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Treatment of Acute Myeloid Leukemia


Medical editor Lorentz Brinch MD
Hematologist
Oslo University Hospital

General

Acute myeloid leukemia is treated with chemotherapy which reduces, or optimally, eradicates the leukemic clone. The stipulation for achieving long-term survival or curing the disease is that the patient must reach complete hematological remission (CHR).

CHR is defined as < 5% blasts in normal cellular bone marrow combined with normalized cell count in the blood. In practice, this is only achievable after infusion of chemotherapy with such a high dose intensity that the treatment is life-threatening. Chemotherapy will heavily affect normal hematopoiesis causing bone marrow aplasia with serious neutropenia, thrombocytopenia, and anemia, in periods from one to multiple weeks.

The patient's age is an indicator for what can reasonably be achieved. Induction treatment is appropriate for patients below about 60 years, while patients between 60-70 years can be treated to cure the disease only in certain cases. Patients older than 70 years will in the majority of cases, benefit most from good palliative treatment. An exception is patients with acute hypergranular promyelocyte leukemia (M3).

Curative treatment should take place at the hematology section of a regional hospital or a well-equipped central hospital with a designated section for blood diseases. There should be sufficient resources of blood banking and competent on-call personnel. If necessary, there should be cooperation with a regional hospital.

Indication

  • Acute myeloid leukemia

Goal

  • Control the disease, possibly cytogenetically and molecularly. 
  • Cure the disease.

Treatment Plan

Experience shows that certain patient groups will not benefit from the most intensive chemotherapy schedules. In these cases, the treatment is "watchful waiting" or less potent chemotherapy. This applies to:

  • Patients over 70 years, or patients under 70 with reduced health condition not due to leukemia, or other serious illness in addition to leukemia.
  • Older patients with certain forms of acute leukemia which, from experience, are refractory to intensive chemotherapy combinations. These types are the terminal acute leukemia occurring during treatment for other diseases, for example, polycythemia vera, myelofibrosis, aplastic anemia, myelodysplastic syndrom (MDS), and after treatment of Hodgkin's or non-Hodgkin's lymphoma or multiple myeloma.

With these exceptions, combinations of chemotherapy are given to all patients with acute myeloid leukemia, but treatment is adapted for age, health status, and comorbidity.

Treatment program

Cytarabine (cytosine arabinoside) is included in all chemotherapy combinations administered to induce remission of acute myeloid leukemia.

 

Treatment plan for acute myeloid leukemia < 60 years
Medication Administration method

Treatment 1A

 
Daunorubicin 50 mg/m2 day 1, 2, 3 intravenous infusion
Cytosine arabinoside 200 mg/m2 day 1–7 intravenous infusion over 24 hours
Treatment 1B is administered if there is no marrow aplasia and < 5% blasts in marrow smear 14 days after start

Treatment 1B

 
Daunorubicin 50 mg/m2 dag 1, 2 intravenous infusion
Cytosine arabinoside 200 mg/m2 day 1–5 intravenous infusion over 24 hours
Consolidation treatment: Treatment 2–5 assumed CHR after treatment 1A, possibly 1A + 1B

Treatment 2-5

 
Cytosine arabinoside 3 g/m2 x 2 days 1,3, 5 intravenous infusion over 3 hours

For FAB subgroup M3, a modified regimen is given in addition to the vitamin A derivative, tretinoin (ATRA).

Cytarabine combined with idarubicin is about as effective as daunorubicin in an equipotent dose, in terms of bringing the patient into remission.

Complete hematological remission

Remission criteria:

  • B-neutrophile > 1 x 109/l
  • Thrombocytes > 100 x 109/l
  • no need for blood transfusion
  • < 5% blasts in normal cellular bone marrow smear
  • absence of extramedullary leukemia

All patients under 60 years and their siblings, parents, and sometimes children, should have their tissue typed after remission is reached. All patients who have reached complete hematological remission (CHR), must have additional treatment (consolidation treatment (treatment 2-5)), otherwise there will be recurrence of the disease, almost without exception. This treatment regimen causes complete hematological remission (CHR) in about 80% of patients, and 4 year survival of 40-45%. Four year recurrence-free survival in patients with t(8;21) and Inv(16) is 70–80 %. Patients with cytogenetic anomalies and a high risk for recurrence have about 20% chance of recurrence-free survival.

