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Drug therapy for acute lymphoblastic leukemia in children


Medical editor Bernward Zeller MD
Pediatric Oncologist
Oslo University Hospital

General

Treatment of ALL is principally chemotherapy to reduce, and in most cases, eliminate the leukemic clone.

This treatment, unfortunately, also causes intense side effects on normal hematopoiesis. After chemotherapy treatments, for periods of one to multiple weeks, the child will have bone marrow aplasia with varying degrees of neutropenia, thrombocytopenia and anemia. The child is therefore susceptible to potentially serious infections and/or bleeding.  

Norway follows the NOPHO ALL 2008 protocol (Nordic Society for Pediatric Hematology and Oncology). Patients are separated into 3 intensity groups:

  • Standard risk
  • Intermediate risk
  • High risk

In principle, the treatment has the same staging in all risk groups:

  • Consolidation
  • Maintenance

Indication

  • Acute lymphoblastic leukemia

Goal

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

Treatment Plan

Before starting treatment, the patient should be well hydrated and urinating well. Alkalinization and allopurinol treatment are given based on clinical indications in all intensity groups.

All children recieve trimethoprim-sulfa during the entire treatment to prevent Pneumocystis jirovecii pneumonia. Trimethoprim-sulfa is given during the entire treatment period in the high intensity groups as well as the first 6 months of maintenance therapy in SR/IR intensity groups. Trimethoprim-sulfa is not given in the last 48 hours before high-dose methotrexate. This is to avoid an interaction with methotrexate metabolism.

  • It is important to be well hydrated when receiving cyclophosphamide (≥ 1000 mg/m2), 2,000–3,000 ml/m2/24 hours (dose-dependent). Mesna is given to prevent hemorrhagic cystitis. A urine test should be taken once a day.
  • With high-dose cytarabine, prednisolone eye drops are given to prevent chemical conjunctivitis during and for 2 days after a treatment. Temperature and CRP elevation caused by cytarabine are normal and are frequently drug-induced. Infection must be considered as a differential diagnosis. 
  • For high-dose methotrexate, it is important to have forced alkalinized diuresis (3000 ml/m2/day or more). Creatinine and serum concentration of methotrexate (MTX) should be monitored regularly. Calcium folinate "rescue" is given as described in the treatment plan depending on serum MTX. Furosemide is given as necessary.
  • For asparaginase, be prepared for anaphylaxis. Check urine 1-2 days per week and look for glucosuria and hyperglycemia. Be aware of the possibility of acute pancreatitis and thromboembolism.  
  • With etoposide, be prepared for anaphylaxis and hypotension.

NOPHO-ALL 2008 protocol

Induction treatment

Induction treatment consists of:

  • Prednisolone tablets for SR/IR induction or dexamethasone tabletsfor HR induction
  • Weekly vincristine intravenously
  • 2 doses of doxorubicin intravenously day 1 and day 22.
  • 1 dose of PEG-asparaginase intramuscularly toward the end of induction treatment.

Consolidation

Standard and intermediate risk

Consolidation treatment consists of:

  • Mercaptopurine tablets orally. In the NOPHO-ALL 2008 protocol, the patients are randomized to either a continuous low dose or 2 x dosage increases if blood values allow it. 
  • 2 vincristine doses intravenously
  • 4 doses of PEG asparaginase im in 2 week intervals
  • Intrathecal methotrexate is given together with all high-dose methotrexate courses.

Mercaptopurine treatment should be stopped if blood values are so low that an intravenous course must be postponed.  

Consolidation

High risk

Consolidation treatment consists of "block treatment" with very intensive combinations ofchemotherapy given over multiple days. Nine courses are given, blocks A-B-C-A-B-C-A-B-C. (spell out the abbreviated meds as this is the first usage) A FLAMSA block was an option for insufficient effect of course A and B, but has been excluded due to lack of available amascrine. After these courses, GCSF is given.

  • Block A consists of triple intrathecal day 1, cyclophosphamide 440 mg/m2 day 1-5, etoposide 100 mg/m2 day 1-5, PEG asparaginase day 6.
  • Block B includes dexamethasone and mercaptopurine orally, vincristine day 3 and 8, 5 g-MTX day 3, cytarabine 2 g/m2 x 2 day 7 and 8, triple intrathecal day 4, PEG asparaginase day 8.
  • Block C consists of triple intrathecal day 1, fludarabine 30 mg/m² days 2-6, cytarabine 2g/m² days 2-6, idarubicin 8 mg/m² days 2 and 4, PEG-asparaginase day 7. 

Delayed intensity

Standard and intermediate risk

This treatment block is given to the standard and intermediate risk groups. The intermediate risk group has two similar intensive phases separated from the "maintenance 1" period.

