What Is Acute Promyelocytic Leukemia?

Acute promyelocytic leukemia (APL) is a special type of acute myelogenous leukemia (AML), and has been classified as acute myeloid leukemia M3 by the FAB collaboration.

Overview of Acute Promyelocytic Leukemia

Malignant disease of hematopoietic tissue. It is characterized by the unrestricted proliferation of a large number of leukemia cells in the bone marrow and other hematopoietic tissues, and enters the peripheral blood, while the production of normal blood cells is significantly inhibited. The disease ranks first among young patients with malignant diseases. Viruses may be the main pathogenic factor, but there are many factors such as radiation, chemical poisons (benzene, etc.) or drugs, genetic qualities, etc. that may be cofactors that cause disease. According to the immature degree of leukemia cells and the natural course of leukemia, it is divided into two categories: acute and chronic.

Acute Promyelocytic Leukemia Typing

Urgent onset, mainly blasts in bone marrow and peripheral blood. Patients often die within six months without treatment. According to the type of leukemia cells, it is clinically divided into two categories, acute lymphocytic leukemia (ALL) and acute non-lymphocytic leukemia (ANLL). The current types at home and abroad are as follows:

ANLL8 Acute promyelocytic leukemia ANLL is classified as type 8

That is, granulocytic leukemia undifferentiated (M1), granulocytic leukemia partially differentiated (M2), promyelocytic (M3), granulocyte-monocyte type (M4), monocyte type (M5), red leukemia (M6), megakaryocyte type (M7), acute myeloid microdifferentiation type (M0);

ALLL1 L2L3 Acute promyelocytic leukemia ALL is divided into L1, L2 and L3 types

In recent years, it has been divided into T, B, pre-B, common type and undifferentiated type according to the immunological characteristics of cells. Patients often experience sudden anemia, infection, and bleeding, as well as hepatosplenomegaly, lymphadenopathy, and sternal tenderness. A blood test and bone marrow examination can confirm the diagnosis. In recent years, the efficacy has been greatly improved. Some patients have been cured. In addition to symptomatic supportive treatment such as blood transfusion and anti-infection, combined chemotherapy is currently the main treatment method. Due to the continuous emergence of new effective chemotherapeutic drugs and the improvement of combined drug methods, it is completely The remission rate has reached more than 80%. In addition, the differentiation inducer retinoic acid can induce the differentiation of mature promyelocytic leukemia cells with significant curative effects. It is an important discovery in recent years. Bone marrow transplantation can be cured, but there are still some problems to be solved. .

Epidemiology of acute promyelocytic leukemia

Acute promyelocytic leukemia is not uncommon in clinical practice. Patients are often younger than the median age of 30 to 38 years old. Rarely according to Chinese statistics, the incidence of M3 is higher than about 10% in Western countries, accounting for AML in the same period. In some regions, such as the Northeast Oilfield, the incidence of M3 may be as high as 20% to 30% in AML, and even higher. According to foreign data, the incidence of Latinos in Europe, Central and South America is higher, and APL accounts for adult primary 10% to 15% of AML, although there may be differences in age and ethnicity.

Causes of acute promyelocytic leukemia

The etiology of primary APL is not fully understood. Secondary patients are often found in patients with tumors receiving chemotherapy and / or radiation therapy. There are also reports of APL caused by alkylating agents and topoisomerase II inhibitors. Well, its response to treatment and long-term survival rate are similar to those of the primary, but chemotherapy-related AML is significantly different.

Characteristics of acute promyelocytic leukemia

Promyelocytic plasma is full of abnormal particles;

46, XX, t (15

Often accompanied by a bleeding tendency of 72% to 94%, severe cases of DIC;

Specific chromosome t (15; 17) (q22; q12) changes in 90% of patients;

Sensitive to chemotherapy, but early mortality is high, especially in the case of alpha cytotoxic chemotherapy, about 10% to 20% of patients die from periodical bleeding;

Retinoic acid can induce the differentiation and maturation of APL cells, and arsenic can induce its apoptosis;

Longer duration of remission. In the past, the treatment effect of APL was very poor, and the prognosis was very dangerous. Most of them were caused by complicated diffuse intravascular coagulation (DIC) or primary fibrinolysis, leading to severe bleeding and early death. In recent years, with the continuous improvement of understanding of the biological characteristics of APL cells and the improvement of treatment methods, treatment results and prognosis have been greatly improved, and early mortality has been significantly reduced.

Pathogenesis of acute promyelocytic leukemia

APL is a type that responds better to induced differentiation therapy in leukemia, which is related to changes in chromatin induced by the retinoic acid receptor (RAR) fusion protein expressed in APL cells. The five chromosomal translocations of APL have all involved the RAR gene on chromosome 17. The 39398bp full-length gene contains 9 exons and 8 introns. The t (15; 17) translocation is found in most patients with APL. The retinoic acid receptor alpha gene and the promyelocytic leukemia (PML) gene of chromosome 15 form a PML-RAR fusion gene. The proteins encoded by this fusion gene are different The function of the wild-type retinoic acid receptor encoded by the normal RAR allele is located in the 2l region of the long arm of chromosome 17 and its function is a nuclear hormone receptor. Retinoic acid binds to RAR receptor elements to transcriptionally regulate many genes. PML is a nuclear protein that includes a proline-rich region from the amino terminus to the carboxyl terminus, a cystine-rich region required for nucleosome localization, a helical loop nuclear structure signal NLS, and serine required for homo / heterodimer formation. And proline-rich regions. PML is normally located in a structure called POD (PML oncogenic domain) (also known as the nucleosome polyprotein nuclear apparatus). The function of POD with a speckled number of 15-20 PML in the nucleus has not been fully elucidated. Recent studies suggest that PML has the activity of inhibiting tumor growth through transcriptional co-activation, and PML may also play an important role in a variety of apoptotic pathways. In M3 type AML (acute promyelocytic leukemia), the translocation of RAR on chromosome 17 and the PML on chromosome 15 occurs as t (15; 17) (q22; q21) the mutual translocation of PML and RAR Has the following consequences:

