How is acute myeloblastic leukemia treated?

General strategy for the treatment of acute myeloid leukemia

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

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

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

Post-remission therapy should consist of at least three blocks. This may be chemotherapy alone or chemotherapy followed by autologous or allogeneic hematopoietic stem cell transplantation. Some therapeutic regimens include maintenance therapy. An important element is the prevention and treatment of CNS lesions by intrathecal administration of cytostatic drugs, systemic high-dose therapy, and sometimes cranial irradiation. The main drug for intrathecal therapy in acute myeloid leukemia is cytosine arabinoside; some protocols additionally use prednisolone and methotrexate.

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

Induction therapy

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

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

In 1989-1993, the CCG conducted a study of 589 children with acute myeloid leukemia. The study showed the advantage of induction in the intensive timing regimen. The essence of this regimen 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 at a fixed interval, regardless of the hematopoiesis indices, is due to the fact that leukemic cells that were outside the mitotic phase during the first course will enter it by the time the second course begins and will be exposed to the cytotoxic effect of chemotherapy drugs. The advantage of intensive timing is a reliable increase in EFSc 27% in patients who received the same therapy in the standard regimen, to 42%. The CCG has now published data from a pilot study of intensive timing induction using idarubicin, showing the benefits of this drug in induction therapy in children.

The MRC group in the AML-9 study (1986) showed the advantages of prolonged induction therapy (5-day induction with daunorubicin, cytosine arabinoside and thioguanine was compared with 10-day induction). Despite a higher rate of death from toxicity (21 versus 16%), the rate of achieving remission was higher in the prolonged therapy group. 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 with the addition of a T-drug - etoposide or thioguanine, depending on the randomization group. Induction in AML-12 (529 children were included in the study) consisted of the ADE (cytosine arabinoside + daunorubicin + etoposide) regimen, and in the other randomization group, the AME (cytosine arabinoside + mitoxantrone + etoposide) regimen. Remission in both studies was 92%, death in induction and resistant acute myeloid leukemia were 4% each. The remission rate in both arms of the AML-12 protocol (ADE and AME) was virtually identical - 90 and 92%. In the early 1990s, DFS in acute myeloid leukemia increased from 30 to 50%; since 1995 (AML-12 protocol), this figure has been 66%.

Induction according to the LAME study group protocol consists of standard doses of cytosine arabinoside and mitoxantrone (total dose 60 mg/m2 ⁾, remission was achieved in 90% of patients.

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

Post-induction therapy

Most protocols for post-remission 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/m2 ⁱⁿ one administration). Additional drugs are etoposide and/or anthracyclines (idarubicin or mitoxantrone).

The most successful protocols include three post-remission chemotherapy blocks, some of which are administered in an intensive timing regimen and/or using high doses of cytosine arabinoside.

Hematopoietic stem cell transplantation

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

Allogeneic hematopoietic stem cell transplantation is an effective but highly toxic method of antileukemic therapy. The antileukemic effect of allo-HSCT 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, improvement in treatment results has been noted in children who received standard remission induction based on the use of cytosine arabinoside and anthracyclines, consolidation therapy and, in the presence of a related HLA-identical donor, allogeneic HSCT. Allogeneic hematopoietic stem cell transplantation is the most effective method for relapse prevention, however, during the first remission of acute myeloid leukemia, it is indicated only for high-risk patients.

Compared with allogeneic transplantation, the role of autologous transplantation in preventing relapse is not so obvious.

Therapy for acute promyelocytic leukemia

Option M, according to EAB, is a special type of acute myeloid leukemia. It is registered in all regions of the world, but in some it significantly prevails. Among all cases of acute myeloblastic leukemia in the USA and Europe, acute promyelocytic leukemia accounts for 10-15%, while in China - about a third, and among the Latin American population - up to 46%. The main link in the pathogenesis and diagnostic sign of acute promyelocytic leukemia is the translocation t (15; 17) (q22; ql2) with the formation of the chimeric gene PML-RARa. In the clinical picture, coagulopathy is the leader (DIC and hyperfibrinolysis are equally likely), which can worsen against the background of chemotherapy, forming a high mortality rate from hemorrhagic syndrome at the beginning of treatment (20%). Unfavorable prognostic factors include initial leukocytosis (the number of leukocytes exceeds 10x10 ⁹ /l) and expression of CD56 on leukemic promyelocytes.

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

Most patients achieve remission with ATRA monotherapy, but without additional therapy the disease almost always relapses within the first six months. The best strategy is to combine ATRA with induction chemotherapy. Induction with all-trans retinoic acid in combination with anthracyclines, several courses of anthracycline-based consolidation, and low-dose maintenance therapy with or without ATRA have been shown to provide 75-85% EFS at 5 years in adults. The use of ATRA in induction simultaneously with chemotherapy provides higher relapse-free survival than sequential use of drugs. The use of maintenance therapy also reduces the likelihood of relapse, and increasing the dose of anthracyclines in induction therapy and ATRA in consolidation can improve the treatment outcomes of high-risk patients.

The results of studies on the effectiveness of treatment of acute promyelocytic leukemia in children have not yet been published, however, the nature of the disease and the principles of therapy are the same in all age groups.

What is the prognosis for acute myeloid leukemia?

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