Childhood Acute Lymphoblastic Leukemia: Diagnosis, Management, and Complications

Mihir D. Bhatt, MD; Uma H. Athale, MD, MSc

November 4, 2014


Childhood leukemia is a prototype of curative cancer.[1] Although it is painful disease, acute lymphoblastic leukemia (also known as acute lymphocytic leukemia) (ALL) has a 5-year survival rate of about 90% for those younger than 15 years, and the survival rate is about 70% for those aged 15-19 years.[2,3] The majority of affected children and adolescents are able to return to their normal routine with minimal healthcare follow-up.

The left image shows a chest x-ray with an implantable venous access system (port) in place. Ports are implanted under a patient's skin and accessed with a needle for the administration of chemotherapy and other agents. The right image depicts a port. These devices are among the many advances used in the management of pediatric ALL patients that help to preserve their quality of life throughout the treatment process.

Chest x-ray and port images courtesy of Wikipedia.

Slide 1.

An estimated 15,780 US cases of childhood cancer (patients aged <20 y) is expected to be diagnosed in 2014.[4] ALL is the most common form of cancer in children aged 15 years or younger, comprising 25% of all malignancies.[2] Its incidence peaks between ages 2 and 3 years,[2] and it is more common in boys than girls. In adolescents aged 15 to 19 years, ALL comprises only 7% of all cancers as the incidence of lymphoma and solid tumors has increased.[4] In the United States, 2500-3500 children are diagnosed with ALL every year, and the incidence of ALL appears to be increasing.[2] A study of European registries demonstrated a 1.4% increase in incidence from 1970 to 1999,[5] whereas an analysis of the US National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) database showed a 0.7% increased incidence from 1975 to 2010.[4,5]

Image courtesy of Mihir D. Bhatt, MD, and Uma H. Athale, MD, MSc.

Slide 2.

Genetic factors play an important role in the pathogenesis of ALL. Although children with congenital chromosomal abnormalities have an increased risk of developing ALL, the majority of ALL patients have acquired genetic abnormalities detectable in leukemia clones. Congenital genetic syndromes reported to have an increased risk for childhood ALL include Down syndrome (10-20–fold increased risk), Bloom syndrome, neurofibromatosis, Fanconi anemia, and Shwachman-Diamond syndrome.[2,6] Congenital immunodeficiency syndromes such as Wiskott-Aldrich syndrome and ataxia-telangiectasia also increase a child's risk of developing ALL. In contrast, studies examining the role of etiologic factors such as environmental exposures, viral infections, and socioeconomic status in the pathogenesis of ALL have yielded inconsistent results.[7]

Left and right images courtesy of Wikipedia.

Slide 3.

The clinical manifestations of ALL depend on the extent of bone marrow infiltration by leukemic cells. Disruption of normal hematopoiesis causes anemia, thrombocytopenia and neutropenia, leading to signs/symptoms such as pallor, fatigue, petechiae (shown), bruising, bleeding, and fever. Extramedullary infiltration of leukemic cells can cause lymphadenopathy, hepatomegaly and splenomegaly, which are usually asymptomatic. Bone pain due to periosteal involvement is present in about 25% of children with ALL,[8] and it can be the sole presenting symptom in some patients. Children with central nervous system (CNS) involvement may present with headache, vomiting, and lethargy. In general, testicular infiltration is uncommon (2%), presents as painless swelling, and is treated aggressively with chemoradiotherapy.[2]

Image courtesy of Wikipedia/James Heilman, MD.

Slide 4.

Although the CNS, liver, spleen, and lymph nodes are common sites of extramedullary spread of leukemia, rare involvement of organs other than these and the testes can also occur (eg, skin, eyes, pleural space, ovaries).[1] Infants younger than 1 year are more likely than older children to have unusual presentations of leukemia, and they also have a poorer prognosis. Chloromas (granulocytic sarcomas) are solid tumors composed of leukemia cells that can be found virtually anywhere in the body, but the most common sites are the brain or spine (shown). Affected patients may present with cranial nerve palsies or focal neurologic deficits due to compression of the involved nerves by leukemic deposits. Leukemia cutis is infiltration of the dermis by leukemia cells.[1]

Image courtesy of Wikipedia.

