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Childhood Acute Lymphoblastic Leukemia: An Overview see photo
Cancer accounts for 10 percent of childhood deaths in the United States, and is the second leading cause of childhood deaths after accidents. Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, and accounts for almost 25% of childhood cancers.

Each year in the U.S. there are approximately 2,400 children and adolescents younger than 20 years of age diagnosed with ALL. It is 30% more common in boys than girls, and about twice as common in white children than in black children. There is a sharp peak in ALL incidence among children ages 2 to 3 years. Due to a number of advances in the treatment of ALL during the past 20 years, the survival rate of children treated for this disease is now approaching 80 percent.

WHAT IS CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA?

The term leukemia is derived form the Greek words leuk, white - and emia, blood. Leukemia was first identified by researchers Virchow and Bennet in 1845.
Childhood acute lymphoblastic leukemia (ALL) is a disease in which too many underdeveloped, infection fighting, white blood cells (lymphoblasts) are found in the blood, bone marrow, and lymphoid tissues.
These precursor cells (lymphoblasts) crowd out the other cells in the blood and bone marrow - resulting in red blood cell anemia, bleeding problems, and infections.

WHAT CAUSES CHILDHOOD ALL?
In most cases the cause of childhood ALL is unknown. The most popular theory is that ALL develops from a single, mutant lymphoid precursor cell.
It has been shown that hereditary factors do play a role in the development of leukemia. Many cases of childhood ALL start prenatally, and become fully malignant after birth.
Possible causes of ALL include: ionizing radiation (x-rays), industrial chemicals such as benzene, and other environmental factors.
About 5% of ALL cases are associated with: Down syndrome, Bloom syndrome, ataxia telangiectasia, and congenital immunodeficiency.
Most leukemias begin in the spongy tissue inside the large bones of the body (bone marrow), and spread to other parts of the body.

WHAT ARE THE SIGNS AND SYMPTOMS OF CHILDHOOD ACUTE ALL?
The first symptoms of ALL may be similar to those of the flu or other common viral infections. The symptoms include: fever, lack of appetite, weight loss, weakness, and aching bones. Fever and infections may be due to a decrease in the number of infection-fighting neutrophils (neutropenia). Fatigue and pallor are due to anemia. Bone pain is due to an excess number of blast cells in the bone marrow (blast cell hyperplasia).
Physical signs include: enlargement of the lymph nodes (lymphadenopathy), and enlargement of the liver and spleen (hepatosplenomegaly).
Other signs include: abnormal bleeding, small points of bleeding (petechiae), black-and-blue areas on the body (ecchymosis), and bleeding inside of the mouth. These bleeding problems are due to a lower than normal number of platelets (thrombocytopenia).

WHAT INITIAL TESTS ARE USED TO DIAGNOSE ALL?
The initial blood tests used to diagnose leukemia are: a complete blood count (CBC) with a white blood cell differential and a reticulocyte (immature red blood cell) count. These tests count the number of each of the different kinds of cells in the blood. The likelihood of leukemia is high if the blood tests show anemia, especially when accompanied by: reticulocytopenia, leukopenia, or thrombocytopenia.
The presence of an excessive percentage of blast cells (immature cells) indicates the presence of leukemia.
If the results of the blood tests are not normal, a bone marrow biopsy may need to be performed. A spinal tap may also need to be done.

METHODS OF TREATMENT FOR ALL:
The primary treatment for ALL is chemotherapy. Chemotherapy drugs may be administered by mouth, intravenously, or intramuscularly. Intrathecal therapy occurs when drugs are administered into the fluid that surrounds the brain and spinal cord.
The first treatment for childhood leukemia was developed by Farber and his colleagues in the late 1940's. The first chemotherapy protocol employed aminopterin, which is a folic acid antagonist.
Radiation therapy is used in certain cases. X-rays or other high-energy rays can be used to kill cancer cells.
Bone marrow transplantation is used in high risk cases. First, all of the bone marrow is destroyed using chemotherapy and possibly radiation. Next, healthy bone marrow from a well-matched donor is given to the child undergoing treatment. This donated marrow replaces the marrow that was destroyed by ablative therapy. Bone marrow that is taken from another person is called allogenic bone marrow.

