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Childhood Acute Lymphoblastic Leukemia

ALL in Childhood

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.


Presentation

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 [1].

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 [2]. 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.

Additional complaints refer to the gastrointestinal system and consist of anorexia and weight loss. These are encountered in almost one third of patients.

Easy Bruising
  • Signs and symptoms may include fever; easy bruising or bleeding; bone or joint pain; painless lumps in the neck, underarm, stomach, or groin; weakness; fatigue; and/or loss of appetite.[rarediseases.info.nih.gov]
  • Acute lymphoblastic leukemia is usually diagnosed because patients have signs and symptoms of leukemia including fatigue, weight loss, bleeding, easy bruising or unexplained infections.[news.cancerconnect.com]
  • Symptoms of ALL include: Frequent infections Fever Easy bruising Bleeding that is hard to stop Flat, dark-red skin spots (petechiae) due to bleeding under the skin Pain in the bones or joints Lumps in the neck, underarm, stomach or groin Pain or fullness[stjude.org]
  • Symptoms include: Bone and joint pain Easy bruising and bleeding (such as bleeding gums, skin bleeding, nosebleeds, abnormal periods) Feeling weak or tired Fever Loss of appetite and weight loss Paleness Pain or feeling of fullness below the ribs from[medlineplus.gov]
  • These include: being very tired, weak, or pale swollen lymph nodes infections (like bronchitis or tonsillitis) that keep coming back a fever night sweats easy bruising or petechiae (tiny red spots on the skin caused by easy bleeding) bone and joint pain[kidshealth.org]
Splenomegaly
  • The child redeveloped splenomegaly and fever, and then suffered an acute decompensation with hypoxemia, tachypnea, splenomegaly, and cardiac gallop. Open-lung biopsy revealed lymphomatoid granulomatosis.[ncbi.nlm.nih.gov]
  • 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[symptoma.com]
Fever
  • We report a case of a 3 years old boy who presented with prolonged fever, nausea, vomiting and increasing lower limbs pain. Skeletal X-rays and CT scan showed severe osteolytic lesions of the skull and extremities.[ncbi.nlm.nih.gov]
  • The child redeveloped splenomegaly and fever, and then suffered an acute decompensation with hypoxemia, tachypnea, splenomegaly, and cardiac gallop. Open-lung biopsy revealed lymphomatoid granulomatosis.[ncbi.nlm.nih.gov]
  • Abstract A 2 years old male child was admitted in Dhaka Shishu Hospital with one month history of fever, swelling and pain in joints of right leg.[ncbi.nlm.nih.gov]
  • They include: Fatigue Fever Loss of appetite or weight Night sweats Many symptoms of acute lymphoblastic leukemia are the result of a shortage of normal blood cells. That's because leukemia cells crowd out these normal cells in the bone marrow.[webmd.com]
  • Risk of assisted mechanical ventilation, need for insulin, pseudocysts, or death was associated with older age (median ages for patients with vs without complications 10.5 vs 6.1 years, P .0001) and with having one or more vs no affected vital signs (fever[ascopost.com]
Weakness
  • NFKB relative expression levels, in comparison to the GSK-3β immunohistochemistry results of the bone marrow samples, showed significant differences between positive and negative cases (p 0.001) and between weak-positive and negative cases (p 0.002).[ncbi.nlm.nih.gov]
  • Abstract Muscle weakness is one of the most serious problems during chemotherapy for childhood hematological malignancies. It may be caused by long-term hospitalization, unfavorable physical conditions, and restricted activities.[ncbi.nlm.nih.gov]
  • A shortage of red blood cells may cause symptoms of anemia , including: Fatigue or weakness Dizziness Feeling cold Light-headedness Shortness of breath A shortage of normal white blood cells may result in: Fevers Recurring infections A shortage of blood[webmd.com]
  • Signs and symptoms may include fever; easy bruising or bleeding; bone or joint pain; painless lumps in the neck, underarm, stomach, or groin; weakness; fatigue; and/or loss of appetite.[rarediseases.info.nih.gov]