Slide 5.

When leukemia is suspected, workup to confirm the diagnosis and the presence of any associated complications includes laboratory studies such as complete blood counts, chemistry panels, liver and renal function studies, and coagulation studies.[1,2,6] Examination of the peripheral blood smear may reveal the presence of lymphoblasts. The presence of abnormalities in electrolyte levels (eg, calcium, phosphate) and levels of uric acid and lactate dehydrogenase reflect leukemic cell burden and, potentially, tumor lysis syndrome. Use coagulation studies rule out the presence of disseminated intravascular coagulation. The diagnosis of ALL is consfirmed with bone marrow aspiration and biopsy (shown); these procedures can be used to evaluate the numbers of blasts present and leukemic phenotype. Most children undergoing bone marrow aspiration/biopsy will require sedation because of pain. Other tests, procedures, and/or imaging studies may be required on the basis of the patient's clinical and laboratory findings.[1,2,6]

Images courtesy of Flickr (left); Wikimedia Commons/Photographer's Mate 2nd Class Chad McNeeley (top right); and Wikimedia Commons/Gabriel C. Caponetti, MD (bottom right).

Slide 6.

All pediatric patients with suspected ALL should have a chest radiograph to assess for the presence of a mediastinal mass, which is most common in older children and those with ALL of T-cell lineage. The presence of a mediastinal mass (shown) may signify a medical emergency, as there is a risk of imminent respiratory arrest caused by compression of the trachea or a risk of superior vena cava syndrome from obstruction of the superior vena cava. Other imaging studies may be necessary to evaluate specific signs/symptoms. For example, if the testes are enlarged, an ultrasonogram may rule out leukemic infiltration. In the presence of cranial nerve palsy, magnetic resonance imaging (MRI) of the brain may be used to evaluate for chloromas or solid leukemic deposits. Obtain a baseline echocardiogram if anthracyclines are going to be administered as part of the patient's treatment.

Image courtesy of Mihir D. Bhatt, MD, and Uma H. Athale, MD, MSc.

Slide 7.

Lumbar puncture (LP) is performed in ALL patients to assess for CNS involvement. The initial diagnostic LP is typically performed by an experienced pediatric oncologist to minimize the risk of a traumatic (bloody) LP (red blood cells in the subarachnoid space caused by a traumatic LP may cause diagnostic uncertainty). Cerebrospinal fluid (CSF) cytospin preparations are used to assess for the presence of lymphoblasts and to categorize the patient's CNS status at leukemia diagnosis, as follows[9]:

  • CNS1: absence of blasts, white blood cell (WBC) count less than 5 x 106/L
  • CNS2: presence of blasts, WBC count less than 5 x 106/L
  • CNS3: presence of blasts, WBC count greater than 5 x 106/L (nontraumatic LP)

The presence of leukemic cells in the CNS (CNS2 or CNS3) is considered to be an unfavorable prognostic marker; affected patients should receive additional CNS-directed therapy.[9,10] Patients with CNS3 are particularly at increased risk for CNS relapse and should receive intense intrathecal therapy.[9]

Images courtesy of Wikipedia/James Heilman, MD (top left) and Wikipedia (bottom left; right).

Slide 8.

ALL is a biologically heterogeneous disease[9] that may develop at any stage of lymphoid differentiation. The current standard for diagnosis is based on immunophenotype and cytogenetic or molecular analysis. The World Health Organization (WHO) classifies ALL as B or T lymphoblastic leukemia.[11,12] Some acute leukemias can have both lymphocytic and myeloid features. Previously, ALL lymphoblasts were classified using the French-American-British (FAB) criteria [6,11] on the basis of cell size, quantity of cytoplasm and granules, nucleoli prominence, and immunochemistry (shown), as follows:

  • L1 (85% of childhood ALL): small blasts, scant cytoplasm, indistinct nucleoli
  • L2 (14% of childhood ALL): large blasts, abundant cytoplasm, prominent nucleoli
  • L3 (1% of childhood ALL): large blasts, abundant basophilic cytoplasm, prominent vacuoles (arrows), prominent nucleoli

The FAB classification is no longer in favor, because the subgroups do not correlate with the lineage or risk category.[9]

Images courtesy of Medscape.

