(A) Applicable subjects.
First diagnosis of acute promyelocytic leukemia (ICD-10: C92.4, M9866/3)
(B) Diagnosis basis.
According to the World Health Organization Classification of Tumors. Pathology and Genetic of Tumors of Haematopoietic and Lymphoid Tissue (2008), Diagnostic and Efficacy Criteria for Hematologic Diseases (edited by Zhang Zhinan and Shen Ti, Science Press, 2008, 3rd edition)
1. Physical examination with or without the following signs: fever, pale skin and mucous membranes, bleeding spots and petechiae on the skin, enlarged lymph nodes and liver and spleen, sternal pressure pain, etc.
2. Blood cell count and classification.
3. Bone marrow examination: morphology (including histochemical examination).
4. Immunophenotyping.
5. Cytogenetics: karyotype analysis (t(15;17) and its variants), FISH (if necessary).
6. Leukemia-related genes (PML/RARa and its variants).
(iii) Basis for selecting treatment options.
According to the Expert Consensus on the Treatment of Acute Promyelocytic Leukemia (APL) (Chinese Medical Association, Hematology Section, Leukemia Group)
1. Induction therapy.
(1) All-trans retinoic acid (ATRA) alone or in combination with erythromycin (DNR).
ATRA: 25-45mg・m-2 ・d-1 × 28-40d;
If combined with DNR, DNR is started on day 4 after ATRA treatment with a maximum amount of 135mg・m-2, split into at least 3 days of administration.
(2) ATRA combined with arsenic trioxide (ATO).
ATRA:25-45mg・m-2 ・d-1×28-40d;
ATO:10mg/d×28-35d.
Cytotoxic drugs such as DNR and hydroxyurea can be added in appropriate amounts according to the changes in leukocyte count during treatment.
2. After remission, consolidation therapy is feasible with 3 courses of chemotherapy, which are DA, MA and HA regimens.
(1) DA regimen: DNR 40-45mg・m-2・d-1×3d, Ara-C 100-200mg・m-2・d-1×7d;
(2)MA regimen: Mitoxantrone (MTZ) 6-10mg・m-2 ・d-1×3d,Ara-C 100-200mg・m-2 ・d-1×7d;
(3) HA regimen: hypertrigonelline (HHT) 2.0-2.5mg・m-2 ・d-1×7d,Ara-C 100-200mg・m-2・d-1×7d.
In case of high-risk patients (WBC ≥10×109/L at initial diagnosis), Ara-C in DA or MA regimen can be replaced with 1-2g・m-2, q12h ×3d.
3. Prevention and treatment of central nervous leukemia (CNSL): lumbar puncture and intrathecal injection at least 4 times to confirm the diagnosis of CNSL withdraw from this pathway. The sheath injection regimen is as follows.
Methotrexate (MTX) 10-15mg, Ara-C 40-50mg, Dexamethasone (DXM) 5mg.
4. Maintenance therapy after remission, sequential application of ATO, ATRA, 6-mercaptopurine (6-MP) + methotrexate (MTX) three regimens, each regimen for 1 month, 3 months as a cycle, a total of 5 cycles.
(1)ATO 10mg・d-1×21-28d.
(2)ATRA 25-45mg・m-2 ・d-1×28d.
(3)6-MP+MTX: 6-MP 100mg, d-1-7th, d-15th-21st;
MTX 20mg, day 9, 12, 23, 26.
(iv) Pathway selection according to the patient’s disease status.
Clinical pathway for primary APL and clinical pathway for APL in complete remission (attached).
Primary APL clinical pathway
I. Standard hospitalization process of primary APL clinical pathway
(a) The standard hospitalization days are within 40 days.
(B) The criteria for entering the pathway.
1. The first diagnosis must meet the ICD-10: C92.4, M9866/3 acute promyelocytic leukemia (APL) disease code for induction of differentiation therapy.
2. When the patient has other disease diagnoses at the same time, but does not require special treatment during hospitalization and does not affect the implementation of the clinical pathway process for the first diagnosis, he/she can enter the pathway.
(C) Clear diagnosis and routine examination for hospital admission takes 3-5 days (referring to working days).
1. Necessary examination items.
(1)Routine blood, routine urine, routine stool;
(2) Liver and kidney function, electrolytes, coagulation function, blood type, pre-transfusion examination;
(3) Chest X-ray, electrocardiogram, abdominal ultrasound, fundus examination.
