How is acute myeloblastic leukemia treated?

General strategy of treatment of acute myelogenous leukemia

In modern hematology, leukemia therapy, including acute myeloblastic therapy, must be performed in specialized hospitals according to strict programs. The program (protocol) includes a list of necessary for diagnostic studies and a rigid schedule for their conduct. After the completion of the diagnostic stage, the patient receives the treatment prescribed by this protocol, with strict observance of the timing and order of the elements of therapy. Currently, there are several leading research groups in the world that analyze the diagnosis and treatment of acute myelogenous leukemia in children in multicenter studies. These are the American research groups CCG (Children's Cancer Group) and POG (Pediatric Oncology Group), the British group MRC (Medical Research Council), the German group BFM (Berlin-Frankfurt-Miinster), the Japanese CCLG (Children's Cancer and Leukemia Study Group) LAME (Leucamie Aique Mycloi'de Enfant), Italian AIEOP (Associazione Italiana Ematologia ed Oncologia Pediatric), etc. The results of their research are the main sources of modern knowledge about the diagnosis, prognosis and treatment of acute myelogenous leukemia in children.

The main goal of the treatment is the eradication of the leukemic clone with the subsequent restoration of normal hematopoiesis.

The first stage is the induction of remission. For the prognosis, an assessment of the sensitivity to therapy after an induction course is important. The final evaluation, according to most protocols, is carried out after two courses of treatment.

Postremission therapy should consist of at least three blocks. It can only be chemotherapy or chemotherapy followed by autologous or allogeneic transplantation of hematopoietic stem cells. Some therapeutic regimens include maintenance therapy. An important element is the prevention and treatment of CNS lesions by intrathecal administration of cytotoxic drugs, systemic high-dose therapy, and sometimes cranial irradiation. The main drug for intrathecal therapy with acute myeloblastic leukemia is cytosine arabinoside, in some protocols, prednisolone and methotrexate are additionally used.

Modern therapy with acute myelogenous leukemia should be differentiated, i.e. Different in intensity (and therefore also in toxicity), depending on the risk group. In addition, treatment should be as specific as possible.

Induction Therapy

Cytotoxic therapy of acute myeloblastic leukemia causes transient, but severe myelosuppression with a high risk of infections and hemorrhagic complications. The spectrum of cytotoxic drugs effective against acute myeloblastic leukemia is rather small. The basic drugs are cytosine-arabinoside, anthracyclines (daunorubicin, mitoxantrone, idarubicin), etoposide, thioguanine.

Classically, the induction of remission of acute myeloblastic leukemia is administered by a seven-day course. During all 7 days, the patient receives cytosine-arabinoside at a dose of 100-200 mg / (m ² xut), which for three days is combined with daunorubicin at a dose of 45-60 mg / (m ² xut). Most protocols are based on this classic "7 + 3" scheme, to which may be added thioguanine, etoposide or other drugs. In the application of such therapeutic regimens, remission is achieved in 90% of patients.

In 1989-1993, the CCG group conducted a study of 589 children with acute myeloblastic leukemia. The study showed the advantage of induction in the intensive timing mode. The essence of this regime is that patients receive induction therapy consisting of two identical 4-day courses with an interval of 6 days. Each course of treatment includes cytosine-arabinoside, daunorubicin, etoposide and thioguanine. The need to repeat the course of treatment strictly through a fixed interval, regardless of hemopoiesis, is due to the fact that leukemia cells that were in the first course outside the mitotic phase will enter it at the time of the second course and will be cytotoxic to chemotherapy. The advantage of intensive timing in a significant increase in EFSc was 27% in patients who received the same therapy in the standard regimen, up to 42%. Currently, the CCG group has published data on the pilot study of intensive timing induction using idarubicin, showing the benefits of this drug in induction in children.

The MRC group in the AML-9 study (1986) showed the benefits of prolonged induction therapy (5-day induction using daunorubicin, cytosine-arabinoside and thioguanine was compared with a 10-day induction). Despite the higher mortality from toxicity (21 vs. 16%), the level of achievement of remission was higher in the group of prolonged therapy. The next study of this group - AML-10 - included 341 children. Induction therapy in AML-10 was based on standard doses of cytosine-arabinoside and daunorubicin supplemented with a trefoil preparation - etoposide or thioguanine, depending on the randomization group. Induction in AML-12 (529 children included in the study) consisted of the ADE scheme (cytosine-arabinoside + daunorubicin + etoposide), in another randomization group - from the AME scheme (cytosine-arabinoside + mitoxantrone + etoposide). Remission in both studies was 92%, death induction and resistant acute myeloblastic leukemia - 4% each. The level of remission in both branches of the protocol AML-12 (ADE and AME) was almost the same - 90 and 92%. In the early 1990s DFS in acute myelogenous leukemia increased from 30 to 50%; Since 1995 (AML-12 protocol) the value of this indicator is 66%.

Induction according to the protocol of the LAME research group consists of standard doses of cytosine arabinoside and mitoxantrone (total dose of 60 mg / m ² ), remission is achieved in 90% of patients.