PROGNOSIS:
A child's chances for recovery depends on the following factors: the age at diagnosis, the white blood cell count at diagnosis, how far the disease has spread, the characteristics of the leukemia cells, and the response to treatment.
The biggest obstacle to curing children with ALL is relapse in the bone marrow and/or relapse elsewhere, such as in the central nervous system or testes. Relapse from remission can occur during therapy, or after completion of therapy.

THREE PHASES OF TREATMENT FOR ALL:
Treatment for childhood acute ALL is divided into three phases: remission induction, consolidation with CNS prophylaxis, and maintenance treatment.

PHASE I - REMISSION INDUCTION:
This first phase is a 1-month schedule of chemotherapy whose goal is the reduction in the number of harmful blast cells in the bone marrow down to 5% or less.
The goal is the rapid restoration of normal bone marrow function.
The chemotherapy drugs used include: vincristine, dexamethasone, and L-asparaginase.
In some cases, a bone marrow transplant (with allogenic hematopoietic stem cells) is needed for children who have the Philadelphia chromosome, or other high-risk factors.

PHASE II - CONSOLIDATION WITH CNS PROPHYLAXIS:
This second phase of treatment is comprised of several additional courses of chemotherapy designed to eradicate any residual leukemia cells - especially those hiding in the central nervous system and the brain.
Radiation therapy to the brain may also be used in addition to chemotherapy.

PHASE III - MAINTENANCE TREATMENT:
This final phase of therapy continues for approximately 2 to 3 years, and uses chemotherapy to maintain the remission.
The chemotherapy drugs used during this third phase include: methotrexate and 6-mercaptopurine. Pulses of dexamethasone are often added to the standard maintenance regimen.

SOME LONG-TERM COMPLICATIONS OF TREATMENT:
Some long-term, life-threatening complications of treatment include: cirrhosis of the liver due to hepatitis C, and cardiomyopathy due to the chemotherapy agent anthracycline.
Other long-term complications include: obesity, osteopenia, reproductive problems, eye disorders, thyroid-related disorders, and oral/dental problems.

Parents, patients, and clinicians are referred to http://cancernet.nci.nih.gov for comprehensive information on cancer and leukemia. In addition, the National Cancer Institute can be contacted at 1-800-4-CANCER for more information.

An article in The Journal of Family Practice reviewed the challenge of providing health care for children who have survived childhood acute ALL. The article discussed some of the late effects caused by leukemia treatment including: cirrhosis of the liver, heart problems caused by chemotherapy, cognitive disorders, blood disorders, reproductive problems, eye problems, oral problems, and thyroid problems.

Oeffinger KC, et al.: Providing primary care for long-term survivors of childhood acute lymphoblastic leukemia. J Fam Pract December 2000; 49:1133-1146.

Oral And Craniofacial Complications Of Childhood Leukemia Treatment see photo
Each year in the U.S. there are approximately 2,400 children and adolescents, younger than 20 years of age, who are diagnosed with childhood acute lymphoblastic leukemia (ALL). Due to a number of advances in the treatment of ALL during the past 20 years, the survival rate of children treated for this disease is now approaching 80 percent.

Neither chemotherapy nor radiotherapy differentiates between normal and malignant cells. The result is that the treatment for leukemia causes both oral and craniofacial complications. Oral problems may make it difficult for a child to receive all of his or her cancer treatment. For many leukemia patients, the oral complications are very painful and have potentially lethal consequences. Sometimes, the leukemia treatment must be stopped completely.