  • 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.[symptoma.com]
Fatigue
  • In female survivors, fatigue was associated with poor executive function (r 0.41; P .02), processing speed (r 0.56; P .001), and attention (r 0.36-0.55; P .05).[ncbi.nlm.nih.gov]
  • They include: Fatigue Fever Loss of appetite or weight Night sweats Many symptoms of acute lymphoblastic leukemia are the result of a shortage of normal blood cells. That's because leukemia cells crowd out these normal cells in the bone marrow.[webmd.com]
  • Long-Term and Late Effects of Treatment Some side effects of cancer treatment, such as fatigue, can linger for months or years after therapy.[lls.org]
  • Signs and symptoms may include fever; easy bruising or bleeding; bone or joint pain; painless lumps in the neck, underarm, stomach, or groin; weakness; fatigue; and/or loss of appetite.[rarediseases.info.nih.gov]
  • Acute lymphoblastic leukemia is usually diagnosed because patients have signs and symptoms of leukemia including fatigue, weight loss, bleeding, easy bruising or unexplained infections.[news.cancerconnect.com]
Weight Loss
  • Additional complaints refer to the gastrointestinal system and consist of anorexia and weight loss. These are encountered in almost one third of patients. Workup of childhood acute lymphoblastic leukemia includes common and highly specialized tests.[symptoma.com]
  • Both leukemia itself and the treatment can lead to many problems such as bleeding, weight loss, and infections. Call your provider if you or your child develops symptoms of ALL.[medlineplus.gov]
  • Acute lymphoblastic leukemia is usually diagnosed because patients have signs and symptoms of leukemia including fatigue, weight loss, bleeding, easy bruising or unexplained infections.[news.cancerconnect.com]
  • loss a purple skin rash (purpura) In some cases, the affected cells can spread from your bloodstream into your central nervous system.[nhs.uk]
Abdominal Obesity
  • Fine-motor processing speed was slower in adult survivors with dyslipidemia (P 0.04) and abdominal obesity (P 0.04). Poorer attention was marginally associated with hypertension (P 0.06).[ncbi.nlm.nih.gov]
Dyspnea
  • PATIENT AND METHODS: An 11-year-old boy had a cough and exertional dyspnea 34 months after an initial diagnosis of ALL and 10 months after completion of therapy. Imaging studies revealed a large left pleural effusion.[ncbi.nlm.nih.gov]
Respiratory Distress
  • A mass effect can be caused by a mediastinal T-cell tumor, leading to the appearance of stridor and respiratory distress.[symptoma.com]
Vomiting
  • We report a case of a 3 years old boy who presented with prolonged fever, nausea, vomiting and increasing lower limbs pain. Skeletal X-rays and CT scan showed severe osteolytic lesions of the skull and extremities.[ncbi.nlm.nih.gov]
  • 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.[symptoma.com]
  • […] cells are present, other symptoms may include: A full or swollen belly from leukemia cells in the liver or spleen Enlarged lymph nodes such as in the neck or groin, under arms, or above the collarbone Bone or joint pain Headache , trouble with balance, vomiting[webmd.com]
  • This can cause a series of neurological symptoms (related to the brain and nervous system), including: headaches seizures (fits) vomiting blurred vision dizziness When to get medical advice If you or your child has some or even all of the symptoms listed[nhs.uk]
Loss of Appetite
  • They include: Fatigue Fever Loss of appetite or weight Night sweats Many symptoms of acute lymphoblastic leukemia are the result of a shortage of normal blood cells. That's because leukemia cells crowd out these normal cells in the bone marrow.[webmd.com]
  • Signs and symptoms may include fever; easy bruising or bleeding; bone or joint pain; painless lumps in the neck, underarm, stomach, or groin; weakness; fatigue; and/or loss of appetite.[rarediseases.info.nih.gov]
  • 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.[symptoma.com]
  • Symptoms include: Bone and joint pain Easy bruising and bleeding (such as bleeding gums, skin bleeding, nosebleeds, abnormal periods) Feeling weak or tired Fever Loss of appetite and weight loss Paleness Pain or feeling of fullness below the ribs from[medlineplus.gov]
