Objective: To compare the effects of two administration time strategies for rabbit antihuman thymocyte immunoglobulin (rATG) of 5mg/kg total dose in matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) . Methods: This study retrospectively analyzed the clinical data of 32 patients who received MSD-HSCT with 5 mg/kg rATG conditioning regimen at the Department of Hematology of the First Medical Center of the People's Liberation Army General Hospital from October 2020 to April 2022. The patients were classified into two groups: the 4d-rATG group (16 cases), who received antithymocyte globulin (ATG) from day -5 to day -2, and the 2d-rATG group (16 cases), who received ATG from day -5 to day -4. Between the two groups, the transplantation outcomes, serum concentrations of active antithymocyte globulin (ATG) in patients from -4 days to 28 days after graft infusion (+28 days), and the reconstitution of lymphocyte subsets on days +30, +60, and +90 were compared. Results: The cumulative incidences of acute graft-versus-host disease at 100 days after graft infusion were 25.0% (95% CI 7.8% -47.2% ) and 18.8% (95% CI 4.6% -40.2% ) (P=0.605) in the 4d-rATG group and 2d-rATG group, respectively. The 1-year cumulative incidences of chronic graft-versus-host disease were 25.9% (95% CI 8.0% -48.6% ) and 21.8% (95% CI 5.2% -45.7% ) (P=0.896). The 1-year cumulative incidence of relapse was 37.5% (95% CI 18.9% -65.1% ) and 14.6% (95% CI 3.6% -46.0% ) (P=0.135), and the 1-year probabilities of overall survival were 75.0% (95% CI 46.3% -89.8% ) and 100% (P=0.062). The total area under the curve (AUC) of serum active ATG was 36.11 UE/ml·d and 35.89 UE/ml·d in the 4d-rATG and 2d-rATG groups, respectively (P=0.984). The AUC was higher in the 4d-rATG group than that in the 2d-rATG group (20.76 UE/ml·d vs 15.95 UE/ml·d, P=0.047). Three months after graft infusion, the average absolute count of CD8(+) T lymphocytes in the 4d-rATG group was lower than that in the 2d-rATG group (623 cells/μl vs 852 cells/μl, P=0.037) . Conclusion: The efficiencies of GVHD prophylaxis in MSD-PBSCT receiving 4d-ATG regimen and the 2d-rATG regimen were found to be similar. The reconstruction of CD8(+)T lymphocytes in the 2d-rATG group was better than that in the 4d-rATG group, which is related to the lower AUC of active ATG after transplantation.
Animals ; Rabbits ; Humans ; Antilymphocyte Serum/therapeutic use* ; Siblings ; Retrospective Studies ; Hematopoietic Stem Cell Transplantation ; Tissue Donors ; Graft vs Host Disease/drug therapy* ; Transplantation Conditioning

Objective: To investigate the clinical features of children with chronic nonbacterial osteomyelitis (CNO), and raise awareness among clinicians. Methods: In this retrospective study, 18 patients with CNO who were diagnosed in Children's Hospital of Fudan University from January 2015 to December 2021 were included. Results: Eighteen children with CNO (12 males, 6 females) were identified. Their age at onset was 9 (5, 11) years, the delay in diagnosis was 2 (1, 6) months, and follow-up-was 17 (8, 34) months. The most common symptoms were fever in 14 children, as well as bone pain and (or) arthralgia in 14 children. In terms of laboratory results, normal white blood cell counts were observed at onset in 17 patients; increased erythrocyte sedimentation rate (ESR) in all patients; increased C reactive protein (CRP) over the normal value in 14 patients. Of the 18 patients, 2 had positive antinuclear antibodies, while none had positive human leukocyte antigen-B27 or rheumatoid factor. Imaging examination revealed that all the patients had symmetrical and multifocal skeletal lesions. The number of structural lesions detected by imaging investigation was 8 (6, 11). The most frequently affected bones were tibia in 18 patients and femur in 17 patients. Bone biopsy was conducted in 14 patients and acute or chronic osteomyelitis manifested with inflammatory cells infiltration were detected. Magnetic resonance imaging (MRI) found bone lesions in all the patients and bone scintigraphy were positive in 13 patients. All the patients were treated with nonsteroidal anti-inflammatory drugs, among whom 10 cases also treated with oral glucocorticoids, 9 cases with traditional disease modifying anti-rheumatic drugs, 8 cases with bisphosphonates and 6 cases with tumor necrosis factor inhibitors. The pediatric chronic nonbacterial osteomyelitis disease activity score, increased by 70% or more in 13 patients within the initial 6-month follow-up. Conclusions: The clinical manifestations of CNO are lack of specificity. The first symptom of CNO is fever, with or without bone pain and (or) arthralgia, with normal peripheral blood leukocytes, elevated CRP and (or) ESR. Whole body bone scanning combined with MRI can early detect osteomyelitis at subclinical sites, and improve the diagnostic rate of CNO.
