CI 9.4% -34.6% ), and 26.3% (95% CI 9.1% -47.5% ), respectively (P=0.690) . Conclusion: Allo-HSCT is an effective treatment for MDS-EB, with monomeric karyotype, HCI-CI, and grade Ⅱ-Ⅳ acute gastrointestinal GVHD as independent risk factors affecting the patient's OS. The WHO 2022 classification helps distinguish the efficacy of allo-HSCT in different subgroups of patients. Allo-HSCT can improve the poor prognosis of patients with MDS-f, but those with MDS-biTP53 have a higher risk of recurrence post-transplantation.

[The efficacy and safety of protein A immunoadsorption combined with rituximab treatment for highly sensitized patients undergoing haplo-hematopoietic stem cell transplantation].

Objective: To investigate the efficacy and safety of protein A immunoadsorption (PAIA) combined with rituximab (RTX) in highly sensitized patients who underwent haplo-hematopoietic stem cell transplantation (haplo-HSCT) . Methods: The clinical data of 56 highly sensitized patients treated with PAIA and RTX before haplo-HSCT at the First Affiliated Hospital of Soochow University and Soochow Hopes Hematonosis Hospital between March 2021 and June 2023 were retrospectively analyzed. The number of human leukocyte antigen (HLA) antibody types and the mean fluorescence intensity (MFI), humoral immunity, adverse reactions during adsorption, and survival within 100 days before and after adsorption were measured. Results: After receiving the PAIA treatment, the median MFI of patients containing only HLA Ⅰ antibodies decreased from 7 859 (3 209-12 444) to 3 719 (0-8 275) (P<0.001), and the median MFI of HLA Ⅰ+Ⅱ antibodies decreased from 5 476 (1 977-12 382) to 3 714 (0-11 074) (P=0.035). The median MFI of patients with positive anti-donor-specific antibodies decreased from 8 779 (2 697-18 659) to 4 524 (0-15 989) (P<0.001). The number of HLA-A, B, C, DR, and DQ antibodies in all patients decreased after the PAIA treatment, and the differences were statistically significant (A, B, C, DR: P<0.001, DQ: P<0.01). The humoral immune monitoring before and after the PAIA treatment showed a significant decrease in the number of IgG and complement C3 (P<0.001 and P=0.002, respectively). Forty-four patients underwent HLA antibody monitoring after transplantation, and the overall MFI and number of antibody types decreased. However, five patients developed new antibodies with low MFI, and nine patients continued to have high MFI. The overall survival, disease-free survival, non-recurrent mortality, and cumulative recurrence rates at 100 days post-transplantation were 83.8%, 80.2%, 16.1%, and 4.5%, respectively. Conclusions: The combination of PAIA and RTX has a certain therapeutic effect and good safety in the desensitization treatment of highly sensitive patients before haplo-HSCT.

[Retrospective clinical study on cryopreservation-free integrated autologous hematopoietic stem cell transplantation model for newly diagnosed multiple myeloma].