HOW DOES THE ORAL CAVITY PROTECT ITSELF DURING HEALTH?
The “nonspecific” oral defense system includes: the inside lining of the mouth (mucosa), the cleansing effect of the normal salivary flow, the protective components of the saliva (enzymes, defensins, cytokines, protegrins), and the protective effect of the normal oral microflora. The “nonspecific” defense system also includes: the rapid regeneration of the inside lining of the mouth – which functions to shed harmful or infectious microorganisms.
The “specific” oral defense system includes salivary antibodies, especially secretory IgA. IgA protects the mouth by clumping microorganisms together – thereby preventing their adherence to the mucosa. The lower the concentration of IgA in the saliva, the greater the severity of periodontal problems.

WHAT CAUSES ORAL AND CRANIOFACIAL COMPLICATIONS OF LEUKEMIA TREATMENT?
Cancer treatment has a toxic effect on normal cells, as well as on cancer cells. The mouth is especially affected because its cells are replaced at a high rate. Chemotherapy and radiation therapy affect the ability of cells to divide – which creates big problems for the normal tissue repair process in the mouth.
Chemotheraputic agents work by affecting the rapidly dividing cells of the target tumor. These drugs also affect the protective mucosal lining of the oral cavity, the oral microbial balance, and the healing response of the oral cavity.
Toxic changes to the oral mucosa develop when destruction of the basal cells of the epithelium exceeds the growth (proliferation) of new cells. These toxic changes result in stomatitis – which is an inflammation of the oral mucosa. Some of the highly stomatotoxic, chemotheraputic agents include: methotrexate, mercaptopurine, 5-fluorouracil, and bleomycin.
Oral and craniofacial complications are a result of the following: the effect of chemotheraputic agents on the bone marrow; the direct cytotoxic effects on the mucosal lining of the oral cavity; the tissue changes associated with total body radiation and radiation to the head and neck; the body’s response to allogenic bone marrow transplantation and the associated immunosuppression during therapy; and the side-effects of drugs other than the anti-neoplastic drugs.
Chemotheraputic agents also affect the hemopoietic cells of the bone marrow, and decreases the number of neutrophils – all of which raises the risk of oral infection and immunosuppression.
The peak age of chemotherapy treatment for childhood leukemia occurs between 2 and 3 years of age, and coincides with a critical period for dental and craniofacial growth and development in children.

WHAT ARE THE COMPLICATIONS CAUSED BY CHEMOTHERAPY?
The most common oral problems are: inflammation of the mucous membranes of the mouth; infection and suppression of leukocyte formation; problems with sense of taste; pain; dry mouth; and weakness of the immune system.
Mucositis is the inflammation of the oral lining of the mouth (the mucosa) - along with redness, loss of the epithelial barrier, and ulceration.
For many patients, mucositis is the worst part of cancer treatment. Oral mucositis may appear from 4 to 7 days after the initiation of chemotherapy. Mucositis most commonly affects the soft (nonkeratinized) oral mucosa - including the soft palate, oropharynx, buccal and labial mucosa, floor of the mouth, and the underside (ventral) and lateral surfaces of the tongue. Complete resolution of mucositis occurs seven to fourteen days after its onset.
A dramatic decrease in the amount of salivary immunoglobulins IgA and IgG occurs.
A dramatic decrease in the number of infection-fighting neutrophils. As a result, oral infections are common.
Fungal (candida) infections of the oral mucosa are common, and can cause a burning sensation, distortion of taste, and problems with swallowing.
Viral infections, especially the reactivation of herpes simplex virus type I (HSV-1), are serious because they can cause pain and problems with hydration and nutrition.
Spontaneous oral bleeding is due to a cytotoxic, drug-induced, decrease in the number of platelets (thrombocytopenia). This dramatic decrease in platelets leads to spontaneous oral bleeding when the platelet count goes below 20,000 per cubic mm.
The cells which form dentin (the odontoblasts), and the cells which form enamel (the ameloblasts), can be damaged by chemotherapy agents if these cells are in a susceptible phase of their cell cycle (the M or S stage). The end result may be teeth which have short, thin, tapered roots, or hypomineralized or hypomature enamel.