Hepatomegaly
  • RESULTS: Among 130 children receiving PEG-asparaginase biweekly, 29 developed SOS ( 2 criteria: hyperbilirubinemia, hepatomegaly, ascites, weight gain 2.5%, unexplained thrombocytopenia 9 l -1 ) at a median of 30 days (interquartile range [IQR]: 17-66[ncbi.nlm.nih.gov]
  • 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[symptoma.com]
Bone Pain
  • On examination, the boy was mildly pale, severe bone pain, no organomegaly but few occipital group of lymphnode were palpable. He had extensive red tender swelling over the hands and legs.[ncbi.nlm.nih.gov]
  • 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[symptoma.com]
Osteoporosis
  • Skeletal survey showed diffuse osteolytic lesion and osteoporosis with evidence of transverse metaphyseal radiolucent bands (leukemic line), lamellar periosteal reactions and cortical erosions widespread throughout the skeleton with subperiosteal new[ncbi.nlm.nih.gov]
Night Sweats
  • They include: Fatigue Fever Loss of appetite or weight Night sweats Many symptoms of acute lymphoblastic leukemia are the result of a shortage of normal blood cells. That's because leukemia cells crowd out these normal cells in the bone marrow.[webmd.com]
  • sweats These symptoms can occur with other conditions.[medlineplus.gov]
  • These include: being very tired, weak, or pale swollen lymph nodes infections (like bronchitis or tonsillitis) that keep coming back a fever night sweats easy bruising or petechiae (tiny red spots on the skin caused by easy bleeding) bone and joint pain[kidshealth.org]
Petechiae
  • Bone marrow failure manifests as signs of anemia (tiredness, paleness), thrombocytopenia (bruising, bleeding or petechiae) or neutropenia (fever and infection).[symptoma.com]
  • Symptoms of ALL include: Frequent infections Fever Easy bruising Bleeding that is hard to stop Flat, dark-red skin spots (petechiae) due to bleeding under the skin Pain in the bones or joints Lumps in the neck, underarm, stomach or groin Pain or fullness[stjude.org]
  • […] bleeding (such as bleeding gums, skin bleeding, nosebleeds, abnormal periods) Feeling weak or tired Fever Loss of appetite and weight loss Paleness Pain or feeling of fullness below the ribs from an enlarged liver or spleen Pinpoint red spots on the skin (petechiae[medlineplus.gov]
  • These include: being very tired, weak, or pale swollen lymph nodes infections (like bronchitis or tonsillitis) that keep coming back a fever night sweats easy bruising or petechiae (tiny red spots on the skin caused by easy bleeding) bone and joint pain[kidshealth.org]
Headache
  • If the lymphoblasts spread to the brain, headaches and nausea can result, while cancerous cells spreading to the liver and spleen irritate the tissues there, causing them to swell.[sharecare.com]
  • 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.[symptoma.com]
  • Depending upon where leukemia cells are present, other symptoms may include: A full or swollen belly from leukemia cells in the liver or spleen Enlarged lymph nodes such as in the neck or groin, under arms, or above the collarbone Bone or joint pain Headache[webmd.com]
  • This can cause a series of neurological symptoms (related to the brain and nervous system), including: headaches seizures (fits) vomiting blurred vision dizziness When to get medical advice If you or your child has some or even all of the symptoms listed[nhs.uk]
Dizziness
  • A shortage of red blood cells may cause symptoms of anemia , including: Fatigue or weakness Dizziness Feeling cold Light-headedness Shortness of breath A shortage of normal white blood cells may result in: Fevers Recurring infections A shortage of blood[webmd.com]
  • This can cause a series of neurological symptoms (related to the brain and nervous system), including: headaches seizures (fits) vomiting blurred vision dizziness When to get medical advice If you or your child has some or even all of the symptoms listed[nhs.uk]
Lethargy
  • 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.[symptoma.com]
Paresis
  • Both patients experienced transient facial nerve paresis. The incidence of SMN in children successfully treated for primary malignancies is 3% to 12%. Salivary gland tumors are being increasingly described in this setting.[ncbi.nlm.nih.gov]