2. Fever or suspected infection may be selected: pathogenic microbial culture, imaging examination.
(3) Bone marrow examination (morphology including histochemistry), immunophenotyping, cytogenetics, leukemia-related gene (PML/RAR and its variants) testing.
(iv) Pre-chemotherapy preparation.
1. It is recommended to perform pathogenic microbial culture and use antibacterial drugs immediately for patients with fever. Cephalosporins (or penicillins) ± aminoglycosides may be used for anti-inflammatory treatment, and those whose fever does not resolve after 3 days may be considered for replacement with carbapenems and/or glycopeptides and/or antifungal treatment; patients with definite organ infections should choose the appropriate antibacterial drugs according to the site of infection and pathogenic microbial culture results.
2. For patients with Hb80g/L, PLT30×109/L or active bleeding, transfuse concentrated red blood cells and platelets respectively; if there is a tendency of disseminated intravascular coagulation (DIC), platelets should be transfused when PLT50×109/L. The indications for transfusion can be relaxed in the presence of cardiac insufficiency.
3. For patients with coagulation abnormalities, transfuse the appropriate blood products. In case of fibrinogen 1.5g/L, fresh plasma or concentrated fibrinogen should be transfused.
(v) Chemotherapy is started on day 1 of diagnosis.
(F) Chemotherapy regimen.
1. Induction therapy: one of the following regimens can be used for treatment
(1) ATRA regimen:ATRA 25-45mg・m-2・d-1×28-40d.
(2) ATRA + DNR regimen: ATRA 25-45mg・m-2・d-1×28-40d, DNR starts on day 4 after ATRA treatment, up to 135mg・m-2, split into at least 3 days.
(3) ATRA + ATO regimen: ATRA 25-45mg・m-2・d-1×28-40d, ATO 10mg・d-1×28-35d, with the addition of cytotoxic drugs such as DNR and hydroxyurea in appropriate amounts according to changes in leukocyte counts during the course of treatment.
(vii) Examination items that must be reviewed within 30 days after treatment.
1.Blood routine, liver and kidney function, electrolytes.
2.Organ function assessment.
3.Bone marrow examination.
4.Micro residual lesion detection (when available).
(H) Treatment during and after chemotherapy.
1. Infection prevention and control: Patients with fever are recommended to have immediate pathogenic microbial culture and use antibacterial drugs. Cephalosporins (or penicillins) ± aminoglycosides may be used for anti-inflammatory treatment; those whose fever does not resolve after 3 days may be considered for replacement with carbapenems and/or glycopeptides and/or antifungal treatment; patients with definite organ infections should choose appropriate antibacterial drugs according to the site of infection and pathogenic microbial culture results.
2. Corresponding prevention and control of organ function damage: antiemetic, hepatoprotective, hydration, alkalinization, prevention and control of uric acid nephropathy (allopurinol), treatment of induced differentiation syndrome (dexamethasone), acid suppressant, etc.
3. Component transfusion: For patients with Hb80g/L, PLT30×109/L or active bleeding, transfuse concentrated red blood cells and platelets respectively; if there is a tendency of DIC, then PLT50×109/L should be transfused with platelets. The indications for transfusion can be relaxed if there is cardiac insufficiency.
4. Hematopoietic growth factor: If the absolute neutrophil value (ANC) is ≤1.0×109/L after chemotherapy, granulocyte colony-stimulating factor (G-CSF) 5μg・Kg-1 ・d-1 can be used.
(ix) Discharge criteria.
1. Good general condition.
2. No complications and/or comorbidities requiring hospitalization.
(J) Variation and cause analysis.
1. Infection, anemia, bleeding and other comorbidities occurring during treatment require relevant diagnosis and treatment, and the hospital stay may be extended appropriately.
2. Those who do not achieve complete remission after 40 days of induction differentiation therapy withdraw from this pathway.
3. If the cerebrospinal fluid examination after lumbar puncture shows the presence of leukemic neurological invasion, it is recommended to inject chemotherapeutic drugs by lumbar puncture sheath on alternate days until the cerebrospinal fluid examination is normal, while withdrawing from this pathway and entering the related pathway.
Clinical pathway of APL in complete remission
I. Standard hospitalization process of APL clinical pathway in complete remission
(A) The standard hospitalization day is within 28 days.
(ii) Criteria for entering the pathway.
