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T-cell acute lymphoblastic leukemia (T-ALL) represents an area of high unmet medical needs. Once relapsed, patients have limited treatment options and usually a poor prognosis. T-ALL antigens such as CD7 is extensively expressed in normal T cells and natural killer (NK) cells, and extending the success of CAR-T therapy to T cell malignancies was challenged by CAR-T cell fratricide, the high production cost, long lagging time and potential product contaminations. GC027 is an “off-the-shelf” allogeneic CD7 targeted CAR-T therapeutic product for T cell malignancies. It demonstrated superior cell expansion and anti-leukemia efficacy in mouse xenograft model. In our previous study, we observed promising efficacy result in the first two r/r T-ALL patient treated with GC027. Deep and durable response in these two patients suggests the potential of a “off-the-shelf” allogeneic CAR-T product as a promising standalone therapy. In the expanded study, 11 out of 12 patients had extensive GC027 cell expansion, rapid eradication of T-lymphoblasts, and reached complete response within 1-month post infusion. At data cut-off of Nov. 30, 2022, 1 patient had progression free survival of > 3 years. With manageable toxicity profile, GC027 demonstrated superior clinical efficacy and durability in T cell malignancies.

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 intermediate/high-risk DLBCL patients.

Introduction: CD19 targeted autologous CAR-T therapies have been approved for the treatment of r/r B-ALL and greatly improved outcome. However, some patients may not be eligible to receive autologous CAR-T. TruUCAR™ GC502 is an allogeneic, universal CAR-T product with CD19/CD7 dual directed CAR. Preclinical data of GC502 were reported at ASH 2021 (Abstract 148500). Here, we report early clinical results from a phase I open-label, non-randomized, prospective investigator initiate trial (IIT) of GC502 in r/r B-ALL patients. Methods: GC502 is manufactured using leukopaks from HLA-unmatched healthy donors. It contains a 4-1BB based CD19/CD7 dual directing CAR, a T cell enhancer, and genetically disrupted TRAC and CD7 loci to avoid GvHD and fratricide. Patients (pts) with r/r B-ALL were enrolled and treated with one of two different formulations (A or B) in escalating dose levels ranging from 1.0x107 (DL1) to 1.5x107 (DL2) cells/kg. Prior to infusion of GC502, pts received a Flu/Cy based lymphodepletion regimen. Adverse events, disease response and expansion kinetics were evaluated in this study. Results: To date, 4 pts (15-34 yrs) were enrolled from Sep. 2021 to Jan. 2022. All patients were heavily pretreated, and had received either autologous or donor derived CD19 or CD19-CD22 targeted CAR-T therapy. Baseline marrow blast levels ranged from 19.5% to 92% (median 48.1%). 1 pt had extramedullary involvement. At data cut-off (Jan. 28, 2022), all patients had received a single dose of GC502: 1 pt at DL 1 1.0x107cells/kg and 3 patients at DL 2 1.5x107cells/kg. At day 28 post CAR-T infusion, 2 out of 3 response evaluable patients had achieved CR/CRi; 1 pt achieved PR at month 1 and subsequently received HSCT on day 39. TEAEs presented as Gr 3 febrile neutropenia (2/3), Gr 4 thrombocytopenia (1/3) and Gr 3 anemia (3/3). All TEAE resolved after treatment with SOC. Non-hematological TEAE presented as Gr≤3 γ-GT increase (3/3), Gr≤3 AST increase (2/3) and Gr≤3 ALT increase (3/3). CRS presented as Gr 2 in 2 patients with formulation B. 2 pts received formulation A and experienced Gr 3 CRS with a duration of 7 and 10 days respectively (CRS was graded according ASTCT Consensus Grading). CRS in all pts was manageable and resolved after treatment with Ruxolitinib, SOC and supportive care. No ICANS or aGvHD were observed. The pt treated in DL 1 did not show adequate GC502 cellular expansion. Peak expansions of GC502 in peripheral blood were observed between week 1-2 in DL 2. Median peak CAR copies were 149,945 copies/ug DNA (range 10,849-195,400). Conclusions: TruUCAR™ GC502 demonstrated promising early results with a manageable safety profile. Robust CAR-T cell expansion was observed in DL2 at 1.5x107cells/kg in heavily pretreated r/r B-ALL patients, including those previously treated with CD19 CAR-T therapies. The study is ongoing and continues accruing patients. Citation Format: Shiqi Li, Xinxin Wang, Zhongtao Yuan, Lin Liu, Yu Li, Jia Liu, Jiaping He, Zhimin Li, Wei Zhao, Jianning Ge, Yajin Ni, Lianjun Shen, Wei Cao, Xi Zhang, Martina Sersch, Sanbin Wang. Early results of a safety and efficacy study of allogeneic TruUCAR™ GC502 in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT196.