Patients with a family donor are offered allogeneic stem cell transplant treatment in the first CHR except for patients with favorable prognostic signs. Critical weight is put on  the cytogenetic deviations of the leukemia cells at the time of diagnosis. In some patients with high risk criteria, who do not have a family donor, it is possible to search for an unrelated donor.

In patients who are in complete or partly hematological remission, blood values and bone marrow must always be checked before starting a new course. It is important to be aware that patients undergoing combination treatment rarely have normal blood and bone marrow function even if they are in complete hemotological remission. These blood and bone marrow changes are therefore not a sign of leukemia, but rather a result of the treatment.

Patients over 60 years

High-dose consolidation treatment or allogeneic stem cell transplantion treatment with myloablative pre-treatment are not appropriate for patients over 60 years due to the high risk of toxicity and death related to treatment. All patients must be assessed individually. An alternative is to administer 2-4 courses with combinations of amsacrine, etoposide, mitoxantron, and cytarabine, which are adapted for patient response and possible observed toxic damage. Other regimens are also used. It has not been shown whether any specific regimen is clearly the best. 

Refractory disease and recurrence during treatment

These patients have a poor prognosis and should receive palliative treatment with transfusions, antibiotics for infections, and chemotherapy combinations to control the disease. Patients who have suitable family donors and are not transplanted in the first remission are candidates for an allogeneic stem cell transplantation at the start of remission, and should therefore be followed carefully. A transplantation at the start of recurrence, from a donor who is not a biological relative, is not feasible for practical reasons. 


Preparation

  • Inform the patient about the disease, treatment, and side effects.
  • Evaluate familial donor relations.
  • Insertion of central vein catheter.

Implementation

High-dose cytarabine is standard treatment for patients < 60 years and is administered as four repeated courses with 4 week intervals.

Alternative treatment protocols including high dose treatment with autologous stem cell support have not, so far, been shown to give better results.


Follow-up

Intensive chemotherapy treatment leads to significant granulocytopenia and thrombocytopenia. Therefore, frequent blood tests are necessary.

While the patient is hospitalized and receives aggressive combination treatment, and between later courses, hemoglobin, rod and segmental nucleated granulocyte counts, as well as platelets, should be checked at least twice a week after a course of chemotherapy until bone marrow regeneration.

Consolidation treatment also causes bone marrow aplasia for 1–2(3) weeks. There is a certain risk for serious CNS toxicity from high doses of cytarabine, which is not given to patients over 60 years. Caution must also be taken for patients with liver and kidney involvement.

Side effects

During the intensive treatment period, the patient will, in periods from weeks to months, require hospitalization as a result of the treatment due to infections, the need for transfusions, and/or organ failure.

Chemotherapy of this intensity unfortunately leads to death in some patients, due to sepsis or other complications during the first months of treatment. This applies especially to elderly patients.

Liberal use of thrombocyte concentrates in combination with optimal doses of antimicrobial and antifungal agents is a prerequisite for safe treatment.  

Nutrition

Nutritional problems occur, more or less, among patients receiving this treatment. This is due to nausea, vomiting, mucositis, diarrhea, dry mouth, pain, constipation, and changes in smell and taste senses. Many will require intravenous nutrition. Good nutritional guidance is important.  

Mucositis

Mucositis, both in the mouth and other mucosa, often occurs when blood values are at their lowest. The intensity of the soreness is individual. Sore mucosa in the mouth is not only an entrance for bacteria, but can also be painful. Prophylactic mouth hygiene should be given during the entire treatment. 

Nausea

Nausea improves 1-2 days after a treatment. Some patients have lasting problems often of multifactorial etiology.  

Hair loss

Hair loss will occur 2-3 weeks after starting chemotherapy.

Recurrence after treatment is finished

For recurrence of the disease, the possibility for reaching new remission with the original induction regimen is about 30-50% better the longer it has been since the conclusion of treatment. Therefore, if recurrence occurs more than 12 months after concluded treatment, it is usually recommended to try the original induction regimen first.  

Recurrence during the first year after treatment will rarely reach remission with the original induction regimen, and the prognosis is poor. Treatment is planned individually.

If patients under 60 years reach a new CHR, an allogeneic stem cell transplantation is an option if a familial donor is available. A transplant from an unrelated donor may also be appropriate.


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