PML-RAR fusion protein inhibits promyelocytic differentiation and maturation through dominant negative inhibition;

PML delocalized to form hundreds of fine particles distributed in the nucleus and cytoplasm to destroy the structure of POD. PML's normal inhibition of proliferation and pro-apoptotic functions caused cell proliferation and decreased apoptosis;

When RAR is normal, it can be combined with transcription co-inhibition complex (N-CoR / Sin3a / HDAC-1) (N-CoR = nuclear receptor co-inhibitor, HDAC = histone deacetylase) at physiological dose of vitamin A Under the action of acid, RAR can dissociate from the co-suppression complex and act as a transcriptional activation, that is, activation of the regulated target gene PML-RAR can promote the combination of RAR and the co-suppression complex. Inhibition of the target gene regulated by RAR inhibits Differentiation and maturation cause proliferation of M3 type AML. ATRA can degrade PML-RAR at therapeutic doses. In addition, ATRA can separate the co-inhibition complex from RAR and recruit coactivators, including CBP / P300, P / CAF. Proteins such as NcoA-1 / SRC-1P / CIF, among which CBF / P300 and P / CAF have strong histone acetylase activity. After acetylation of histone acetylation, the function of transcriptional activation of the target gene is restored. Granulocytes are mature and differentiated.

1% to 2% of APLs have variant t (11; 17) (q23; q21) that fuse the promyelocytic leukemia zinc finger gene (PLZF) on chromosome 11 to the RAR gene on chromosome 17. All patients reported so far express both PLZF-RAR and RAR-PLZF fusion proteins in vivo suggest that t (11; 17) (q23; q21) the onset of APL may require the RARot-PLZF fusion protein to play a corresponding role t (11; 17) (Q23; q21) APL is less sensitive to ATRA. The rare chromosomal translocations have t (5; 17) (q35; q21) leading to fusion of NPM (nucleophosmin) and RAR gene; t (11; 17) (q13; q21 ) Produces NuMA-RAR fusion gene; dup (17) (q21.3-q23) produces STATSb-RAR fusion gene. The patients in the first two translocations are sensitive to ATRA, but ATRA is not effective in patients with STAT5b-RAR fusion gene positive.

The leukemic effect of APL fusion genes has been confirmed in transgenic animal models. hCG-PML-RAR transgenic mice expressing PML-RAR under the regulation of hMRP8 or human cathepsin G microgenes develop APL-like leukemia about 1 year after birth, while hCG-PLZF-RAR transgenic mice are born Chronic myelogenous leukemia-like lesions occur with increased promyelocytic cells in the bone marrow within 3 to 12 months; transgenic mice expressing PLZF-RAR and RAR-PLZF simultaneously develop human-like APL; Typical APL or chronic myeloid leukemia-like lesions occur 1 year after birth.

Clinical manifestations of acute promyelocytic leukemia

Promyelocytic leukemia (M3) bone marrow tablets

Clinical manifestations of acute promyelocytic leukemia Normal bone marrow hematopoietic failure-related manifestations, such as anemia, hemorrhagic infection; leukemia cell infiltration-related manifestations, such as liver and spleen and lymphadenopathy, bone pain, etc. bleeding in addition to the general leukemia manifestations of these leukemias Tendency is its main clinical feature, with 10% to 20% of patients dying from early bleeding, and about 60% of patients with diffuse intravascular coagulation (DIC) have DIC.

Complications of acute promyelocytic leukemia

Acute promyelocytic leukemia infection

The most common complications include bacterial, viral, and fungal infections, which are mainly manifested as fever, and the site of infection is usually severe in the mouth, lungs, and skin. Septicemia and toxic shock may occur.

DIC Acute promyelocytic leukemia DIC

The most important complication of APL occurs in approximately 60% of patients. With the use of retinoic acid and arsenic in recent years, the incidence of DIC has been significantly reduced.

Acute promyelocytic leukemia hyperleukemia

During the application of retinoic acid treatment, hyperleukocytosis and retinoic acid syndrome may be combined, and a small amount of hydroxyurea Ara-C or a reduced AADA regimen may be given at the same time.

Diagnosis of acute promyelocytic leukemia

The diagnosis was established according to the morphological diagnostic criteria of the FAB. Acute promyelocytic leukemia (APL) classified by FAB is also called AML-M3 type. Its typical characteristics are:

Bone marrow morphology is abnormal promyelocytic proliferation with cytoplasm containing coarse particles and Auer bodies (also with microparticle variants);

Clinically, there is often severe bleeding and it is easy to be combined with DIC and fibrinolysis;

90% of patients show specific ectopic t (15; 17);

Chemosensitivity (chemotherapy resistance <5%), long remission survival but high early mortality.

Differential diagnosis: It is mainly distinguished from other types of leukemia. The main points of differentiation are based on cytomorphology and cytoimmunology. Cytogenetic examination is generally not difficult to identify.

Acute Promyelocytic Leukemia

Basic examination of acute promyelocytic leukemia

1. The typical blood picture of peripheral blood shows anemia, changes in the number of white blood cells, and juvenile cells, thrombocytopenia.

2.Bone marrow is mainly promyelocytic hyperplasia with abnormal granule increase> 30%, most> 50%, and the cell morphology is more consistent, below the original cell

Pathological examination There are fewer cells in each stage, and the nucleus has more irregular morphology with inner and outer pulp, no particles in the outer pulp, and particles of uneven size in the inner pulp can be divided into:

M3a (coarse particle type): The cytoplasm is filled with coarse aniline blue particles and densely fused and distributed. The particles can also be covered on the school.

M3b (fine particle type): aniline blue particles are small and densely distributed in the cytoplasm.