7008 Background: CD19 chimeric antigen receptor (CAR) T cell therapy has shown promising efficacy in the r/r B-ALL. However, the life-threatening side effects especially high grades of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) limited its wide application. To overcome these limitations, we established a novel PrimeCAR platform based on moderate activation and short expansion to manufacture MC-1-50, an autologous CD19-directed CAR T cell. Our preclinical study showed that MC-1-50 exerted a great efficacy and less cytokines secretion. Methods: In this Phase I /II study (NCT04271410), CAR T cells were manufactured by PrimeCAR platform, which reduces manufacture periods to about 2 days. T cells were transducted with a lentiviral vector encoding a humanized CD19 specific scFv following 4-1BB and CD3ζ cytoplasmic domain. Patients (pts) received single-dose of MC-1-50 at dose level 1 (1×105 CAR+/kg), level 2 (3×105 CAR+/kg), and level 3 (1×107 CAR+ totally, ranged 1.67-3.85×105 CAR+/kg). Pts were pre-conditioned with fludarabine (25-30 mg/m2) and cyclophosphamide (200-300 mg/m2) daily for 3 days. Toxicity was graded by CTCAE, CRS and ICANS were graded by ASTCT criteria. Results: As of Feb 10, 2022, 13 pts with r/r B-ALL were infused with MC-1-50. Disease characteristics and outcomes are shown in the table. No DLTs were reported. Eleven pts (84%) experienced CRS, including 7 (54%) at grade 1 and 4 (30%) at grade 2, no ≥ 3 CRS were observed. One pts (7%) experienced grade 1 ICANS, no ≥ 2 ICANS occurred. The Tmax for IL-6 was detected around day 11 (123.3±165.16 pg/ml). There were similar low secretion features of other cytokines, which is consistent with low CRS and ICANS. In all dose levels, 13 pts finished 1M evaluation and the CR rate in 1M is 100%. Four pts finished 3M evaluation and the CR rate in 3M is 75%, 1 pts relapsed at the month 3 with CD19 mutation. One pts had a CR statue at the month 11. Cmax for CAR copy number in 3 dose levels are similar and the average number of Cmax of CAR is 275901.6 copies/ug genomic DNA. Conclusions: PrimeCAR platform could produce CAR T cells in very short time with high percentage of Tscm. Treatment of r/r B-ALL at very low dose resulted in excellent safety profile, while exhibited a promising efficacy. That make this PrimeCAR platform potential for outpatient administration in the future. Clinical trial information: NCT04271410. [Table: see text]

Nearly 30% of patients with advanced-stage Hodgkin lymphoma (HL) are not cured. We should better control tumors with initial treatment for patients with advanced stage HL whose interim positron emission tomography/computed tomography (PET/CT) was positive. The objective of our study was to confirm the superiority of autologous hematopoietic stem cell transplantation (ASCT) therapy in these patients.Eighty-nine HL patients with stage III-IV, international prognostic score (IPS) ≥3 and Deauville more than 3° at the interim PET/CT were analyzed. Forty five patients received ASCT. The other 44 patients received two cycles DHAP chemotherapy.The 3-year overall survival (OS) of patients who received ASCT was 91.1%, and for the patients who received chemotherapy, it was 72.7% (P = 0.025). The 3-year progression free survival (PFS) of patients in the ASCT group was 88.9%, but for patients in the chemotherapy group, it was only 70.5%(P = 0.017). No patient died of toxicity from ASCT. Additionally, there was no difference in the rates of secondary malignancies between the ASCT and chemotherapy groups. Extranodal and bone marrow involvement were poor prognostic factors, while ASCT was a good prognostic factor.The use of ASCT as a first-line consolidation treatment could improve outcome of patients with advanced-stage high risk HL whose interim PET/CT was positive.

T-cell lymphoblastic lymphoma (T-LBL) is a highly aggressive form of lymphoma with poor clinical outcomes and no standard treatment regimen. In this study, we assessed the safety and efficacy of tandem autologous hematopoietic stem cell transplantation (auto-HSCT) for adult T-LBL and evaluated prognostic factors affecting survival. A total of 181 newly-diagnosed adult T-LBL patients were enrolled: 89 patients were treated with chemotherapy alone, 46 were allocated to the single auto-HSCT group, 46 were treated with tandem auto-HSCT. Median follow-up time was 37 months; the 3-year progression/relapse rate of the tandem auto- HSCT group was significantly lower than that of the single auto-HSCT and chemotherapy groups (26.5% vs. 53.1% and 54.8%). The 3-year progression- free survival (PFS) and overall survival (OS) rates of the tandem auto- HSCT group (73.5% and 76.3%) were significantly higher than those of the single auto-HSCT group (46.9% and 58.3%) and the chemotherapy group (45.1% and 57.1%). In the tandem auto-HSCT group, age and disease status after the first transplant impacted OS and PFS. Multivariate analysis identified that disease status after the first transplant was the only independent prognostic factor for patients treated with tandem-HSCT. In addition, diagnostic models of the initial CD8+CD28+/CD8+CD28– T-cell ratio in predicting the disease status were found to be significant. Taken together, tandem auto- HSCT can be considered an optimal strategy for adult T-LBL patients. (Study registered at: ChiCTR-ONN-16008480).

PURPOSE Relapse is a major cause of treatment failure after allogeneic hematopoietic stem-cell transplantation (allo-HSCT) for high-risk acute myeloid leukemia (HR-AML). The aim of this study was to explore the effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) combined with minimal-dose decitabine (Dec) on the prevention of HR-AML relapse after allo-HSCT. PATIENTS AND METHODS We conducted a phase II, open-label, multicenter, randomized controlled trial. Two hundred four patients with HR-AML who had received allo-HSCT 60-100 days before randomization and who were minimal residual disease negative were randomly assigned 1:1 to either rhG-CSF combined with minimal-dose Dec (G-Dec group: 100 µg/m2 of rhG-CSF on days 0-5 and 5 mg/m2 of Dec on days 1-5) or no intervention (non–G-Dec group). The primary outcome was relapse after transplantation, and the secondary outcomes were chronic graft-versus-host disease (cGVHD), safety of the treatment, and survival. RESULTS The estimated 2-year cumulative incidence of relapse in the G-Dec group was 15.0% (95% CI, 8.0% to 22.1%), compared with 38.3% (95% CI, 28.8% to 47.9%) in the non–G-Dec group ( P < .01), with a hazard ratio (HR) of 0.32 (95% CI, 0.18 to 0.57; P < .01). There was no statistically significant difference between the G-Dec and non–G-Dec groups in the 2-year cumulative incidence of cGVHD without relapse (23.0% [95% CI, 14.7% to 31.3%] and 21.7% [95% CI, 13.6% to 29.7%], respectively; P = .82), with an HR of 1.07 (95% CI, 0.60 to 1.92; P = .81). After rhG-CSF combined with minimal-dose Dec maintenance, increasing numbers of natural killer, CD8+ T, and regulatory T cells were observed. CONCLUSION Our findings suggest that rhG-CSF combined with minimal-dose Dec maintenance after allo-HSCT can reduce the incidence of relapse, accompanied by changes in the number of lymphocyte subtypes.