Objective: To explore the efficacy and safety of cryopreservation-free integrated autologous hematopoietic stem cell transplantation (HSCT) model for patients with multiple myeloma. Methods: A total of 96 patients with newly diagnosed multiple myeloma (NDMM) between July 31, 2020, and December 31, 2022, were retrospectively analyzed, of which 41 patients in the observation group received integrated non-cryopreserved transplantation mode. After hematopoietic stem cells were mobilized and collected, melphalan was started immediately for pre-transplant conditioning, and non-cryopreserved grafts from the medical blood transfusion refrigerator were directly injected intravenously into the patient within 24-48 h after the melphalan conditioning. The control group consisted of 55 patients who received traditional transplantation mode. After hematopoietic stem cells were collected, stem cell cryopreservation was performed in liquid nitrogen, and then the transplant plans were started at the right time. All patients received mobilization of autologous hematopoietic stem cells using the G-CSF combined with the plerixafor. Results: ① A total of 34 patients (82.9% ) with VGPR plus CR in the observation group were significantly higher than 33 patients (60.0% ) in the control group (P=0.016). ②Compared with the control group, the incidence of grade 1 oral mucosal inflammation was higher in the observation group (P<0.001) ; however, the incidence of grades 2 and 3 oral mucosal inflammation was lower (P=0.004, P=0.048), and neither group experienced grade 4 or above oral mucosal inflammation. The incidence of grade 1 diarrhea was higher in the observation group (P=0.002), whereas the incidence of grade 3 diarrhea was lower (P=0.007). No statistically significant difference was observed in the incidence of grade 4 diarrhea (P=0.506), and neither group experienced grade 5 diarrhea. ③ The incidence of bacterial infection in the observation group was lower than that in the control group (34.1% vs 65.5%, P=0.002), whereas no statistically significant difference was observed in the incidence of fungal infection (29.3% vs 31.4%, P=0.863) and viral infection (4.88% vs 3.64%, P=0.831). ④No statistically significant difference was observed in the implantation time of granulocytes and platelets between the observation and control groups [10 (8-20) days vs 11 (8-17) days, P=0.501; 13 (10-21) days vs 15 (10-20) days, P=0.245]. ⑤ All patients did not receive lenalidomide treatment 100 days post-transplantation. At 30 days post-transplantation, the CTL, NK, and Th cell counts in the observation group were lower than those in the control group (P<0.001, P=0.002, P=0.049), and the NKT cell counts were higher than those in the control group (P=0.024). At 100 days post-transplantation, the CTL, NKT, and Th cell counts in the observation group were higher than those in the control group (P=0.025, P=0.011, P=0.007), and no statistically significant difference in NK cell counts was observed between the two groups (P=0.396). ⑥ The median follow-up was 18 (4-33) months. The overall 2-year survival rates of the observation and control groups post-transplantation were 91.5% and 78.2%, respectively (P=0.337). The recurrence-free survival rates were 85.3% and 77.6%, respectively (P=0.386), and the cumulative recurrence rates were 9.8% and 16.9%, respectively (P=0.373) . Conclusion: In NDMM, the cryopreservation-free integrated autologous HSCT model can achieve similar therapeutic effects as traditional transplantation models, with lower rates of severe mucosal inflammation and infection compared with traditional transplantation models.

The Effect of Hematopoietic Stem Cell Transplantation on Treatment Outcome in Children with Acute Lymphoblastic Leukemia.

Purpose: Hematopoietic stem cell transplantation (HSCT) has been an important method of treatment in the advance of pediatric acute lymphoblastic leukemia (ALL). The indications for HSCT are evolving and require updated establishment. In this study, we aimed to investigate the efficacy of HSCT on the treatment outcome of pediatric ALL, considering the indications for HSCT and subgroups. Materials and Methods: A retrospective analysis was conducted on ALL patients diagnosed and treated at a single center. Risk groups were categorized based on age at diagnosis, initial white blood cell count, disease lineage (B/T), and cytogenetic study results. Data on the patients' disease status at HSCT and indications of HSCT were collected. Indications for HSCT were categorized as upfront HSCT at 1st complete remission, relapse, and refractory disease. Results: Among the 549 screened patients, a total of 418 patients were included in the study; B-ALL (n=379) and T-ALL (n=39). HSCT was conducted on a total of 106 patients (25.4%), with a higher frequency as upfront HSCT in higher risk groups and specific cytogenetics. The overall survival (OS) was significantly better when done upfront than in relapsed or refractory state in T-ALL patients (p=0.0016). The KMT2A-rearranged ALL patients showed superior event-free survival (p=0.0023) and OS (p=0.0221) when HSCT was done as upfront treatment. Conclusion: HSCT had a substantial positive effect in a specific subset of pediatric ALL. In particular, frontline HSCT for T-ALL and KMT2A-rearranged ALL offered a better prognosis than when HSCT was conducted in a relapsed or refractory setting.

The effectiveness of live music intervention on psychological distress among adolescent and young adult patients undergoing hematopoietic stem cell transplantation.

OBJECTIVE: To explore the effects of live music to decrease psychological distress in adolescent and young adult (AYA) patients undergoing hematopoietic stem cell transplantation (HSCT). METHOD: A quasi-experimental study was conducted. Sixty patients undergoing HSCT were divided into two groups, receiving either 4 week of live music (n = 31) or standard care (n = 29). Psychological distress, anxiety, the severity of symptom clusters and symptom interference were measured. RESULTS: When compared with the immediately and 1 month after intervention, patients in LM intervention group had significantly lower psychological distress and anxiety level than wait-list group. AYA undergoing HSCT reported significantly milder general symptom cluster and neurological symptom cluster at T3 than at baseline. CONCLUSIONS: Live music intervention showed a positive effect on relieving psychological distress and anxiety in AYA patients undergoing HSCT. However, further researches are warranted to explore the effects of live music intervention on symptom cluster.