3. Protein immunoassay CD33, 13 (HLA-Dr negative).

4. Cytogenetic examination for chromosomal abnormalities, t (15; 17) (q22; q21).

5, clotting time, 3P test, fibrinogen content, plasminogen content and active ATPP (activated partial thromboplastin time), PT (thrombin time).

6, biochemical and electrolyte tests, liver and kidney function tests

Other auxiliary tests for acute promyelocytic leukemia

X-ray CT, MRI, and B-mode ECG were selected according to the condition, clinical manifestations, symptoms, and signs.

Acute Promyelocytic Leukemia Treatment

1. APL is a very dangerous type of acute leukemia. Its bleeding symptoms are very common, with an incidence of 72% to 94%, which is significantly higher than other acute leukemias. It is often diffuse intravascular blood (DIC). It is especially manifested that DIC can be aggravated during chemotherapy, and often causes early death in patients. Because APL has its unique chromosomal abnormality, t (15; 17), it produces fusion gene PML-RAR and its encoded protein, so its treatment is similar to other AML. With the recent research progress on APL, its treatment has become one of the most successful examples of leukemia treatment. As early as the 1970s, it was clear that APL is very sensitive to anthracycline drugs, and the effect of chemotherapy alone is better than AML. In other types, the appearance of retinoic acid (ATRA) and arsenic has greatly improved the efficacy of APL. While inducing treatment, it is also important to give active supportive treatment, including anti-infective platelet transfusion, blood transfusion, etc.

Treatment of Acute Promyelocytic Leukemia Induction and Differentiation

Prior to the clinical application of retinoic acid (ATRA), in vitro experiments confirmed that retinoic acid (ATRA) can induce the differentiation of leukemia cell lines (such as HL-60 cells) and APL primary cells. In 1986, Chinese scholars used all-trans retinoic acid to induce differentiation for the first time in the treatment of APL and achieved success. At present, retinoic acid (ATRA) induced differentiation therapy is mainly used for APL, and has begun to try other types of AML and some entities. The mechanism of tumor acid A on tumor cells is different from that of chemotherapeutics. It promotes the differentiation of APL cells to correct the abnormality of the coagulation mechanism, avoids the possibility of bone marrow suppression caused by chemotherapy and induces DIC, which makes the treatment of leukemia significant. The breakthrough has greatly improved the prognosis of APL.

Usage and efficacy of ATRA

A. General dose: The general dose of ATRA for APL is 45mg / (m2 · d). Oral treatment for 30 to 45 days. For newly treated APL patients, the CR rate of ATRA can reach 90. % (Table 1).

B. Low dose: A small dose of ATRA 15 ~ 25mg / (m2 · d) oral oral treatment of APL in order to reduce the toxic and side effects of vitamin A. The results show that the CR rate of general dose can be achieved with small dose treatment. However, reports on reducing the side effects of retinoic acid (ATRA) are not consistent. Castaigne et al. Treated APL with 25mg / m2 and 15mg / m2 retinoic acid (ATRA) respectively and concluded that there were no significant differences between the two groups in terms of efficacy, stimulating hyperleukocytic retinoic acid syndrome, and pharmacokinetics.

Improvement of treatment methods in the induction period: It is generally advisable to combine chemotherapy in the treatment of retinoid acid (ATRA), and apply chemotherapy when the leukocytes have risen above 3 × 109 / L, which can prevent the occurrence of retinoid syndrome and improve it. CR rate, prolong CR period Domestic Meng reported that it is safe to switch to chemotherapy for APL 15 days after taking retinoic acid (ATRA). The European Collaborative Group's study of 93 cases of primary APL with leukocyte counts below 5 × 109 / L showed that there was no difference in the complete clinical response rate between the two groups of patients receiving pre-retinoic acid (ATRA after chemotherapy and retinoic acid (ATRA) + chemotherapy) However, the recurrence rate of patients with retinoid acid (ATRA) + chemotherapy within 2 years was significantly lower than that of patients receiving retinoid acid (ATRA) after chemotherapy. It showed that the simultaneous use of retinoid acid (ATRA) and chemotherapy can better play the role of chemotherapy in retinoid acid. (ATRA) supplementation and reduce the recurrence rate. The Italian collaboration group received 12 mg / (m2 · d) of DA at the same time on the 6th to 8th days of induction therapy with 45mg / m2 of ATRA, and the complete remission rate was 92%. In some cases, the application of ATRA alone cannot control the condition, and a small amount of cytarabine (Ara-C) or a reduced amount of AADA can also be added.

The main problem with patients receiving retinoic acid (ATRA) induction and maintenance therapy is early relapse, with a median CR phase of only 5 months. The main reason for ATRA resistance and leukemia recurrence at this time may be the long-term use of retinoic acid (ATRA) to produce ATRA metabolic enzymes in the plasma, so that the blood concentration of retinoic acid (ATRA) is not sufficient to maintain the differentiation and maturity of leukemia cells. Or, leukemia cells synthesize ATRA binding protein under the induction of retinoic acid (ATRA) to prevent the drug from entering the nucleus and play a role in inducing differentiation. Many authors have found that most of the patients with remission treated with ATRA alone have the PML-RAR fusion gene expression continue to be positive and Its expression is highly correlated with leukemia relapse, but the remission survival of patients with negative PML-RAR expression can be significantly prolonged if chemotherapy is added. Therefore, despite the high CR rate achieved with retinoic acid (ATRA) treatment, chemotherapy is still essential for long-term remission and even cure of APL.

However, the use of retinoic acid (ATRA) in induction remission therapy can also help APL to prolong remission. Table 2 summarizes the effects of APL treatment reported by foreign authors: patients were treated with retinoic acid (ATRA) ± chemotherapy for induction of remission, and all were consolidated and strengthened with chemotherapy after remission. The results show that EFS reported by various companies, where retinoic acid was used in induction chemotherapy The (ATRA) + chemotherapy group was significantly better than the chemotherapy group in the same period or historical control. This shows that retinoid acid (ATRA) can increase the sensitivity of APL to chemotherapy and significantly reduce the recurrence of the disease.

