Acute lymphoblastic leukemia is a relatively rare disease in children, but it still represents the most frequent malignancy in this age group, 25% of all pediatric cancer cases. During the last few decades, prognosis has dramatically improved due to the use of risk-adapted treatment protocols, thus the malignancy being cured in 90% of patients.
Symptoms of pediatric acute lymphoblastic leukemia are caused either by the infiltration of the bone marrow or by invasion of extramedullary sites. Lymph nodes, spleen, testis and liver can be invaded by leukemic blasts, leading to the enlargement of these organs. Testicular enlargement in unilateral and painless. When bone marrow is replaced with cancer cells, it fails to produce normal blood cells, leading to anemia, neutropenia and thrombocytopenia. Therefore, patients will be pale and suffer from fatigability and opportunistic infections will find favorable ground. Many patients are febrile at the time they seek medical care. However, sepsis is an uncommon first presentation. Thrombocytopenia manifests itself as bleeding, bruising and, in severe cases, petechiae. In about 5% of patients, symptoms are confined to the bone system: bone or articular pain, leading to limping. In theses cases, the differential diagnosis is very wide, which leads to unwanted delay of the correct diagnosis .
Further symptoms depend on the nature of the abnormal invading cells. Mature B cells acute lymphoblastic leukemia is characterized by the presence of extra medullary masses located in the central nervous system, neck or abdomen, and symptoms are caused by compression of the neighboring structures. Cranial involvement patients present with nausea and vomiting, headache, lethargy or nuchal rigidity, but these signs are more frequently noted in mature B cell and T lineage disease . Cranial nerve palsy can also be encountered.
A mass effect can be caused by a mediastinal T-cell tumor, leading to the appearance of stridor and respiratory distress. The physician should keep in mind that this can lead to sudden respiratory arrest and order that the child be transferred to the Pediatric Intensive Care Unit, even if the diagnosis is not yet clear.
Workup of childhood acute lymphoblastic leukemia includes common and highly specialized tests. A complete blood cell count with differential and peripheral smear is useful because it can establish the peripheral presence of blasts. Extreme leukocytosis is seen in many cases, but this finding can be absent in aleukemic forms. Anemia and thrombocytopenia are frequently encountered and are caused by medullar failure. 20% of patients do not have peripheral blasts at the initial evaluation, instead they present with pancytopenia .
Uric acid, lactate dehydrogenase, potassium, calcium and phosphorus levels should be determined at the time of the first evaluation and during treatment, as they establish the presence of the tumor lysis syndrome. Increased D-dimer levels suggest disseminated intravascular coagulation. Cerebrospinal fluid analysis is necessary in order to determine whether the central nervous system is involved. A chest radiography is needed in order to assess the presence of mediastinal masses. Abdominal and testicular ultrasonography may be ordered if clinical examination suggests renal or testis involvement. An echocardiogram and an electrocardiogram are needed prior to anthracyclines administration and serial cardiology reevaluation should be performed during therapy.
The blasts lineage can be confirmed by performing flow cytometry. Much more detailed information is obtained from bone marrow aspirate analysis by immunohistochemistry and immunofenotyping. Blasts can express B-lineage–associated antigens like CD 79, CD 24, CD 22, CD 21, Cd 19 or CD14 or T-lineage–associated antigens, such as CD117, CD34, CD 33 or CD13.Cytogenetic and molecular studies can highlight the presence of chromosomal abnormalities in some cases: hypodiploidy, Philadelphia chromosome positivity or other translocations . Histological evaluation further divides patients into three categories: L1, L2 and L3, depending on blast morphology.
Childhood acute mature B-cell lymphoblastic leukemia therapy recognizes three phases: remission induction phase, intensification or consolidation phase and continuation therapy. The other types of the disease undergo other phases: components: induction, consolidation, interim maintenance, delayed intensification, and maintenance. The physician should keep in mind that the eye, testicle and central nervous system represent blast sanctuaries, where they can live on despite appropriate therapy in some cases and represent the relapse substrate. Therefore, special attention should be paid to these territories. After the induction phase is completed, remission should be achieved. This implies the fact that the bone marrow should contain less than 5% blasts. This is usually achieved by using vincristine, asparaginase, anthracyclines and glucocorticoids. Consolidation therapy is performed by administering 6-mercaptopurine, cyclophosphamide and cytarabine. Methotrexate and vincristine are given during interim maintenance for a period of 4 to 8 weeks. Delayed intensification is essential in high risk and very high risk patients, but is beneficial in all cases. Continuation therapy involves methotrexate, steroid pulses and vincristine administration. Mature B-cell childhood acute lymphoblastic leukemia treatment lasts for 6 to 8 months, whereas immature B-lineage and T-lineage disease necessitates 2-2.5 years of continuation therapy. Hematopoietic stem cell transplant is a needed in certain cases.
Prognosis of acute lymphoblastic leukemia patients depends on several parameters, such as age at the time of diagnosis, type of leukemic cells and their gene characteristic and white blood cell count. T cell leukemia has a poorer prognosis . Risk stratification (low, standard, high or very high) is very important and the physician should begin thinking about it as soon as possible, even before treatment begins, because it dictates the appropriate therapeutic regime . The risk of the patient becomes more clear after treatment has begun, because response to the induction chemotherapy and minimal residual disease burden are additional parameters.
