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Prolonged isolated thrombocytopenia (PIT) is a common complication after umbilical cord blood transplantation (UCBT). However, data on PIT prediction and impacts on transplantation outcomes for UCBT patients are rare. We retrospectively analyzed 244 patients with hematological malignancies who received single-unit UCBT at the First Affiliated Hospital of USTC between August 2018 and December 2019. Among them, PIT occurred in 49 recipients, with a crude incidence of 20.1%. In the PIT patients, the 2-year cumulative incidence of transplant-related mortality (TRM) was significantly higher, and the probabilities of 2-year overall survival, leukemia-free survival and graft-versus-host disease (GVHD)-free relapse-free survival were significantly poorer (57.1% vs. 88.6%; 53.1% vs. 81.9%; 22.4% vs. 59.8%; p

BACKGROUND Juvenile myelomonocytic leukemia (JMML) is a rare hematological malignancy in young children and can only be cured through the allogeneic stem cell transplantation. PROCEDURE We have retrospectively analyzed the outcomes of nine children with JMML after unrelated cord blood transplantation (UCBT). RESULTS Eight patients who have received a myeloablative conditioning regimen of fludarabine (FLU), busulfan (BU), and cyclophosphamide (CY) have gotten engraftment. None of the nine patients has relapsed following initial UCBT. Six patients are still alive and in complete remission after UCBT with a median observation time of 43 months (range: 10-80 months). CONCLUSIONS This study shows that UCBT with FLU-BU-CY conditioning regimen can represent a suitable option for children with JMML.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for most of acute myeloid leukemia (AML) patients. But relapse remains the leading cause of mortality after transplant. Ex vivo expanded allogeneic CD4- and CD8- double negative T cells (allo-DNTs) effectively target AML cells without attacking normal tissues in preclinical models. In this first-in-human phase I/IIa trial, twelve patients with relapsed AML after allo-HSCT were treated with allo-DNTs. Nine patients had hematological relapse, 2 with molecular relapse, and 1 had both molecular and extramedullary relapse. The median times from transplant to relapse and relapse to DNT therapy were 10 months (3-18 months) and 4.7 months (1.75-11.7 months), respectively. At the time of DNT-treatment, 11/12 patients had active or residual disease. After lymphodepleting preconditioning, patients received allo-DNTs in three dose cohorts (5x107-4x108/kg). None of the patients developed graft-versus-host disease or > grade 2 DNT treatment-related toxicity; hence, the maximum tolerated dose was not reached. One patient withdrew from this trial. The initial response was observed in 7 out of 11 patients, where 4 patients achieved complete remission (CR), 2 achieved CR with incomplete hematologic recovery, and 1 achieved partial remission. Five patients remain alive and 4 are in continuing CR 374 to 609 days after DNT-treatment. The predicted 1-year overall survival after DNT treatment is 45.5% (95% CI, 16.7%-70.7%). Collectively, the study supports the feasibility, safety, and potential efficacy of allo-DNTs as a new treatment option for patients with relapsing/relapsed AML after allo-HSCT. Trial Registration: The trial was registered on the Chinese Clinical Trial Registry (ChiCTR-IPR-1900022795). Funding: This work was supported by the National Natural Science Foundation of China (grant # 81670165), International Cooperation Projects in Anhui Province (grant # 1804b06020352), the Fundamental Research Funds for the Central Universities (grants # WK9110000001 and WK9110000060), the Canadian Cancer Society Impact Grant (grant # 704121), Canadian Institutes of Health Research (grant # 419699), the Leukemia & Lymphoma Society (grant #R6509-18) and WYZE Biotech Inc. Declaration of Interest: LZ is a co-inventor on several DNT cell technology related patents and intellectual properties (IPs), received a grant and consulting fees from WYZE Biotech Co. Ltd. WYZE Biotech Co. Ltd licensed the Chinese right for one of the patents; and LZ owns shares in WYZE Biotech Co. Ltd.. LY, JL, and ADS are co-inventor on DNT cell technology related patents/IPs. LY, ZX, MW and PT own shares in WYZE Biotech Co., Ltd and are employees of WYZE Biotech Co., Ltd. MISSING REMAINING AUTHORS Ethical Approval: This study protocol was approved by Chinese Ethics Committee of Registering Clinical Trials. Written informed consent was obtained from all the patients or guardians in accordance with the Declaration of Helsinki.