Post-remission treatment: Retinoic acid (ATRA) combined with chemotherapy can significantly improve the patient's prognosis. Shanghai Institute of Hematology (DAA) administered DA or HA to a group of 70 patients. Retinoic acid (ATRA) thiopurine (6-MP) Retrospective study of sequential methotrexate (MTX) therapy showed an average 5-year disease-free survival rate of 70% ± 6%. Another retrospective study showed that 64 patients were treated with retinoic acid (ATRA) and chemotherapy. The 5-year disease-free survival rate of patients was 58.5% ± 10.4%, while only 26.7% ± 9.4% of patients in the other group (47 patients) received chemotherapy alone. Prospective studies conducted by Tallman et al. Patients who used retinoic acid (ATRA) for enhanced consolidation were better than those treated with chemotherapy alone. On the basis of effective prevention of AT-RA syndrome, 90% of first-stage patients with chemotherapy can be relieved, and chemotherapy alone can hardly reach 80% even in the first-stage patients. French Fenaux et al. Reported a group of 54 cases of APL treated with retinoic acid (ATRA), with a CR rate of 90%, and later consolidation with strong chemotherapy. The 2-year event free survival (EFS) rate was 68% and the survival rate was 81%. In 1995, the Japanese Adult Leukemia Research Group reported 109 cases of APL given retinoid acid (ATRA) or retinoid acid (ATRA) plus chemotherapy after obtaining CR (89%), and the EFS of 23 months after chemotherapy consolidation was 75% (66% ~ 83%) The DFS of CR was 81% (71% -91%). Generally, the regimen of chemotherapy and retinoid should be used after remission.

APL variant treatment: APL has a rare variant translocation t (11; 17) (q23; q21) in addition to the typical t (15; 17) translocation, which accounts for 1 of APL. % ~ 2% It fuses RAR with another transcription factor PLZF (promyelocytic leukemia zincfinger) gene. Patients at t (11; 17) had poor or ineffective response to ATRA-induced differentiation therapy or chemotherapy, and their leukemia cells did not differentiate when treated with ATRA in vitro. This group of patients is effective for retinoic acid (ATRA) + G-CSF or retinoic acid (ATRA) + chemotherapy; another variant of translocation t (11; 17) (q13; q11) is less involved The fusion gene is NuMA- RAR. This type of ATRA treatment is effective. Another variant of M3, t (5; 17) (q32; q21), involved the nucleophosmin (NPM) gene on chromosome 5. The NPM-RAR fusion gene is formed, and this type of patients is effective in retinoid acid (ATRA) treatment.

Side effects of retinoic acid (ATRA): including dry lips and skin (70% to 90%), headache (25% to 40%), bone and joint pain (15% to 30%), impaired liver function, and increased blood lipids ( 12% to 30%) and so on. Two-thirds to three-quarters of patients have varying degrees of leukocyte elevation. The most serious complication is retinoic acid syndrome and thrombosis. The former is manifested as fever, chest tightness, dyspnea, water retention with edema, pleural or pericardial effusion. Hypertension, respiratory distress, hypoxia, respiratory failure, and a few renal failures. The incidence of 10% to 25% of patients with high white blood cells is often the cause of death. After combined chemotherapy, this serious complication has been reduced to 5% to 7%. The treatment method is high-dose dexamethasone intravenous injection of 10 mg / time 2 times / d for 3 to 5 days.

Therapeutic mechanism: The mechanism of retinoic acid (ATRA) -induced differentiation in the treatment of APL has not been fully elucidated. Due to the discovery of retinoic acid (ATRA) receptors , , and and the further clarification of their structure and function, retinoic acid (ATRA) The research on the mechanism of action has been greatly developed. According to the available data and domestic research results, it can be summarized into the following aspects: Retinoic acid (ATRA) changes the biological properties of APL cells while inducing differentiation, and relieves its effects on Inhibition of bone marrow hematopoietic cells; APL-specific fusion protein PML / RAR degrades the distribution of PML under the action of ATRA, returns to normal, the normal function of RARRARX and the differentiation of promyelocytes originally inhibited by PML / RAR are restored; retinoic acid (ATRA) promotes apoptosis of APL cells; retinoic acid (ATRA) up-regulates the following proteins and genes RAR, RAR, IRF-2STATlaSTATlbSTAT2, RIG-E, FGH, I, IL-lbG-CSF receptor, GM-CSF receptor, CD11cCD11bCDl5CD18, CD45RO, protein kinase C tissue glutamyl transferase ornithine decarboxylase alkaline phosphatase, urokinase-type plasminogen activator, MCP-1IFN- plasmin activator inhibitor (PAI). In contrast, aATRA down-regulates the following proteins and genes: tissue factor tumor procoagulant, tissue factor connexin C-MYCCD33 telomerase activity, BCL-2, PARP (poly ADP ribose polymerase), tissue elastase G elastase myeloperoxidase It can be seen from the enzymes and CD45RA antigens that the role of retinoic acid (ATRA) involves a wide range, and some directly affect the binding and effect of retinoic acid (ATRA), such as binding to RAR; some are related to promyelocytic cells. Functional related changes such as some enzymes; some involve coagulation, such as the down-regulation of tissue factor tumor procoagulant substances, which may explain why DIC improves during the differentiation of retinoic acid (ATRA); some genes are closely related to signal transduction, Such as STAT, PKC; Many gene changes can clarify the pro-apoptotic effects of retinoic acid (ATRA), such as the decline of BCL-2 and PARP. Upregulation of G-CSF and GM-CSF receptors may explain the cause of increased white blood cells during retinoic acid (ATRA) treatment , FGHI) Although their properties have been clarified, such as RIG-G has a high homology with a family of interferon-stimulated genes (ISG) and the same chromosomal localization. Growth factor receptor), LDL-RuPAR, etc. have certain homology, but the exact mechanism of them in the treatment of APL induced by retinoic acid (ATRA) needs to be further elucidated.