Female ; Male ; Humans ; Child ; Retrospective Studies ; Osteomyelitis/drug therapy* ; Arthralgia ; Diphosphonates ; Fever ; Graft vs Host Disease

Objective: To evaluate the efficacy and prognosis of basiliximab in the treatment of steroid-refractory or steroid-dependent acute graft-versus-host disease (SR/SD-aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Methods: Clinical data of 87 patients with SR/SD-aGVHD in the skin, intestine, and liver after allo-HSCT at the Institute of Hematology & Blood Diseases Hospital Transplantation Center from January 2015 to December 2018 were retrospectively analyzed. The administration plan of basiliximab was as follows: 20 mg for adults and children weighing ≥35 kg and 10 mg for children weighing<35 kg. The drug was administered once on the 1st, 4th, and 8th days, respectively, and then once weekly. The efficacy was evaluated on the 7th, 14th, 21st, and 28th days after basiliximab treatment. Results: ①There were 51 males (58.6%) and 36 females (41.4%) , with a median (range) age of 34 (4-63) years. There were 54 cases of classic aGVHD, 33 of late aGVHD, 49 of steroid-refractory aGVHD, and 38 of steroid-dependent aGVHD. ②Thirty-five patients (40.2%) achieved complete remission (CR) , 23 (26.4%) achieved partial remission (PR) , and 29 had no remission (NR) . The total effective rate[overall response rate (ORR) ] was 66.7% (58/87) . ③The ORR of the classic and late aGVHD groups was 77.8% (42/54) and 48.5% (16/33) , respectively. ④The median (range) follow-up time was 154 (4-1813) days, the 6-month overall survival (OS) rate of the 87 patients was 44.8% (95% CI 39.5%-50.1%) and the 1-year OS was 39.4% (95%CI 34.2%-44.3%) . ⑤After treatment with basiliximab, the 6-month OS in the CR (35 cases) , PR (23 cases) , and NR (29 cases) groups was 80.0% (95%CI 73.2%-86.8%) , 39.1% (95%CI 28.9%-49.3%) , and 6.9% (95%CI 2.2%-11.6%) , respectively (χ(2)=34.679, P<0.001) , and the 1-year OS was 74.3% (95%CI 66.9%-81.7%) , 30.4% (95%CI 20.8%-40.0%) , and 3.4% (95%CI 0%-6.8%) , respectively (χ(2)=43.339, P<0.001) . The OS of the classic and late aGVHD groups was 57.4% (95%CI 50.7%-64.1%) and 24.2% (95%CI 16.7%-31.7%) , respectively (χ(2)=9.109, P=0.004) , and the 1-year OS was 51.9% (95%CI 45.1%-58.7%) and 18.2% (95%CI 11.5%-24.9%) , respectively (χ(2)=9.753, P=0.003) . ⑥Univariate and multivariate analyses showed that late aGVHD (OR=3.121, 95%CI 1.770-5.503, P<0.001) , Minnesota score high-risk group before medication (OR=3.591, 95%CI 1.931-6.679, P<0.001) , active infection before medication (OR=1.881, 95%CI 1.029-3.438, P=0.040) , and impairment of important organ function caused by non-GVHD (OR=3.100, 95%CI 1.570-6.121, P=0.001) were independent risk factors affecting the efficacy of basiliximab. Conclusion: Basiliximab has good efficacy and safety for SR/SD-aGVHD, but not in patients with late aGVHD, high-risk group of Minnesota score, and infection or impaired function of important organs.
