I. Chemotherapy
(A) Strategy of chemotherapy The aim is to achieve complete remission and prolong survival. By complete remission, the signs and symptoms of leukemia disappeared, blood picture Hb ≥ 100g/L (male) or 90g/L (female and children), absolute neutrophil value ≥ 1.5×109/L, platelets ≥ 100×109/L, and no leukemic cells in peripheral blood leukocyte classification. Bone marrow picture: progranulocytes + promyelocytes (promonocytes + young monocytes or prolymph + young lymphocytes) ≤ 5%, normal erythrocyte and megakaryocyte series.
Currently, combined chemotherapy is mainly used to treat leukemia, and the principles of chemotherapy implementation are early treatment, combined, adequate, intermittent, and phased.
Chemotherapy should be administered to leukemia as early as possible, because the smaller the leukemic clone and the lighter the degree of infiltration, the more pronounced the effect of chemotherapy and the better the prognosis. It is important to strive for early diagnosis and create conditions for early treatment. If necessary, chemotherapy should be administered on one side of anti-infection and supportive treatment.
The combination of chemotherapy should meet the following conditions: (i) the drugs should act in different stages of the cell cycle; (ii) the mechanism of action of each drug should not be the same, there is mutual synergy; (iii) the side effects of each drug do not overlap. A chemotherapy regimen composed of such drugs can maximize the killing of leukemia cells with less damage to vital organs.
The proliferation cycle of leukemia cells is approximately 5 days. Some anti-leukemic drugs act in specific proliferative phases of the cycle, such as vincristine in the mitotic phase (M phase), cytarabine in the DNA synthesis phase (S phase), and anthracycline antibiotics in each phase of the cell cycle, so each course of chemotherapy must last for 7-10 days to give the leukemic cells in each proliferative phase a chance to be killed by the drug.
Therefore, not only should the chemotherapy regimen be composed of drugs that act at different stages of the cell cycle, but the dosage of drugs should be appropriate and the duration of chemotherapy should be sufficient to maximize the effect of drugs to kill leukemia cells.
After each course of treatment, there should be an interval of 2-3 weeks before entering the second course of treatment. Most leukemia cells are in the proliferation cycle and are easily killed by chemotherapy during the course of treatment. The resting phase (Go phase) leukemia cells that are difficult to be killed by chemotherapy will enter the proliferative cycle during the interval between courses.
Therefore, the interval between courses facilitates the killing of residual leukemic cells by the next course of chemotherapy. Since most leukemic cell lines take longer to multiply, the recovery of leukemic cells is slower than the recovery of normal hematopoiesis, so an appropriate interval is beneficial for the recovery of normal hematopoiesis. The remission of leukemia depends on the relationship between leukemic hematopoiesis and normal hematopoiesis; if normal hematopoiesis cannot be restored, then leukemia cannot be remitted.
The number of leukemic cells in untreated acute leukemia is quite large, estimated to be 1010~1013, and three stages of remission induction, remission consolidation and remission maintenance are needed to gradually eliminate the remaining leukemic cells to prevent relapse and prolong disease-free survival. The leukemia cells in the body are about 106~108 when the standard of complete remission is reached. At this time, leukemia cells can still infiltrate in some hidden places outside the medulla, therefore, after complete remission, 4~6 courses of treatment should be implemented to consolidate remission, so that leukemia cells can be reduced to 104 and then enter the maintenance phase.
(B) Chemotherapy for acute gonorrhea The classic regimen for induction of remission in acute gonorrhea patients is the VP regimen, i.e. vincristine 1~2mg sedated once a week plus prednisone 40~60mg orally daily until remission. Complete remission rates are as high as 80% to 90% in children and only 50% in adults. The relapse rate of this regimen is relatively high and requires the addition of menadione (VLP regimen) or erythromycin (VDP regimen) or four drugs simultaneously (VLDP regimen) to the VP regimen. the VLDP regimen not only reduces the relapse rate, but also increases the complete remission rate to 72%-77.8% in adults.