The aim of the study was to analyze the efficacy of posaconazole for the prophylaxis and treatment of invasive fungal diseases (IFDs) in patients with hematological malignancies. In this retrospective observational multi-center study, 762 patients from 25 Chinese hematological centers were enrolled. Inclusion criteria were patients with hematological malignancy or they had undergone hematopoietic stem cell transplantation and received at least 1 dose of posaconazole. The primary endpoints were the observation of breakthrough rates and the clinical efficacy of posaconazole prophylaxis. The secondary endpoint was the efficacy of posaconazole for the treatment of IFDs. Of the 762 enrolled patients, 456 (59.8%) were prescribed posaconazole prophylactically while 243 (31.9%) received posaconazole as an IFD treatment (12 proven, 61 probable, 109 possible, and 61 unclassified IFD cases) for ≥7 days. The overall IFD breakthrough rate (probable cases) for the ≥4 days prophylactic treatment (n = 445) group was 1.6% (95% Cl: 0.6%–3.2%), with breakthrough rates of 2.6% for acute myeloid leukemia/myelodysplastic syndrome patients undergoing chemotherapy and 2.2% for hematopoietic stem cell transplantation patients. For primary antifungal prophylaxis, the breakthrough rate was 1.9% and for secondary antifungal prophylaxis 0%. The overall effective IFD remission rate of patients treated for ≥7 days with posaconazole was 56.0% and the effective remission rate of proven/probable/possible IFD cases was 59.3%. The effective remission rate of posaconazole as salvage therapy was 50% (95% CI: 32.4%–67.6%) including 75% (CI: 19.4%–99.4%) for Aspergillus infections. The present retrospective study confirmed posaconazole as IFD prophylaxis and medication for hematological malignancy patients undergoing various treatments in China.

Purpose: Although chimeric antigen receptor T-cell (CAR-T) therapy development for B-cell malignancies has made significant progress in the last decade, broadening the success to treating T-cell acute lymphoblastic leukemia (T-ALL) has been limited. We conducted two clinical trials to verify the safety and efficacy of GC027, an “off-the-shelf” allogeneic CAR-T product targeting T-cell antigen, CD7. Here, we report 2 patients as case reports with relapsed/refractory T-ALL who were treated with GC027. Patients and Methods: Both the trials reported here were open-label and single-arm. A single infusion of GC027 was given to each patient after preconditioning therapy. Result: Robust expansion of CAR-T cells along with rapid eradication of CD7+ T lymphoblasts were observed in the peripheral blood, bone marrow, and cerebrospinal fluid. Both patients achieved complete remission with no detectable minimal residual disease. At data cutoff, 30 September 2020, 1 of the 2 patients remains in ongoing remission for over 1 year after CAR T-cell infusion. Grade 3 cytokine release syndrome (CRS) occurred in both patients and was managed by a novel approach with a ruxolitinib-based CRS management. Ruxolitinib showed promising activity in a preclinical study conducted at our center. No graft-versus-host disease was observed. Conclusions: The two case reports demonstrate that a standalone therapy with this novel CD7-targeted “off-the-shelf” allogeneic CAR-T therapy may provide deep and durable responses in select patients with relapsed/refractory T-ALL. GC027 might have a potential to be a promising new approach for treating refractory/relapsed T-ALL. Further studies are warranted.

HLA-haploidentical hematopoietic stem cell transplantation (HSCT) may be an option for severe aplastic anemia (SAA) patients. However, to date, no large-sample studies have been performed to determine which types of SAA patients are suitable for HLA-haploidentical HSCT. We retrospectively studied 189 consecutive patients with SAA who underwent HLA-identical or HLA-haploidentical HSCT at seven transplant centers in China. Propensity score matching (PSM) was applied in this study to reduce the influence of potential confounders. The 5-year overall survival (OS) rate was 72.0% in the HLA-haploidentical group and 76.5% in the HLA-identical group. The median time to achieve engraftment and the incidence of acute GVHD/chronic GVHD were not significantly different between the two groups. In the subgroup analysis, the outcome of patients older than 40 years in the HLA-haploidentical group was significantly poorer than that of patients younger than 40 years in the same group and that of patients older than 40 years in the HLA-identical group. Based on the above results, we suggest that HLA-haploidentical relative HSCT should be considered as a valid alternative option for patients younger than 40 years with SAA for whom no matched sibling donor is available.