WHAT ARE THE COMPLICATIONS CAUSED BY RADIATION THERAPY?
Radiation damages the blood vessels, cartilage, salivary glands, bone, and muscles of the neck and jaw. This results in exposed bone, tissue breakdown, pain, and tissue death (necrosis).
Mucositis occurs when doses of radiation greater than 180cGy/day are given 5 days per week.
When radiotherapy in adolescents is directed at the salivary glands, the most immediate effect is oral dryness (xerostomia), caused by damage to the salivary glands. The parotid gland then produces only thick, ropy saliva - after two or three doses of irradiation of 200cGy/dose. Irreversible salivary gland injury occurs when the radiation dose exceeds 5,000cGy.
Direct radiation of the jaw, face, and head produces the most serious side effects in children, because they are growing and developing so rapidly. Head and neck radiation in children may cause incomplete development of the jaws, the bone around the eyes (the orbits), and the facial skeleton. These complications are due to damage to the cartilaginous growth centers.
Head and central nervous system irradiation may interfere with normal craniofacial development. This is because radiation directed at the hypothalamus and pituitary glands will affect their function – resulting in decreased production of Growth Hormone and Thyroid-Stimulating Hormone.
Head and neck radiation in children may cause arrested tooth development, which causes: small teeth (microdontia), wasting-away (atrophy) of the overlying soft tissue, enamel malformation (hypoplasia), incomplete calcification of teeth, and arrested root development. Teeth with arrested root development have roots with severe tapering and narrowing, and blunting of the apex.

WHAT ARE THE COMPLICATIONS CAUSED BY BONE MARROW TRANSPLANTATION?
The “pre-transplant” protocol includes chemotherapy and/or radiotherapy. Both of these can cause undesirable oral and craniofacial effects. The effects include graft-versus-host-disease (GVHD), xerostomia, infections, and late dental and craniofacial abnormalities.
Children undergoing an allogenic bone marrow transplant (BMT) often develop GVHD, in which the transplanted T-lymphocytes recognize the child’s body as foreign, and attack it. The oral cavity may be the first or only site showing GVHD.
An increasing level of xerostomia and/or generalized stomatitis which appears 100 or more days after the BMT are indications of chronic GVHD. Xerostomia may be present as long as 6 to 8 months after the BMT.
Chronic GVHD causes oral infections after 100 days post-BMT. These opportunistic infections are facilitated by: xerostomia, long-term steroid or antibiotic use, and systemic immunosuppression. The oral infections include: periodontal infections, dental abscesses, herpes simplex infections, cytomegalovirus infections, and candida infections.
The younger the child, the greater the risk for craniofacial and dental developmental abnormalities. Children who receive total body irradiation have more severe problems with dental development than those who receive only chemotherapy.

Parents, patients, and clinicians are referred to http://cancernet.nci.nih.gov for comprehensive information on cancer and leukemia. In addition, the National Cancer Institute can be contacted at 1-800-4-CANCER for more information.

A recent case report in the Journal of the American Academy of Pediatric Dentistry described the orthodontic treatment of an adolescent who had been previously treated for acute lymphoblastic leukemia. The young patient had teeth whose roots were shortened throughout the mouth, especially in the lower jaw. The authors concluded that the shortened dental roots were probably caused by chemotherapy and radiation therapy, which the patient received during early childhood. The authors were concerned about causing further root resorption during orthodontic treatment. No significant root resorption occurred during orthodontic treatment, however.

Runge ME, Edwards DL: Orthodontic treatment for an adolescent with a history of acute lymphoblastic leukemia. Pediatric Dentistry. Nov-Dec 2000. 22(6):494-498.

Management Of The Oral Complications Of Leukemia Treatment In Children see photo
The greatest challenge for young patients may be dealing with the oral complications of leukemia treatment. The oral complications are very painful and have potentially lethal consequences. Up to 90 percent of children undergoing leukemia treatment may suffer oral complications. The complications occur because neither chemotherapy nor radiotherapy differentiates between normal and malignant cells. Oral problems may make it difficult for a child to receive all of his or her cancer treatment. Sometimes, the leukemia treatment must be stopped completely.

