Safety and efficacy assessment of allogeneic human dental pulp stem cells to treat patients with severe COVID-19: structured summary of a study protocol for a randomized controlled trial (Phase I / II)
OBJECTIVES To assess the safety and therapeutic effects of allogeneic human dental pulp stem cells (DPSCs) in treating severe pneumonia caused by COVID-19. TRIAL DESIGN This is a single centre, two arm ratio 1:1, triple blinded, randomized, placebo-controlled, parallel group, clinical trial. PARTICIPANTS Twenty serious COVID-19 cases will be enrolled in the trial from April 6th to December 31st 2020. INCLUSION CRITERIA hospitalised patients at Renmin Hospital of Wuhan University satisfy all criteria as below: 1)Adults aged 18-65 years;2)Voluntarily participate in this clinical trial and sign the "informed consent form" or have consent from a legal representative.3)Diagnosed with severe pneumonia of COVID-19: nucleic acid test SARS-CoV-2 positive; respiratory distress (respiratory rate > 30 times / min); hypoxia (resting oxygen saturation < 93% or arterial partial pressure of oxygen / oxygen concentration < 300 mmHg).4)COVID-19 featured lung lesions in chest X-ray image. EXCLUSION CRITERIA Patients will be excluded from the study if they meet any of the following criteria. 1.Patients have received other experimental treatment for COVID-19 within the last 30 days;2.Patients have severe liver condition (e.g., Child Pugh score >=C or AST> 5 times of the upper limit);3.Patients with severe renal insufficiency (estimated glomerular filtration rate <=30mL / min/1.73 m(2)) or patients receiving continuous renal replacement therapy, hemodialysis, peritoneal dialysis;4.Patients who are co-infected with HIV, hepatitis B, tuberculosis, influenza virus, adenovirus or other respiratory infection viruses;5.Female patients who have no sexual protection in the last 30 days prior to the screening assessment;6.Pregnant or lactating women or women using estrogen contraception;7.Patients who are planning to become pregnant during the study period or within 6 months after the end of the study period;8.Other conditions that the researchers consider not suitable for participating in this clinical trial. INTERVENTION AND COMPARATOR There will be two study groups: experimental and control. Both will receive all necessary routine treatment for COVID-19. The experimental group will receive an intravenous injection of dental pulp stem cells suspension (3.0x10(7) human DPSCs in 30ml saline solution) on day 1, 4 and 7; The control group will receive an equal amount of saline (placebo) on the same days. Clinical and laboratory observations will be performed for analysis during a period of 28 days for each case since the commencement of the study. MAIN OUTCOMES 1. Primary outcome The primary outcome is Time To Clinical Improvement (TTCI). By definition, TTCI is the time (days) it takes to downgrade two levels from the following six ordered grades [(grade 1) discharge to (grade 6) death] in the clinical state of admission to the start of study treatments (hDPSCs or placebo). Six grades of ordered variables: GradeDescriptionGrade 1:Discharged of patient;Grade 2:Hospitalized without oxygen supplement;Grade 3:Hospitalized, oxygen supplement is required, but NIV / HFNC is not required;Grade 4:Hospitalized in intensive care unit, and NIV / HFNC treatment is required;Grade 5:Hospitalized in intensive care unit, requiring ECMO and/or IMV;Grade 6:Death. ABBREVIATIONS NIV, non-invasive mechanical ventilation; HFNC, high-flow nasal catheter; IMV, invasive mechanical ventilation. 2. Secondary outcomes 2.1 vital signs: heart rate, blood pressure (systolic blood pressure, diastolic blood pressure). During the screening period, hospitalization every day (additional time points of D1, D4, D7 30min before injection, 2h +/- 30min, 24h +/- 30min after the injection) and follow-up period D90 +/- 3 days. 2.2 Laboratory examinations: during the screening period, 30 minutes before D1, D4, D7 infusion, 2h +/- 30min, 24h +/- 30min after the end of infusion, D10, D14, D28 during hospitalization or discharge day and follow-up period D90 +/- 3 days. 2.3 Blood routine: white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils, neutrophils, lymphocytes, monocytes, eosinophils Acidic granulocyte count, basophil count, red blood cell, hemoglobin, hematocrit, average volume of red blood cells, average red blood cell Hb content, average red blood cell Hb concentration, RDW standard deviation, RDW coefficient of variation, platelet count, platelet specific platelet average Volume, platelet distribution width,% of large platelets; 2.4 Liver and kidney function tests: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, prealbumin, total protein, albumin, globulin, white / globule ratio , Total bilirubin, direct bilirubin, cholinesterase, urea, creatinine, total carbon dioxide, uric acid glucose, potassium, sodium, chlorine, calcium, corrected calcium, magnesium, phosphorus, calcium and phosphorus product, anion gap, penetration Pressure, total cholesterol, triacylglycerol, high density lipoprotein cholesterol, Low density lipoprotein cholesterol, lipoprotein a, creatine kinase, lactate dehydrogenase, estimated glomerular filtration rate. 2.5 Inflammation indicators: hypersensitive C-reactive protein, serum amyloid (SAA); 2.6 Infectious disease testing: Hepatitis B (HBsAg, HBsAb, HBeAg, HBeAb, HBcAb), Hepatitis C (Anti-HCV), AIDS (HIVcombin), syphilis (Anti-TP), cytomegalovirus CMV-IgM, cytomegalovirus CMV-IgG; only during the screening period and follow-up period D90 +/- 3. 