What is known and objective Many refractory/relapsed haematological malignancies, in non-remission state, still have poor prognosis even after allogeneic haematopoietic stem cell transplantation. Recently, decitabine or umbilical cord blood transplantation (UCBT) seemed to be effective in these patients. However, few studies have added decitabine to myeloablative conditioning regimens for UCBT in patients with haematological malignancies not in remission. Therefore, the objective was to evaluate the clinical outcomes of patients with refractory/relapsed acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) using decitabine as part of a myeloablative conditioning regimen prior to salvaged unrelated UCBT at our centre. Methods We enrolled 20 consecutive patients with refractory/relapsed AML/MDS between 2013 and 2018. All patients were in non-remission state before transplantation. All transplants were performed with decitabine as part of the myeloablative conditioning regimen, which was decitabine + fludarabine/busulfan/cyclophosphamide. Results and discussion All patients achieved neutrophil and platelet engraftment. Incidence of grade III/IV acute graft-vs-host disease (GVHD) was 20.0%, which was also decreased compared to non-decitabine group (P = .025). The median follow-up time after UCBT was 29 months (range 14-64 months). The 2-year probability of GVHD-free relapse-free survival (GRFS) was higher in the decitabine group. Univariate showed that the decitabine group was associated with a higher GRFS than the non-decitabine group. The estimated probability of overall survival and relapse was 55% and 20.0%, respectively. What is new and conclusions Our results suggest that addition of decitabine as part of the myeloablative conditioning regimen prior to UCBT for refractory/relapsed AML/MDS in patients who are not in remission is safe and might be an effective treatment option.

Background Several studies have indicated that chimeric antigen receptor T-cell (CAR-T) therapy followed by allogeneic hematopoietic stem cell transplantation is beneficial for relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). Whether consolidative unrelated cord blood transplantation (UCBT) is suitable in R/R B-ALL after CAR-T therapy remain uncertain. Objective We aimed to assess the efficacy and safety of CAR-T therapy before UCBT for children and young adults R/R B-ALL patients. Study design : We retrospectively analyzed 43 R/R B-ALL and under 18 years patients who underwent single-unit UCBT at the First Affiliated Hospital of University of Science and Technology of China (USTC) between February 2012 and November 2020. Among them, 21 patients achieved complete remission (CR) following CAR-T therapy before UCBT (the CAR-T group), and the remaining 22 patients remained non-remission (NR) without prior CAR-T therapy before UCBT (the NR group). The clinical outcomes between two groups were analyzed. Results : The median time from CAR-T therapy to UCBT was 62 (range,42 to 185) days. There were no significant differences in the incidences of grade II-IV, III-IV acute graft-versus-host disease (GVHD) and 2-year extensive chronic GVHD between the two groups. Compared with the NR group, a lower 2-year cumulative incidence of transplant-related mortality and higher probabilities of 2-year overall survival, leukemia-free survival, and GVHD-free relapse-free survival were found in the CAR-T group (P = 0.037, 0.005, 0.028 and 0.017, respectively). However, the 2-year cumulative incidence of relapse (CIR) was comparably high between two groups (26.7% in the CAR-T group and 38.3% in the NR group, P = 0.41). In the CAR-T group, patients with minimal residual disease (MRD) positive before UCBT had a high CIR comparing with those with MRD negative before UCBT (66.7% vs.19.2%, P = 0.006). Conclusion : CAR-T therapy followed by UCBT produces superior survival in R/R B-ALL, but treated patients still exhibit a high posttransplant relapse rate.

