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Drug therapy for childhood acute myelogenous leukemia


Medical editor Bernward Zeller MD
Pediatric Oncologist
Oslo University Hospital

General

In Norway, the Nordic protocol NOPHO (Nordic Society for Pediatric Hematology and Oncology) AML 2004 is followed for treating AML. The exception is children with Down's syndrome who should be treated with the European protocol ML-DS 2006 according to NOPHO's AML working group. This protocol is not formally approved in Norway, but resembles the NOPHO-AML protocol and is used as "best available treatment."  

For acute promlyelocyte leukemia (APL, M3-AML), NOPHO’s AML group uses the international protocol ICC APL study 01 as "best available treatment.”

Drug therapy for AML is divided into 6 courses of chemotherapy.  

Indication

  • Acute myelogenous leukemia

Goal

  • Control the disease on a hematological, cytogenetic, and molecular level
  • Cure

Treatment Plan

AML treatment in children is very toxic and requires advanced supportive care. Bone marrow aplasia should be expected after each course of treatment, most prominently after AIET and HA1M. Broad spectrum antibiotics should be started immediately in the event of febrile neutropenia. A prophylaxis for pneumocystic jirovecii (trimethoprim) and fungal infections (fluconazol) should be given during the entire treatment period.

Induction consists of two treatment courses:

AIET

Cytarabine and etoposide in continuous intravenous doses days 1-4. Intravenous idarubicin x days 2,4,6, tioguanine per os days 1–4, intrathecal methorexate day 1. The response (judged by bone marrow taken from day 14 of starting AIET) determines the subsequent treatment plan. 

  • < 5 % blasts (morphologically determined): wait for bone marrow regeneration before starting AM treatment. Caution: Patients with t(8;21) are given FLADx instead of AM (await bone marrow regeneration in this case as well).
  • 5–15 % blasts. FLADx should start immediately (unless septic or other complication). For remission after FLA treatment, the patient remains in the standard risk group. If not, they are moved to the high risk group.
  • > 15 % blasts: AM treatment begins immediately and the patient is moved to the high risk group, which involves a stem cell transplantation.

AM

Cytarabine continuously days 1–5, intravenous infusion of mitoxantrone days 1–3, intrathecal methotrexate day 1.

FLADx (alternative to AM for 8-15% blasts after AIET and for t(8;21) according to NOPHO amendment January 2011).

Methotrexate intrathecally day 1. Fludarabine intravenously 30 mg/m² x 1 days 1-5. Cytarabine intravenously 2 g/m² x 1 days 1-5. Liposomal daunorubicin 60 mg/m² days 2, 4, 6.

Consolidation consists of 4 treatment courses:

HA1M

Cytarabine intravenously 1 g/m2 every 12 hours, for a total of 6 doses. Intravenous infusion of mitoxantrone days 3,4,5. Intrathecal methotrexate day 1. Before this treatment course, an echocardiogram is obligatory due to significant anthracycline toxicity after courses 1 and 2.  

HA2E

Cytarabine intravensouly 2g/m2 every 12 hours, for a total of 6 doses. Intravenous infusion of etoposide days 2-5, intrathecal methotrexate day 1.

HA3

Cytarabine intravenously 3 g/m2 every 12 hours, for a total of 6 doses. Intrathecal methotrexate day 1.

HA2E

Cytarabine intravenously 2 g/m2 evey 12 hours, for a total of 6 doses. Intravenous infusion of etoposide days 2-5. Intrathecal methotrexate day 1.

High risk group

If the response to treatment is unsatisfactory, the patient is moved to the high risk group. Provided a donor can be found, these patients should have a bone marrow transplant between the first and last consolidation treatments. Patients with FLT3-ITD (and NPM1 wild type) are also placed in the HR group and are candidates for stem cell transplantation (NOPHO amendment January 2011).


Preparation

  • An IV line is inserted and fluids started to prevent tumor lysis syndrome.
  • A heart function test is done (Carditox – echocardiogram)
  • A central vein catheter is inserted under general anesthesia.

The child and their parents are informed of the disease, treatment, and side effects.

With the parents' consent, the child's school/preschool/public health nurse will be informed of the diagnosis and what treatment involves. Written information is also sent. If the child is attending school, a nurse will visit the school and inform the child's class about the disease and treatment.  

  • The parents receive help to write an informative letter to family and friends.
  • The hospital's teacher will contact the child and family and inform them about the hospital school.
  • The child will be offered a wig/scarf/hats and a wig maker will take measurements.
  • Boys over 12 at a sexually mature age are offered sperm banking
  • The child and parents are instructed on oral hygiene.
  • The child should not have any immunizations during the treatment.