1. The first diagnosis must meet the ICD-10: C92.4, M9866/3 acute promyelocytic leukemia (APL) disease code.
2. CR achieved with induction chemotherapy.
3. Patients can enter the pathway when they also have other disease diagnoses but do not require special treatment during hospitalization and do not affect the implementation of the clinical pathway process for the first diagnosis.
(C) It takes 2 days (meaning working days) to perfect the routine examination for admission.
1. Required examination items.
(1)Routine blood, routine urine, routine stool;
(2) Liver and kidney function, electrolytes, blood type, coagulation function, pre-transfusion examination;
(3) Chest X-ray, electrocardiogram, abdominal ultrasound.
2. Fever or suspected infection of a system can be selected: pathogenic microbial culture, imaging examination.
3. bone marrow examination (biopsy if necessary), detection of micro residual lesions.
(iv) Chemotherapy is started within the 3rd day of admission.
(V) Chemotherapy regimen.
1. Post-remission consolidation therapy: 3 courses of chemotherapy are feasible, namely DA, MA and HA regimens.
(1) DA regimen: DNR 40-45mg・m-2 ・d-1×3d, Ara-C 100-200mg・m-2 ・d-1×7d.
(2)MA regimen: Mitoxantrone (MTZ) 6-10mg・m-2 ・d-1×3d,Ara-C 100-200mg・m-2 ・d-1×7d.
(3) HA regimen: hypertrigonelline (HHT) 2.0-2.5mg・m-2 ・d-1×d days, Ara-C 100-200mg・m-2 ・d-1×d days.
In case of high-risk patients (WBC ≥10×109/L at initial diagnosis), Ara-C in DA or MA regimen can be changed to 1-2g・m-2, q12h ×3d.
2. Prevention and treatment of central nervous leukemia (CNSL): lumbar puncture and intrathecal injection at least 4 times (confirmed CNSL withdrawal from this pathway). The sheath injection regimen is as follows.
MTX 10-15mg, Ara-C 40-50mg, DXM 5mg.
3. Maintenance therapy after remission: sequential application of three regimens of ATO, ATRA, and 6-MP + MTX for 1 month each, with 3 months as 1 cycle, using a total of 5 cycles.
(1)ATO 10mg・d-1×21-28d.
(2)ATRA 25-45mg・m-2 ・d-1×28d.
(3)6-MP+MTX: 6-MP 100mg, day 1-7, day 15-21; MTX 20mg, day 9, 12, 23, 26 .
(F) Examination items for review during the recovery period after chemotherapy.
1. Blood routine, liver and kidney function, electrolytes.
2. Organ function assessment.
3. Bone marrow examination (if necessary).
4. Detection of micro residual lesions (when necessary).
(VII) Treatment during and after chemotherapy.
1. Prevention and control of infection: febrile patients are recommended to have immediate pathogenic microbial culture and use antibacterial drugs, cephalosporins (or penicillins) ± aminoglycosides can be used for anti-inflammatory treatment; those whose fever does not resolve after 3 days may be considered for replacement of carbapenems and/or glycopeptides and/or antifungal treatment; patients with definite organ infections should choose appropriate antibacterial drugs according to the site of infection and pathogenic microbial culture results.
2. Prevention and control of damage to other organ functions: antiemetic, hepatoprotective, hydration, alkalinization.
3. Component transfusion: For patients with Hb80g/L, PLT20×109/L or active bleeding, transfuse concentrated red blood cells and single-collected platelets, respectively. The indications for transfusion can be relaxed in patients with cardiac insufficiency.
4. Hematopoietic growth factor: G-CSF 5μg・Kg-1 ・d-1 can be used if the absolute value of neutrophils (ANC) is ≤1.0×109/L after chemotherapy.
(H) Discharge criteria.
1. Good general condition.
2. No complications and/or comorbidities that require hospitalization.
(ix) Variation and cause analysis.
1. If there are infections, anemia, bleeding and other comorbidities during or after treatment, relevant diagnosis and treatment will be performed, and the hospital stay will be extended appropriately.
2. If the cerebrospinal fluid examination after lumbar puncture indicates the presence of leukemic CNS invasion, it is recommended to inject chemotherapeutic drugs into the lumbar puncture sheath on alternate days until the cerebrospinal fluid examination is normal, while withdrawing from this pathway and entering the relevant pathway.