Effect of peptide-binding motif on survival of HLA-haploidentical transplantation with post-transplant cyclophosphamide.

Peptide-binding motif (PBM) model, a hierarchical clustering of HLA class I based on their binding specificity, was developed to predict immunopeptidome divergence. The effect of PBM mismatches on outcomes is unknown in HLA-haploidentical haematopoietic cell transplantation with post-transplant cyclophosphamide (PTCy-haplo). We therefore conducted a retrospective study using national registry data in PTCy-haplo. Overall, 1352 patients were included in the study. PBM-A bidirectional mismatch was associated with an increased risk of overall mortality in multivariable analysis (hazard ratio, 1.26; 95% confidence interval, 1.06 to 1.50; p = 0.010). None of relapse, non-relapse mortality (NRM) and graft-versus-host disease showed significant differences according to PBM-A bidirectional mismatch status in the entire cohort. The impact of PBM-A bidirectional mismatch on overall survival (OS) was preserved within the HLA-A genotype bidirectional mismatch population, and their lower OS stemmed from higher relapse rate in this population. The worse OS due to high NRM with PBM-A bidirectional mismatch was prominent in lymphoid malignancies receiving reduced-intensity conditioning. The PBM model may predict outcomes more accurately than HLA genotype mismatches. In conclusion, this study demonstrated that the presence of PBM-A bidirectional mismatch elevated the risk of mortality of PTCy-haplo. Avoiding PBM-A bidirectional mismatch might achieve better outcomes in PTCy-haplo.

Pharmacokinetics of Briquilimab as a Conditioning Agent for Hematopoietic Stem Cell Transplantation in Patients with Severe Combined Immunodeficiency, Myelodysplastic Syndrome, or Acute Myeloid Leukemia.

BACKGROUND: For successful engraftment of donor hematopoietic stem cells (HSC), conditioning with chemotherapy and/or radiation prior to hematopoietic cell transplantation (HCT) has been required to open marrow niche space and minimize the risk of immune rejection. Briquilimab, a humanized IgG1 monoclonal antibody that blocks the interaction between the c-Kit receptor and stem cell factor on various C-Kit expressing tissues including HSC, is a potential nonmyeloablative conditioning agent in clinical development for patients with severe combined immunodeficiency (SCID), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). OBJECTIVE(S): This study aimed to characterize pharmacokinetics (PK) and develop a population PK model of briquilimab after single intravenous infusions of 4 different doses in patients with SCID, MDS, or AML receiving HCT. STUDY DESIGN: The PK data was collected from 2 different studies: JAS-BMT-CP-001 and JSP-CP-003. JAS-BMT-CP-001 is a phase 1/2 open-label study of briquilimab as a conditioning agent prior to allogenic HCT in SCID patients. The participants received single intravenous infusions of 0.1, 0.3, 0.6, or 1.0 mg/kg. JSP-CP-003 was a phase 1a/b open-label study of briquilimab in combination with a standard conditioning regimen of low dose total body irradiation and fludarabine in MDS or AML subjects undergoing HCT. The participants received a single intravenous dose of 0.6 mg/kg briquilimab. In both studies, briquilimab PK samples were obtained at pre-treatment, 5 minutes post-end of infusion, 4- and 24-hours post-start of infusion, any time between 2 days and 30 days post-infusion, and on the day of HCT prior to donor cell infusion.The population PK model was developed using the PK data from these 2 clinical studies, and the effect of participants' baseline characteristics on the briquilimab PK was evaluated. PK simulations were performed using the developed PK model to calculate the time to reach target concentrations for HCT. RESULTS: A total of 49 participants (21 SCID adult and pediatric participants with a median age of 12 years and 28 MDS/AML adult participants with a median age of 70 years) were included in the PK analysis. A two-compartment model with combined linear and non-linear elimination best described the PK of briquilimab. Body weight was determined as the sole covariate of the PK parameters among the explored covariates. For a typical subject with a body weight 70 kg, the estimated parameters for clearance, maximum metabolic rate of Michaelis Menten elimination, Michaelis Menten constant, central volume, peripheral volume, and intercompartmental clearance were 17.6 mL/hr, 51434.8 ng/hr, 71.5 ng/mL, 3444.0 mL, 1613.3 mL, and 21.2 mL/hr, respectively. The median time to reach target concentrations of 500, 1000, and 2000 ng/mL after a single dose of 0.6 mg/kg was calculated as 12.3, 10.4, and 7.7 days, respectively. CONCLUSIONS: The PK of intravenous briquilimab was characterized in subjects with SCID, MDS, or AML receiving HCT, and a population PK model was developed to estimate briquilimab clearance to use as a guide to the timing of donor cell infusion post-briquilimab. Body weight was identified as a significant covariate on elimination and volume of distribution of briquilimab.