Arsenic therapy for acute promyelocytic leukemia

Induced remission: Although retinoid acid (ATRA) treatment can achieve a high remission rate in the initial treatment of APL, most cases are prone to relapse of drug resistance and then treated with retinoid acid (ATRA). The effect is poor since the 1970s. In the early 1950s, Harbin Medical University used "arsenic" as its main component to treat APL with good effect. Induction remission treatment plan: Adult 0.1% As2O3 injection 10ml / d, 5% glucose solution 250 500ml intravenous drip for 3 to 4 hours, children can be measured as 6mg / m2, 4 weeks as a course of treatment can be intermittent 5 to 7 days can also be continued for 2 courses of treatment without remission as invalid.

In 1995, Huang Shilin and others reported the results of applying the traditional Chinese medicine compound Qingdai tablet containing arsenic sulfide to treat newly treated APL. The plan is as follows: oral compound Qingdai tablets, 15 tablets (0.25g / tablet) per day, gradually increase to 30 tablets per day after one week, continuous medication for 30 to 60 days, the CR rate can reach 98.3%. Since February 1998, Lu Daopei and others have applied moderate purity As4S4 (TATS) to treat APL. The method is: take 0.5g orally 3 times a day for 2 to 4 weeks and take a rest for 2 to 3 weeks. After maintaining a total of 3 to 4 years, high purity is carried out. The clinical application method of TATS is: 1g 3 times / d until CR rest 2 to 3 weeks. The interval of rest in the 4th year can be extended to 4 to 6 weeks. After applying TATS, the plasma arsenic concentration reached a peak on the 15th day (40 to 104mcg / L). ), The plasma arsenic concentration decreased to <2 22mcg / L (average 15mcg / L) after 2 weeks of discontinuation, and the average plasma concentration was 3mcg / L after 30 days of discontinuation.

Acute promyelocytic leukemia bone marrow A, As2O3 indications for the treatment of APL:

a. Initial treatment of APL, especially t (15; 17) or PML-RAR fusion gene positive

b. Retinoic acid (ATRA) or combined chemotherapy for refractory or relapsed APL

c. Insufficient or unsuitable application of retinoic acid (ATRA) or APLd.APL CR combined with chemotherapy for consolidation maintenance therapy.

e. Other types of leukemia (chronic myelogenous leukemia, ANLL M2M4, M6 type) and MDS with abnormal promyelocytosis.

APL should not be treated with As203: those with severe liver and kidney dysfunction caused by non-leukemia itself; those with As2O3 consolidation therapy for relapse; those with arsenic poisoning manifestations.

B. Toxic side effects: Acute toxic side effects mainly include fluid retention (pleural effusion, pericardial effusion, weight gain), short-term use of diuretics is effective, and dexamethasone has no obvious effect in about 20% of patients with gastrointestinal reactions. Patients with nausea and vomiting, abdominal pain, diarrhea, and appetite loss of 10% had varying degrees of numbness of hands and feet and facial edema. 20% to 30% of patients at regular doses may have varying degrees of renal dysfunction, but most of them return to normal within 1 to 2 weeks after discontinuation. For the liver, in the original cases of chronic hepatitis, hepatocellular necrosis is easily induced, causing liver failure. ECG may show sinus tachycardia - degree AV block complete AV block and various ventricular arrhythmias. It must be pointed out that during the treatment of arsenic, 2/3 of the patients had increased white blood cells, and 10% to 15% of patients had similar retinoid syndrome and their clinical manifestations and treatment were the same as those occurred during retinoid treatment. Some patients have chronic side effects manifested as skin pigmentation, palmar keratosis polyneuropathy (the sensory motor nerve function is impaired), and muscle atrophy. Serious side effects such as flaccid paralysis and renal failure can occur at doses> 0.2 mg / (kg · d). Chronic As203 poisoning depends not only on the amount used, but also on the individual's susceptibility. When severe arsenic poisoning occurs, drugs can be used to reduce its side effects, such as sodium dimercaptopropanesulfonate (2,3-dimercaptopropanesulfonate).

C. Mechanism of arsenic treatment of APL: morphologically, nuclear chromatin is condensed to form apoptotic bodies. In vitro studies found that low concentrations of arsenic (0.1 mol / L) can induce differentiation of NB4 cells. At high concentrations (> 0.5-1 mol / L), arsenic induces apoptosis. DNA analysis showed that apoptotic peaks appeared before the G1 peak in cell flow cytometry. DNA electrophoresis showed a typical apoptotic trapezoidal change. Cell and molecular biological research results showed that As2O3 can degrade BCL-2 gene by degradation of PML / RAR fusion protein. No effect on BAX gene. The above results suggest that the mechanism of As2O3 treatment of APL may mainly induce APL cell apoptosis, and induce differentiation at low concentrations. In addition, some molecular mechanisms in the action of arsenic agents include:

a. The mitogen-activated protein kinase (cMAPK) signal channel and stress-related JNK / SAPK (stress-activated protease) and P38 kinase are activated, leading to apoptosis.

b. Arsenic increases the permeability of the PT (permeability change) pores on the mitochondrial membrane, causing AIF and cytochrome C in the mitochondria to be released to the outside of the mitochondria.

c. It acts on G1 / S and G2 / M and prolongs the cell cycle.

d. Trivalent arsenic can induce changes in ornithine decarboxylase (ODC) activity of erythroleukemia cells, affecting polyamine synthesis and inhibiting tumor growth.