Objective: We observed the efficacy and safety of umbilical cord blood microtransplantation (UCBMT) in the treatment of newly diagnosed with acute myeloid leukemia (AML) in the elderly. Methods: Prospective one-arm phase I clinical study. The patients should meet the following criteria: 60-80-year-old; newly diagnosed AML; receive the treatment of chemotherapy combined with UCBMT. Result: In total, 11 patients newly diagnosed with AML received chemotherapy in combination with UCBMT, from November, 2019 to January, 2021, including 7 males and 4 females. The average age was 71 (60-80). For the patients, 7 cases with normal chromosome karyotype, and 2 cases with +8 chromosome, 1 case with 7q- chromosome, and 1 case with karyotype of monomer. In the 7 patients with normal chromosome karyotype, 3 cases were FMS-liketyrosine kinease 3 (FLT3) positive (2 of them in combination with nucleophosmin 1 (NPM1) mutation); in addition, in 4 patients of the 7, one showed double mutation of CEBPA, one showed NPM1 mutation, one showed IDH1 mutation, and one showed IDH2 mutation. In 4 patients with chromosomal abnormalities, one patient showed no special gene, one patient showed ASXL1 mutation, one patient was IDH1 mutation, and one patient was TP53 mutation. All of the patients were treated with IA (IDA 8-10 mg/ m 2/day x 3 days, cytarabine 100 mg/ m 2/day x 7 days) for inducing chemotherapy. For the patients with 60-70-year-old, they were treated with IDA (8 mg/ m 2/day); and for the patients with 70-80-year-old, they were treated with darubicin (10 mg/ m 2/day). In the consolidation phase, the patients were treated with cytarabine (1 g/ m 2, q12h) for 3 consecutive days. There were 3 courses of consolidation chemotherapy. Next, patients received single unrelated cord blood transplantation (UCBT) from China's public umbilical cord blood bank, HLA matching was performed for all patients before treatment. A total of 4 units of UCB with HLA 0-3/6（HLA-A,-B,-DR）matching and the ABO blood type matched with the patient were transfused after induction and consolidation chemotherapy for 24-48 hours, then with follow-up. At the same time, the immunological characteristics of these patients were fully analyzed. We demonstrated that, 8 of 11 patients received one course of induction chemotherapy, and achieved a complete response. The complete response rate was 72.7%. What's more, the median time for neutrophils ≥ 0.5 x 10 9/L and platelete ≥ 20 x 10 9/L was 12 days. There were no treatment-related deaths during induction therapy. The median follow-up was 14 (7-31) months. 1 patient showed monomer karyotype with P53 gene mutation, and got complete remission after one course of induction chemotherapy with IA. However, the patient died for AML recurred. For the other 10 patients, they were alive, and the OS of 1 year was 89.8%. Moreover, we found the expression of PD-1 on CD8 +T cells decreased, while the expression of CD38 increased after therapy. Besides, the proportion of NKp30 +NK cells, as well as the IFN-γ +TFN-α +NK cells increased significantly. Conclusion: UCBMT therapy for newly diagnosed elderly AML patients could accelerate the recovery of hematopoietic function and improve the safety of chemotherapy. This method is effective and worthy of further promotion. Disclosures No relevant conflicts of interest to declare.

Relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) has poor long-term survival even after chimeric antigen receptor (CAR)-T cell therapy or allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several studies supported that CAR-T therapy followed by allo-HSCT is benefit for improving long-term leukemia free survival (LFS). Since probably a stronger graft versus leukemia (GVL) effect of unrelated cord blood transplantation (UCBT), it is uncertain whether consolidative UCBT is suitable for R/R B-ALL after CAR-T therapy. Here, we conducted a retrospective comparative study for R/R B-ALL patients receiving UCBT in our transplantation center. Totally 43 cases with R/R B-ALL who underwent UCBT were assigned to CAR-T group (patients achieved CR or CRi by CAR-T cell therapy before bridging to UCBT, n = 21) or non-remission (NR) group (n = 22). The median time from CAR-T infusion to UCBT was 62 (range, 42-185) days. All patients achieved neutrophil engraftment by day 42 in CAR-T group. The 180-day cumulative incidence of platelet engraftment was higher in CAR-T group than in NR group (90.5% vs 65.7%, P = 0.16). Incidence of grade II-IV and III-IV acute graft-versus-host disease (GVHD) were 28.6% and 23.8% in CAR-T group, which were both tendency lower than in NR group (45.5% and 31.8%, P = 0.32 and P = 0.63, respectively). No patient suffered from extensive chronic GVHD in CAR-T group, which was lower than in NR group (9.1%, P = 0.23). Lower 2-year cumulative incidence of transplant-related mortality (TRM), and higher probabilities of 2-year overall survival, leukemia free survival (LFS), graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) were found in CAR-T group (4.8% vs 28.2%; 75.0% vs 37.7%; 49.8% vs 23.0%; 42.4% vs 14.8%; P = 0.037, 0.005, 0.028 and 0.017; respectively). However, 2-year cumulative incidence of relapse was comparably high between CAR-T and NR group (26.7% vs 38.3%; P = 0.41). CAR-T therapy followed by UCBT has a superior survival for R/R B-ALL, but remains relatively high post-transplant relapse rate. Prevention of relapse after UCBT is warranted in this patient cohort. Disclosures No relevant conflicts of interest to declare.

