COVID-19 impact in Crohn’s disease patients submitted to autologous hematopoietic stem cell transplantation

BACKGROUND Severe acute respiratory syndrome coronavirus 2 is the virus responsible for coronavirus disease 2019(COVID-19),a disease that has been blamed for inducing or exacerbating symptoms in patients with autoimmune diseases.Crohn's disease(CD)is an inflammatory bowel disease that affects genetically susceptible patients who develop an abnormal mucosal immune response to the intestinal microbiota.Patients who underwent hematopoietic stem cell transplantation(HSCT)are considered at risk for COVID-19.AIM To describe for the first time the impact of COVID-19 in CD patients who had undergone autologous,non-myeloablative HSCT.METHODS In this descriptive study a series of 19 patients were diagnosed with positive COVID-19.For two patients there were reports of the occurrence of two infectious episodes.Parameters related to HSCT,such as time elapsed since the procedure,vaccination status,CD status before and after infection,and clinical manifestations resulting from COVID-19,were evaluated.RESULTS Among the patients with COVID-19,three,who underwent Auto HSCT less than six months ago,relapsed and one,in addition to the CD symptoms,started to present thyroid impairment with positive anti-TPO.Only one of the patients required hospitalization for five days to treat COVID-19 and remained in CD clinical remission.Nine patients reported late symptoms that may be related to COVID-19.There were no deaths,and a statistical evaluation of the series of COVID-19 patients compared to those who did not present any infectious episode did not identify significant differences regarding the analyzed parameters.CONCLUSION Despite the change in CD status in three patients and the presence of nine patients with late symptoms,we can conclude that there was no significant adverse impact concerning COVID-19 in the evaluated patients who underwent HSCT to treat CD.

Quality-adjusted time without symptoms or toxicity analysis of haploidentical-related donor vs.identical sibling donor hematopoietic stem cell transplantation in acute myeloid leukemia

Objective:We aimed to compare the quality-adjusted time without symptoms or toxicity(Q-TWiST)in acute myeloid leukemia(AML)patients who received haploidentical-related donor(HID)and identical sibling donor(ISD)hematopoietic stem cell transplantation(HSCT).Methods:Five clinical health states were defined:toxicity(TOX),acute graft-versus-host disease(GVHD),chronic GVHD(cGVHD),time without symptoms and toxicity(TWiST)and relapse(REL).The equation used in this study was as follows:Q-TWiST=UTOX×TOX+UTWiST×TWiST+UREL×REL+UaGVHD×aGVHD+UcGVHD×cGVHD.Results:A total of 239 AML patients were enrolled.We established a mathematical model,i.e.,Q-TWiST HID HSCT>Q-TWiST ISD HSCT,to explore the range of utility coefficients satisfying the inequality.Based on the raw data,the utility coefficient is equivalent to the following inequality:10.57067UTOX-46.27733UREL+105.9374+3.388078UaGVHD-210.8198UcGVHD>0.The model showed that when UTOX,UREL,and UaGVHD were within the range of 0-1,as well as when UcGVHD was within the range of 0-0.569,the inequality Q-TWiST HID HSCT>Q-TWiST ISD HSCT was valid.According to the results of the ChiCTR1800016972 study,the median coefficients of TOX,acute GVHD(aGVHD),and cGVHD were 0.56(0.41-0.76),0.56(0.47-0.72),and 0.54(0.37-0.79),respectively.We selected a series of specific examples of the coefficients,i.e.,UTOX=0.5,UREL=0.05,UaGVHD-0.5,and UcGVHD-0.5.The Q-TWiST values of ISD and HID HSCT were 896 and 900 d,respectively(P=0.470).Conclusions:We first observed that Q-TWiST was comparable between AML patients receiving HID HSCT and those receiving ISD HSCT.

Autologous hematopoietic stem cell transplantation in chemotherapy-sensitive lymphoblastic lymphoma: treatment outcome and prognostic factor analysis

Objective： The study evaluated the effectiveness of autologous hematopoietic stem cell transplantation （AHSCT） in the treatment of lymphoblastic lymphoma （LL）. Methods： We relxospectively analyzed the data from 41 patients with chemotherapy-sensitive LL who underwent hematopoietic stem cell transplantation （HSCT） from December 1989 to December 2009 in a single institution. Results： HSCT was conducted as first-line consolidation therapy and salvage therapy in 36 and 5 patients, respectively. The median follow-up was 97.1 months （range, 24.6-173.1 months）. The 5-year overall survival （OS） and event-free survival （EFS） rate were 64% and 47% for the initially treated patients, respectively, and were both 20% for the relapsed ones. Bone marrow （BM） involvement and chemotherapy cycles prior to transplantation were identified as significant prognostic factors for EFS in multivariate analysis. Conclusions These results confirm that AHSCT is a reasonable option for chemotherapy-sensitive LL patients in first complete remission （CR1）.