The National Leukemia Symposium recommends 6 courses of intensive consolidation after complete remission: courses 1 and 4 with the original induction regimen; courses 2 and 5 with VP-16 (75 mg/m2 intravenously, days 1~3) and cytarabine (100~150 mg/m2 intravenously, days 1~7); courses 3 and 6 with high-dose methotrexate, 1~1.5 g/m2 intravenously on day 1, maintained 24h, and then relieved by calcium tetrahydrofolate (6~9mg/m2, intramuscular injection every 6h, 8 times in total) 12h after discontinuation. Because high-dose MTX can cross the blood-cerebrospinal fluid barrier, it can be an alternative to intrathecal injection. It has been advocated that adults with acute gonorrhea should be treated with mercaptopurine and methotrexate alternating with long-term oral dosing during the intensive interval of consolidation. The maintenance phase can be treated with the above-mentioned regimen for 3 to 5 years with progressively longer intervals.
Prophylactic treatment of central nervous system leukemia is required at the beginning of remission of acute gonorrhea.
(C) Acute non-gonococcal leukemia chemotherapy The standard remission induction regimen in common use is the DA regimen, with a remission rate of up to 85%. Another commonly used regimen in China is HOAP, with an average remission rate of about 60%. In recent years, HA regimen is commonly used, and the remission rate can be close to that of DA regimen. However, the overall remission rate is not as good as that of acute leukemia, and the induction process must pass through a period of extreme granulocyte deficiency before it is possible to enter remission.
Our hematologists found that all-trans retinoic acid can induce remission in M3 leukemia, and its remission rate can reach 85%. However, after remission, consolidation and intensive treatment with retinoic acid alone is prone to relapse, so it is advisable to combine with other chemotherapy or alternate maintenance treatment. In addition, our scholars have clinically tried arsenic trioxide to induce a complete remission rate of up to 65%~98% for M3, and it also has good efficacy for relapsed patients. heparin therapy should be used for M3 with combined DIC tendency.
The treatment of acute non-gonorrhea leukemia after remission is very inconsistent. In recent years, it has been found that long-term treatment does not significantly prolong disease-free survival in patients with acute NHL, and thus there is a trend toward early consolidation chemotherapy after remission, without long-term maintenance.
The methods of consolidation therapy are.
① Consolidation by the original induction method for 4~6 courses;
② Intensive therapy with medium-dose cytarabine. Cytarabine can be used alone or with other drugs (e.g., erythromycin, anacrine, mitoxantrone, etc.);
(iii) A new regimen with no cross-resistance to the original induction regimen (e.g. VP-16 plus mitoxantrone, etc.). Chemotherapy was administered every 1 to 2 months for a total of 1 to 2 years. Chemotherapy is discontinued later and closely followed up with re-treatment in case of recurrence.
(iv) Others Elderly patients with poor tolerance to chemotherapy, the dose should be reduced in the conventional chemotherapy regimen. Patients who are too weak to receive combination chemotherapy should be treated with low-dose cytarabine (or triptolide) in static doses until remission. Small doses of cytarabine (12.5-25 mg IV or intramuscularly once daily) can also be used to treat leukemia transformed from MDS, hypoproliferative leukemia and secondary leukemia.
High leukocyte leukemia, which is critical, should be treated with chemotherapy immediately after removing excess leukocytes from the blood with a blood cell separator to eliminate the stagnant state of leukocytes. For acute NHLs, allopurinol and alkalinization of urine are also given before chemotherapy, followed by hydroxyurea 4~6g/d for 3 days to cause rapid reduction of granulocytes. Chemotherapy is started on the day after hydroxyurea is administered. For refractory and relapsed cases, medium-dose cytarabine (100-200 mg/m2 every 12 h for 4 consecutive doses) can be used along with other drugs (e.g., anacrine, erythromycin, mitoxantrone, or etoposide). The use of anti-CD33 monoclonal antibodies for the treatment of acute granulocytic leukemia has also been in clinical trials.
(E) Treatment of CNS leukemia CNS leukemia is the most common extramedullary leukemia, with acute leukemia being particularly prominent. Prophylactic intrathecal methotrexate injection of 10 mg each time twice a week for 3 weeks is usually started after remission of acute lymphoblastic leukemia. If clinical manifestations of increased intracranial pressure, meningeal irritation or cerebral nerve damage occur; elevated cerebrospinal fluid pressure and leukemic cells are found, the diagnosis of CNS leukemia can be confirmed, then methotrexate is administered slowly intrathecally at 10-15 mg each time, twice a week until the cerebrospinal fluid cell count and biochemical tests return to normal, and then switched to intrathecal injection at 5-10 mg each time, once every 6-8 weeks, with Discontinue with the end of systemic chemotherapy.