Slide 9.

Leukemic cells express a unique set of cell surface markers depending on their lineage (B or T) and stage of maturation. Immunophenotyping is a process used to identify cells by detecting cluster-of-differentiation (CD) markers with the use of monoclonal antibodies. B-precursor lineage accounts for about 80%-85% of childhood ALL,[6] and it is detected by the presence of CD10+ (formerly "common ALL antigen" [CALLA+]), CD19+ and CD20+. Mature B-cell ALL or Burkitt leukemia (about 2%-3% of childhood ALL)[6] is characterized by specific surface and cytoplasmic immunoglobulins and negativity for Tdt (terminal deoxynucleotidyl transferase) marker. T-cell ALL accounts for 15%-18% of childhood ALL[6]; it is diagnosed by positivity for CDs 2,3,5,7 and 8.[1,6,13] Early T-cell precursor (ETP) phenotype (CD8- and CD5dim) has been shown to be associated with poor prognosis.[14] These cell surface markers can also be used as targets for immunotherapy (eg, rituximab against CD20).[13,15]

Image courtesy of Mihir D. Bhatt, MD, and Uma H. Athale, MD, MSc.

Slide 10.

Recurrent chromosomal abnormalities (structural/numeric) are common in leukemic cells. Certain cytogenetic abnormalities may have prognostic significance (shown).[14,16,17] Thus, identification of chromosomal abnormalities and translocations have allowed for improved risk stratification as well as the development of targeted therapy. Methods used to decipher chromosomal abnormalities include standard and spectral karyotyping, fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR), and comparative genomic hybridization. Cytogenetic abnormalities discovered in B-lineage ALL have better-defined prognostic significance compared to those found in T-lineage ALL.[2,9,16]

Table courtesy of Mihir D. Bhatt, MD, and Uma H. Athale, MD, MSc.

Slide 11.

The Philadelphia chromosome (Ph) was the first leukemic translocation to be discovered. The proto-oncogene and tyrosine kinase c-abl on chromosome 9 is translocated and fused to the transcription factor BCR (breakpoint cluster region) on chromosome 22, leading to leukemogenesis (ALL or chronic myeloid leukemia [CML]). This t(9;22) translocation is found in 3%-5% of childhood ALL.[2,18] The development of tyrosine kinase inhibitors such as imatinib and dasatinib has changed the outcome of patients who have positive Ph chromosome (Ph+) ALL, paving the way for targeted therapy. Patients with Ph+ ALL who receive standard chemotherapy have higher rates of induction failure, higher frequency of CNS disease, and higher rates of relapse; targeted therapy with imatinib has improved early event-free survival (3-y survival) to 80%.[19,20]

Image courtesy of Wikimedia Commons.

Slide 12.

An important indicator of prognosis is a patient's response to treatment. It is possible to quantify minimal residual disease (MRD), the small amount of remaining leukemia cells in a patient following therapy, using techniques such as PCR or flow cytometry (shown).[2] MRD techniques can be 10-100 times more sensitive than morphologic examination: These assays can detect as few as 1 leukemia cell in 10,000 to 100,000 normal cells.[2,21,22] MRD negativity (defined in most studies as <1 leukemia cell in 10,000) at the end of induction therapy is considered to be a good prognostic marker; patients with MRD positivity at end of induction and persistent or rising MRD levels at later times in therapy have an increased risk of relapse.[23,24]

Image courtesy of Cunha FG, da Rocha FF, Lorand-Metze IG. Rev Bras Hematol Hemoter. 2012;34(5):396. [Open access.] PMID: 23125550; PMCID: PMC3486832.

Slide 13.