Multiple small-dose infusions of G-CSF-mobilized haploidentical lymphocytes after autologous haematopoietic stem cell transplantation for acute myeloid leukaemia.

This retrospective study analysed 106 acute myeloid leukaemia (AML) patients undergoing autologous haematopoietic stem cell transplantation (ASCT) to assess the impact of multiple small-dose infusions of granulocyte-colony-stimulating factor (G-CSF)-mobilized haploidentical lymphocytes as post-ASCT maintenance therapy. Among them, 50 patients received lymphocyte maintenance therapy, 21 received alternative maintenance therapy, and 35 received no maintenance therapy. Patients receiving lymphocyte maintenance therapy demonstrated significantly higher overall survival (OS) and disease-free survival (DFS) compared to those without maintenance therapy, with 4-year OS and DFS rates notably elevated. While there were no significant differences in recurrence rates among the three groups, lymphocyte maintenance therapy showcased particular benefits for intermediate-risk AML patients, yielding significantly higher OS and DFS rates and lower relapse rates compared to alternative maintenance therapy and no maintenance therapy. The study suggests that multiple small-dose infusions of G-CSF-mobilized haploidentical lymphocytes may offer promising outcomes for AML patients after ASCT, particularly for those classified as intermediate-risk. These findings underscore the potential efficacy of lymphocyte maintenance therapy in reducing disease relapse and improving long-term prognosis in this patient population.

Recent advances in cancer therapy-associated oral mucositis.

Oral mucositis (OM) is a common and debilitating toxicity of cancer treatments - chemotherapy, radiotherapy, hematopoietic cell transplant, or combinations. OM is associated with severe oral pain and has negative impacts on patient function and quality of life. Additionally, OM has accompanying systemic complications that may have critical implications. These local and systemic consequences can alter cancer treatment, and add an economic burden. This review covers the clinical presentation and course of OM, differential diagnosis, clinical and economic impacts, pathogenesis, risk factors, assessment measures, biomarkers and prediction of OM, management, research advances in the development of new drugs and treatments, and big data.

WT1 gene mutations impact post-transplant relapse in myelodysplastic syndrome with excess blasts 2 patients.

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.

Suppression of P53 Pathway is an Important Factor Inducing Acute Graft-versus-Host Disease Through T Cell Activation Based on Bioinformatics Analysis.

Purpose: 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.

[Comparison of etoposide combined with G-CSF and cyclophosphamide combined with G-CSF in the mobilization of autologous peripheral blood stem cells in patients with multiple myeloma].