Background: T-cell lymphoblastic lymphoma (T-LBL) is a highly aggressive form of lymphoma with poor clinical outcomes and lack of a standard treatment regimen. Accordingly, this study evaluated the safety and efficacy of tandem autologous hematopoietic stem cell transplantation (auto-HSCT) treatment for adult T-LBL and assessed factors affecting survival. Methods: Newly-diagnosed adult T-LBL patients (n=181) were divided into three groups: chemotherapy (no HSCT) group (89 patients), single auto-HSCT group (46 patients), and tandem auto-HSCT group (46 patients). The measurement of primary outcome was progression-free survival (PFS). The secondary outcomes were progression/relapse rate and overall survival (OS). Additionally, this study analyzed factors influencing toxicities related to tandem auto-HSCT treatment and patient prognosis. Results: The 3-year progression/relapse rate of the tandem auto-HSCT group was significantly lower than that of the single auto-HSCT group and chemotherapy group (26.5% vs 53.1% and 57.6%, p < 0.05). The 3-year PFS rate and OS rate of the tandem auto-HSCT group (73.5% and 76.3%, respectively) were significantly higher than those of the single auto-HSCT group (46.9% and 58.3%, respectively, p < 0.05) and the chemotherapy group (42.3% and 56.1%, respectively, p < 0.05). In the tandem auto-HSCT group, age and disease status after the first transplantation impacted the OS and PFS. Multivariate analysis identified disease status after the first transplantation as the only independent prognostic factor for outcome in T-LBL treated with tandem-HSCT. Conclusions: Tandem auto-HSCT improves long-term survival of adult T-LBL patients compared to recipients of chemotherapy alone or chemotherapy plus single auto-HSCT, and disease status after the first transplantation is an independent prognostic indicator for these patients. Funding Statement: This work was supported by grants from the National Natural Science Foundation of China (No.81370594, 81070388, 81270569, 81600166), the Scientific and Technological Innovation Program of Chongqing social undertakings and people's livelihood guarantee (cstc2016shms-ztzx10003), and Youth Innovation Project of Military Medicine of Chinese People’s Liberation Army (No.13QNP116). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The study was performed in accordance with the Declaration of Helsinki and local laws. The protocol was approved by the ethic committee of each center, and written informed consent was obtained from all patients.

Background: Recurrence is a major cause of treatment failure after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for high-risk acute myeloid leukemia (HR-AML). Recent studies have indicated that granulocyte colony-stimulating factor (G-CSF) and DNA methyltransferase inhibitor Decitabine (Dec) have regulatory effects on T/B/NK lymphocytes and could help enhance the graft versus leukemia (GVL) effect after allo-HSCT. The aim of this study was to prove G-CSF combined with minimal-dose Dec could effectively prevent AML relapse after allo-HSCT. Methods: We did an open-label, multicenter, randomized, controlled, phase 2 trial. 204 HR-AML patients 60-100 days after allo-HSCT were randomized 1:1 to either rhG-CSF combined with minimal-dose decitabine (G-Dec: G-Dec group: 100 µg/m2 of rhG-CSF subcutaneous injection on days 0-5 and 5 mg/m2 of Dec infusion on days 1-5) or no intervention (non-G-Dec) groups. The primary outcome of the trial was relapse after transplantation, and the secondary outcomes were chronic graft-versus-host disease (cGVHD), the safety of the treatment, leukemia-free survival and overall survival. Findings: Between Apr 1, 2016, and Mar 21, 2019, 220 patients from 12 transplant centers were included in the clinical study, and 204 patients were randomly assigned to the study groups (102 patients in the G-Dec group and 102 patients in non-G-Dec group). Median follow-up was 30 months (IQR 6-38). Of 204 evaluable patients, the estimated cumulative incidence of 2-year relapse in the G-Dec group was 15.1 (95% CI 8.0-22.2) %, compared with 38.3 (95% CI 28.9-47.7) % in the non-G-Dec group (P

A 27-year-old male with HIV-associated naïve and high-risk Burkitt’s lymphoma sequentially received short-term, high-dose non-myeloablative chemotherapy and autologous CD34-positive stem cell transfusion in the setting of combined antiretroviral therapy (cART). Prompt hematopoietic recovery was observed after 2 weeks and clinical remission from Burkitt’s lymphoma within approximately 30 months after transplantation. The HIV RNA load was inhibited persistently, and drug resistance was not observed. The CD4+ T cell count approached 323 cells/μL in a recent follow-up study. This case suggests that the use of intensive non-myeloablative chemotherapy with transplantation, combined with antiretroviral therapy, in HIV-related naive and high-risk Burkitt’s lymphoma was tolerated and safe.