BACKGROUND Relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the main cause of treatment failure for patients with acute myeloid leukemia (AML). Conventional treatments such as donor lymphocyte infusions (DLI) or secondary allo-HSCT as a monotherapy or in combination with novel agents or immunotherapy showed limited improvements on long-term survival. Our previous studies have shown that a rare subset of CD4- and CD8- double negative T cells (DNTs) expanded from periphery of healthy donors are effective in targeting AML cells in vitro and in xenograft models. Also, allogeneic DNTs can be used as an off-the-shelf adoptive cellular therapy (ACT) for AML. We undertook a first in-human phase I/IIa trial to assess the safety and efficacy of escalating doses of DNTs for the treatment of AML patients relapsed post allo-HSCT. This study protocol was approved by Chinese Ethics Committee of Registering Clinical Trials. Informed consent was obtained in accordance with the Declaration of Helsinki. The trial was registered on the Chinese Clinical Trial Registry (ChiCTR-IPR-1900022795). METHODS From June 2019 to June 2020, 12 patients with relapsed AML after allo-HSCT were enrolled in the trials. Three patients received HLA-matched sibling stem cell transplant, and 9 patients received umbilical cord blood transplantation (UCBT). Hematological relapse was found in 9 cases, and molecular relapsed in 3 cases. None of the patients were able to obtain DLI from previous donors for various reasons. Clinical-grade DNTs from peripheral blood of healthy donors were expanded. After lymphodepleting chemotherapy with fludarabine and cyclophosphamide, each patient received three infusions of HLA-mismatched DNTs expanded from healthy volunteers at escalating doses of 5×107, 1×108, or 2-4×108 per kilogram of body weight at one week interval. Numbers of total DNTs and donor-derived DNTs, inflammatory cytokines levels in vivo were measured according to the study protocol. Post-remission therapy was permitted 14 days after the last DNTs infusion according to treating physician's discretion. RESULTS All surviving patients were followed until August 1st, 2020. At a median follow-up of 4.3 months (range 1.7 to 12.2 months), 1 patient withdrew from the trial after the second DNT infusion for a personal reason. 6/11 patients (54.5%) achieved complete response (CR) with 5 of these patients negative for (45.4%) minimal/measurable residual disease (MRD). 4/11 patients (36.3%) achieved partial remission. Up to the last follow-up, 4/11 patients remain CR. Increase in the levels of serum inflammatory cytokines, including interleukin (IL)-6, TNF-alpha, MCP-1, and MIP-1-beta over baseline were observed without signs of cytokine release syndrome, neurotoxicity, or graft-versus-host disease. The most common adverse events related to DNTs treatment were fever and headache. None of the patients showed >grade 2 adverse event (AE). The maximum tolerated dose was not reached. Donor DNT cell expansion was detected as early as 6 hours after infusion and reached the peak at 24 hours after the 1st infusion in most patients, slightly increased after the 2nd and 3rd infusions, and lasted for 2 weeks after 3rd infusion. However, total DNTs increased and reached the peak at 2 weeks after 3rd infusion. CONCLUSIONS Our results show that allogeneic DNTs therapy is safe, well tolerated, and potentially effective in treating AML patients who relapsed after allo-HSCT. The total number of DNTs increased after infusion. Compared to other agents, DNTs more effectively induced complete responses in this patient population. Our on-going study is to elucidate the mechanism of DNTs-mediated leukemia clearance, and explore the use of DNTs as carrier for Chimeric Antigen Receptor or transgenic TCR to further enhance the efficacy targeting resistant AML cells. Disclosures Zhang: AbbVie: Current equity holder in publicly-traded company; University Health Network: Consultancy, Current equity holder in private company, Other: Principal Investigator, Patents & Royalties.