Workup

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 [3].

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 [4]. Histological evaluation further divides patients into three categories: L1, L2 and L3, depending on blast morphology.

Mediastinal Mass
  • 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.[symptoma.com]

Treatment

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

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 [5]. 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 [6]. 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 [7], of Janus kinase mutations [8] 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 [9]. 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 [10]. These patients should receive additional intrathecal chemotherapy and dexamethasone based regimens [11].

Modern therapy has improved five-year survival rates and 5-year event-free survival and cure rates in all risk groups [12]. 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 [13], 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 [14].

Etiology

The etiology of childhood acute lymphoblastic leukemia remains unknown. In some cases, the disease is associated with Down syndrome or congenital immunodeficiencies, such as ataxia-telangiectasia or Wiskott-Aldrich syndrome.

Epidemiology

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 [15]. The numbers may be slightly lower in low-income countries [16], 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 [17].

Sex distribution
Age distribution

Pathophysiology

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 [18].

Prevention

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.

Summary

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.

Patient Information

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.

References

Article

  1. Muwakkit S, Al-Aridi C, Samra A, et al. Implementation of an intensive risk-stratified treatment protocol for children and adolescents with acute lymphoblastic leukemia in Lebanon. Am J Hematol. 2012;87(7):678-83.
  2. Pui CH, Robison LL, Look AT. Acute lymphoblastic leukaemia. Lancet. 2008;371(9617):1030-43.
  3. Ganesan P, Thulkar S, Gupta R, Bakhshi S. Childhood aleukemic leukemia with hypercalcemia and bone lesions mimicking metabolic bone disease. J Pediatr Endocrinol Metab. 2009;22(5):463-7.
  4. de Labarthe A, Rousselot P, Huguet-Rigal F, et al. Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study. Blood. 2007;109(4):1408-13.
  5. Uckun FM, Gaynon PS, Sensel MG, et al. Clinical features and treatment outcome of childhood T-lineage acute lymphoblastic leukemia according to the apparent maturational stage of T-lineage leukemic blasts: a Children’s Cancer Group study. J Clin Oncol. 1997:15(6):2214-21.
  6. Ribeiro KB, Buffler PA, Metayer C. Socioeconomic status and childhood acute lymphocytic leukemia incidence in São Paulo, Brazil. Int J Cancer. 2008;123(8):1907-12.
  7. Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360(5):470-80.
  8. Mullighan CG, Zhang J, Harvey RC, et al. JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 2009;106(23):9414-8.
  9. Pieters R, Schrappe M, De Lorenzo P, et al. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet. 2007;370(9583):240-50.
  10. Gajjar A, Harrison PL, Sandlund JT, et al. Traumatic lumbar puncture at diagnosis adversely affects outcome in childhood acute lymphoblastic leukemia. Blood. 2000:96(10):3381-84.
  11. Burger B, Zimmermann M, Mann G, et al. Diagnostic cerebrospinal fluid examination in children with acute lymphoblastic leukemia: significance of low leukocyte counts with blasts or traumatic lumbar puncture. J Clin Oncol. 2003:21(2):184-8.
  12. Hunger SP, Lu X, Devidas M, et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children's oncology group. J Clin Oncol. 2012;30(14):1663-9.
  13. Magrath I, Shanta V, Advani S, et al. Treatment of acute lymphoblastic leukaemia in countries with limited resources; lessons from use of a single protocol in India over a twenty year period [corrected]. Eur J Cancer. 2005;41(11):1570-83.
  14. Neglia JP, Meadows AT, Robison LL, et al. Second neoplasms after acute lymphoblastic leukemia in childhood. N Engl J Med. 1991;325:1330-6.
  15. Ribera JM, Oriol A. Acute lymphoblastic leukemia in adolescents and young adults. Hematol Oncol Clin North Am. 2009;23(5):1033-42.
  16. Pui CH, Mullighan CG, Evans WE, Relling MV. Pediatric acute lymphoblastic leukemia: where are we going and how do we get there?. Blood. 2012;120(6):1165-74.
  17. Steliarova-Foucher E, Colombet M, Ries LAG, et al. International incidence of childhood cancer, 2001-10: a population-based registry study. Lancet Oncol 2017;18:719.
  18. Bailey LC, Lange BJ, Rheingold SR, Bunin NJ. Bone-marrow relapse in paediatric acute lymphoblastic leukaemia. Lancet Oncol 2008;9(9):873-83.

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Last updated: 2018-06-21 17:17