Introduction: Patients with T cell malignancies usually have high relapse and mortality rates. Due to shared common surface antigen and potential contamination by malignant cells, development of CAR-T therapies for r/r T-ALL has been lagged, regardless of the costly and lengthy process of autologous CAR-T production. To overcome these challenges, we developed a universal CAR-T platform (TruUCAR™) that displayed superior expansion in patients without using preconditioning biologics such as αCD52 antibody. Here we report results from a prospective study of GC027, the first-in-human, universal CAR-T therapy for treating adult patients with r/r T-ALL to evaluate the safety and clinical efficacy. Methods: TruUCART™ GC027 contains a second-generation CAR with genomic disruption of TCRα and CD7 by CRISPR/Cas9 system to avoid GvHD and fratricide. It is manufactured using lentivirus and leukopaks from HLA-mismatched healthy donors. A T-ALL xenograft murine model were used to assess anti-leukemic efficacy and expansion. Preliminary safety, anti-leukemic activity and expansion kinetics of GC027 are being evaluated in in a single-arm, open-label, multi-center, prospective study for treating adult r/r T-ALL. To date, a total of 5 patients (age 19-38 yrs, median 24 yrs) were enrolled with marrow tumor load 4-80.2% (median prior lines 5). All 5 pts have received a 6-day enhanced preconditioning chemotherapy followed by a single infusion of GC027. Adverse events, disease response, and expansion kinetics were evaluated in this study. Results: GC027 demonstrated robust anti-leukemic activity and expansion in a highly malignant CCRF-CEM xenograft murine model. All mice infused with GC027 exhibited significantly reduced tumor burden and prolonged survival compared to control groups. As of Feb. 6, 2020, 5 pts had received a single dose of GC027, including 1 at 0.6x107/kg, 3 at 1x107/kg and 1 at 1.5x107/kg. 4 pts achieved MRD negative complete responses (MRD- CR) at D28 evaluation: 3 of them remained MRD- at follow-up re-evaluations (D118, 61, 161, respectively, and none was bridged to HSCT); 1 just achieved MRD- CR at D28 and follow-up results will be updated at the meeting. 1 pt achieved MRD+ CR at D14 but had relapsed disease at D29. In all 4 pts with MRD- CR, peak expansions of GC027 in peripheral blood were observed between week 1-2. In 1 pt with CNS disease, GC027 was detected in specimens from his bone marrow and cerebrospinal fluid (CSF). 4 pts experienced Grade 3 cytokine release syndrome (CRS) and 1 pt had Grade 4 CRS (by ASBMT Consensus Grading) along with elevated levels of IL6, IFNγ and TNFα. CRS symptoms were manageable and resolved after treatment and supportive care. None developed neurotoxicity or GvHD. 1 pt had prolonged cytopenia due to fungal infection and required anti-fungal therapy. Conclusions: With a single infusion of GC027, 80% of the patients had robust CAR-T cell expansion and achieved persistent MRD- CR without using any biologics as part of the preconditioning therapy or bridging to HSCT. As the first-in-human, universal CAR-T therapy for adult r/r T-ALL, GC027 has demonstrated superior clinical efficacy and induced deep response in patients with acceptable safety profile. The trial enrollment is ongoing and updated data will be presented at the meeting. Citation Format: Xinxin Wang, Shiqi Li, Lei Gao, Zhongtao Yuan, Kun Wu, Lin Liu, Le Luo, Yao Liu, Cheng Zhang, Jia Liu, Chunhui Yang, Yu Li, Zhimin Li, Jiaping He, Duanpeng Wang, Xun Ye, Xu Tan, Ruihao Huang, Jianning Ge, Yu Han, Dingsong Zhang, Youcheng Wang, Lihua Fang, Yingnian Chen, Wei Cao, Sanbin Wang, Xi Zhang. Clinical safety and efficacy study of TruUCAR™ GC027: The first-in-human, universal CAR-T therapy for adult relapsed/refractory T-cell acute lymphoblastic leukemia (r/r T-ALL) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT052.

3013 Background: Patients with r/r T-ALL usually have high relapse and mortality rates. Due to shared common surface antigen and potential contamination by malignant cells, development of autologous CAR-T therapies for r/r T-ALL has been lagged, regardless of the costly and lengthy process of autologous CAR-T production. Through targeting CD7, a common T cell antigen highly expressed in >95% T-ALL samples, universal CAR-T product GC027 has been developed using lentivirus and CRISPR/Cas9 system with demonstrated anti-leukemia ability in a murine xenograft model. Methods: Preliminary safety, anti-leukemic activity and expansion kinetics of GC027 are being evaluated in a single-arm, open-label, multi-center, prospective study for treating adult patients with r/r T-ALL. To date, a total of 5 patients (age 19-38 yrs, median 24 yrs) were enrolled with marrow tumor load 4-80.2% (median prior lines 5). All 5 pts have received a 6-day enhanced preconditioning chemotherapy followed by a single infusion of GC027. No patient was bridged to HSCT. Adverse events, disease response, and expansion kinetics were evaluated in this study. Results: As of Feb. 6, 2020, 5 pts had received a single dose of GC027, including 1 at 0.6x107/kg, 3 at 1x107/kg, 1 at 1.5x107/kg. 3 pts achieved MRD negative complete responses (MRD- CR) at D28 evaluation and remained MRD- at follow-up re-evaluations (161, D118, 61, respectively) without bridging to HSCT. 1 pt just achieved D28 MRD- CR at time of submission. 1 pt achieved MRD+ CR at D14, but his disease progressed at D29 and deceased due to relapse. In all 4 pts with MRD- CR, peak expansions of GC027 in peripheral blood were observed between week 1-2, analyzed by flow cytometry and Q-PCR. Grade 3 cytokine release syndrome (CRS) occurred in 4 pts and Grade 4 CRS occurred in 1 pt (ASBMT Consensus Grading). CRS symptoms were manageable and resolved after treatment and supportive care. None developed neurotoxicity or GvHD. One had prolonged cytopenia due to fungal infection and required anti-fungal therapy. Conclusions: With a single infusion of GC027, 80% of the patients had robust CAR-T cell expansion and achieved persistent MRD- CR without using any biologics as part of the preconditioning therapy or bridging to HSCT. The first-in-human, universal CAR-T therapy for r/r T-ALL, GC027 has demonstrated superior clinical efficacy and induced deep response in patients with acceptable safety profile. The trial enrollment is ongoing and updated data will be presented at the meeting. Clinical trial information: ChiCTR1900025311 .