In Russia, the most well-known protocols are the BFM group. Until 1993, induction therapy consisted of the ADE course (cytosine-arabinoside + daunorubicin + etoposide). According to AML-BFM-93 protocol (the study includes 471 children), induction therapy in one randomization group was formerly ADE, in the other group consisted of cytosine-arabinoside, etoposide and idarubicin. The rate of achievement of remission among all patients was 82.2%. It was shown that the administration of idarubicin significantly increased the reduction of blasts in patients by the 15th day from the onset of induction therapy, but this did not affect the remission and remission rates of remission and DFS, which in these groups was similar.

Post-treatment therapy

Most protocols in the quality of post-treatment therapy involve two or more courses of cytostatics. As a rule, at least one course of polychemotherapy is based on high doses of cytosine-arabinoside (1-3 g / m ² per single administration). Additional drugs are etoposide and / or anthracyclines (idarubicin or mitoxantrone).

The most successful protocols are three postreissive chemotherapy blocks, some of which are performed in intensive timing and / or using high doses of cytosine-arabinoside.

Hematopoietic Stem Cell Transplantation

Modern therapy for acute myeloblastic leukemia provides for transplantation of hematopoietic stem cells (TSCC) for certain categories of patients. There are two fundamentally different types of transplantation - allogeneic and autologous.

Allogeneic transplantation of hematopoietic stem cells is an effective but highly toxic method of antileukemic therapy. The antileukemic effect of allo-TTSK is provided by conditioning with ablative chemotherapy and the immunological effect of "graft versus leukemia" - the reverse side of the "graft versus host" syndrome. Since 1990, there has been an improvement in the results of therapy in children who received standard induction of remission based on the use of cytosine-arabinoside and anthracyclines, consolidating therapy and, in the presence of a related HLA-identical donor, allogeneic TSCA. Allogeneic transplantation of hematopoietic stem cells is the most effective method of preventing relapse, however, in the first remission of acute myeloblastic leukemia, it is only indicated in patients at high risk.

In comparison with allogeneic, the role of autologous transplantation in the prevention of relapse is not so obvious.

Therapy of acute promyelocytic leukemia

Option M, according to EAB - a special type of acute myelogenous leukemia. It is registered in all regions of the world, but in some it is significantly prevailing. Among all cases of acute myelogenous leukemia in the United States and Europe, 10-15% of acute promyelocytic leukemia occurs, while in China it is about one-third, and among the Latin American population - up to 46%. The main link of pathogenesis and the diagnostic sign of acute promyelocytic leukemia is the translocation t (15; 17) (q22; ql2) with the formation of the chimeric PML-RARa gene. In the clinical picture, coagulopathy is leading (equal probability of DIC and hyperfibrinolysis), which can be aggravated by chemotherapy, forming a high mortality rate from hemorrhagic syndrome at the beginning of treatment (20%). Adverse factors for prognosis are the initial leukocytosis (the number of leukocytes exceeds 10x10 ⁹ / L) and the expression of CD56 on leukemic promyelocytes.

Over the past 20 years, the prognosis for patients with acute promyelocytic leukemia has changed from "fatal in high probability" to "recovery in high probability." The greatest contribution to these changes was made by the introduction to the therapy of all-trans retinoic acid (ATRA). ATRA is a pathognomonic differentiating agent that suppresses the transcription of PML-RARa, terminating the pathway of leukemogenesis and initiating the ripening of atypical promyelocytes to granulocytes in vivo and in vitro. The use of ATRA induction allows achieving remission in 80-90% of patients with de novo acute acute promyelocytic leukemia. ATRA neutralizes the manifestations of coagulopathy and does not cause aplasia of hematopoiesis, which reduces the likelihood of bleeding and sepsis in the early period of treatment. The standard dose of ATRA is 45 mg / (m ² xut). The possibility of reducing the dose of the drug without changing the efficacy is shown.

For most patients to achieve remission, it is sufficient to use ATRA as a monotherapy, but without additional therapy, the disease almost always recurs during the first half of the year. The best strategy is to combine ATRA with induction chemotherapy. Induction using all-transretinic acid in combination with anthracyclines, several courses based on anthracycline consolidation and supporting low-dose therapy with or without ATRA provides 75-85% EFS for 5 years in adults. The use of ATRA induction together with chemotherapy gives a higher disease-free survival rate than the consistent use of drugs. The use of maintenance therapy also reduces the likelihood of relapse, and an increase in the dose of anthracyclines in induction therapy and ATRA in consolidation may improve the outcome of treatment in patients at risk.

Results of studies on the efficacy of treatment of acute promyelocytic leukemia in children have not been published to date, but the nature of the disease and the principles of therapy are the same in all age groups.

What prognosis does acute myeloblastic leukemia have?

Current ideas about the prognosis of acute myeloblastic leukemia look as follows: in the "good prognosis" group, the probability of a 5-year survival rate is 70% or more, the probability of relapse is less than 25%; in the "intermediate prognosis" group, the survival rate is 40-50%, relapse occurs in 50% of patients; the category "bad prognosis" is characterized by a high probability of relapse (more than 70%) and a low probability of 5-year survival rate - less than 25%.