2.7 Immunological testing: Collect peripheral blood to detect the phenotype of T lymphocyte, B lymphocyte, natural killer cell, Macrophage and neutrophil by using flow cytometry. Collect peripheral blood to detect the gene profile of mononuclear cells by using single-cell analyses. Collect peripheral blood serum to detect various immunoglobulin changes: IgA, IgG, IgM, total IgE; Collect peripheral blood serum to explore the changes of cytokines, Th1 cytokines (IL-1 beta, IL-2, TNF-a, ITN-gamma), Th2 cytokines (IL-4, IL-6, IL -10). 2.8 Pregnancy test: blood beta-HCG, female subjects before menopause are examined during the screening period and follow-up period D90 +/- 3. 2.9 Urine routine: color, clarity, urine sugar, bilirubin, ketone bodies, specific gravity, pH, urobilinogen, nitrite, protein, occult blood, leukocyte enzymes, red blood cells, white blood cells, epithelial cells, non-squamous epithelial cells , Transparent cast, pathological cast, crystal, fungus; 2.10 Stool Routine: color, traits, white blood cells, red blood cells, fat globules, eggs of parasites, fungi, occult blood (chemical method), occult blood (immune method), transferrin (2h +/- 30min after the injection and not detected after discharge). RANDOMIZATION Block randomization method will be applied by computer to allocate the participants into experimental and control groups. The random ratio is 1:1. BLINDING (MASKING): Participants, outcomes assessors and investigators (including personnel in laboratory and imaging department who issue the sample report or image observations) will be blinded. Injections of cell suspension and saline will be coded in accordance with the patient's randomisation group. The blind strategy is kept by an investigator who does not deliver the medical care or assess primary outcome results. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): Twenty participants will be randomized to the experimental and control groups (10 per group). TRIAL STATUS Protocol version number, hDPSC-CoVID-2019-02-2020 Version 2.0, March 13, 2020. Patients screening commenced on 16(th) April and an estimated date of the recruitment of the final participants will be around end of July. . TRIAL REGISTRATION Registration: World Health Organization Trial Registry: ChiCTR2000031319; March 27,2020. ClinicalTrials.gov Identifier: NCT04336254; April 7, 2020 Other Study ID Numbers: hDPSC-CoVID-2019-02-2020 FULL PROTOCOL The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
Efficacy and safety of anti-CD19 CAR T-cell therapy in 110 patients with B-cell acute lymphoblastic leukemia with high-risk features
Blood advances. 2020;4(10):2325-2338
Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is effective in patients with advanced B-cell acute lymphoblastic leukemia (B-ALL). However, efficacy data is sparse in subgroups of patients with high-risk features such as BCR-ABL+, TP53 mutation, extramedullary disease (including central nervous system leukemia) or posttransplant relapse. It is also uncertain whether there is an added benefit of transplantation after anti-CD19 CAR T-cell therapy. We conducted a phase 1/2 study of 115 enrolled patients with CD19+ B-ALL. A total of 110 patients were successfully infused with anti-CD19 CAR T cells. In all, 93% of patients achieved a morphologic complete remission, and 87% became negative for minimal residual disease. Efficacy was seen across all subgroups. One-year leukemia-free survival (LFS) was 58%, and 1-year overall survival (OS) was 64% for the 110 patients. Seventy-five nonrandomly selected patients (73.5%) subsequently received an allogeneic hematopoietic stem cell transplant (allo-HSCT). LFS (76.9% vs 11.6%; P < .0001; 95% confidence interval [CI], 11.6-108.4) and OS (79.1% vs 32.0%; P < .0001; 95% CI, 0.02-0.22) were significantly better among patients who subsequently received allo-HSCT compared with those receiving CAR T-cell therapy alone. This was confirmed in multivariable analyses (hazard ratio, 16.546; 95% CI, 5.499-49.786). Another variate that correlated with worse outcomes was TP53 mutation (hazard ratio, 0.235; 95% CI, 0.089-0.619). There were no differences in complete remission rate, OS, or LFS between groups of patients age 2 to 14 years or age older than 14 years. Most patients had only mild cytokine release syndrome and neurotoxicity. Our data indicate that anti-CD19 CAR T-cell therapy is safe and effective in all B-ALL subgroups that have high-risk features. The benefit of a subsequent allo-HSCT requires confirmation because of nonrandom allocation. This trial was registered at www.clinicaltrials.gov as #NCT03173417.