The first course of treatment starts depending on blood values. The second course of treatment is started depending on blood values. If the bone marrow taken 15 days from the first treatment shows more than 5% blasts, the second treatment course is started. Later courses require neutrophiles > 1.0 and thrombocytes over 80.

Before each course, the following is taken:

  • Blood tests. The blood test results should be improving before starting a new course.
  • Weight and height
  • Blood pressure and pulse
  • Temperature
  • Urine test

Implementation

Treatment duration

In the NOPHO-AML 2004 protocol, the treatment duration is about 6 months.

The treatment occurs in cooperation between the University hospital and local pediatric unit. For AML, all diagnostics and evaluations, as well as treatments take place at the University hospitals. Parts of the supportive treatment are often taken care of by the local hospital.  

Children undergoing treatment for cancer must be seen immediately under an open door policy.

Caution: AML treatment is very toxic, and life-threatening complications can occur during the periods between courses. If the parents call the hospital and are worried about the status of the child, the child should always be admitted for blood tests and examination by a doctor, even if the child is afebrile. 
 

 


Follow-up

The child is often followed-up by their local hospital during block treatments. Due to falling blood values after treatments, regular blood tests are taken. Transfusions and treatment for infections are also necessary.

The treatment causes many side effects for the child, therefore, it is very important to have cooperation among the parents, local hospital, and regional hospital. 

The danger of side effects, especially potentially life-threatening infections, is greater in treatment for AML than ALL. Treatment for infection should be started at the slightest suspicion. It is very important that the parents/guardian observe the child at home and contacts the hospital for advice and guidance if the child develops symptoms of:

  • Infection (fever over 38.5°C at one measurement or two of 38.0°C with one hour interval) If the child has a fever, the hospital should be contacted not matter the time of day/night. The child should always be assessed clinically and blood tests must be taken. Intravenous antibiotics must often be started. Remember that the child can have a serious infection without a fever.
  • Bleeding, either small spots on the skin (petechiae), larger hematomas, or mucosal bleeding, for example, a nosebleed.
  • Lethargia
  • Poor appetite
  • Significant constipation
  • Pain

Common side effects during AML treatment 

Nutritional

Nutritional problems occur in varying degrees in patients undergoing this treatment. This is due to nausea, vomiting, mucositis, dry mouth, pain, constipation, and sensory changes. Many will need tube-feeding to meet their nutritional needs. Steroids can lead to an increase in appetite and good nutritional guidance is important. 

Pain

Mucositis, in the mouth and other mucosal lining occurs when blood values are at the lowest. The degree of soreness is individual. Sore mucosa in the mouth is not only an entrance for bacteria but it can also be painful. Prophylactic oral hygiene is practiced during the entire treatment. 

For sore mucosa in the rectum, lubrication is necessary. A remedy is to use soft toilet paper with peanut oil and lubricating after each toilet visit. Bathing in green soap is also soothing. Avoid taking temperatures rectally, suppositories, enemas, etc. during chemotherapy to avoid the risk of bleeding and infections.  

Nausea

The nausea will diminish 1-2 days after finishing a course of chemotherapy depending on the drug. Parents will receive a prescription for anti-nausea medication. 

Cardiotoxicity

Anthracyclines (doxorubicin, daunorubicin, idarubicin, mitoxantron) are cardiotoxic, especially in high cumulative doses. The AML protocol has a high cumulative anthracycline dose, therefore, monitoring is required with ECHO/Doppler before the first treatment course, in other stages of the protocol, and as needed otherwise. Cardiac testing is more important the longer the treatment. In doses over 200 mg/m2 , an ECHO should be performed before each course. To calculate cumulative dose in mg: dauno = doxo = 1 = mitoxantrone x 5 = idarubicin x 5.

Change in appearance

Hair loss starts 7-14 days after starting chemotherapy. The hair will usually fall out in clumps.

Change in self-image

The treatment is usually a major burden for the child both physically and psychologically. This can change the way the child thinks of himself/herself.

Mood swings

Use of steroids makes the child susceptible to change of mood. This may be a great burden for both the child and the rest of the family. 

Isolation

Treatment for ALL usually leads to isolation from the local community. The child is usually not included in normal play. It is difficult to find a balance between protecting the child from infection and allowing him/her to live a normal life, since the child is susceptible to infection during the entire treatment period. The child should avoid crowds, for example shopping centers, or public transportation. Ten to fourteen days after finishing a course of chemotherapy, the blood values are at their lowest. This is when the child is most susceptible to infection. 

If the child feels well and does not have too low a white blood cell count, they may go to school. Otherwise, the child receives home-schooling. Younger children should not go to nursery school/kindergarten during treatment during the first months after treatment is over.

The child's general health condition should determine whether they go to school, not their blood values.


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