Arsenic treatment after complete remission of APL: As2O3 is applied at regular doses, and the interval of application of As2O3 is 123 or 4 and 6 months after 12, 3, and 3 years after CR, respectively; Combined chemotherapy (HA, DA, or Am-C + Mitoxantrone (NVT) / Etoposide (VP-16) alternately with intermittent periods as above.

ATBAAs203APL Acute promyelocytic leukemia ATBA combined with As203 in the treatment of APL

Retinoic acid (ATRA) can achieve a complete response rate (CR) of 80% to 90% compared with typical cytotoxic drugs. Retinoic acid (ATRA) can improve coagulation disorders in patients with APL without causing bone marrow depression. A acid (ATRA) may cause fatal drug-related syndromes. At the same time, maintenance of ATRA alone often causes recurrence of leukemia, which limits its application. As203 can not only induce initial APL to obtain CR, but also induce Cytotoxic drugs, retinoic acid (ATRA) and other patients who have relapsed after treatment reached 90% of CR in vitro experiments proved that the mechanism of action of As2O3 is different from retinoic acid (ATRA), which can cause leukemia cells to undergo apoptosis. ATRA ) The study of the effect of combined As203 on APL cell lines and fresh APL cells shows that the two drugs have a synergistic and pro-differentiation effect, and can also promote the sensitivity of drug-resistant cells to drugs. / (M2 · d) As203 0.16mg / (kg · d) combined treatment of initial APL until CR. The results showed that 31 patients died early in 2 cases, 29 cases received a CRCR rate of 93.5%, and the average time to obtain a CR was (25.1 ± 3.9) days. 66.5% of patients had an increase in white blood cells after treatment, 65.5% of them had abnormal liver function, but decreased or stopped Recovery within 1 week. At CR, 10.3% of PML / RAR turned negative after 77.0% turned negative.

Acute promyelocytic leukemia hematopoietic stem cell transplantation

In initial cases, CR can reach 70% to 80% with retinoic acid (ATRA) combined with chemotherapy. Most patients can use As203 after the first recurrence or use retinoic acid (ATRA) and chemotherapy again. Secondary response rate (CR2), so patients with first response are generally not considered to be HSCT

Comparison of the efficacy of chemotherapy Treatment Although the current treatment method can achieve a higher remission rate of APL, the recurrence rate is still 25%, which may be a salvage treatment method for autologous or allogeneic stem cell transplantation in these patients. Prior to the clinical application of retinoic acid (ATRA), HSCT could cure 45% of patients with secondary remission. Recent studies have shown that the application of autotransplantation after secondary remission is very effective, can reduce the recurrence of leukemia and make disease-free survival rate exceed 70 %. Reports at home and abroad indicate that after 3 years of bone marrow transplantation after CR, DFS is more than 77% to 80%, which is superior to single-chemotherapy or chemotherapy combined with retinoic acid (ATRA) after CR treatment. The 5-year survival rate can reach 50% to 70%, and considering the treatment-related mortality, HSCT treatment may not be required after the first complete remission of the disease. It is mainly suitable for patients with relapse or long-term positive PML-RAR fusion gene. Patient. However, despite the existence of 15% to 20% of transplant-related mortality, allogeneic HSCT is still an important treatment option for patients with two or more remissions. For young and patients who cannot achieve genetic remission, if there is a suitable donor, , Should also choose HSCT treatment.

New treatment for acute promyelocytic leukemia

Liposomal retinoic acid (ATRA): At present, clinically used retinoic acid (ATRA) only uses oral preparations. Recently, a kind of intravenous liposome retinoic acid (ATRA) has been developed. Absorbed patients and pediatric patients can overcome the instability of blood concentration caused by oral administration of these patients. The maximum tolerated dose of liposomal retinoic acid (ATRA) is 140 mg / m2, and a dose of 90 mg / m2 can safely and effectively make remissions in patients with initial and recurrent APL. So despite the ease of use of liposomal retinoic acid (ATRA) in oral formulations, it may still be a convenient alternative.

Histone deacetylase inhibitors: The transcriptional activity of many genes is determined by the histone acetylation status; the histone acetylation status is determined by histone acetyltransferases (HATs) and histone deacetylases (HDACs) ) Regulation. HDACs inhibitors have the effects of promoting differentiation, anti-proliferation and apoptosis. They mainly include butyrate, trichostatin, benzamide, and cyclic peptides. These components have obvious effects in combination with retinoic acid (ATRA). Anti-leukemia effect.

Monoclonal antibody: HuM195 is a humanized anti-CD33 monoclonal antibody that has been successfully used for the treatment of minimal residual lesions of APL with hematological remission and PCR-positive after retinoid acid (ATRA) and / or chemotherapy. HuM195 can be linked to 131I90Y and 213Bi. Its clinical therapeutic effect remains to be seen. Another humanized anti-CD33 monoclonal antibody combined with calicheamicin (CMA676Mylotary) has been developed. This monoclonal antibody has been approved by the FDA for the treatment of relapsed Preliminary results from AML show that it can control minimal residual lesions in APL patients with evidence of molecular relapse. Latest achievements:

Zhang Mao, Secretary of the Party Leadership Group and Vice Minister of the Ministry of Health, sent a letter to Academician Wang Zhenyi and Academician Chen Zhu on behalf of the Ministry of Health to congratulate them on winning the 7th St. Jorge Cancer Research Innovation Achievement Award.

Zhang Mao said in his congratulatory letter that for more than 30 years, you have unremittingly explored the causes, treatment mechanisms and drug selection of acute promyelocytic leukemia, and successfully combined traditional Chinese medicine arsenic with western medicine to treat acute Promyelocytic leukemia has greatly improved the survival rate of patients with this disease, and turned the highly lethal disease in the past into a highly curable disease, which has been recognized by the world. This remarkable achievement represents the world's highest level of research in this field, not only filling academic gaps, but also giving birth to millions of patients in China and the world.