Myeloablative Conditioning for Allogeneic Transplantation Results in Superior Disease-Free Survival for Acute Myeloid Leukemia and Myelodysplastic Syndromes with Low/Intermediate, but not High Disease Risk Index: A CIBMTR Study: Superior DFS with MAC compared to RIC HCT in AML/MDS with low/intermediate risk DRI
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Myeloablative (MAC) as compared to reduced-intensity conditioning (RIC) is generally associated with lower relapse risk after allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). However, disease specific risk factors in AML/MDS can further inform when MAC vs. RIC may yield differential outcomes. We analyzed HCT outcomes stratified by the disease risk index (DRI) in 4387 adults (age 40-65 years) to identify the impact of conditioning intensity. In the low/intermediate risk DRI cohort, RIC was associated with lower non-relapse mortality (NRM) (HR=0.74, 95% CI 0.62-0.88; p<0.001), but significantly higher relapse risk (HR=1.54, 95% CI 1.35-1.76; p<0.001) and thus inferior disease-free survival (DFS) (HR=1.19, 95% CI 1.07-1.33; p=0.001). In the high/very high risk DRI cohort, RIC resulted in marginally lower NRM (HR=0.83, 95% CI 0.68-1.00; p=0.051), and significantly higher relapse risk (HR=1.23, 95% CI 1.08-1.41; p=0.002) leading to similar DFS using either RIC or MAC. These data support MAC over RIC as the preferred conditioning intensity for AML/MDS with low/intermediate risk DRI, but similar benefit to RIC in high/very high risk DRI. Novel MAC regimens with less toxicity could benefit all, but more potent anti-neoplastic approaches are needed for the high/very high risk DRI group.
[Efficacy of Haploidentical Hematopoietic Stem Cell Transplantation in Treatment of Intermediate Risk Acute Myeloid Leukemia with Negative for FLT3-ITD, NPM1 or Biallelic CEBPA Mutation]
Adult patients aged 40-65 years with acute myeloid leukaemia or myelodysplastic syndrome (AML/MDS) (n=4387)
Reduced intensity conditioning (RIC) and low/intermediate risk (n=999), RIC and high/very high risk (n=728)
Myeloablative conditioning (MAC) and low/intermediate risk (n=1539), MAC and high/very high risk (n=1121)
In the low/intermediate risk disease risk index (DRI) cohort, RIC was associated with lower non-relapse mortality (NRM) , but significantly higher relapse risk and thus inferior disease-free survival (DFS). In the high/very high risk DRI cohort, RIC resulted in marginally lower NRM, and significantly higher relapse risk leading to similar DFS using either RIC or MAC.
Zhongguo shi yan xue ye xue za zhi. 2020;28(3):731-736
OBJECTIVE To compare the efficacy of haploidentical hematopoietic stem cell transplantation (hi-HSCT) HLA-matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) and post-remission chemotherapy (PR-CT) in treatment of intermediate risk acute myeloid leukemia with negative for FLT3-ITD, NPM1 or biallelic CEBPA mutation. METHODS The clinical data of patients with intermediate risk NPM1(wt)/non-CEBPA(dm)/FLT3-ITD(neg) AML from October 2009 to May 2016 were retrospectively analyzed. RESULTS The overall survival rate of the patients treated with PR-CT, MSD-HSCT or hi-HSCT was 63.7%, 71.7%, 75.5%, respectively (P0.05); the disease-free survival (DFS) rate was 52.8%, 67.1%, 71.3% respectively (P0.001); the cumulative incidence of relapse was 24.7%, 16.9%, 14.4% respectively (P0.05); the non-relapse mortality was 26.2%, 17.3%, 14.4% reapectively (P0.05). The analysis of transplantation, related adverse events showed that II-IV grade of aGVHD in the MSD-HSCT group and hi-HSCT group was 48.9% and 45.6% respectively (P0.05); the extensive cGVHD event was 21.6% and 8.8% (P0.05) respectively. CONCLUSION The efficiency of hi-HSCT and MSD-HSCT is superior to that of PR-CT for treatment of patients with intermediate risk NPM1(wt)/non-CEBPA(dm)/FLT3-ITD(neg) AML after CR1, there is no statistically significant difference in the efficiency of consolidatorg treatment and the transplantation-related mortality between hi-HSCT and MSD-HSCT.