The severity of oral complications can be greatly reduced when an aggressive approach to oral care is taken prior to leukemia treatment. Elimination of pre-existing dental problems, as well as good oral hygiene during leukemia therapy can reduce the occurrence and severity of oral complications. Managing the oral complications is therefore important for the young patient’s well-being.

MANAGEMENT OF ORAL COMPLICATIONS:
Oral management before leukemia treatment.
Oral management during leukemia treatment.
Oral hygiene during leukemia treatment.
Emergency dental care during leukemia treatment.
Oral management after bone marrow transplantation.
Oral management after completion of leukemia treatment.

ORAL MANAGEMENT BEFORE LEUKEMIA TREATMENT:
At least one month prior to initiation of leukemia treatment, all children should be evaluated by either a general dentist or pediatric dentist. During this evaluation, the dentist will note the health status of the oral cavity, identify any potential oral problems, and plan for treatment which may reduce oral complications during and after cancer therapy.
A panoramic radiograph should be attempted in all children who can cooperate before cancer treatment is started.
Oral hygiene and dental rehabilitation should be as aggressive as possible before cancer treatment is started, especially when a bone marrow transplantation is planned. Dental treatment should only be provided after consultation with the child’s oncologist
The dentist should treat existing dental problems in a manner which will decrease the risk of oral complications later. The dentist will extract teeth which: have acute or chronic infection, are mobile, or grossly carious. Pulpotomies and pulpectomies should not be performed on primary teeth, due to possible treatment failure and subsequent infection. Ideally, all extractions should be completed 10 days prior to the initiation of cancer treatment.
Orthodontic appliances, braces, removable retainers, and space maintainers should be removed prior to cancer treatment.

ORAL MANAGEMENT DURING LEUKEMIA TREATMENT:
The child should rinse with cold sterile water, or cold normal saline as often as possible, but at least 6 times a day. This will: keep the oral tissues clean and wet, help with the removal of thick saliva, remove debris, and decrease the risk of opportunistic infections.
An effective way to increase the child’s comfort during leukemia treatment is to encourage the intake of popsicles, ice chips, and icy drinks.
Lip moisturizer should be used, and it should be water or lanolin based. It should be applied with a cotton tip applicator several times each day.
Young patients should also rinse and spit with water after episodes of vomiting or emesis. This will prevent stomach acids from decalcifying the teeth and irritating the oral tissues. To control persistent nausea, the dentist or physician may need to prescribe Ondansetron (Zofran).
A good dietary management program should encourage the intake of: bland, non-acidic foods with a high moisture content ( ice-cream, popsicles, milk shakes, custard, cream soups, mashed potatoes, Carnation Instant Breakfast, and puree foods).
Chlorhexidine rinses are not recommended for children because: they contain alcohol, desiccate the oral tissue, and have an unpleasant taste.
The daily use of topical fluoride gel is contraindicated in children under six years of age because of the increased risk of fluorosis.
Fungal infections, such as candida, need to be treated aggressively. Fluconazole (Diflucan) is often prescribed for fungal infections related to cancer treatment.
All mucositis lesions should be biopsied for the presence of Herpes Simplex Virus, unless the child is already taking Acyclovir (Zovirax).