Objective: The effect and safety of etoposide combined with G-CSF were compared with those of cyclophosphamide combined with G-CSF in autologous peripheral blood mobilization in patients with multiple myeloma (MM) . Methods: Patients with MM who received autologous peripheral blood stem cell mobilization and collection in the Department of Hematology, Beijing Chaoyang Hospital Affiliated to Capital Medical University from January 1, 2020 to July 31, 2023 were included. A total of 134 patients were screened by propensity score matching technology according to a 1∶1 ratio. A total of 67 cases were each treated with ETO combined with G-CSF mobilization scheme (ETO group) and CTX combined with G-CSF mobilization scheme (CTX group). Their clinical data were retrospectively analyzed. Results: ①Collection results: the ETO and CTX groups [2 (1-3) d vs 2 (1-5) d; P<0.001] and CD34(+) cells [7.62×10(6) (2.26×10(6)-37.20×10(6)) /kg vs 2.73×10(6) (0.53×10(6)-9.85×10(6)) /kg; P<0.001] were collected. The success rate of collection was 100.0% (67/67) versus 76.1% (51/67) (P<0.001). Excellent rate of collection was 82.1% (55/67) versus 20.9% (14/67; P<0.001). Two patients in the ETO group switched protocols after 1 day of collection, and 11 patients in the CTX group switched protocols after 1-2 days of collection. ②Adverse reactions: granular deficiency with fever (21.5%[14/65] vs. 10.7%[6/56]; P=0.110), requiring platelet transfusion [10.7% (7/65) vs 1.8% (1/56) ; P=0.047]. ③Until the end of follow-up, 63 cases in the ETO group and 54 cases in the CTX group have undergone autologous transplantation. The median number of CD34(+) cells infused in the two groups was 4.62×10(6) (2.14×10(6)-19.89×10(6)) /kg versus 2.62×10(6) (1.12×10(6)-5.31×10(6)) /kg (P<0.001), neutrophil implantation time was 11 (9-14) d versus 11 (10-14) d (P=0.049), and platelet implantation time was 11 (0-19) d vs. 12 (0-34) d (P=0.035). One case in the CTX group experienced delayed platelet implantation. Conclusion: The mobilization scheme of etoposide combined with G-CSF requires relatively platelet transfusion, but the collection days are shortened. The collection success rate, excellent rate, and the number of CD34(+) cells obtained are high, and the neutrophil and platelet engraftment is accelerated after transplantation.

[Efficacy and safety of gilteritinib-based combination therapy bridging allo-HSCT in relapsed or refractory acute myeloid leukemia patients with positive FLT3-ITD mutation].

Objective: This study aims to evaluate the safety and effectiveness of gilteritinib (Gilt) -based combination therapy bridging allo-HSCT for FLT3-ITD(+) R/R AML. Additionally, it aims to assess the impact of Gilt maintenance therapy on the prognosis of patients after allo-HSCT. Methods: The clinical data of 26 patients with FLT3-ITD(+) R/R AML treated at the First Affiliated Hospital of Soochow University from August 2019 to January 2023 were retrospectively analyzed. The analysis included an assessment of the composite complete remission rate (CRc), overall survival (OS) time, disease-free survival (DFS) time, and adverse events experienced by all enrolled patients. Results: A total of 26 patients with FLT3-ITD(+) R/R AML were enrolled, including 14 men and 12 women with a median age of 38 (18-65) years. A total of 18 cases were refractory, and eight cases were relapsed. The curative effect evaluation conducted between 14 and 21 days showed that the complete remission (CR) rate was 26.9% (7/26), the CR with hematology incomplete recovery was 57.7% (15/26), and the partial response (PR) rate was 7.7% (2/26). The CRc was 84.6% (22/26), and the minimal residual disease (MRD) negativity rate was 65.4%. The 12 month cumulative OS rate for all patients was 79.0%, and the 24 month cumulative OS rate was 72.0%. The median OS time was not determined. The median follow-up time was 16.0 months. Among the patients who responded to treatment, the 12 month cumulative DFS rate was 78.0%, and the 24 month cumulative DFS rate was 71.0%. The median DFS time was not determined. Patients who received allo-HSCT had a median OS time that was significantly longer than those who did not receive allo-HSCT (3.3 months, 95%CI 2.2-4.3 months, P=0.005). The median OS time of patients with or without Gilt maintenance therapy after allo-HSCT was not determined, but the OS time of patients with Gilt maintenance therapy after allo-HSCT treatment was longer than that of patients without Gilt maintenance therapy after allo-HSCT treatment (P=0.019). The FLT3-ITD mutation clearance rate in this study was 38.5%, and the median OS time of patients with FLT3-ITD mutation clearance was not determined but was significantly longer than the median OS of patients without FLT3-ITD mutation clearance (15.0 months; P=0.018). The most common grade 3 and above hematological adverse events of Gilt-based combination therapy included leukopenia (76.9%), neutropenia (76.9%), febrile neutropenia (61.5%), thrombocytopenia (69.2%), and anemia (57.7%). One patient developed differentiation syndrome during oral Gilt maintenance therapy after allo-HSCT treatment, but his condition improved after treatment. Conclusion: The Gilt-based combination therapy is highly effective in treating FLT3-ITD(+) R/R AML. It demonstrates a high CRc, MRD negativity rate, and rapid onset, leading to a significant improvement in patients' survival. Furthermore, the clearance rate of FLT3-ITD mutation is notably high. Additionally, implementing bridging allo-HSCT and Gilt maintenance therapy after allo-HSCT treatment has considerably enhances patients' survival. Closely monitoring and managing any adverse event that may occur during treatment are crucial.