Hepatitis B-related events in autologous hematopoietic stem cell transplantation recipients

AIM: To investigate the frequency of occult hepatitis B, the clinical course of hepatitis B virus (HBV) reactivation and reverse seroconversion and associated risk factors in autologous hematopoietic stem cell transplantation (HSCT) recipients. METHODS: This study was conducted in 90 patients undergoing autologous HSCT. Occult HBV infection was investigated by HBV-DNA analysis prior to transplantation, while HBV serology and liver function tests were screened prior to and serially after transplantation. HBV-related events including reverse seroconversion and reactivation were recorded in all patients. RESULTS: None of the patients had occult HBV prior to transplantation. Six (6.7%) patients were positivefor HBV surface antigen (HBsAg) prior to transplantation and received lamivudine prophylaxis; they did not develop HBV reactivation after transplantation. Clinical HBV infection emerged in three patients after transplantation who had negative HBV-DNA prior to HSCT. Two of these three patients had HBV reactivation while one patient developed acute hepatitis B. Three patients had anti-HBc as the sole hepatitis B-related antibody prior to transplantation, two of whom developed hepatitis B reactivation while none of the patients with antibody to HBV surface antigen (anti-HBs) did so. The 14 anti-HBs-and/or anti-HBc-positive patients among the 90 HSCT recipients experienced either persistent (8 patients) or transient (6 patients) disappearance of anti-HBs and/or anti-HBc. HBsAg seroconversion and clinical hepatitis did not develop in these patients. Female gender and multiple myeloma emerged as risk factors for loss of antibody in regression analysis (P < 0.05). CONCLUSION: Anti-HBc as the sole HBV marker seems to be a risk factor for reactivation after autologous HSCT. Lamivudine prophylaxis in HbsAg-positive patients continues to be effective.

Prognostic value of ^(18)F-fluorodeoxyglucose positron emission tomography using Deauville criteria in diffuse large B cell lymphoma treated with autologous hematopoietic stem cell transplantation

Objective: High-dose chemotherapy(HDC) followed by autologous hematopoietic stem cell transplantation(auto-HSCT) plays an important role in improving outcomes of diffuse large B cell lymphoma(DLBCL) patients.18 F-fluorodeoxyglucose(18 F-FDG) positron emission tomography(PET)/computed tomography(CT) has been widely accepted in response assessment and prediction of prognosis in DLBCL. Here, we report the value of 18 FFDG PET/CT pre-and post-HSCT in predicting outcomes of patients with DLBCL.Methods: DLBCL patients who had PET/CT scan before and after HSCT were included. PET results were interpreted based upon Deauville criteria. The prognostic value of 18 F-FDG PET/CT in auto-HSCT was evaluated.Results: Eighty-four patients were enrolled. In univariate analysis, pre-and post-HSCT PET findings were correlated with 3-year progression-free survival(PFS) [hazard ratio(HR)=4.391, P=0.001; HR=7.607, P<0.001] and overall survival(OS)(HR=4.792, P=0.008; HR=26.138, P<0.001). Patients receiving upfront auto-HSCT after firstline treatment had better outcomes than relapsed/refractory DLBCL patients(3-year PFS, P<0.001; 3-year OS,P<0.001). In the relapsed/refractory patients, pre-and post-HSCT PET findings were also associated with 3-year PFS(P=0.003 vs. P<0.001) and OS(P=0.027 vs. P<0.001). A significant correlation was observed between clinical response to chemotherapy before auto-HSCT and outcomes of patients in the entire cohort(3-year PFS, P<0.001;3-year OS, P<0.001) and in the subgroup of 21 patients with positive pre-HSCT PET(3-year PFS, P=0.084; 3-year OS, P=0.240). A significant association between survival and post-HSCT PET findings was observed in multivariate analysis(HR=5.168, P<0.001).Conclusions: PET results before and after HSCT are useful prognostic factors for DLBCL patients receiving HSCT. Patients who responded to chemotherapy, even those with positive pre-HSCT PET, are appropriate candidates for auto-HSCT.