A patient is considered to have standard risk if they are aged 1 to 9.9 years, have initial white blood cell count below 50.000 per cube millimeter at presentation, respond well to induction therapy and do not have unfavorable cytogenetic features. The white blood cell count reflects tumor burden and high numbers are associated with a greater risk of relapse, as are the presence of a mediastinal mass and severe hepatosplenomegaly. After therapy is initiated, standard risk patients respond well: 8 days into the therapeutic regimen, blast number will decrease to less than 1% in peripheral blood and 21 day later, less than 0.01% blasts will be encountered in the bone marrow. Low-risk patients have even better responses to therapy and less than < 0.01% blasts present in both days 8 and 29 and favorable cytogenetic traits (trisomy 4 or 10). Unfavorable cytogenetics is considered to be the presence of the Philadelphia chromosome, of IKZF1 alteration , of Janus kinase mutations  or that of hypodiploidy and they define very high risk patients. High-risk patients may also have poor responses to therapy or extra medullary involvement. Infants also have poor outcomes . Unfavorable outcomes are signaled by the presence of blasts and red blood cells, but not of increased white blood cells numbers in the cerebrospinal fluid . These patients should receive additional intrathecal chemotherapy and dexamethasone based regimens .
Modern therapy has improved five-year survival rates and 5-year event-free survival and cure rates in all risk groups . Infants, especially those from low income countries, still have the worse prognosis, probably due to suboptimal supportive measures, but also because of the delayed diagnosis and therapy , while low risk patients have a 5-year event-free survival rate of 95%. Girls have a superior event free survival rate compared to boys.
Prognosis is also influenced by long term and short term complications. Acute events may include bleeding, thrombosis, renal failure, sepsis, encephalopathy, seizures, typhlitis, renal failure and tumor lysis syndrome, all of which can be addressed, but need to be actively diagnosed. Even after the disease is considered to be cured, the patients needs periodical evaluation, because they are prone to develop a secondary malignancy or experience late effects of therapy, such as learning disability or cognitive defects in those that have received cranial irradiation [2 ]. Malignant brain tumors occur 6 to 30 times more often in these patients .
Studies have highlighted the presence of a peak regarding the childhood incidence of acute lymphoblastic leukemia: the ages of 2 to 5 years old. The worldwide incidence of this disease is considered to be 3.7-4.9 cases per 100,000 children aged 0 to 14 . The numbers may be slightly lower in low-income countries , but this can be due to reporting and diagnosing difficulties. Hispanic and Caucasian children are more often affected than black patients. A slight male predominance has been observed by many studies .
Acute childhood lymphoblastic leukemia is characterized by aberrant clonal expansion of a genetically altered lymphoid progenitor. Lymphoblastic cells invade bone marrow and lead to medullar failure with potentially dramatic consequences and extra medullary sites, such as the central nervous system, testis, liver, spleen and lymph nodes. Relapse after treatment is caused by the selection of a resistant clone .
Since the etiology of childhood acute lymphoblastic leukemia remains unclear, prevention methods for the disease itself have not yet been established. However, when a child is diagnosed with conditions that are known to be frequently associated with this condition, such as Down and Whiskott-Aldrich syndromes, the parents should be informed about their increased risk and need for active surveillance.
Childhood acute lymphoblastic leukemia patients are immunocompromised by their disease and by the therapy they receive. Therefore, infectious complications such as Pneumocystis carinii pneumonia should be avoided by trimethoprim- sulfamethoxazole or pentamidine administration. Candidiasis can be prevented using fluconazole. Tumor lysis syndrome complications are partially prevented by appropriate hidratation and urine alkalinization. Allopurinol can prove effective in preventing hyperuricemia.
Acute lymphoblastic leukemia is the most frequent of childhood malignancies. Patients complain about various symptoms, caused by leukemic infiltration of the bone marrow or of extramedullary sites. Bone marrow failure manifests as signs of anemia (tiredness, paleness), thrombocytopenia (bruising, bleeding or petechiae) or neutropenia (fever and infection). Other manifestations include bone pain and arthritis, hepatomegaly, splenomegaly, lymphadenopathy, extramedullary masses located in the abdomen (compression of neighboring structures), mediastinum (respiratory distress), neck or head (headache, lethargy or vomiting). Testicular involvement manifests as unilateral testis enlargement.
The type of the acute lymphoblastic leukemia can only be established after immunologic and genetic examination of the blasts. Immunofenotyping, cytogenetic and molecular studies are also useful. Lumbar puncture is useful in assessing central nervous system involvement, whereas bone marrow aspiration and biopsy are needed to evaluate medullar status at the time of diagnosis. Chest radiographies are used when the presence of mediastinal masses is suspected. Testicular and renal disease can be diagnosed by ultrasonography. An echocardiogram is needed prior to anthracyclines administration and during treatment.
Treatment consists of different chemotherapy regimens, depending on leukemic subtype. Most protocols include a remission-induction phase, a intensification or consolidation phase and a continuation phase. Central nervous system disease needs aggressive therapy with intrathecal administration. Supportive therapy includes antibiotics, antifungals and blood transfusions. Hematopoietic stem cell transplant is a valid option in selected cases.
Childhood acute lymphoblastic leukemia is a type of cancer that involves the bone marrow and the blood. Normal cells in the bone marrow are replaced by leukemic cells. Thus, the body cannot fight infection, there's anemia and easy bleeding. Patients complain about fever, bone or joint pain, the presence of lumps in the underarm or neck, weakness, unilateral enlargement of testis and loss of appetite.
In order to establish the diagnosis, the physician will conduct a history inquiry and physical examination, will order several types of blood tests, will perform a bone marrow aspiration and biopsy and a lumbar tap if needed. Chest X-rays, abdominal, pelvic, testicular and cardiac echography may also be needed. Specific diagnosis methods include cytogenetic analysis and immunofenotyping.
Treatment consists of chemotherapy administration for a long period of time. Prognosis is good in more than 80% of patients, but even after the leukemia is gone, the patient needs to be monitored because secondary malignancies can occur.