UBE2C Is Upregulated by Estrogen and Promotes Epithelial-Mesenchymal Transition via p53 in Endometrial Cancer
Molecular Cancer Research : Mcr. 2020;18(2):204-215
Ubiquitin-conjugating enzyme E2C (UBE2C) plays important roles in tumor progression; nevertheless, its function in endometrial cancer remains unclear. This study elucidated the impact of UBE2C on endometrial cancer and its underlying mechanism. Human endometrial cancer and normal endometrial tissues were acquired from patients at Wuhan Union Hospital and UBE2C expression was detected by Western blotting and qRT-PCR. Endometrial cancer cells were transfected with a UBE2C overexpression plasmid or UBE2C-specific short hairpin RNA (shRNA) to up- or downregulate UBE2C expression, respectively. CCK8 and transwell assays were applied to assess the effects of UBE2C on cell proliferation, migration, and invasion. We found a significant elevation of UBE2C expression in patients with endometrial cancer, and that UBE2C upregulation was associated with advanced histologic grade, FIGO stage, recurrence, and shorter overall survival. UBE2C knockdown inhibited endometrial cancer cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), whereas UBE2C overexpression exerted the opposite effects. UBE2C downregulation increased p53 and its downstream p21 expression, with p53 overexpression reversing the EMT-promoting effects of UBE2C. UBE2C enhanced p53 ubiquitination to facilitate its degradation in endometrial cancer cells. Estradiol (E2) induced UBE2C expression via estrogen receptor α, which binds directly to the UBE2C promoter element. Silencing of UBE2C inhibited E2-promoted migration, invasion, and EMT in vitro and in vivo. IMPLICATIONS UBE2C-mediated tumor EMT promotion by estrogen is a novel mechanism for the progression of estrogen-induced endometrial cancer, which could offer new biomarkers for diagnosis and therapy of endometrial cancer in the future.
Reduced-intensity versus Myeloablative Conditioning Regimens for Younger Adults with Acute Myeloid Leukemia and Myelodysplastic Syndrome: A systematic review and meta-analysis
Journal of Cancer. 2020;11(17):5223-5235
Background: Historically, reduced-intensity conditioning (RIC) was recommended to be performed for older patients who were considered ineligible for myeloablative conditioning (MAC) before allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the evidence regarding the optimal conditioning intensity in younger patients with AML or MDS is weak and contradictory. Methods: PubMed, Medline, Embase, and other online sources were searched from the initial period to February 25, 2020. Odds ratios and 95% confidence intervals were calculated to estimate pooling effects. Results: Four randomized controlled trials (RCTs) about conditioning intensity involving 633 patients were included. There were no significant differences of 1/2/4/5 years progression-free survival (PFS) and relapse incidence (RI) between two conditioning intensities. Overall survival (OS) was similar at 1/2/4 years, but patients receiving RIC had a higher OS at 5 years. Additionally, RIC were associated with lower non-relapse mortality, less grade II-IV and grade III-IV acute graft-versus-host disease (GVHD), and lower incidence of chronic GVHD compared with MAC regimens. Subgroup analysis showed similar OS and RI for AML patients, and there was a trend towards lower NRM and grade II-IV aGVHD in RIC group. Available data for MDS indicated that OS, PFS, and RI were comparable. For intermediate-risk patients, there was no evidence that RIC is inferior to MAC. However, for high-risk patients, MAC tends to perform better. Conclusions: Based on the above results, it might be concluded that RIC is a feasible treatment option for adults with AML or MDS younger than 66 years, particularly those with intermediate-risk disease. Future RCTs incorporating of risk stratifications are warranted to guide the optimal decision under certain conditions.
