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Malilane 3.2mg/kg/d \*4d (-5,-4,-3,-2day) cyclophosphamide 25mg/kg/d\*4d (-9-8,-7,-6 day) fludarabine 30mg/m2/d\*4d (-9-8,-7,-6 day) Donor stem cells will be transfused at 0 days.

malilane 3.2mg/kg \*4d (-5,-4,-3,-2day) cyclophosphamide 50mg/kg/d\*2d (-2,-1day) Donor stem cells will be transfused at 0 days.

The combination of fludarabine and cyclophosphamide has synergistic effect, which can better kill B lymphocyte, and can enhance the killing effect of pretreatment regimen on B lymphocyte tumor.

Yu Cai, MD

Xianmin Song, M.D.

Lianghong Fang, doctor

Xianmin Song, MD

Comparing the efficacy and safety of fludarabine-containing BFC conditioning regimen with traditional BuCy conditioning regimen in Acute B-cell lymphoblastic leukemia patients who treated with allogeneic hematopoietic stem cell transplantation, to establish a conditioning regimen for improving the survival rate of patients with B-cell ALL after transplantation.

Acute B-cell lymphoblastic leukemia (B-ALL) is a hematologic malignancy . The incidence of B-All is higher in children than in adults, but more than 80% of children patients can be cured by chemotherapy, while the survival rate of adult patients is less than 40%. Recurrence or progression of the disease is the main reason affecting the survival of patients.

Although CD19-targeted CAR T cell therapy is an effective salvage treatment for relapsed and refractory B-ALL, bridging allogeneic hematopoietic stem cell transplantation is required after remission. 1-year LFS and 1-year OS were 11.6% and 32% in patients without bridging grafts after CAR T.

Allogeneic hematopoietic stem cell transplantation is an effective treatment for ALL. Before the transplant, patients receive high doses of chemotherapy plus or total body irradiation（TBI） to 'creation of space' ，immunosuppression and disease eradication. This is called conditioning regimen. Conditioning regimen plays a key role in reducing tumor load and diseaseconditioning regimen recurrence.

Conditioning regimen for different diseases are different. Conditioning regimen are based on TBI and chemotherapy BuCy, with low TBI recurrence rate but high treatment-related mortality (TRM). BuCY chemotherapy had low TRM but high recurrence rate, so there was no difference in total OS. Therefore, it is of great clinical value to explore a conditioning regimenprogram. How to optimize the preconditioning program before transplantation, so as to reduce the recurrence rate and prolong the survival period of adult B-cell ALL patients after transplantation has become a issue that needs to be solved urgently in clinical practice.

BFC (Malilane + fludarabine + cyclophosphamide) is the addition of fludarabine to BuCy (malilane + cyclophosphamide). The combination of fludarabine and cyclophosphamide has synergistic effect, which can better kill B lymphocyte, and can enhance the killing effect of pretreatment regimen on B lymphocyte tumor.

This study was a prospective, randomized, controlled, single-center clinical study. A total of 142 patients eligible for the inclusion of acute B lymphoblastic leukemia were randomly divided into two groups: the experimental group (n = 71) and the control group (n = 71). The treatment group was given BFC conditioning regimen (fludalabine, marylan, cyclophosphamide), and the control group was given BuCY conditioning regimen (marylan, cyclophosphamide), and the patients were followed up to 1 year after transplantation. The 1-year disease-free survival rate of patients in the two groups was compared to evaluate whether increasing fludarabine could reduce the recurrence rate of patients after transplantation and thus improve the overall survival rate.

Comparative Study of BFC and BuCy Conditioning Regimen for Allo-PBSCT in Acute B-cell ALL

Shanghai General Hospital, Shanghai, Jiao Tong University School of Medicine

Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine

Department of Hematology，Director, Head of Otolaryngology, Principal Investigator,

Symptoms and General Pathology

Recurrence

After preconditioning with chemotherapy, CAR-NK-CD19 Cells will be evaluated.

CAR-NK-CD19 Cells, 1-3×10\^7 /KG, treatment follows a lymphodepletion. Drug: Fludarabine Recommendation: 25-30 mg/m2 (D-5\~D-3), determined by tumor burden at baseline. Drug: Cyclophosphamide Recommendation: 250-300 mg/m2 (D-5\~D-3), determined by tumor burden at baseline.

CAR-NK-CD19 Cells

This study is a single arm clinical study to observe the safety ，dose tolerance and pharmacokinetic characteristics of CAR NK-CD19 in patients with recurrent or refractory CD19 positive acute lymphoblastic leukemia, and preliminarily evaluate the effectiveness, the immunogenicity of the product and the correlation between the changes of cytokines after infusion and CRS , ICANS.

It is planned to select 9-21 patients with recurrent or refractory CD19 positive acute lymphoblastic leukemia （ALL）, from the lowest dose group. It is expected that 3-6 cases will be enrolled in each dose group. The protocol will be performed into screening period (-30\~-10 days), prophase of lymophodepletion (-10\~-5 days), Lymophodepletion (-5\~-3 days), pre-infusion evaluation (-2\~-1 days), infusion (day 0), and follow-up period (1-720 days). The incidence of DLT is observed after infusion. There are three preset dose groups in this clinical trial. The initial dose is 1.0 × 107 CAR positive NK cells/kg (body weight). Subsequent dose groups included 2.0 × 107 and 3.0 × 107 CAR positive NK cells/kg (body weight). The specific dose is determined by SRC based on the patient safety data and PK data. The maximum sample size of this study is tentatively 21 cases.

Anti-CD19 CAR-Engineered NK Cells in the Treatment of Relapsed/Refractory Acute Lymphoblastic Leukemia

A Phase Ⅰ Clinical Study on the Safety and Efficacy of Chimeric Antigen Receptor Gene Modified NK Cells Targeting CD19 in Patients With Recurrent or Refractory CD19 Positive Acute Lymphoblastic Leukemia

Incidence of adverse events associated with CAR NK-CD19 treatment, abnormal clinically significant laboratory findings, including dose-limiting toxicity (DLT) and maximum-tolerated Dose (MTD).

Other related pharmacokinetic parameters in peripheral blood and bone marrow

Total response rate (ORR) in 12 weeks (inclusive) after infusion of CAR NK-CD19 cells. CR/CRi ratio at 4 and 12 weeks; Duration of response (DOR); Progression free survival (PFS); Minimal residual disease (MRD) negative rate and duration at 4 and 12 weeks; Overall survival (OS)

Detection of anti-drug antibody (ADA) in CAR NK-CD19 cells

Detect the changes of cytokines in peripheral blood before and after CAR NK-CD19 cell infusion and the recovery time

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Comparative Study of BFC and BuCy Conditioning Regimen for Allo-PBSCT in Acute B-cell ALL	NCT05379569	Acute B Lymphob... Allogeneic Hema...	Fludarabine	18 Years - 55 Years	Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Anti-CD19 CAR-Engineered NK Cells in the Treatment of Relapsed/Refractory Acute Lymphoblastic Leukemia	NCT05563545	Acute Lymphobla...	CAR-NK-CD19 Cel...	3 Years -	Shanghai Simnova Biotechnology Co.,Ltd.

Spots Global Cancer Trial Database for acute b lymphoblastic leukemia