Background Micro (mi) RNAs play an important role in the pathogenesis and development of acute myeloid leukemia (AML), and their abnormal expression may be sufficient to predict the prognosis and outcomes in AML patients. We evaluated the clinical diagnostic value of miRNA-181a-3p in predicting prognosis and outcomes in patients with AML. Methods A total of 119 newly diagnosed adult patients with AML and 60 healthy controls were recruited. Blood specimens were obtained from all AML patients at diagnosis, and 10 blood specimens were obtained on day 28 after induction chemotherapy. The controls also provided blood samples. Relative gene expression was quantified by PCR and determined using the comparative Ct method. Publicly available clinical data and gene expressions for 188 patients with AML were downloaded from TCGA data portal. Results Compared with healthy controls, the expression of miRNA-181a-3p was significantly increased in patients with AML. MiR-181a-3p expression could be used to discriminate AML patients from controls, with up-regulated expression correlating with favorable prognosis. Moreover, miRNA-181a-3p expression was significantly decreased in patients who achieved a complete response after induction chemotherapy. The multivariate Cox analysis highlighted the prognostic value of miR-181a-3p for patients with AML. Finally, we found that miR-181a-3p expression was negatively correlated with the expression of the NF-κB essential modulator (NEMO/IKBKG). Conclusions MiR-181a-3p may be clinically useful as a disease marker for AML, and enhanced the prediction of patient outcomes to chemotherapy.

Primary graft failure (pGF) is a frequent complication following cord blood transplantation (CBT). For those patients who will not experience autologous recovery, salvage transplantation should be performed as early as possible. However, standardized treatment protocols for pGF, such as the optimal stem cell source, preparative regimen and the ideal time for salvage transplantation, have yet to be determined. Therefore, we analyzed 17 hematologic malignancy patients who received unmanipulated haploidentical peripheral blood (PB) and BM transplantation with reduced-intensity conditioning (RIC) as a salvage therapy for pGF after CBT. The median interval between the two transplantations was 38 days. The RIC regimen for salvage transplantation consisted of fludarabine, antithymocyte globulin, CY and low-dose TBI. The neutrophil and plt engraftments were achieved in 14 (82.4%) and 13 (76.4%) patients, respectively. The cumulative incidences of grades II-IV and grades III-IV aGVHD were 35.3% and 17.6%, respectively. The cumulative incidence of chronic GVHD was 29.4%. After a median follow-up of 43 months, 10 of 17 patients remained alive in CR. The cumulative incidence of TRM at 180 days was 29.4%. The probability of 3-year OS and leukemia-free survival was 57.5%. Our results show that unmanipulated haploidentical PB and BM transplantation under a RIC regimen is an effective treatment for pGF after CBT.

Treatments for patients with hematologic malignancies not in remission are limited, but a few clinical studies have investigated the effects of salvaged unrelated cord blood transplantation (CBT). We retrospectively studied 19 patients with acute leukemia, 5 with myelodysplastic syndrome (MDS with refractory anemia with excess blasts [RAEB]), and 2 with non-Hodgkin's lymphoma who received 1 CBT unit ≤ 2 loci human leukocyte antigen (HLA)-mismatched after undergoing myeloablative conditioning regimens between July 2005 and July 2014. All of them were in non-remission before transplantation. The infused total nucleated cell (TNC) dose was 4.07 (range 2.76-6.02) × 10⁷/kg and that of CD34⁺ stem cells was 2.08 (range 0.99-8.65) × 10⁵/kg. All patients were engrafted with neutrophils that exceeded 0.5 × 10⁹/L on median day +17 (range 14-37 days) and had platelet counts of20 × 10⁹/L on median day +35 (range 17-70 days). Sixteen patients (61.5%) experienced pre-engraftment syndrome (PES), and six (23.1%) patients progressed to acute graft-versus-host disease (GVHD). The cumulative incidence rates of II-IV acute GVHD and chronic GVHD were 50% and 26.9%, respectively. After a median follow-up of 27 months (range 5-74), 14 patients survived and 3 relapsed. The estimated 2-year overall survival (OS), disease-free survival (DFS), and non-relapse mortality (NRM) rates were 50.5%, 40.3%, and 35.2%, respectively. Salvaged CBT might be a promising modality for treating hematologic malignancies, even in patients with a high leukemia burden.