I. Applicable targets
Patients in the standard-risk and intermediate-risk groups with the first diagnosis of childhood acute lymphoblastic leukemia (ICD-10:C91.0).
Second, the basis of diagnosis
According to the Clinical Diagnosis and Treatment Guide-Pediatrics Internal Medicine Booklet (edited by Chinese Medical Association, People’s Health Publishing House), Zhu Futang Practical Pediatrics (7th edition) (People’s Health Publishing House), Diagnostic and Efficacy Criteria for Blood Disorders (3rd edition) (edited by Zhang Zhinan and Shen Ti, Science Publishing House).
(I) Physical examination: there may be fever, pale skin and mucous membranes, bleeding spots and petechiae on the skin, enlarged lymph nodes and liver and spleen, and sternal pressure pain.
(B) Blood cell count and classification.
(C) Bone marrow examination: morphology (including histochemical examination).
(iv)Immunophenotyping.
(V) Cytogenetics: karyotype analysis, FISH (if necessary).
(vi) Leukemia-related genes.
III. Risk grouping criteria
(i) Standard risk group: all of the following conditions must be met simultaneously.
1. age ≥ 1 year and < 10 years;
2. WBC<50×109/L;
3. Good response to prednisone (peripheral blood leukemia cells <1×109/L on day 8);
4. Non-T-ALL;
5. Non-maturing B-ALL;
6. no t(9;22) or BCR/ABL fusion gene; no t(4;11) or MLL/AF4 fusion gene; no t(1;19) or E2A/PBX1 fusion gene;
7. Bone marrow showed M1 (promyelocytes <5%) or M2 (promyelocytes 5%-25%) on day 15 of treatment, and complete remission of bone marrow on day 33.
(ii) Intermediate risk group: the following 4 conditions must be met simultaneously.
1. no t(9;22) or BCR/ABL fusion gene;
2. Good response to prednisone (<1×109/L peripheral blood leukemia cells on day 8);
3. M3 bone marrow (promyelocytes >25%) on day 15 of standard risk induction remission therapy or M1/M2 bone marrow on day 15 of intermediate risk induction remission therapy;
4. MRD <10-2 on day 33 if conditionally tested for microscopic residual disease (MRD).
Also meet at least one of the following conditions.
5. WBC ≥ 50×109/L;
6. age ≥ 10 years;
7. T-ALL;
8. t(1;19) or E2A/PBX1 fusion gene positive;
9. age <1 year and no MLL gene rearrangement.
(C) High risk group: one of the following conditions must be met.
1. poor response to prednisone (peripheral blood leukemic cells >1×109/L on day 8);
2. t(9;22) or BCR/ABL fusion gene positive;
3. t(4;11) or MLL/AF4 fusion gene positive;
4. M3 bone marrow on day 15 of intermediate-risk induction remission treatment;
5. morphologically unremitting bone marrow (>5%) on day 33, M2/M3;
6. MRD ≥ 10-2 at day 33 or MRD ≥ 10-3 at week 12 if conditions for MRD testing are available.
IV. Basis for choosing treatment plan
According to the Clinical Diagnosis and Treatment Guide-Pediatrics Internal Medicine Sub-volume (edited by Chinese Medical Association, People’s Health Publishing House), Zhu Futang Practical Pediatrics (7th edition) (People’s Health Publishing House)
(I) Initial induction chemotherapy regimen.
VDLP(D) regimen.
Vincristine (VCR) 1.5mg・m-2・d-1, once a week, 4 times, maximum absolute amount not exceeding 2mg each time;
Doxorubicin (DNR) 30mg/m-2/d-1 once a week for 2-4 times;
L-asp 5000-10000u/m-2/d-1, 6-10 times;
Prednisone (PDN) 45-60mg・m-2・d-1, d1-28, decreasing to stop on day 29-35. Or PDN 45-60mg・m-2・d-1, d1-7, dexamethasone (DXM) 6-8mg・m-2・d-1, d8-28, decreasing to stop on day 29-35.
