Study of Sequential CAR-T Cell Treating Leukemia Children

Inclusion Criteria:

* Patients who were diagnosed as primary refractory or relapsed B-ALL. (Criterion-reference: NCCN, 2020.1); All the patients matched the diagnostic criteria of ALL according to the WHO classification, and conducted morphological evaluation, immunophenotype analysis by flow cytometry (FCM), cytogenetic analysis by routine G-banding karyotype analysis, screen of 56 leukemia-related fusion genes by multiplex nested reverse transcriptase polymerase chain reaction (RT-PCR), and quantification of fusion genes by real-time PCR with ABL1 as reference. 339 hematological malignancies-related genes were also screened by Illumina sequencing. Extramedullary diseases (EMDs) were confirmed CD19+ and CD22+ by FCM and evaluated by positron emission tomography/computed tomography (PET/CT), CT, MRI or ultrasonography. The patient relapsed during chemotherapy, failed from re-induction chemotherapy (including first and second generation TKIs) after relapse or had a persistent positive MRD for three months or relapsed after allo-HCT. Patients had positive CD19 and CD22 expression on leukemia blasts by FCM (\>95% CD19 and CD22 positive);
* Age from 1 to 18 years old;
* Children candidates can be recruited after the legal guardian or patient advocate has signed the treatment consent form and voluntary consent form.

Exclusion Criteria:

* Intracranial hypertension or unconscious;
* Acute heart failure or severe arrhythmia;
* Acute respiratory failure;
* Other types of malignant tumors;
* Diffuse intravascular coagulation;
* Serum creatinine and/or blood urea nitrogen over 1.5 times than normal range;
* Sepsis or other uncontrolled infection;
* Uncontrolled diabetes mellitus;
* Severe psychological disorder;
* Obvious cranial lesions with cranial MRI;
* More than 20 counts/ul leukemic cells in cerebrospinal fluid;
* More than 30% leukemic cells in the blood;
* Stage III WHO/ECOG score;
* Organ recipients;
* Pregnant or breastfeeding;
* Active, uncontrolled infection, including hepatitis B, hepatitis C or human immunodeficiency virus (HIV);