ORAL HYGIENE DURING LEUKEMIA TREATMENT:
The child should rinse with cold sterile water, or cold normal saline as often as possible, at least 6 times a day. This will keep the oral tissues clean and wet, help with removal of thick saliva, remove debris, and decrease the risk of opportunistic infections.
The child should brush with a soft toothbrush after every meal. Toothbrushing should be done under the supervision of hospital staff to ensure that it is being done safely. Sponges or foam toothettes are not recommended because they are not effective in removing plaque and debris; the use of toothettes is a last resort.
Brushing should be discontinued when the platelet count is less than 20,000 per cubic mm, or when the absolute neutrophil count is less than 500 per cubic mm. Below these levels, dental hygiene should be performed using only a moist gauze or spongy toothette.
Children under 3 years of age should use a Baby Tooth Cleanser instead of toothpaste. Children older than 3 should use a non-tartar control, non-peroxide, flavor-free children’s fluoridated toothpaste.
Hydrogen peroxide rinses are not recommended because they may delay wound healing and cause drying of the mucosa.

EMERGENCY DENTAL CARE DURING LEUKEMIA TREATMENT:
All emergency dental procedures should be performed after consultation with the pediatric oncologist.
Appropriate timing of dental procedures is critical, since the peripheral white blood cell counts change dramatically during chemotherapy. The risk of infection is greatest when the child’s neutrophil count reaches a low point, generally 7 to 10 days after induction therapy.
Dental treatment should only be performed if the absolute neutrophil count (ANC) has improved and exceeds 1,000 per cubic mm, and if the platelet count (at least 50,000 per cubic mm) and function are adequate.
Dental surgical procedures, as well as administration of local anesthetic blocks should be avoided during periods of thrombocytopenia. Clotting factors should be normal. A platelet transfusion may be needed if the platelet count is less than 50,000 per cubic mm.
Prophylactic antibiotic coverage should be provided according to the American Heart Association’s recommendations, and in consultation with the child’s oncologist.
Some of the circumstances requiring prophylaxis: when chemotherapy is delivered through a vascular access device, such as a central venous catheter or Hickman line; when the child has an ANC of less than 1,000 per cubic mm and/or the WBC count is less than 2,000 per cubic mm; when the child is on long-term immunosuppressive drugs, such as cyclosporine or prednisone.
All patients who have a central line must have antibiotic coverage according to the American Heart Association’s guidelines before undergoing dental procedures that are likely to cause bleeding or bacteremia. The dentist may need to provide extra antibiotic coverage even if the child is already taking prophylactic antibiotics.

ORAL MANAGEMENT AFTER BONE MARROW TRANSPLANTATION:
Children who have received a BMT may not be able to undergo any dental procedures for up to one year after the procedure, due to the profound impairment of the immune function and Graft Versus Host Disease.
Before providing any dental treatment for BMT patients, the dentist should at least be aware of the child’s platelet count and the absolute neutrophil count. The child’s oncologist must also be consulted.
Elective dental work should be deferred when the ANC is less than 1,000 per cubic mm, due to the increased risk of developing an infection. The severity of infection is inversely related to the number of neutrophils, since they are the body’s first line of defense.

ORAL MANAGEMENT AFTER COMPLETION OF LEUKEMIA TREATMENT:
The child should have a dental recall appointment every 3 months for the first year after treatment, and every 6 months thereafter.
During the dental recall visits, the dentist should review the latest blood laboratory studies to determine if the child’s hematologic status has returned to normal.
The dentist should inform the parents about the possible long-term side-effects of cancer treatment on the teeth, oral mucosa, and craniofacial complex.
If radiation therapy was directed at the head or neck region, the dentist should consult with the radiation oncologist before performing any dental extractions or osseous surgery. A panoramic radiograph should be attempted in all children who can cooperate, especially if the BMT was performed prior to 7 years of age.

A previous article entitled: “Oral And Craniofacial Complications Of Childhood Leukemia Treatment” may be accessed at http://kidsdental.tsx.org

Parents, patients, and clinicians may obtain additional information on this topic from the National Cancer Institute at 1-800-4-CANCER, or by visiting their web site at http://cancernet.nci.nih.gov

A recent article in General Dentistry reviewed pretreatment oral care, treatment of oral complications, and the need for continuing oral care after the completion of cancer therapy.

Massler CF: Preventing and treating the oral complications of cancer therapy. General Dentistry. Nov-Dec 2000. 48(6) 652-655.

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