Acute Disease ; Adult ; Basiliximab/therapeutic use* ; Child ; Female ; Graft vs Host Disease/drug therapy* ; Hematopoietic Stem Cell Transplantation/adverse effects* ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Steroids/therapeutic use*

OBJECTIVE: To investigate the effect of acute graft-versus-host disease (aGVHD) mouse models established respectively by total body irradiation (TBI) and busulfan combined with cyclophosphamide (BU/CY) conditioning regimens after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: Bone marrow cells and splenic mononuclear cells were isolated respectively from femur, tibia, and spleen of C57BL/6 male mice (H-2Kb) which were selected as donors. After TBI pretreatment, BALB/c female mice (H-2Kd) were injected with donor bone marrow cells 1×10⁷/50 μl and splenic mononuclear cells 2×10⁷/100 μl through caudal vein, while CB6F1 female mice (H-2Kd/b) with donor bone marrow cells 2×10⁷/100 μl and splenic mononuclear cells 1×10⁸/500 μl after BU/CY pretreatment. The successful establishment of the aGVHD models were determined by post-transplant manifestations, rate of chimerism, target organ damage, etc. Results: After transplantation, mice of both groups showed listlessness, low activity, continued weight loss, and typical manifestations of aGVHD such as alopecia, hunched posture, diarrhea, and anal swelling. and died within 4 weeks. Flow cytometry detection showed complete chimerism in all the mice. Pathological examination of skin, intestines, liver, lung, and spleen tissues showed obvious aGVHD pathological changes. However, the weight loss, ruffled fur, and alopecia combined with severe scurf on those hair-free areas were significantly apparent in TBI group than BU/CY group, as well as higher aGVHD score, and the differences were statistically significant (P<0.05). CONCLUSION Both TBI and BU/CY as conditioning regimens can successfully establish stable mouse models of aGVHD after fully allo-HSCT and haploidentical HSCT for further research about mechanism of aGVHD. BU/CY conditioning regimen can more truly simulate physiological status in vivo of patients with chemotherapy based conditioning regimen, while TBI conditioning regimen shows significantly more typical aGVHD symptoms and easier to operate.
Alopecia/drug therapy* ; Animals ; Busulfan/therapeutic use* ; Cyclophosphamide ; Female ; Graft vs Host Disease/drug therapy* ; Hematopoietic Stem Cell Transplantation ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Transplantation Conditioning ; Transplantation, Homologous ; Weight Loss ; Whole-Body Irradiation

OBJECTIVE: To investigate the clinical efficacy and survival factors of microtransplantation (MST) in adult patients with acute myeloid leukemia (AML). METHODS: For a retrospective analysis of 27 adult patients with AML receiving MST from July 2014 to October 2021, the median age was 59(29-77) years old, 13 cases were ≥60 years old, 14 case were <60 years old, 13 cases were male and 14 cases were female. Classification by FAB: AML-M2 6 cases, AML-M4 6 cases, AML-M5 2 cases, AML-M6 2 cases, AML（Undivided type） 9 cases, AML myeloid sarcoma 2 cases (primary AML 21 cases, AML secondary to MDS 6 cases). Cytogenetic analysis showed 25 patients with a normal karyotype, 2 patients with an abnormal karyotype, and 20 patients with an abnormal molecular biology. Induction chemotherapy regimens mainly include: IA, DA, MA or HA regimen, including CAG or CIG in combination with decitabine, and single-agent decitabine. 17 patients achieved complete remission (CR) after 1 course of induction chemotherapy and 4 patients achieved CR after 2 courses of induction chemotherapy. 