PDN trial d1-7, starting from 25% of the full dose, gradually increase to the full dose according to clinical response, cumulative dose >210mg・m-2 in 7 days, for patients with large tumor load can reduce the starting dose (0.2-0.5mg・kg-1・d-1) to avoid tumor lysis syndrome, d8 assessment.
(ii) Post-remission consolidation therapy.
1.CAM regimen:
Cyclophosphamide (CTX) 800-1000mg・m-2・d-1, 1 time;
Cytarabine (Ara-C) 75-100mg/m-2/d-1 for 7-8 days;
6-Mercaptopurine (6-MP) 60-75mg・m-2・d-1 for 7-14 days.
The CAM regimen was repeated once for patients in the intermediate risk group.
2. mM regimen.
High-dose methotrexate (MTX) 3-5g/m-2/d-1 once every two weeks for 4-5 times;
Calcium tetrahydrofolate (CF) 15mg・m-2
3-8 times a day, once every 6 hours, adjusted according to MTX blood concentration;
6-MP 25mg・m-2・d-1 ,no more than 56 days, dose adjusted according to WBC.
Hydration and alkalinization are required during the implementation of the above protocol.
(iii) Delayed intensive therapy.
1.VDLP(D) regimen.
VCR 1.5mg・m-2・d-1 once a week for 3 times, maximum absolute amount not exceeding 2mg each time;
DNR or Adriamycin (ADR) 25-30mg・m-2・d-1, once a week, 1-3 times in total;
L-asp 5000-10000u/m-2/d-1, 4-8 times;
PDN 45-60mg・m-2・d-1 or DXM 6-8mg・m-2・d-1, d1-7, d15-21.
2. CAM regimen:
CTX 800-1000mg・m-2・d-1, 1 time;
Ara-C 75-100mg/m-2/d-1 for 7-8 days;
6-MP 60-75mg・m-2・d-1 for 7-14 days.
Patients in the intermediate-risk group were inserted into 8-week maintenance therapy (i.e., with an 8-week 6-MP + MTX regimen, as described below).
Patients in the intermediate-risk group repeat the above VDLP(D) and CAM regimen once.
(iv) Maintenance treatment regimen.
1. 6-MP+MTX regimen.
6-MP 50mg・m-2・d-1 by mouth on an empty stomach continuously before bedtime;
MTX 15-30mg・m-2, once a week, orally or intramuscularly, until termination of treatment (2.5-3 years for men and 2-2.5 years for women).
Adjust the drug dose in the regimen according to WBC.
2. VD regimen (inserted every 4-8 weeks during 6-MP+MTX regimen).
VCR 1.5mg・m-2・d-1, 1 dose, maximum absolute amount not exceeding 2mg per dose;
DXM 6-8mg・m-2・d-1, d1-7.
(E) Prevention and treatment of central nervous leukemia (CNSL): lumbar puncture and intrathecal injection at least 16-24 times. MTX alone or triple intrathecal injection can be used according to risk grouping with the following drug doses.
MTX: age <12 months 6mg, age 12-36 months 9mg, age >36 months 12.5mg;
Ara-C: age <12 months 15mg, age 12-36 months 25mg, age >36 months 35mg;
DXM: age <12 months 2.5mg, age 12-36 months 2.5mg, age >36 months 5mg.
Children diagnosed with CNSL at the initial diagnosis are not treated with radiotherapy at age <1 year, and those aged ≥1 year need to receive the appropriate dose of cranial radiotherapy.
V. Selection of pathway according to the patient’s disease status
The clinical pathway for primary childhood ALL and the clinical pathway for childhood ALL in complete remission (CR) (attached).
VI. Reference cost criteria
(a) The average full course reference cost standard for patients in the standard-risk group is controlled within 80,000 yuan.
(b) The average full reference cost standard for patients in the intermediate risk group is controlled within 150,000 RMB.