Background CAR-T targeting CD19 has been a success in treating B-cell acute lymphoblastic leukemia (B-ALL). However, relapse rate is high and the long term survival in pateints is not satisfactory, which is partly due to the limited expansion and persistence of the conventionally-manufactured CAR-T cells. In addition, long manufacturing time and high cost of CAR-T product further limit the wider applications of CAR-T therapy. To solve these issues, we have developed a new manufacturing platform, FasT CAR-T, which shorten the manufacturing time to one day as compared to the conventional CAR-T manufacturing time of 9-14 days, which is critical for patients with rapidly progressing disease. More importantly, CD19-directed FasT CAR-T has been shown to have superior expansion capability, younger and less exhausted phenotype, and higher potency in eliminating B-ALL both in vitro and in vivo. Based on the preclinical study, we initiated a multi-center clinical study to determine the safety, feasibility and efficacy of CD19-FasT CAR-T in treating patients with CD19+ relapsed/refractory B-ALL. Methods CD19-directed CAR-T was manufactured using the FasT CAR-T platform. Peripheral blood (PB) mononuclear cells were obtained by leukapheresis and T cells were separated. CD19-FasT CAR-T manufacturing were all successful. Conventional CAR-T (C-CAR-T) from healthy donor were also made in parallel for comparison in preclinical study. From Dec. 2018 to July 2019, 10 adult CD19+ R/R ALL patients were recruited and all patients received fludarabine and cyclophosphamide as pre-conditioning followed by a single CAR-T infusion 48-72 hours later. Doses used in this study were: 3 DL1 (5 x 104 CAR+ T/kg), 4 DL2 (1 x 105 CAR+ T/kg), and 3 DL3 (1.5 x 105 CAR+ T/kg). The endpoints of the study were clinical toxicity, feasibility, PK of CAR-T and efficacy. Results: In comparison to conventional CAR-T cells, CD19-FasT CAR-T cells had several key features (Table 1). 1) More robust expansion. Upon antigen stimulation, the FasT CAR-T proliferated 5-30 times stronger than that of C-CAR-T. 2) Higher percentage of CD62L+CD45RO- (Tscm) and CD62L+CD45+ (Tcm) population in FasT CAR-T. 3) Lower expression of PD-1+, LAG3+ and Tim3+ in FasT CAR-T. 4). More potent in eliminating Raji tumor in an in vivo xenograft mouse model. 5) More efficient migration to bone marrow which is likely due to the higher expression of CXCR4 on the FasT CAR-T cells. The trial was conducted during Dec. 2018 to July 2019. The pre-treatment bone marrow (BM) blasts were < 5% in 5 cases, 5%-50% in 3 cases, and >50% in 2 cases (Table 2). All 10 patients achieved complete remission (CR) 4 weeks after FasT CAR-T infusion, and 9 were with negative minimal residual disease (MRD-). CAR-T cells proliferation and persistence in peripheral blood (PB) were monitored by qPCR and flow cytometry. CAR-T cells peaked at Day 10 (range Day 8-13) after infusion. The median persistence period of CAR-T in PB was 56 days ((range 28-212 days) after infusion, and the longest persistence is 7 months and still being monitored at the last follow-up. The median peak of CAR copy number is 90,446/mg DNA (range 4,670-247,507/mg DNA) (Figure). The major adverse event was cytokine release syndrome (CRS) which was observed in 9 patients, including 1 patient with grade IV in DL3 group, 3 grade III, 4 grade II and 1 grade I. The clinical manifestation of CRS mainly included fever and hypotension. The median time to the development of CRS was 5 days (2-10 days), and the peak body temperature was at Day 7 (Day 5- 11) and fever lasted for an average of 5 days (3-8 days). Serum IL-6 level increased and peaked on Day 7 post-infusion, which coincided with fever but slightly preceded the CAR-T expansion peak. Three patients experienced CAR-related encephalopathy syndrome (CRES) after CAR-T infusion, in which 1 was grade III CRES. All patients who developed CRS or CRES recovered after intervention. Conclusion FasT CAR-T have superior expansion capacity with younger and less exhausted phenotype, and more potent cytotoxicity against B-ALL. This first-in-human clinical study in China showed CD19-directed FasT CAR-T therapy is highly effective in treating R/R B-ALL with manageable toxicity. The safety, efficacy and potential long-term clinical benefit of FasT CAR-T therapy will be further evaluated in large multi-center trial. (http://www.chictr.org.cn/listbycreater.aspx:ChiCTR1900023212) Disclosures No relevant conflicts of interest to declare.

HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is an effective and immediate treatment for high-risk acute myeloid leukemia (HR-AML) patients lacking matched donors. Relapse remains the leading cause of death for HR-AML patients after haplo-HSCT. Accordingly, the prevention of relapse remains a challenge in the treatment of HR-AML. In a multicenter randomized controlled trial in southwestern China, 178 HR-AML patients received haplo-HSCT with conditioning regimens involving recombinant human granulocyte colony–stimulating factor (rhG-CSF) or non–rhG-CSF. The cumulative incidences of relapse and graft-versus-host disease (GVHD), 2-year leukemia-free survival (LFS), and overall survival (OS) were evaluated. HR-AML patients who underwent the priming conditioning regimen with rhG-CSF had a lower relapse rate than those who were treated with non-rhG-CSF (38.2%; 95% confidence interval [CI], 28.1% to 48.3% versus 60.7%, 95% CI, 50.5% to 70.8%; P < .01). The cumulative incidences of acute GVHD, chronic GVHD, transplantation-related toxicity, and infectious complications appeared to be equivalent. In total, 53 patients in the rhG-CSF–priming group and 31 patients in the non-rhG-CSF–priming group were still alive at the median follow-up time of 42 months (range, 24 to 80 months). The 2-year probabilities of LFS and OS in the rhG-CSF–priming and non-rhG-CSF–priming groups were 55.1% (95% CI, 44.7% to 65.4%) versus 32.6% (95% CI, 22.8% to 42.3%) (P < .01) and 59.6% (95% CI, 49.4% to 69.7%) versus 34.8% (95% CI, 24.9% to 44.7%) (P < .01), respectively. Multivariate analyses indicated that the 2-year probability of LFS of patients who achieved complete remission (CR) before transplantation was better than that of patients who did not achieve CR. The 2-year probability of LFS of patients with no M4/M5/M6 subtype was better than that of patients with the M4/M5/M6 subtype in the G-CSF–priming group (67.4%; 95% CI, 53.8% to 80.9% versus 41.9%; 95% CI, 27.1% to 56.6%; P < .05). This study suggests that the rhG-CSF–priming conditioning regimen is an acceptable choice for HR-AML patients, especially for the patients with no M4/M5/M6 subtype who achieved CR before transplantation.