High-dose Chemotherapy Combined with Autologous Hematopoietic Stem Cell Transplantation as Frontline Therapy for Intermediate/High-risk Diffuse Large B Cell Lymphoma

The role of autologous hematopoietic stem cell transplantation(auto-HSCT)following high-dose chemotherapy has been validated and accepted as a standard treatment for patients with relapsed diffuse large B-cell lymphoma(DLBCL).However,its clinical efficacy as frontline therapy remains to be elucidated.This study aimed to examine the feasibility of frontline auto-HSCT for newly diagnosed intermediate/high-risk DLBCL patients.We retrospectively reviewed the data of 223 patients treated with frontline auto-HSCT or chemotherapy alone(year 2008-2014)from four hospitals.The median follow-up time was 29.4 months.Between the two treatment arms among the intermediate/high-risk DLBCL patients,the 3-year overall survival(OS)and progression-free survival(PFS)rates of patients given frontline auto-HSCT were 87.6%and 81.9%,respectively,and the chemotherapy-alone group showed 3-year OS and PFS rates of 64.9%and 59.59%,respectively.Compared with the chemotherapy-alone group,the frontline auto-HSCT could eliminate the adverse impact of non-germinal center B-cell(GCB)type.In addition,in the frontline auto-HSCT group,patients who achieved complete response(CR)at auto-HSCT had a longer survival time than those who did not achieve CR.Our results suggested that frontline auto-HSCT could improve the prognosis of intennediate/high-risk DLBCL patients.

Day 100 Absolute Monocyte/Lymphocyte Prognostic Score and Survival Post Autologous Peripheral Blood Hematopoietic Stem Cell Transplantation in Diffuse Large B-Cell Lymphoma

Day 100 prognostic factors post-autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT) to predict clinical outcomes in diffuse large B-cell lymphoma (DLBCL) patients have not been studied. Thus, we retrospectively examined if day 100 absolute monocyte/lymphocyte prognostic score (AMLPS-100) affects clinical outcomes by landmark analysis from day 100 post-APBHSCT in DLBCL. Only DLBCL patients in complete remission at day 100 post-APBHSCT were evaluated. From 2000 to 2007, 134 consecutive DLBCL patients are qualified for the study. Patients with a day 100 absolute monocyte count (AMC-100) ≥ 630 cells/μL and day 100 absolute lymphocyte count (ALC-100) ≤ 1000 cells/μL experienced inferior overall survival (OS) and progression free survival (PFS). On multivariate analysis, the AMC-100 and ALC-100 remained independent predictors of OS and PFS. Combining both values into the AMLPS-100, the 5-year OS rates for low, intermediate, and high AMLPS-100 risk groups were 94% (95% CI, 83.0% - 98.1%), 70% (95% CI, 58.6% - 80.1%), and 13% (95% CI, 3.4% - 40.5%), respectively;and the 5-year PFS rates were 87% (95% CI, 74.0% - 94.1%), 68% (95% CI, 56.0% - 77.8%), and 13% (95% CI, 3.4% - 40.5%), respectively. The AMLPS-100 is a simple biomarker score that can stratify clinical outcomes from day 100 post-APBHSCT in DLBCL patients.

Autologous hematopoietic stem cell transplantation for diabetic foot:A meta-analysis

Objective:To systematically evaluate the efficacy and safety of autologous hematopoietic stem cell(AHSCs)transplantation for diabetic foot(DF).Methods:A systematic search of literatures in PubMed,Embase,the Cochrane Library,CNKI,WanFang and VIP from inception to March 2020 was conducted.Clinical randomized controlled trials of AHSCs transplantation for DF were screened according to inclusion and exclusion criteria,and meta-analysis was performed using RevMan 5.3 software.Results:A total of 13 articles were included,including 582 patients within 292 received conventional treatment in the control group and 290 additionally received AHSCs in the transplantation group.Meta-analysis results showed that compared with the control group,the transplantation group improved ulcer healing rate[RR=2.38,95%CI(1.91,2.98),P<0.00001],ankle brachial index[MD=0.14,95%CI(0.11,0.16),P<0.00001]and skin temperature of injured limb[MD=1.39,95%CI(0.93,1.86),P<0.00001].And lowered mutation rate[RR=0.10,95%CI(0.04,0.26),P<0.00001],pain scores[MD=-1.37,95%CI(-1.62,-1.12),P<0.00001]and indirect claudication scores[MD=-0.89,95%CI(-1.04,-0.75),P<0.00001].The above differences were all statistically significant(P<0.05).Conclusion:Existing evidence shows that AHSCs transplantation for DF has certain clinical effects and safety.However,more high-quality research are needed to further demonstrate the above results.

AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR LYMPHOMA: AN EVALUATION OF GRAFTS SOURCE AND MINIMAL RESIDUAL DISEASE

Objective： To determine whether the source of autologous hematopoietic stem cells altered the clinical outcomes of patients undergoing high dose chemotherapy and autologous hematopoietic stem cell transplantation （AHSCT） for aggressive lymphoma and to study the problem of minimal residual disease （MRD）. Methods： 14 lymphoma patients who had lymphoma with high risk factors, relapsed lymphoma or refractory lymphoma received autologous bone marrow transplantation （ABMT）. 14 lymphoma patients who were similar to ABMT group received autologous peripheral blood stem cells transplantation （APBSCT）. Regimen of CBV （cyclophos phamide 50-60 mg/kg/d×2 d, carmustine 15 mg/kg/d×1 d, etoposide 45-60 mg/kg/d×1 d） was received by all the patients as conditioning regimen in the transplant pretreatment followed by ABMT or APBSCT. Autologous peripheral blood stem cell （APBSC） was mobilized by CTX 2g-3g/m^2/d×2 d iv and G-CSF 5 μg/kg/d for five to seven days. MRD was continually supervised by PCR in bone marrow before and after transplantation. Cellular immunocyte function, such as natural killer cell （NK）, CD3, CD4, CD8 and slL-2R was tested before and twenty days after transplantation. Results： In ABMT group, the median time for hematopoietic recovery of absolute neutrophilia counts ≥0.5×10^9/L and platelet counts ≥20×10^9/L. was ＋18 days and ＋20 days respectively. In contrast, the APBSCT group was both at 12 days. Patients who have undergone ABMT all got complete remission （CR）, while 81.8% patients in APBSCT group got CR. The 3-year disease free survival （DFS） in APBSCT and ABMT group was 75% and 72.7% respectively （P〉0.05）. The mean days of immunity recovering in APBSCT was ＋20 days. After transplantation, MRD in 11 patients were positive, in whom 6 patients died. Conclusion： Aggressive lymphoma patients＇ hemapoiesis recovered more rapidly in APBSCT group than that in ABMT group, but 3-year DFS had no statistical difference. Patients positive for IgH/TCR-γ by molecular PCR analysis had poor DFS. Molecur monitoring of MRD using PCR techniques seems to represent a reliable prognostic indicator. Immunotherapy in the patients whose bone morrow was positive for MRD post-AHSCT may intensify remission and reduce relapse rates.

THE PRELIMINARY RESULTS OF TREATMENT OFADVANCED AND RECURRENT MALIGNANT LYMPHOMA BY BEAC REGIMEN SUPPORTED WITH AUTOLOGOUS HEMATOPOIETIC STEM CELLS TRANSPLANTATION

Objective: High dose chemotherapy supported by autologous hematopoietic stem cells transplantation (AHSCT) has developed dramaticly in recent years and become the most effective approach to improve radical treatment for the chemo-sensitive lymphoma. The purposes of this study was to evaluate the efficacy and tolerance of preparative regimen BEAC and hematopoietic reconsti- tution after high dose chemotherapy in Chinese patients with advanced and recurrent lymphoma. Methods: After confirmed complete or partial remission from conventional chemotherapy, 24 patients with advanced or recurrent lymphoma including 1 recurrent HD and 23 NHL, 16 male and 8 female with median age of 29 (13-50) years, were enrolled into this study and treated by BEAC regimen (CTX 3600-4000 mg/m2, VP-16 1200 mg/m2. BCNU 300 mg/m2 and Ara-C 1500-2000 mg/m2). 3 patients were supported by ABMT and 21 by APBSCT. Mobilization regimen for APBSCT was CTX 3500 mg/m2 + G-CSF 3.5-5 mg/kg + Dexamethasone 10 mg. Autologous hematopoietic stem cells was re-infused 24-48 h after completion of high dose chemotherapy. Results: MNC 1.3 (1.0-1.7) 108/kg and MNC 1.8 (1.0-4.4) 108, CFU-GM 5.1 (1.9-9.6) 105/kg plus CD34 + cells 2.9 (1.9-8.7) 106/kg were re-infused in the ABMT group and APBSCT group respectively. All patients obtained prompt and sustained hematopoietic reconstitution. ANC 0.5 109/L and Pt 2.0 109/L were at day 9 (6-17) and day 10 (0-31) respectively. 16 patients were alive with median 21 (2-69) months follow-up till end of May, 2001. 1, 2 and 3 years survival rate were 60.5%, 50.1% and 50.1%, respectively. Non-hematologic toxicity was mild and tolerable. Conclusions: High dose chemotherapy supported by AHSCT in the treatment of previously-untreated poor- prognostic and recurrent lymphoma was a safe and effective modality. Further investigation was warranted.