3 patients received CR by four courses of decitabine, 2 patients received no remission, and 1 patient underwent no induction chemotherapy and were treated direct MST. There were 16 patients with pretransplant CR and 11 patients were not in remission before transplantation. Follow-up mainly used consult patient's medical records and telephone inquiry to observe the adverse effects and efficacy of MST treatment. Survival analysis was performed by Kaplan-Meier method, with the main observation indicators overall survival(OS) and leukemia-free survival(LFS), and performed with the Log-rank test. Multivariate analysis was performed by the Cox regression model. RESULTS: A total of 79 MST were performed in 27 AML patients with good overall safety and no special serious adverse effects. The median time of leukocyte recovery was 13(4-28) days, and the median time of platelet recovery was 13(4-30) days. There were 50 cases of infection, 5 cases of abnormal liver function and 3 cases of abnormal cardiac function. Except for abnormal cardiac function, all other complications did not affect the treatment and were cure. Acute or chronic GVHD, renal insufficiency, abnormal coagulation function, and severe bleeding were not observed during treatment or during follow-up. As of the follow-up date, the median follow-up time of the 27 patients was 79(14-171) months, the median OS time was 62(1-171) months, and the median LFS time was 15(0-171) months. The 2-year OS rate was 65.7%（17/27）, and the 2-year LFS rate was 47.4%（12/27） . The complete response rate of 27 patients treated with MST was 48.1% (13/27). 8 patients relapsed during MST treatment, including 7 patients after the completion of the first MST course and 1 patient after the completion of the second MST course. 2 patients relapsed after the end of the course of MST. 13 patients died, including 10 patients because of disease progression, two patients from severe infection, and one patient from cardiac damage. CONCLUSION MST has the advantages of small toxic side effects, complete compatibility of HLA matching is not required, effective avoidance of GVHD and rapid hematopoietic recovery, which can improve OS and LFS in elderly AML and young AML patients, and is one of the treatment options for patients without HLA matching.
Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Cytarabine ; Decitabine/therapeutic use* ; Female ; Graft vs Host Disease/drug therapy* ; Humans ; Leukemia, Myeloid, Acute/drug therapy* ; Male ; Middle Aged ; Remission Induction ; Retrospective Studies ; Survival Analysis ; Treatment Outcome

OBJECTIVE: To investigate the efficacy and safety of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in combination of ATG and post-transplant cyclophosphamide (PTCy) -induced immune tolerance after transplantation in treatment of childhood myelodysplastic syndromes(MDS）. METHODS: From July 2016 to November 2020, a total of 8 children with MDS receiving the haploidentical allo-HSCT combined with ATG and PTCy-induced immune tolerance after transplantation in our hospital were enrolled, whose clinical data were retrospected and analyzed. RESULTS: Median age at diagnosis of the 8 children (1 male and 7 females) was 6.4 (range, 10 months to 15 years) years old. The median medical history of MDS was 2.7 years (range, 3 months to 8 years). Among the 8 patients, 7 cases were diagnosed with refractory cytopenia of childhood and one with refractory anemia with excess of blasts. The HSC donors were father, mother or brother of patients and HLA matching in 6-9/12 loci were identical. All the donors were healthy and didn't carry the same pathogenic genes as the recipients. The median age of donors was 36.4 (range, 25 to 49) years old. The median mononuclear cell (MNC) number of the graft was 19.8, ranging in (13.2-47.3)×10⁸/kg, and the median CD34⁺ cell number was 11.8×10⁶/kg, ranging in (5.0-18.3)×10⁶/kg. Graft-versus-host disease prophylactic regimen was started on day 3 and 4 after transplantation, in which cyclophosphamide (50 mg/kg·d) was administered by intravenous infusion. From day 5 after transplantation, low-dose tacrolimus was administered by intravenous infusion and mycophenolate mofetil was administered orally. The median time of neutrophil and platelet engraftment was 12.6 (rang, 11 to 15) days and 13.3 (rang, 11 to 18) days, respectively. All the patients achieved full donor chimerism on neutrophil engraftment after transplantation. The median follow-up time was 1 032 (rang, 747 to 1 536) days. Both overall survival rate and disease-free survival rate were 100%. CONCLUSION Haplo-HSCT combined with ATG and PTCy-induced immune tolerance after transplantation is a safe and effective treatment for children with MDS.