Changes in social support among patients with hematological malignancy undergoing hematopoietic stem cell transplantation in Souzhou, China
Indian journal of cancer. 2020;57(3):253-261
BACKGROUND Evidence regarding social support in patients is mostly from cross-sectional studies. Very few studies have focused on the change in social support systems before and after hematopoietic stem cell transplantation. METHODS A total of 191 patients were investigated before transplantation and at 30, 90 and 180 days post-transplantation. The social support for patients was evaluated by the Perceived Social Support Scale (PSSS). RESULTS The overall PSSS scores showed a continuous decline in means from 71.29 ± 9.73 before the transplantation to 69.44 ± 10.61, 68.73 ± 10.04, and 66.37 ± 12.02 at 30, 90 and 180 days post-transplantation, respectively. In comparison to the baseline, the overall PSSS scores decreased significantly at 90 and 180 days post-transplantation (P < .05). The Generalized Estimated Equation (GEE) analysis found that patients with no transplant-related complications, higher household income, and better educational status had preferable social support. CONCLUSION Social support presented a marked downward trend during the six month period. Patients with no transplant-related complications, higher household income and better educational status had preferable social support. Therefore, social support as a high-priority quality of life should be given close attention in the early phase of transplantation. Positive measures should be taken to improve social support in the early phase of transplantation especially among individuals undergoing this procedure for the first time.
Incidence, risk factors, and clinical significance of Epstein-Barr virus reactivation in myelodysplastic syndrome after allogeneic haematopoietic stem cell transplantation
Annals of hematology. 2019
Epstein-Barr virus (EBV) reactivation is a life-threatening complication after allogeneic haematopoietic stem cell transplantation (allo-HSCT). In this study, we investigated the characteristics of EBV reactivation in 186 consecutive myelodysplastic (MDS) patients who underwent allo-HSCT in our centre. In 35 patients (18.8%) who experienced EBV reactivation after allo-HSCT, the median onset was 53 days (range 4-381 days). The cumulative incidence of EBV reactivation at the first, sixth, and twelfth month after allo-HSCT was 10.7%, 15.1%, and 17.9%, respectively. Twenty-five patients (71.4%) received pre-emptive rituximab therapy, and no patients developed post-transplant lymphoproliferative disorders. Stem cell source was proven to be a risk factor correlated with EBV reactivation. The cumulative incidence of relapse in the EBV-positive group was 11.4%, 25.2%, and 31.0% at the first, second, and third year after transplantation, respectively, being significantly higher than the corresponding 6.8%, 10.2%, and 10.2%, in the EBV-negative group (P = 0.014). Prognostic analysis showed that EBV reactivation was an independent risk factor for relapse-free survival (RFS). Patients in the EBV-positive group showed obviously shorter RFS than those in the EBV-negative group, with 3-year RFS of 62% and 85%, respectively (P = 0.017).
Anti-CD19 CAR-T Therapy Bridging to Allo-HSCT for Relapsed/refractory B-cell Acute Lymphoblastic Leukemia: An Open-Label Pragmatic Clinical Trial
American journal of hematology. 2019
Chimeric antigen receptor-modified T-cell (CAR-T) therapy is effective and safe for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL), but its value has been limited in terms of long-term leukemia-free survival. New strategies that can help CAR-T therapy achieve lasting effect are urgently warranted. This non-randomized interventional pragmatic clinical trial aimed to explore whether consolidative allogeneic hematopoietic stem cell transplantation (allo-HSCT) could improve the long-term prognosis of the minimal residual disease-negative complete remission (MRD(-) CR) patients after CAR-T therapy. In the first stage, 58 r/r B-ALL patients received split doses of CAR-T cells after lymphodepleting chemotherapy, and 51 (87.9%) achieved CR. In the second stage, 21/47 MRD(-) CR patients without previous allo-HSCT and contraindications or other restrictions, on their own accord, received consolidative allo-HSCT within three months after CAR-T therapy. There was no difference in overall survival (OS) between the MRD(-) CR patients who received allo-HSCT and those who didn't, but event-free survival (EFS) and relapse-free survival (RFS) were significantly prolonged by allo-HSCT in the subgroups with either high (≥ 5%) pre-infusion bone marrow MRD assessed by flow cytometry (BM-FCM-MRD) or poor prognostic markers (P < 0.05). However, no difference was found in EFS and RFS for patients with pre-infusion BM-FCM-MRD < 5% and without poor prognostic markers (P > 0.05). To conclude, CAR-T therapy bridging to allo-HSCT is a safe and effective therapeutic strategy for r/r B-ALL patients, and may prolong their EFS and RFS, especially when they have high pre-infusion BM-FCM-MRD or poor prognostic markers. This article is protected by copyright. All rights reserved.