HIGH DOSE CHEMORADIOTHERAPY WITH AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN THE TREATMENT OF ADVANCED HODGKIN's LYMPHOMA:A REPORT OF 11 CASES

Objective: High dose therapy (HDT) with autologous hematopoietic stem cell transplantation (ASCT) has become one of the important salvage treatments for the Hodgkin抯 Lymphoma patients with relapsed or resistant disease, but its role as the primary treatment remains indefinite. This study was designed to further evaluate its status in the combined modality treatment, especially, to discuss its value in the primary treatment of the patients who had advanced disease with poor prognostic factors. Methods: Eleven patients who had advanced or relapsed disease with poor prognostic factors were enrolled in this study. Among them, 9 cases had primary treatment, and 2 cases had secondary treatment; one patient received autologous bone marrow transplantation (ABMT), and 10 patients received autologous peripheral blood stem cell transplantation (APBSCT). After induction treatment 4 cases achieved complete response (CR) and 7 cases achieved partial response (PR). High dose chemotherapy combined with total body irradiation (TBI) or total lymph node irradiation (TLI)/subtotal lymph node irradiation (STLI) were adopted in 7 cases and only high dose chemotherapy were adopted in 4 cases as the transplant preparative regimens. 5 cases received complementary irradiation in the primary sites after transplant. Results: The patients who had CR before transplantation were given consolidative therapy. Among the rest with PR, 2 cases achieved CR, 1 case PR, and 4 cases SD. Furthermore all these patients who maintained SD had bone involvement. With a median follow-up for all patients of 13(1-80) months, all of them are alive currently. Four cases are event-free survival (EFS); 4 cases with bone involvement are progression-free survival (PFS); 3 cases experienced relapse after transplant, one of them is EFS for 42 months again after a local relapsed site irradiation; the other two cases are being given further salvaged treatment now. According to the Life Tables method, the cumulative probability of 6-year PFS and OS is 55.68% and 100% respectively. The dominating transplant- related toxicity was bone marrow suppression in grades IV. No obvious cardiac, hepatic, and nephritic toxicity was found. No transplant related mortality. Conclusion: HDT combined with ASCT is a method worthwhile to further study for the treatment of the patients with advanced or relapsed Hodgkin抯 Lymphoma with poor prognostic factors.

Skin Disinfection with 2% Chlorine Gluconate-Adine in Autologous Peripheral Hematopoietic Stem Cell Transplantation Patients

Background: Autologous peripheral blood hematopoietic stem cell transplantation is widely used in the treatment of malignant lymphoma. Patients are prone to infection during the transplantation immune deficiency period. There has been a lot of clinical research into how to better manage this period of vulnerability. Objective: This study aims to investigate the efficacy of 2% chlorhexidine gluconate (CHG) for skin disinfection in patients undergoing autologous hematopoietic stem cell transplantation (HSCT) and observe any adverse reactions. Methods: A total of 106 patients receiving autologous hematopoietic stem cell transplantation from November 2019 to December 2020 in our district were selected as the control group. From January 2021 to January 2022, 106 patients with autologous hematopoietic stem cells were included in the experimental group. The control group used the immersion bath method. The experimental group was treated with an improved scrub bath method (including 3M 2% chlorhexidine gluconate medical sanitary wipes to wipe the whole skin once). Results: The bacteria-carrying rate of the improved method (37.74%) was significantly better than that of the traditional soaking method (72.64%), and the difference was statistically significant (P Conclusion: The improved bath/wipe method has a significant positive effect on skin disinfection for patients undergoing HSCT.

Comprehensive evaluation of nutritional status before and after hematopoietic stem cell transplantation in 170 patients with hematological diseases