Intrathecal injection of methotrexate can cause acute chemical arachnoiditis with fever, headache and meningeal irritation. Therefore, it is advisable to add 5~10mg of dexamethasone to methotrexate injection, which can reduce the side effects. If methotrexate is ineffective, it can be replaced by intrathecal injection of 30~50mg/m2 of cytarabine twice a week. Meanwhile, cranial radiation irradiation (2400~3000cGy) and spinal cord irradiation (1200~1800cGy) can be considered, but it is more serious for bone marrow suppression.
(vi) Testicular leukemia treatment Drugs are not effective for testicular leukemia, radiation therapy must be used (total dose about 2000cGy), even if one testicle is enlarged, radiation from both sides must be used.
(vii) Bone marrow transplantation
Although bone marrow transplantation has certain efficacy, it is still difficult to promote its use in China because of the high cost, high risk and insufficient donors with the same HLA.
II. Supportive therapy
(a) Prevention and control of infection Leukemia patients have reduced normal granulocytes, and normal granulocytes recover slowly after chemotherapy and radiotherapy, and are prone to various infections. The use of human recombinant colony-stimulating factor can promote the recovery of granulocytes, such as the occurrence of infection should be treated with antibiotics in a timely manner. If the pathogenic bacteria are unknown, broad-spectrum antibiotics should be used first, and sensitive antibiotics should be used after the drug sensitivity test. If necessary, intravenous immunoglobulin can be used to increase the patient’s resistance.
(II) Correction of anemia Severe anemia can be transfused with concentrated red blood cells, however, actively striving for leukemic remission is the most effective way to correct anemia.
(iii) Control of bleeding If bleeding is caused by low platelet count, transfusion of concentrated platelet suspension is a more effective measure to control bleeding. If bleeding is caused by diffuse intravascular coagulation (e.g. M3), heparin should be given immediately. Nasal and gingival bleeding can be stopped with caulking or gelatin sponges.
(iv) Prevention and treatment of uric acid nephropathy Due to the massive destruction of leukemia cells, especially during chemotherapy, the concentration of uric acid in the serum and urine increases, which can cause obstructive nephropathy if crystals are formed in the renal tubules.
There are clinical oliguria, anuria and acute renal failure. To avoid urea acidic nephropathy patients should be encouraged to drink more water and alkalinize the urine. High leukocyte leukemia should be treated with leukocyte monocytosis followed by chemotherapy. Allopurinol 100mg can be given 3 times daily to block hypoxanthine and xanthine metabolism and thus inhibit uric acid synthesis. For oliguria and anuria, it should be treated as acute renal failure.
(E) Maintenance of nutrition Leukemia is a serious wasting disease, and after chemotherapy and radiotherapy, patients often have digestive tract dysfunction, which can lead to more serious malnutrition. Attention should be paid to nutritional supplementation, maintaining water and electrolyte balance, giving patients high-protein, high-calorie, easily digestible food, and if necessary, intravenous high nutrition to ensure adequate support.
Prognosis】 The average survival period of untreated acute leukemia patients is only about 3 months. With modern treatment methods, many patients have achieved remission and even long-term survival. The prognosis for acute leukemia is better for patients aged 1 to 9 years, and some patients can be cured; the prognosis is worse for children under 1 year old and over 9 years old, young and middle-aged people and adults, and worse for those over 60 years old.
The prognosis is also worse with age in acute nonleukemic patients. prognosis is worse in those with peripheral blood leukocytes >50×109/L or (and) platelets <30×109/L before treatment. prognosis is better in M3 type treated with all-trans retinoic acid. Chromosomal abnormalities; those with 5-, 7-, 5q-, 7q- and hyperdiploidy have a worse prognosis in acute non-gonorrhea, while those with t(8;21), Inv(16) or trichromosome 21 have a better prognosis, and those with t(9;22) in acute gonorrhea have a worse prognosis. In addition, those with leukemia secondary to radiotherapy or leukemia after MDS, those with multidrug resistance, and those with slow decline of leukemic cells after chemotherapy or those who require longer chemotherapy for remission have a poorer prognosis.