The National Cancer Research Foundation announced today that it has awarded the seventh St. Jorge Cancer Research Innovation Achievement Award to Wang Zhenyi, an academician of the Chinese Academy of Engineering and Chen Zhu, an academician of the Chinese Academy of Sciences in recognition of their originality in the study of acute promyelocytic leukemia (APL) Sexual results and new treatments developed. The awards ceremony will be held in New York on March 6.

Zhenyi Wang is a tenured professor at the School of Medicine of Shanghai Jiaotong University. Chen Zhu is currently the Minister of Health of China. According to reports, the combination therapy they have developed has become the standard therapy for acute promyelocytic leukemia, which has helped patients' "five-year disease-free survival rate" jump from about 25% to 95%.

Effect of Traditional Chinese Medicine on Treatment of Acute Promyelocytic Leukemia

In July of last year, the journal Nature published an article stating that for scientists, Chinese medicine is so difficult to swallow, and Chinese medicine is still shrouded in a mysterious veil that knows why. Using a typical reduction method, researchers hope to find a key component in a traditional Chinese medicine formula for treating specific diseases, but there are few and few successful examples of artemisinin. The article calls for a new scientific method to study Chinese medicine.

Just over half a year later, on March 14 this year, a team led by Academician Chen Zhu published a paper in the Proceedings of the National Academy of Sciences (PNAS) on the molecular mechanism of traditional Chinese medicine compound Huangdai tablets in treating acute promyelocytic leukemia. Based on a systematic analysis, a biochemical method was used to elucidate the multi-component and multi-target mechanism of a traditional Chinese medicine compound Huangdai tablet developed on the basis of traditional Chinese medicine theory for the treatment of leukemia at the molecular level. The traditional Chinese medicine prescriptions Jun, Chen, Zuo, The compatibility principle of "use" is explained vividly in modern medical methods.

On March 17, the National Two Sessions was about to end. Academician Chen Zhu, who was appointed Minister of Health of the new government, spent nearly two hours in an exclusive interview with our reporter, explaining the research and results in detail, and talking about his Understanding of Modernization of Traditional Chinese Medicine.

Chinese medicine can "tell the truth clearly"

As a scientist, Chen Zhu is best known for her research results in the use of all-trans retinoic acid and arsenic trioxide (arsenic) to treat acute promyelocytic leukemia (APL). Treatment according to this method can make the patient's 5-year disease-free survival rate exceed 90%. APL is expected to be the first adult acute myeloid leukemia that can be cured.

According to reports, acute promyelocytic leukemia is considered to be the most dangerous type of leukemia. A large number of immature promyelocytic cells accumulate in the patient's bone marrow and have severe bleeding symptoms. The etiology of the disease has been studied relatively clearly, mainly due to the translocation of two chromosomes, that is, after the chromosomal arm is broken and exchanged with each other, a new fusion gene PML-RAR appears at the junction, which encodes a fusion protein, which eventually leads to cell cancer .

General blood cells will differentiate and mature after dividing for a certain number of generations, and become cells with various specific structures and functions. But after cancerous cells lose the ability to differentiate, they will continue to "crazy". All-trans retinoic acid is to modify and metabolize the oncoprotein PML-RAR, to re-differentiate cancer cells, to "change evil to normal" and stop "crazy growth"; arsenic trioxide can cause the degradation of this oncoprotein, causing cancer cells to partially differentiate and Eventually entered programmed death (apoptosis).

Chen Zhu, who has a background in Western medical education, always emphasizes that he has been inspired by traditional Chinese medical thought when introducing his research. Synergistic compound therapy, attacking poison with poison, relieving evil and redressing, transforming good and bad ... the wisdom of Eastern philosophy is shining everywhere. It is not difficult to understand that he is keen to use modern molecular biology methods to explain Chinese traditional medicine.

He introduced that as early as the 1980s, molecular research on acute promyelocytic leukemia has not yet begun, and the oncoprotein PML-RAR has not yet been recognized. In the 1980s, Professor Huang Shilin, a TCM expert at the Dalian 210 Hospital of the PLA, combined the dialectics and disease identification. Based on this, a compound Huangdai tablet composed of realgar, Qingdai, Danshen and Taizishen was designed. Since then, Anhui Tiankang Pharmaceutical Co., Ltd. has mass-produced according to strict modern technology. A multi-center clinical study in recent years has confirmed the efficacy of Fufang Huangdai Tablets in treating acute promyelocytic leukemia with a 5-year survival rate of 87%. The study also found that the effective components of realgar, qingdai and salvia were tetraarsenic tetrasulfide, indigo red and tanshinone IIA. However, the mechanism of action of compound Huangdai tablets at the molecular level has not been revealed.

Therefore, under the leadership of Academician Chen Zhu and Academician Chen Saijuan, several research groups such as Ruijin Hospital of Shanghai Jiaotong University and Guangzhou Institute of Biomedicine and Health of the Chinese Academy of Sciences, after more than 4 years of research, found that the risk of acute promyelocytic leukemia In the mouse model, arsenic sulfide alone can prolong the survival time of mice, and the combination of three drugs can achieve a significantly stronger therapeutic effect than that of the combination of two drugs alone. In the leukemia cell model, arsenic sulfide and tanshinone alone can cause a certain degree of differentiation of leukemia cells, and the combination of three drugs can cause leukemia cells to "reform evil to normalization" and differentiate to mature.

Under normal circumstances, during the differentiation of hematopoietic cells from immature to mature, the genes that promote cell differentiation and the factors that are "positive" must be gradually increased, while the genes that inhibit cell differentiation and the factors that are "evil" must be reduced accordingly. Regarding the regulation of the cell cycle, the protein "yang" that promotes the cell cycle and the factor "yin" that inhibits the cell cycle must maintain a balance. With leukemia, "positive" is often suppressed and "evil" flourishes, "yang is hyperactive" and "yin deficiency".