Objective： To investigate the nutritional status of patients before and after hematopoietic stem cell transplantation（HSCT）, and explore optimal methods for assessing nutritional status in patients with hematological diseases.Methods： This cohort study enrolled 170 patients who were diagnosed with hematological diseases and underwent allogeneic HSCT in the Department of Hematology, Peking University People＇s Hospital between May2011 and April 2013. We used fixed-point continuous sampling and four nutritional screening tools, Nutritional Risk Screening 2002（NRS-2002）, Mini Nutritional Assessment（MNA）, Subjective Global Assessment（SGA） and Malnutrition Universal Screening Tools（MUST）, in combination with body measurements, to extensively screen and evaluate nutritional risks and status in patients receiving HSCT before entering and after leaving laminar air flow rooms.Results： After HSCT, patients had significant reduction in weight, hip circumference, waist-hip ratio, calf circumference, mid-upper arm circumference, and suprailiac skinfold thickness compared with pre-HSCT measurements. Before HSCT, NRS-2002 identified that 21.2% of patients were at nutritional risks, compared with100% after HSCT. MUST indicated that before HSCT, 11.77% of patients were at high nutritional risk,compared with 59.63% after HSCT. MNA assessed that 0.06% of patients were malnourished before HSCT,compared with 19.27% after HSCT. SGA identified that before HSCT, 1.76% of patients had mild to severe malnutrition, which increased to 83.3% after HSCT. There is a significant increase in the nutritional risk and malnutrition in patients who received HSCT.Conclusions： Before HSCT, some patients already had nutritional risk or nutritional deficiencies, and prompt and close nutritional screening or assessment should be performed. The nutritional status of patients after HSCT was generally deteriorated compared with that before transplantation. Body measurements should be taken more frequently during the subsequent treatment window in the laminar air flow rooms. After HSCT, it is recommended to combine MNA and SGA to fully evaluate the nutritional status, and thus provide timely and reasonable nutritional support.

Donor-Derived CD19-Targeted T Cell Infusion Eliminates B Cell Acute Lymphoblastic Leukemia Minimal Residual Disease with No Response to Donor Lymphocytes after Allogeneic Hematopoietic Stem Cell Transplantation

Leukemia relapse is still the leading cause of treatment failure after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for B cell acute lymphoblastic leukemia (B-ALL). Relapsed patients with BALL after allo-HSCT have a very short median survival. Minimal residual disease (MRD) is predictive of forthcoming hematological relapse after hematopoietic stem cell transplantation (HSCT);furthermore, eliminating MRD effectively prevents relapse. Donor lymphoblastic infusion (DLI) is the main established approach to treat B-ALL with MRD after allo-HSCT. However, about one-third of patients with MRD are non-responsive to DLI and their prognosis worsens. Although donor-derived cluster of differentiation (CD)19-directed chimeric antigen receptor-modified (CAR) T cells (CART19s) can potentially cure leukemia, the efficiency and safety of infusions with these cells have not yet been investigated in patients with MRD after HSCT. Between September 2014 and February 2018, six patients each received one or more infusions of CART19s from HSCT donors. Five (83.33%) achieved MRD-negative remission, and one case was not responsive to the administration of CAR T cells. Three of the six patients are currently alive without leukemia. No patient developed acute graft-versus-host disease (aGVHD), and no patient died of cytokine release syndrome. Donor-derived CAR T cell infusions seem to be an effective and safe intervention for patients with MRD in B-ALL after allo-HSCT and for those who were not responsive to DLI.

Autologous transplantation of bone marrow mesenchymal stem cells on diabetic patients with lower limb ischemia

Objective： To study the efficacy and safety of autologous transplantation of bone marrow mesenchymal stem cells on diabetic patients with lower limb ischemia. Methods： Fifty Type 2 diabetic patients with lower limb ischemia were enrolled and randomized to either transplanted group or control group. Patients in both group received the same conventional treatment. Meanwhile, 20 ml bone marrow from each transplanted patient were collected, and the mesenchymal stem cells were separated by density gradient centrifugation and cultured in the medium with autologous serum. After three-weeks adherent culture in vitro, 7.32×10^8-5.61×10^9 mesenchymal stem cells were harvested and transplanted by multiple intramuscular and hypodermic injections into the impaired lower limbs. Results： At the end of 12-week follow-up, 5 patients were excluded from this study because of clinical worsening or failure of cell culture. Main ischemic symptoms, including rest pain and intermittent claudication, were improved significantly in transplanted patients. The ulcer healing rate of the transplanted group （1 5 of 18, 83.33%） was significantly higher than that of the control group （9 of 20, 45.00%, P=0.012）.The mean of resting ankle-brachial index （ABI） in transplanted group significantly was increased from 0.61±0.09 to 0.74±0.11 （P〈0.001）. Magnetic resonance angiography （MRA） demonstrated that there were more patients whose score of new vessels exceeded or equaled to 2 in the transplant patients （11 of 15） than in control patients （2 of 14, P=0.001）. Lower limb amputation rate was significantly lower in transplanted group than in the control group （P=0.040）. No adverse effects was observed in transplanted group. Conclusion： These results indicate that the autologous transplantation of bone marrow mesenchymal stem cells relieves critical lower limb ischemia and promotes ulcers healing in Type 2 diabetic patients.