Backgroud T-cell lymphoblastic lymphoma (T-LBL) is a highly aggressive lymphoma with very poor clinical outcomes which has not standard treatment. This study evaluated the efficacy and safety of tandem autologous hematopoietic stem cell transplantation (auto-HSCT) treatment for adult T-LBL and assessed the factors that affect survival. Methods 160 newly diagnosed adult T-LBL patients were divided into three groups: chemotherapy group (68 patients), single auto-HSCT group (46 patients), and tandem auto-HSCT group (46 patients). The primary outcome measure was failure-free survival. The intermediate primary outcomes were progression/relapse rate and overall survival. Factors influencing toxicity related to tandem auto-HSCT treatment and prognosis for the patients were analyzed as well. Results The 3-year progression/relapse rate of the tandem auto-HSCT group was significantly lower than that of the single auto-HSCT group and chemotherapy group (19.6% vs 45.7% and 70.6%, p < 0.05). The 3-year PFS rate and OS rate of the tandem auto-HSCT group (68.3% and 72.5%, respectively) were significantly higher than those of the single auto-HSCT group (41.5% and 55.4%, respectively, p < 0.05) and the chemotherapy group (23.3% and 43.3%, respectively, p < 0.05). In the tandem auto-HSCT group, age and disease status after the first transplant had an influence on the OS and PFS. Multivariate analysis identified disease status after the first transplant as the only independent prognostic factor for outcome in T-LBL. Conclusions Tandem auto-HSCT improves long-term survival of adult T-LBL patients. Disease status after the first transplant was an independent prognostic indicator for those patients. Disclosures No relevant conflicts of interest to declare.

Life-threatening complications, such as severe bleeding and/or differentiation syndrome at admission and/or along with induction treatment, among high-risk patients with acute promyelocytic leukemia (APL) are a worldwide puzzle towards the cure of the disease. Taking the rationale that high WBC count, at least in part, may cause cytokine storm related symptoms, we designed this refined regimen with low dose mitoxantrone and ATRA plus arsenic trioxide to determine the safety and efficiency of this WBC reduction, prevention of differentiation syndrome, and supportive care centered approach. In total there were 50 patients with high risk APL (WBC>10x109) from 2003-2017 were enrolled with a medium follow-up of 39 months (15-72 months). Our treatment strategy and detailed protocol are: 1) WBC reduction: it started with ATRA (25mg/m2/day) and arsenic trioxide (0.15mg/kg/day) based double induction. The advantage of decreased dose of ATRA can help to lower the happening of leukocytosis which will trigger the cytokine releasing related syndrome. Low dose mitoxantrone (3mg/m2) was added from day 2-5 plus hydroxyurea (1.5g, p.o. q6h) started from day 1. The criteria for withdrawal hydroxyurea is once both of the following standard are met: i) the WBC count has continuously decreased for three days after reached the peak value; ii) WBC < 10x109/L. 2) Prevention of Differentiation Syndrome (DS): Dexamethasone (5mg/day) was added once the diagnosis was confirmed at day 1. The criteria to taper dexamethasone are the same as to stop hydroxyurea. We require to withdraw dexamethasone within one week once start the taper process. In general, our goal is to prevent the occurrence of both leukopenia and leukocytosis and maintain the WBC count between 2-20x109. 3) Supportive care: We maintain the PLT count between 20-30x109 and fibrinogen >1.5g/L which helped to decrease the occurrence of myelo-suppression, DS and severe bleeding. 4) CNS Prophylaxis: The Intrathecal injection was given after the CR was achieved. Unless there was evidence of CNS infiltration, we gave intrathecal injection after correcting the coagulation abnormality. The consolidation began at four weeks after the end of induction. It contained four weeks of an on and off schedule of arsenic trioxide (0.15mg/kg/day), in total four cycles, and two weeks of an on and off schedule of ATRA (25mg/m2/day), in total seven cycles. A total of eight intrathecal injections were given on the first and last day of arsenic trioxide. Two death was observed through our strategy during the induction. All patients reached hCR by the end of induction. Relapse occurred in four out of 50 patients, and there was no treatment-related mortality. All the relapsed patients entered CR again after using the same protocol. Grade 3-4 adverse events were observed among 12% of all the cases. Three-year probability of overall survival (pOS) was found to be 92%. Our strategy focus of reducing WBC count sheds new light on maximally eliminating early mortality of high-risk APL patients. Disclosures No relevant conflicts of interest to declare.