Patients are stratified into prognostic risk groups on the basis of information derived from diagnostic tests combined with demographic data.[2,6,16] ALL treatment protocols employ risk-based therapy to reduce toxicity in patients with low-risk ALL (low risk of treatment failure) and to indicate aggressive therapy for those with a high-risk of relapse. Features commonly included in risk stratification are the WBC count at diagnosis, age at diagnosis, immunologic subtype, CNS status, cytogenetic results, and treatment response (shown).[2,6] Different cooperative clinical trial groups use different combinations of these features for risk stratification and therapeutic planning. Risk-adapted therapy on the basis of these features has been well correlated with prognosis. iAMP21 = intrachromosomal amplification of chromosome 21; NCI = National Cancer Institute.

Source of image data: NCI.

Slide 14.

The primary mode of treatment in newly diagnosed children with ALL is chemotherapy via systemic and intrathecal administration and supportive care.[2,6] Radiotherapy is limited for emergencies and patients with CNS or high-risk disease. Multidrug chemotherapy regimens are divided into different phases (shown); different cooperative therapy groups use different combinations of agents in various phases depending on the risk stratification of the patient. Induction therapy is the initial 4-6 weeks of treatment that achieves remission in over 95% of children with ALL.[2,6,9] During this period, patients are managed in the hospital or monitored closely because they can develop life-threatening toxicities as a result of their therapy. The goal of postinduction chemotherapy (lasting 2-3 y) is to remove any residual leukemia cells.[9]

Image courtesy of Mihir D. Bhatt, MD, and Uma H. Athale, MD, MSc.

Slide 15.

Chemotherapeutic agents were first used to treat childhood leukemia more than 50 years ago. Cooperative clinical trial groups have improved the understanding of the mechanism of action of such agents and led to the development of newer drugs and better supportive care for patients; these factors have resulted in increased survival rates for childhood ALL. The chemotherapeutic agents used to treat childhood ALL have variable effects on leukemia cell cycles; the common goal is apoptosis. Treatment protocols are designed to achieve killing of leukemia cells, and they take into account important principles such as combination chemotherapy, low therapeutic index, and dose intensity. Such protocols outline the dosing, timing, and duration of administration for these agents to reduce the risk of acute and long-term toxicities. AVN = avascular necrosis; DHFR = dihydrofolate reductase; SIADH = syndrome of inappropriate antidiuretic hormone.

Table courtesy of Mihir D. Bhatt, MD, and Uma H. Athale, MD, MSc.

Slide 16.

The CNS can be a sanctuary site for leukemia cells; the blood-brain barrier provides these cells with adequate protection from systemic chemotherapy.[2] Thus, preventative CNS therapy represents one of the major breakthroughs in the treatment of childhood ALL. Before the universal use of CNS prophylactic therapy, the majority of patients relapsed with CNS disease, despite fewer than 3% of patients having CNS leukemia at diagnosis.[2] Although cranial radiation therapy was once the standard mode of delivering CNS prophylaxis, it is associated with major neurologic side effects and many acute and late complications. Most protocols have now replaced it successfully with intrathecal chemotherapy (methotrexate, cytarabine, hydrocortisone) and systemic intensification of agents (eg, methotrexate) (<5% relapse rates with standard-risk ALL).[2,26,27] In general, cranial radiation is only used to treat patients with CNS disease at the time of diagnosis (eg, CNS3 at diagnosis).

Image courtesy of Mihir D. Bhatt, MD, and Uma H. Athale, MD, MSc.

Slide 17.

Despite significant advances in ALL treatment, up to 20% of affected children will relapse and their prognosis remains poor (outcomes are worse in developing countries).[28] Typically, these patients are risk-stratified on the basis of the timing and site of relapse, immunophenotype, response to reinduction therapy, and patient and cytogenetic/genomic features.[2] The bone marrow is the most common site of relapse, but isolated extramedullary relapse also occurs in the CNS (<5%) and testes (<1%-2%).[2]

Allogeneic hematopoietic stem cell transplantation (HSCT) is indicated for high-risk patients (eg, those who relapse following treatment, with high MRD after reinduction therapy),[6,9] whereas patients at low-risk for relapse can be treated with chemotherapy alone. Allogeneic HSCT involves administration of intensive cytoreductive therapy followed by infusion of stem cells obtained from a compatible donor (shown).[6,29] Although high-dose chemotherapy and HSCT carry significant risk of morbidity (infection, graft-vs-host disease) and mortality,[2,6] HSCT can lead to 5-year event-free survival in nearly 60% of all patients with ALL.[30]

Image courtesy of Wikimedia Commons.