Decitabine for Relapsed Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

Relapse after allogeneic hematopoietic stem cell transplantation（allo-HSCT） remains a main question on treatment failure. Current strategies for management that usually include salvage chemotherapy, donor lymphocytic infusion and second transplantation. Our study assessed the efficacy of decitabine（DAC） for treating patients with acute lymphoblastic leukemia（ALL） who relapsed after allogeneic hematopoietic stem cell transplantation（allo-HSCT）. We retrospectively analyzed the outcomes of 12 patients with relapsed ALL after allo-HSCT who received DAC therapy. Nine patients received DAC combined with chemotherapy and donor stem cell infusion, and 3 patients received single-agent DAC. Ten of the 12 patients achieved complete remission（CR）, 1 achieved a partial remission（PR）, and 1 had no response（NR） after treatment at the latest follow-up（LFU）, the median survival was 11.2 months（range, 3.8–34, 7 months）. The 1-and 2-year overall survival（OS） rates were 50%（6/12） and 25%（3/12）, respectively. Five patients were still alive; 4 had maintained CR and 1 was alive with disease. Patients with Philadelphia chromosome-positive ALL had higher survival rate than patients with Philadelphia chromosome-negative ALL（57.1% vs. 20%）. No aggravated flares of graft-versus-host disease（GVHD） were observed during DAC treatment. Therefore, DAC may be a promising therapeutic agent for ALL recurrence after allo-HSCT.

Umbilical Cord Blood-derived Mesenchymal Stem Cells Ameliorate Graft-Versus-Host Disease Following Allogeneic Hematopoietic Stem Cell Transplantation through Multiple Immunoregulations

Summary： Although mesenchymal stem cells （MSCs） are increasingly used to treat graft-versus-host disease （GVHD）, their immune regulatory mechanism in the process is elusive. The present study aimed to investigate the curative effect of third-party umbilical cord blood-derived human MSCs （UCB-hMSCs） on GVHD patients after allogeneic hematopoietic stem cell transplantation （allo-HSCT） and their immune regulatory mechanism. Twenty-four refractory GVHD patients after allo-HSCT were treated with UCB-hMSCs. Immune cells including T lymphocyte subsets, NK ceils, Treg cells and dendritic cells （DCs） and cytokines including interleukin-17 （IL-17） and tumor necrosis factor-alpha （TNF-α） were monitored before and after MSCs transfusion. The results showed that the symptoms of GVHD were alleviated significantly without increased relapse of primary disease and transplant-related complications after MSCs transfusion. The number of CD3^＋, CD3＋CD4^＋ and CD3＋CD8^＋ cells decreased significantly, and that of NK cells remained unchanged, whereas the number of CD4^＋ and CD8^＋ Tregs increased and reached a peak at 4 weeks; the number of mature DCs, and the levels of TNF-α and IL-17 decreased and reached a trough at 2 weeks. It was concluded that MSCs ameliorate GVHD and spare GVL effect via immunoregulations.

Clinical Observation of Patients with Hematologic Malignancies Treated with Hematopoietic Stem Cell Transplantation

To evaluate the therapeutic effect of hematopoietic stem cell transplantation (HSCT), we performed HSCT in 30 patients with hematologic maligancies. Of the 30 patients, 10 underwent autologous peripheral blood stem cell transplantation (auto-PBSCT), 13 underwent myeloablative allogeneic HSCT while 7 underwent nonmyeloablative allogeneic HSCT, which were designated as autologous group, myeloablative group and nonmyeloablative group, respectively. All patients except the one who underwent cord blood transplantation, were successfully engrafted. Median time for the granulocytes≥0.5×10\+9/L and platelets≥20×10\+9/L were 12 days and 13 days respectively in autologous group, 16 days and 19 days in myeloablative group, 15 days and 12 days in nonmyeloablative group. In myeloablative group, acute graft-versus-host diseases (aGVHD) was observed in 3 patients, all of which were I—Ⅱgrade. Oral mucous cGVHD was observed in 1 patient. In nonmyeloablative group, 1 patient developed intestinal aGVHD grade Ⅳ and cutaneous cGVHD was induced by donor lymphocyte infusions (DLI) in 3 patients. 1 patient had hematological relapse in autologous group. 1 patient had cytogenetic relapse in myeloablative group. In nonmyeloablative group 3 patients had cytogenetic relapse and were cured by DLI, 1 patient had hematological relapse. 4 of the 30 patients died of infection (2 patients), grade Ⅳ aGVHD (1) and relapse (1) respectively. 26 patients are still alive. 3 years overall survival (OS) and 3 years disease free survival (DFS) were 100 % and 64.81 % respectively in autologous group, 78.75 % and 63 % respectively in myeloablative group while both 66.67 % in nonmyeloablative group. In conclusion, autologous group had less transplant-related complications and mortality. Active prophylaxis of relapse could significantly promote DFS. The transplant-related mortality limited DFS in myeloablative group. More relapses occurred in nonmyeloablative group, but could be cured by DLI.