[Clinical efficacy of allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome-evolved acute myeloid leukemia].

Objective: The outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for myelodysplastic syndromes-evolved acute myeloid leukemia (MDS-AML) were explored. Methods: A retrospective review was conducted for 54 patients with MDS-AML treated with allo-HSCT in the Institute of Hematology and Blood Disease Hospital from January 2018 to August 2022. The clinical effects after transplantation were observed, and the related risk factors influencing prognosis were explored. Results: Of the total 54 patients, 26 males, 28 females, and 53 patients achieved hematopoietic reconstruction. After a median follow-up of 597 (15-1 934) days, the 1 year overall survival (OS) rate, disease-free survival (DFS) rate, relapse rate (CIR) and non-relapse mortality (NRM) rate were 75.8%±5.8%, 72.1%±6.1%, 12.7%±4.9%, and 17.1%±5.2%, respectively. The 3 year estimated OS, DFS, CIR, and NRM rates were 57.8%±7.5%, 58.1%±7.2%, 23.2%±6.6%, and 23.7%±6.6%, respectively. The cumulative incidence of acute graft-versus-host disease (aGVHD) was 57.5%±6.9%, and the cumulative incidence of chronic graft-versus-host disease (cGVHD) was 48.4%±7.7%. Hematopoietic cell transplantation comorbidity index (HCT-CI) before transplantation was ≥2, minimal residual disease (MRD) was positive on the day of reconstitution, grade Ⅲ/Ⅳ aGVHD, bacterial or fungal infection and no cGVHD after transplantation were adverse prognostic factors for OS (P<0.05). COX regression model for multivariate analysis showed that HCT-CI score before transplantation, bone marrow MRD on the day of response, grade Ⅲ or Ⅳ aGVHD, and cGVHD after transplantation were the independent adverse factors for OS (P=0.001, HR=6.981, 95%CI 2.186-22.300; P=0.010, HR=6.719, 95%CI 1.572-28.711; P=0.026, HR=3.386, 95%CI 1.158-9.901; P=0.006, HR=0.151, 95%CI 0.039-0.581) . Conclusion: For patients with MDS-AML and high risk of relapse, allogeneic transplantation must be considered as soon as possible. The enhanced management of post-transplantation complications and maintenance treatment should be provided whenever possible after transplantation.

Allogeneic stem cell transplantation for inherited metabolic disorders: 35 years' experience at a single institution.

Hematopoietic stem cell transplants for inherited metabolic disorders performed at Tokai University Hospital between June 5, 1986, and May 28, 2021, were analyzed and compared between the period before 2007 and the period from 2007 onward based on availability of medical resources. Transplants were performed for 38 patients with mucopolysaccharidosis, 33 with adrenoleukodystrophy, and 16 with another disorder. Before 2007, oral busulfan-based regimens were mainly used. From 2007 onward, intravenous busulfan-based regimens or 4 Gy of thoracoabdominal irradiation (TAI), fludarabine, and melphalan (Mel)/treosulfan were adopted. Between 2002 and 2010, adrenoleukodystrophy was treated with 12 Gy of TAI and Mel. HLA-identical sibling bone marrow was used in 43% of cases before 2007 and 15% from 2007 onward, while alternative donors were selected for other transplants. Overall survival and event-free survival (EFS) before 2007 and from 2007 onward were 76% and 62%, and 97% and 85%, respectively (P = 0.006 and 0.017). Transplant era predicted superior overall survival and EFS, while myeloablative conditioning also predicted EFS. The incidence of primary graft failure decreased from 2007 onward, especially in cord blood transplant when 4 Gy of TAI with 150 mg/m2 fludarabine and 180 mg/m2 Mel or 42 g/m2 treosulfan were used as conditioning.