Treatment consists of:

  • Dexamethasone tablets orally weeks 1 and 3, with a pause during week 2, and a taper during week 4
  • 2 x methotrexate intrathecal
  • Weekly vincristine injection x 4
  • PEG asparaginase injection im every second week, x 4. Patients randomized to the experimental arm receive only 2 injections with a 4 week interval
  • Daunorubicin infusion weekly, only for intermediate intensity (x 4)
  • Cyclophosphamide 1 g/m2 starts week 4. 6 thioguanine tablets orally
  • Low dose cytarabine injections daily x 4 days during weeks 4 and week 5
  • Thioguanine orally daily starting week 4 for 2 weeks

Further treatment

Standard risk and intermediate risk

  • In both groups, maintenance 1 starts with oral mercaptopurine daily and methotrexate orally 1 x weekly. Special precautions apply. The medication should be taken in the evening with the goal to keep the white blood cell level at 1.5-3.5. The dose should be adjusted thereafter. The protocol includes guidelines for dosage changes for cytopenias, infections, liver side effects, etc. 
  • Re-induction courses every 4th week, alternating between high-dose MTX courses of  5g /m2 with it MTX (5 courses) and vincristine/dexamethasone (4-5 courses). The total is 9 and 10 courses respectively for IR/SR.
  • In addition PEG asparaginase im every 2nd week (every 4th week in patients randomized to the experimental arm).
  • After maintenance 1, the SR group follows "maintenance 2" (tablet only treatment with mercaptopurine and methotrexate po). This continues until cessation of treatment after 2.5 years from the time of diagnosis. 
  • The IR group receives "late intensity II." This is identical with the first late intensity, but without daunorubicin. The IR group then follows the same schedule as the SR group to "maintenance 2." Cessation of treatment occurs 2.5 years from the time of diagnosis.  

High risk group

After block treatment described under consolidation, HR patients start the maintenance program of oral chemotherapy mercaptopurine and methotrexate as for SR and IR. In addition, 3 high-dose methotrexate courses of 5g/m2 are given with 11 intrathecal injections, conventional methotrexate alternating with either cytarabine it or DepoCyte® (liposomal cytarabine) after randomization.

Thereafter, late intensity starts as described under SR/IR groups without daunorubicin.
Finally, "maintenance 2" starts and is the same as for SR/IR groups. Treatment continues for 2.5 years from the time of diagnosis.

Stem cell transplant

A small group of patients (estimated to be around 5 %) have a poor prognosis due to poor response. These patients are offered a bone marrow transplant with either related or unrelated donors if a compatible donor can be identified.

Criteria are:

  • ≥ 5% blasts in bone marrow (that is M2-3) on day 29
  • MRD ≥ 10-3 on day 79 (SR/IR) or after the second HR-block (HR)
  • pre-B ALL with white count ≥ 200 and poor MRD result day 29 and 79.

Preparation

Pending the diagnosis, an IV catheter is inserted as usual and fluid treatment is started, frequently with alkalinization (tumor lysis syndrome prophylaxis). During this phase, heart function is checked with echocardiogram (ultrasound, cardiotox) since treatment includes use of potentially cardiotoxic medications (doxorubicin, daunorubicin, idarubicin).

When a leukemia diagnosis is certain, a central vein catheter or venous port is placed. The first intrathecal injection is usually administered during the same general anesthesia.

The child and parents are informed about 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 the 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. There are often blood value requirements for starting new drugs. This is discussed in the protocol.

Before each course, the following is taken:

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

Implementation

Treatment duration

In the NOPHO ALL 2008 protocol, the treatment duration for all risk groups is 2½ years.

The treatment is conducted in cooperation with the University hospital and local pediatric units. All diagnostic testing and evaluations take place at the University hospitals, however, parts of the chemotherapy and supportive care are often taken over by local clinics.

Occasionally, children undergoing treatment for cancer must be attended to immediately as "open door" patients.


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, the local hospital, and regional hospital. 

The parents/guardian must observe the child at home and should contact the hospital immediately 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.
  • Lethargy
  • Poor appetite
  • Significant constipation
  • Pain

Common side effects from treatment for ALL

Nutrition

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. Leukemia patients rarely need tube-feeding to meet their nutritional needs. Steroids can lead to an increase in appetite and good nutritional guidance is important. 

Pain

Vincristine can cause neuromuscular manifestations. Pain often starts with sensory disturbances and paresthesia. Neural pain and delayed serious motor disturbances can occur with continued treatment. The neuromuscular side effects are muscle atrophy, loss of deep tendon reflexes, bone pain, jaw pain, and tracheal pain. Vincristine can also lead to drooping eyelids (ptosis). Side effects eventually disappear after cessation of the drug but may remain longer in some patients.   

Mucositis, in the mouth and other mucosal lining occurs when blood values are at the lowest. The degree of soreness is individual. The 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. Temperatures should not be taken rectally, nor should patients get suppositories, enemas, etc. during chemotherapy to avoid the risk of bleeding and infections.  

Constipation

Vincristine can lead to constipation and is treated prophylactically with laxatives.  

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. 

Gastritis

Because of large steroid doses, the child is susceptible to gastritis. The child should be treated prophylactically with ranitidine.  

Cardiotoxicity

Anthracyclines (doxorubicin, daunorubicin, idarubicin, mitoxantron) are cardiotoxic, especially in high cumulative doses and require monitoring with ECHO/Doppler before the first course and in other stages of the protocol. 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 tufts.
  • The child may become Cushingoid from taking steroids.

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 dramatic changes 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 may not be included in normal play. Finding a balance between protecting the child from infection and allowing him/her to live a normal life is difficult, since the child is susceptible to infection during the entire treatment period. The child should avoid crowds, for example shopping centers and 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. 

School-age children may go to school if they feel well enough. Otherwise, the child receives home-schooling. Younger children should not go to nursery school/kindergarten during treatment, or 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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