Prophylactic antiviral therapy in allogeneic hematopoietic stem cell transplantation in hepatitis B virus patients

AIM: To investigate the timing, safety and efficacy of prophylactic antiviral therapy in patients with hepatitis B virus(HBV) infection undergoing allogeneic hematopoietic stem cell transplantation(allo-HSCT).METHODS: This prospective study recruited a total of 57 patients diagnosed with malignant hematological diseases and HBV infection at the First Affiliated Hospital of Sun Yat-sen University between 2006 and 2013.The patients were classified as hepatitis B surface antigen(HBs Ag)-positive or HBs Ag-negative/ anti HBcpositive.Patients were treated with chemotherapy followed by antiviral therapy with nucleoside analogues.Patients underwent allo-HSCT when serum HBV DNA was < 103 IU/mL.Following allo-HSCT, antiviral therapy was continued for 1 year after the discontinuation of immunosuppressive therapy.A total of 105 patients who underwent allo-HSCT and had no HBV infection were recruited as controls.The three groups were compared for incidence of graft-vs-host disease(GVHD), drug-induced liver injury, hepatic veno-occlusive disease, death and survival time.RESULTS: A total of 29 of the 41 subjects with chronic GVHD exhibited extensive involvement and 12 exhibited focal involvement.Ten of the 13 subjects with chronic GVHD in the HBs Ag(-)/hepatitis B core antibody(+) group exhibited extensive involvement and 3 exhibited focal involvement.Five of the 10 subjects with chronic GVHD in the HBs Ag(+) group exhibited extensive involvement and 5 exhibited focal involvement.The non HBV-infected group did not differ significantly from the HBs Ag-negative/anti HBc-positive and the HBs Ag-positive groups which were treated with nucleoside analogues in the incidence of graft-vs-host disease(acute GVHD; 37.1%, 46.9% and 40%, respectively; P = 0.614; chronic GVHD; 39%, 40.6% and 40%, respectively; P = 0.98), drug-induced liver injury(25.7%, 18.7% and 28%, respectively; P = 0.7),death(37.1%, 40.6% and 52%, respectively; P = 0.4) and survival times(P = 0.516).One patient developed HBV reactivation(HBs Ag-positivity) due to early discontinuation of antiviral therapy.CONCLUSION: Suppression of HBV DNA to < 103 IU/m L before transplantation, continued antiviral therapy and close monitoring of immune markers and HBV DNA after transplantation may assure the safety of alloHSCT.

Determining the optimal time for bortezomib-based induction chemotherapy followed by autologous hematopoietic stem cell transplant in the treatment of multiple myeloma

In our study, we determined the efficacy of bortezomib-based induction therapy followed by autologous stem cell transplant （ASCT） in newly diagnosed and relapsed/refractory （R/R） multiple myeloma （MM） patients and compared the advantages of early versus late transplant. We used a retrospective analysis to examine 62 patients, including 46 cases of newly diagnosed MM （early transplant group） and 16 cases of relapsed/refractory MM （late transplant group）. All of these patients received bortezomib-based induction therapy followed by ASCT. The efficacy and side effects of the treatment regimen were analyzed. Patients＇ overall survival （OS） and progression-free survival （PFS） times were determined. The ratio of complete remission to near-complete remission （CR/nCR） was 69.5% versus 56.2% （P=0.361）, respectively, for the early transplant group versus the late transplant group, respectively, after receiving bortezomib-based induction therapy; the overall response rates of the two group were 91.3 % and 81.2 %, respectively （P=0.369）. After receiving ASCT, the CR/nCR of the two groups increased to 84.8% and 81.3%, respectively. The median time required for neutrophil engraftment of the early transplant group and the late transplant group was 11 and 14.5 days, respectively （P=0.003）; the median time required for platelet engra^nent was 13 and 21.5 days （P=0.031）, respectively. There were no significant differences in the toxic side effects observed during induction therapy and ASCT between the two groups. The OS of the two groups was not statistically different （P=0.058）. The PFS of the early transplant group and the late transplant group was 41.6 and 26.5 months, respectively （P=0.008）. Multivariate analysis demonstrated that the time of receiving ASCT, the types of M protein, and the International Staging System （ISS） stage were all independent factors that influenced PFS. In conclusion, patients in a suitable condition for ASCT should be recommended to have an early ASCT immediately after diagnosis.