The treatment options for patients with acute myeloid leukemia (AML) under inferior performance status (i.e. senior patients, MDS transformed AML, and patients with proven invasive fungal disease) are limited. The conventional "3+7" (idarubicin plus cytarabine) induction for those patients can be either too toxic, which leads to higher mortality rate, or requires prolonged recovery time thus raise medical cost. And the delay of consolidation may compromise outcome thus cause early relapse in such patients. Giving the rationale from the designing art of CPX-351, the prolonged IV time requirement for cytarabine, as well as mini-transplantation for AML treatment, at least in part, reflects the philosophy of a longer exposure to the chemo agent can be a more effective treatment approach for leukemia. On the other hand, the D-CAG protocol, which indicated an encouraging result for elderly patients with AML, indicated effectiveness of the strategy with reduced intensity. However, the cyto-toxic effect of decitabine with standard dose (20mg/m2) could still lead to severe treatment adverse events (AEs) thus raise the need of optimization of D-CAG regimen for patients with inferior PS. When considering the low dose hypo-methylation agent (HMA) can trigger the innate immunity response, the unique effect of homoharringtonine, as well as the effectiveness of CAG, we designed this DHCAG protocol following the principle of "longer exposure, lower intensity preceded by priming" and observed an unexpected excellent outcome with high CR rate, low induction failure and treatment mortality, as well as a higher cost effective value for patients with AML, when compared to "3+7" protocol, whom under inferior PS. From March 2016 - January 2018, we initiated this pilot study and investigated the safety and efficiency of this DHCAG protocol in patients with AML under poor PS. We enrolled 25 patients and administer the regimen as followings: i) G-CSF: 5μg/kg used when WBC 1*10^9/L then increase the dosage of homoharringtonine to 2mg/m2); iv) Cytarabine:10mg/m2 q12h at day 1-14 subcutaneous injection (if WBC >20*10^9/L then increase to 100mg/m2 by 24h CIV, or 50mg/m2 q12h by subcutaneous injection). The primary end point was complete hematologic remission, defined as a bone marrow blast cells ≤5%, Neutrophils in peripheral blood ≥1.0X109 /L, hemoglobin≥90g/L, and platelets ≥100X109/L and no any evidence of extramedullary leukemic infiltration; Secondary end points included numbers of adverse events, length of hospital stay, medical costs, and quality of life as measured with the use of the Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire. Among the 25 patients in the study, 23 completed the induction therapy. And 21/25 patients had a hematologic complete remission after a median time of 19 days. Once complete remission had occurred, all 21 patients received post-remission treatment for another 5 cycles of DHCAG. Median follow-up was 14 months (range, 8 to 19) by June 2018. Interestingly, regardless of grade 3-4 myelo-suppression occurred all of our patients during induction, eight patients did not experienced grade 3-4 myelo-suppression during the following cycles. The median hospital stay is 22 days. The median of total medical costs for induction was $9,815 (range, $5,053 to $16,336) vs $14,705 for "3+7" induction protocol (history control. Data unpublished). Patients resumed their usual lifestyle during post-remission therapy, and their quality of life was rated as nearly normal on the FACT-G questionnaire. At the time of the last follow-up, seven patients had had a hematologic relapse. The results of our pilot study, in which we tested a priming based, low dose and longer exposure in 25 patients with AML under poor PS, showed that the treatment was safe, effective, and economical. A prospective multicenter, randomized trial comparing DHCAG with IA is now under way in China. Disclosures No relevant conflicts of interest to declare.

In a well-controlled multi-center randomized trial in southwestern China, 228 patients with refractory or relapsed AML were received a low-dose CAG regimen either with etoposide (E-CAG) or without etoposide (CAG). The complete remission (CR) rate, overall survival (OS) and toxicity were evaluated. Patients with E-CAG had a higher CR rate (71.1% vs. CAG 50.9%, P=0.0002). The tolerability appeared to be equivalent. Patients with CR who underwent allogenic hematopoietic stem cell transplantation (allo-HSCT) had a higher five-year OS over those without allo-HSCT (73.8% vs. 10.8%, P=0.000). The E-CAG regimen is expected to become a bridge between relapsed or refractory AML and allo-HSCT.

This study was undertaken to explore whether the graft-versus-host-disease could be decreased and graft-versus-leukemia effect be retained by transplantation of allogeneic T helper-2 (Th2) cells. T cells from C57BL/6(H-2b) mice were incubated and polarized with rmIL-4, Con A and ionomycin in vitro, and then, the T cells were mixed with marrow cells and transplanted into recipient BALB/c(H-2d) mice bearing erythroleukemia cells. The occurence of GVHD and GVL effect was observed. The results showed that the mean survival time in the groups of untreated control, cyclophosphamide treatment, marrow and spleen T cell transplantation and marrow and Th2 cell transplantation was 10.6 +/- 1.3, 18.7 +/- 4.2, 22.7 +/- 7.4 and 36.9 +/- 10.8 days, respectively. In untreated control and cycophosphamide treatment groups, all of ten mice died from leukemia. Nine of ten mice died from GVHD in marrow and spleen T cells transplantation group. In marrow and spleen Th2 cell transplantation group, three of ten mice died from GVHD, and GVHD was not occurred in the other seven mice, and there was no any evidence of leukemia in two mice on 50 days after transplantation. It was concluded that tranplantation with polarized Th2 cells could relieve GVHD, and at the same time retain the GVL effect.

Background Since the introduction of tyrosine kinase inhibitors (TKIs) into combination chemotherapy regimens, the majority of newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) patients have achieved complete remission (CR). However, without allogeneic hematopoietic stem cell transplantation (HSCT), long-term outcomes in adults remain unsatisfactory. Indeed, haploidentical HSCT has become a common treatment for adult patients who lack an HLA-matched donor, though limited data are available on the efficacy of haploidentical HSCT in Ph+ ALL patients. Methods We analyzed the clinical outcomes of 82 Ph+ ALL patients who underwent haploidentical HSCT (n = 47) or HLA-matched HSCT (n = 35). Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to assess BCR-ABL expression. All of the patients were treated with an imatinib-based regimen before undergoing HSCT. Imatinib treatment was resumed in the patients’ posttransplantation following detection of BCR-ABL transcripts. Results All of the patients achieved neutrophil and platelet engraftment, with the exception of five patients who died prior to engraftment. Haploidentical HSCT was associated with higher incidences of acute graft-versus-host disease (GVHD) (51.1 vs. 25.7 %, p