At the molecular level, the combination of the three drugs can significantly enhance the degradation and destruction of the pathogenic PML-RAR oncoprotein caused by arsenic sulfide in acute promyelocytic leukemia, so it has a "de-evil" effect. King Medicine. " Under the action of drugs, the expression of genes that promote cell differentiation is significantly increased, the genes that inhibit cell differentiation are significantly reduced, and tanshinone plays an important role in it; proteins that promote cell cycle are significantly suppressed, and proteins that inhibit cell cycle are significantly increased, of which indigo Red plays an important role. Studies have confirmed that tanshinone is a "championship drug" and indigo red is a "adjuvant drug." The study also found that tanshinone and indorubin promote the significant increase of arsenic sulfide entering leukemia cells by increasing the content of water glycerin channel protein 9 responsible for transporting arsenic sulfide, so both of them play a role of "medicine". The compound Huangdai tablets produced a synergistic effect through joint application.

The vitality of Chinese medicine lies in openness and innovation

"This is a very interesting and highly scientific study that opens the example of designing a combined treatment plan using the principle of traditional Chinese medicine compound prescriptions, which is bound to attract great attention from the academic community." An internationally renowned expert in pharmacology gave the paper Got so sure.

Many experts believe that this research is almost impeccable and "perfect" from a molecular and biochemical perspective. A very classic analysis and clarification of a clear target and mechanism of a traditional Chinese medicine compound developed on the basis of traditional Chinese medicine theory at the cellular and molecular level. Moreover, the role of each drug at the molecular level and Chinese medicine's understanding of the status and role of each drug in the compound turned out to be so good, it was simply amazing!

The international mainstream scientific community has also given positive comments on this research result, such as the review published in the journal Nature entitled "Traditional Chinese Medicine: A Modern New Explanation of Ancient Compounds", which holds that this study shows "how the main ingredients of ancient medicines are "Harmonious Action" for treating diseases is of great significance for the communication between traditional Chinese medicine and modern medicine. "Science" also reported on this article in an interview with Chen Zhu.

But Chen Zhu thinks that this research is very lucky to get such results!

"We have a suitable material basis, including purified effective compounds, cell models and animal models." Chen Zhu said, "Of course, the most important thing is that the compound Huangdai tablets have very good clinical efficacy and have been confirmed by multi-center clinical research. Without this foundation, all follow-up research is passive water. From this point of view, the innovation and development of Chinese medicine itself is still the most important. "

The rich development of traditional Chinese medicine theory system and the improvement of practical ability are the foundation of the development of traditional Chinese medicine. We must talk about both innovation and inheritance. Chen Zhu said, "I support the promotion of 'authentic' Chinese medicine in Chinese medicine education and clinical practice!"

Chen Zhu believes that the modernization of Chinese medicine also requires an open mind. The history of TCM for thousands of years has never been a history of self-defeated history, and its connotation has been continuously enriched and progressed. The introduction of Persian medicine and the introduction of "Hu Yao" and "Southern Medicine" have made important contributions to the development of Chinese medicine. Using modern scientific and technological means and multidisciplinary methods to study traditional Chinese medicine will play a supporting and promoting role in the development of traditional Chinese medicine.

In recent years, Western medicine is gradually recognizing the benefits of combined therapies, and Chinese medicine has advocated combined therapies for nearly 2,500 years through nearly 100,000 compound prescriptions. Although the traditional Chinese medicine compound has achieved certain effects in clinical practice, the effective ingredients of most of the compound medicines are still unknown, and the mechanism of action is also unclear, which has limited the promotion and application. "On the basis of determining the clinical efficacy, conducting mechanism research will not only be beneficial to the modernization and internationalization of Chinese medicine, but also provide a basis for optimizing the compatibility of prescriptions."

Chen Zhu believes that in terms of innovation, the Chinese medicine system should be more open and better at drawing from the common wisdom of mankind. The latest research results of genomics, proteomics, metabolomics, nuclear magnetic resonance, bioelectricity, thermal imaging, gene knockout ... all physical and chemical biology technologies, animal models, human imaging, no matter what, can be taken It is used by the Institute of Traditional Chinese Medicine, and the relevant systems must be strictly tested by biomedical statistics. Modern life sciences are not named "West"! It is necessary to create conditions to attract outstanding scientists and outstanding scientific research institutions in the Chinese life sciences circle to the modernized innovation system of Chinese medicine.

System biomedicine has created unprecedented opportunities and platforms for the convergence of Chinese and Western medicine. Integrating Chinese and Western medicine is a very good way to promote the modernization of Chinese medicine. Chen Zhu expects that while maintaining its own characteristics and inheriting development, Chinese medicine will better converge and integrate modern science and technology, thereby creating a new medicine that is higher than traditional Chinese medicine and western medicine.

Symptoms of acute promyelocytic leukemia

Dizziness, fatigue, nausea, persistent high fever, coughing, bleeding gums, swollen gums, gingival atrophy, fundus bleeding, palpitations, spleen, stool, anemia, symptoms

Chemotherapy

All-trans retinoic acid, arsenic trioxide, soft red, cytarabine VP16 combined with chemotherapy has a remission rate of 90%

Mentality

Don't be afraid of being angry in the ordinary mind. Whoever experiences and knows is regarded as an episode in life. It is also a good opportunity to experience the mind. Believe that you can do it.

effect

It feels good and is no different from normal people.It basically cures the recurrence.It doesn't matter.You can continue chemotherapy to get relief.

Prognosis of acute promyelocytic leukemia

In the past, the treatment effect of APL was poor, and the disease was dangerous. With the continuous improvement of the understanding of the cell biological characteristics of APL and the improvement of treatment methods, the treatment results and prognosis have greatly improved, the early mortality rate has decreased significantly, and the duration of remission has been significantly reduced. Prolongation is currently the best type of treatment for leukemia.

Acute promyelocytic leukemia cells