Adult ; Child ; Cyclophosphamide ; Female ; Graft vs Host Disease/drug therapy* ; Hematopoietic Stem Cell Transplantation ; Humans ; Male ; Middle Aged ; Myelodysplastic Syndromes/drug therapy* ; Transplantation Conditioning ; Treatment Outcome

Systemic lupus erythematosus (SLE) is a chronic and autoimmunity-mediated diffuse connective tissue disease. The mainstay of treatments for SLE mainly relies on corticosteroids and immunosuppressants, which have a series of unavoidable side effects. Therefore, it is of fundamental importance to search novel therapeutic targets for better treatment with favorable efficacy and minor side effects. Recent studies shed light on potential therapeutic targets for SLE, mainly covering the followings: B-cell/plasmocyte-related targets [B cell activating factor (BAFF), a proliferation-inducing ligand (APRIL), CD20, CD22, CD19/FcγRIIb, Bruton tyrosine kinase (Btk), and proteasome], T cell-related targets [calcineurin, mammalian target of rapamycin (mTOR), regulatory factor X1 (RFX1), and Rho kinase], macrophage-related targets (macrophage migration inhibitory factor), intracellular signaling molecules, cytokines (cereblon, histone deacetylase 6, Janus activated kinase/signal transducer and activator of transcription), co-stimulating factors (CD28/B7, CD40/CD154), IgE autoantibody, and gut microbiome. Among them, belimumab (a humanized monoclonal antibody against B-lymphocyte stimulator) and telitacicept (a recombinant human B-lymphocyte stimulator receptor-antibody fusion protein) have been sequentially approved for the clinical treatment of SLE in China. A variety of new targeted-therapy drugs are in the Phase 2 or Phase 3 clinical trials,among which anifrolumab (a human monoclonal antibody against type I interferon receptor subunit 1) has completed a Phase 3 clinical trial with good responses achieved, although its incidence of herpes zoster is higher than that in the control group. The research progress in both molecular mechanisms and new drug development for different therapeutic targets have greatly promoted our better and in-depth understanding of the pathogenesis of SLE, and have also reflected the complexity and heterogeneity of the disease. Successful development and clinical application of more novel therapies would no doubt usher in a new era of individualized treatment for SLE in the future.
Antibodies, Monoclonal/therapeutic use* ; B-Lymphocytes ; Graft vs Host Disease ; Humans ; Immunosuppressive Agents ; Lupus Erythematosus, Systemic/drug therapy*

OBJECTIVE: To investigate the efficacy and safety of micro-transplantation in acute myeloid leukemia (AML). METHODS: The clinical data of 13 adult AML patients who received micro-transplantation as consolidation therapy from July 2014 to October 2019 was retrospectively analyzed, and the adverse reactions and efficacy of micro-transplantation were followed up. RESULTS: Eight patients received micro-transpantation were still in complete remission, 5 patients relapsed after micro-transplantation, 1 of them received umbilical cord blood micro-transplantation after remission by reinduction, and all of the 13 patients have survived till now. The median overall survival time was 13 months, and the median relapse-free survival time was 12 months. All 13 patients developed grade 2-4 hematological adverse reactions. The median recovery time of neutrophils and platesets was 13 (11-15) and 15 (13-17) days, respectively. None of the 13 patients developed acute or chronic graft versus host disease. Twelve patients suffered from different infections, however, there were no serious organ function injury complications happened. CONCLUSION The micro-transplomtation of HLA-incompatible stem cells derived from peripheral blood or umbilical and blood is an effective regimen for the consolidation therapy of AML, especially for the patients suffered from low and moderate risk of AML or the aged AML patients.