Slide 18.

Tumor lysis syndrome (TLS) is an oncologic emergency caused by the posttreatment breakdown of leukemia cells; this results in the release of large amounts of intracellular components (potassium, phosphate, nucleic acids) into the systemic circulation.[31] These metabolic changes can also occur before the start of therapy. TLS is characterized by hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia.[31] Hyperuricemia, caused by purine metabolism (left), can result in tubular precipitation and cause acute kidney injury, which may requiring dialysis (right) in extreme cases. Prevention/treatment includes hyperhydration, frequent monitoring with bloodwork, use of allopurinol to decrease uric acid formation, and use of exogenous urate oxidase (eg, rasburicase) to eliminate excess uric acid.[31] APRT = adenine phosphorybosyltransferase; GMP = guanosine monophosphate; HPRT = hypoxanthine phosphorybosyltransferase; IMP = inosine monophosphate; PRPP = 5'-phosphoribosyl-1-pyrophosphate, Ribose-5-P = ribose-5-phosphate.

Images courtesy of Torres RJ, Puig JG. Orphanet J Rare Dis. 2007;2:48. [Open access.] PMID: 18067674; PMCID: PMC2234399 (left); and Wikipedia (right).

Slide 19.

Infection is a major cause of morbidity and mortality in children with ALL. Immunosuppression associated with the disease and its treatment increases the risk for the development of bacterial, fungal, and/or viral infections.[1,32,33] In a Canadian study, about 20% of pediatric ALL patients developed at least one infection during induction treatment, with neutropenia at the time of diagnosis being the most common risk factor.[32] Because infections can lead to life-threatening consequences (eg, sepsis), promptly assess and aggressively treat febrile ALL patients with empiric antimicrobial agents. For example, medical prophylaxis with drugs such as sulfamethoxazole-trimethoprim against Pneumocystis carinii infection has reduced the incidence of this fatal pneumonia.

Images courtesy of the Centers for Disease Control and Prevention (CDC)/Matthew J. Arduino, DRPH, and Janice Haney Carr (top left); Wikimedia Commons (top right); CDC/Dr. Eskine Palmer and BG Partin (bottom left); and CDC/Dr Edwin P. Ewing, Jr (bottom right).

Slide 20.

Long-term morbidity and late effects caused by treatment of childhood ALL include decreased growth, obesity, CNS impairment, cardiotoxicity, osteoporosis, avascular necrosis, infertility, and secondary cancers.[34] Mental health issues such as depression and anxiety are also more common in ALL survivors; these individuals should be closely monitored by health professionals who have an in-depth understanding of these issues. The incidence of these specific complications depends on the patient's type of leukemia, age at diagnosis and treatment, and the type of therapy received. For example, patients who receive anthracyclines are at risk of premature cardiac disease. Research efforts remain ongoing to understand the pathogenesis of leukemia and thereby to improve individualization of therapy, increase cure rates, and reduce toxicities and complications.

Images courtesy of Wikimedia Commons (top left); Wikipedia/Pil Kang (top right); CDC/Dr Edwin P. Ewing, Jr (bottom left); and Wikipedia (bottom right).

Slide 21.

Contributor Information


Mihir D. Bhatt, MD
Fellow, Department of Pediatric Hematology/Oncology
McMaster Children's Hospital
Hamilton, Ontario

Disclosure: Mihir D. Bhatt, MD, has disclosed no relevant financial relationships.

Uma H. Athale, MD, MSc
Associate Professor, Department of Pediatric Hematology/Oncology
McMaster University;
Consultant, Department of Pediatric Hematology/Oncology
McMaster Children's Hospital
Hamilton, Ontario

Disclosure: Uma H. Athale, MD, MSc, has disclosed no relevant financial relationships.


Olivia Wong, DO
Senior Editor
Medscape Drugs & Diseases
New York, New York

Disclosure: Olivia Wong, DO, has disclosed no relevant financial relationships.


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