Adult ; Aged ; Consolidation Chemotherapy ; Graft vs Host Disease ; Hematopoietic Stem Cell Transplantation ; Humans ; Leukemia, Myeloid, Acute/drug therapy* ; Retrospective Studies ; Transplantation Conditioning ; Treatment Outcome

Graft-versus-host disease (GVHD) is the most common complication after allogeneic hematopoietic stem cell transplantation, and also an important factor affecting the survival and quality of life in patients after transplantation. Currently, immunosuppressive therapy is commonly used for GVHD, but the curative effect is not ideal. How to effectively prevent and treat GVHD is one of the difficulties to be solved urgently in the field of transplantation. In this paper, we summarize the latest progress in pathogenesis, prevention and treatment of GVHD with Chinese medicine (CM). We hope it will provide ideas and methods for exploring the mechanism and establishing a new comprehensive therapy for GVHD with CM.
Allografts ; Graft vs Host Disease ; drug therapy ; etiology ; Hematopoietic Stem Cell Transplantation ; adverse effects ; Humans ; Medicine, Chinese Traditional ; Quality of Life

Acute graft-versus-host disease (aGVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the mechanisms of aGVHD are not well understood. We aim to investigate the roles of the three angiogenic factors: angiopoietin-1 (Ang-1), Ang-2 and vascular endothelial growth factor (VEGF) in the development of aGVHD. Twenty-one patients who underwent allo-HSCT were included in our study. The dynamic changes of Ang-1, Ang-2 and VEGF were monitored in patients before and after allo-HSCT. In vitro, endothelial cells (ECs) were treated with TNF-β in the presence or absence of Ang-1, and then the Ang-2 level in the cell culture medium and the tubule formation by ECs were evaluated. After allo-HSCT, Ang-1, Ang-2 and VEGF all exhibited significant variation, suggesting these factors might be involved in the endothelial damage in transplantation. Patients with aGVHD had lower Ang-1 level at day 7 but higher Ang-2 level at day 21 than those without aGVHD, implying that Ang-1 may play a protective role in early phase yet Ang-2 is a promotion factor to aGVHD. In vitro, TNF-β promoted the release of Ang-2 by ECs and impaired tubule formation of ECs, which were both weakened by Ang-1, suggesting that Ang-1 may play a protective role in aGVHD by influencing the secretion of Ang-2, consistent with our in vivo tests. It is concluded that monitoring changes of these factors following allo-HSCT might help to identify patients at a high risk for aGVHD.
Acute Disease ; Adolescent ; Adult ; Angiogenesis Inducing Agents ; immunology ; metabolism ; pharmacology ; Angiopoietin-1 ; genetics ; immunology ; pharmacology ; Angiopoietin-2 ; genetics ; immunology ; pharmacology ; Antineoplastic Agents ; therapeutic use ; Female ; Gene Expression Regulation, Neoplastic ; Graft vs Host Disease ; genetics ; immunology ; pathology ; Hematopoietic Stem Cell Transplantation ; Human Umbilical Vein Endothelial Cells ; cytology ; drug effects ; immunology ; Humans ; Leukemia, Myeloid ; genetics ; immunology ; pathology ; therapy ; Lymphoma, Non-Hodgkin ; genetics ; immunology ; pathology ; therapy ; Male ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; genetics ; immunology ; pathology ; therapy ; Retrospective Studies ; Signal Transduction ; Transplantation, Homologous ; Tumor Necrosis Factor-alpha ; pharmacology ; Vascular Endothelial Growth Factor A ; genetics ; immunology