Hematology / Oncology

Acute Lymphoblastic Leukemia (ALL)

Epidemiology    

ALL is the most common cancer in children, accounting for about 23% of cancer diagnoses in children under 15. 

There are approximately 2,900 patients less than 20 years diagnosed with ALL each year in the United States.  Most are between 2-5 years old. 

The highest incidence is in Hispanic children.  Whites children are affected more than black children, with a 3x greater incidence between 2-3 years of age.  ALL is also more common in boys compared to girls. 

Significant strides have been made in the treatment of this disease with much work still being done.  Between 1975-2002 the 5-year survival rate for ALL increased from 60% to 89% for children younger than 15.  For adolescents 15-19, the five year survival also increased from 28% to 50%.  

Clinical Presentation

ALL is an acute leukemia, so patients often present acutely.  Increased blast cells crowd out normal hematopoiesis in the bone marrow leading to classic presenting symptoms:
                    

  • Fatigue secondary to anemia
  • Bleeding/bruising secondary to thrombocytopenia
  • Infection secondary to neutropenia
                    

Other symptoms are often present including:

  • “B symptoms” of fever, night sweats, weight loss (67%) – often present but mild
  • Lymphadenopathy/hepatomegaly/splenomegaly (50%) – indicative of extramedullary spread
  • Musculoskelatal pain (25%) – classically nocturnal bone pain
  • Headache/neuropathy (5%) – CNS symptoms commonly secondary to meningeal involvement leading to increased ICP

Rarer but important presentations to remember:

  • Testicular enlargement – classically painless
  • Mediastinal mass – classically thymic mass in teenager with T-cell ALL
  • Massive mediastinal adenopathy leading to airway obstruction
  • Renal failure from leukemic infiltration of renal parenchyma
  • Disseminated intravascular coagulation and severe clotting factor deficiencies

Risk factors that should increase index of suspicion:

  • Down syndrome
  • NF-1
  • Shwachman syndrome
  • Bloom syndrome
  • Ataxia telangiectasia
  • Prior radiation exposure

Workup/Diagnosis

Labs:

  • CBC with manual differential and smear – will reveal blast cells (large, immature cells with punched-out nucleoli); may also have varying degrees of anemia, thrombocytopenia; WBCs could range from low to high, but are classically elevated
  • Bone marrow biopsy – will reveal increased cellularity from blasts classified by % infiltration (most commonly M3)
  • M1:  <5% involvement
  • M2:  5-25% involvement
  • M3:  >25% involvement
  • Lumbar puncture with cytology – checking for CNS involvement
  • Comprehensive Labs in preparation for treatment - should include a complete metabolic panel, calcium, phosphate, uric acid, PT/PTT, and viral titers (CMV, EBV, VZV, HIV, HepB)

 

all 1_0.png

Example of peripheral smear findings in ALL.  Large lymphoblasts with a prominent nucleoli and light blue rim of cytoplasm.  Blast cells have more abundant cytoplastm and their nucleus is often fissured or indented.  http://moon.ouhsc.edu/kfung/jty1/HemeLearn/HemeCase/PB-001-M.htm

 

all 2_0.png

Example of bone marrow biopsy findings in ALL with a high degree of blast cells. http://www.cram.com/flashcards/sbm-oncology-2355897

Classification

The World Health Organization (WHO) classifies between B lymphoblastic leukemia and T lympoblastic leukemia based on immunophenotype.  These kinds are further subdivided based on surface markers and the presence of immunoglobulin or other features of cell maturity.  Prior classifications using morphology have largely been abandoned, while cytogenetic analysis is used to aid with prognosis. 

 

B lymphoblastic leukemia: Lymphoblasts (TdT+) commonly expressing CD10 (90% of cases), CD19, CD20, CD79a, and HLA-DR.  More common than T lymphoblastic leukemia, accounting for 80-85% of childhood cases.  

Common types include:

  • Common precursor B-cell ALL: CD10+, no surface or cytoplasmic Ig (75% patients have, associated with best prognosis)
  • Pro-B ALL: CD10-, no surface or cytoplasmic Ig, t(4;11) (5% patients, most common in infants)
  • Pre-B ALL: Cytoplasmic Ig present with many variations of translocations as cells are closer to maturity

 

T lymphoblastic leukemia: Lymphoblasts (TdT+) commonly expressing CD2-CD8 markers, but never CD10.  T-ALL also commonly presents as a thymic mass in male teenagers.  Prognostically similar to B-ALL.

Common types include:

  • NOTCH1 gene mutations: 50% of T-ALL cases have, prognostic significance unknown
  • t(5;14)(q35;q32): 20% of cases, poor prognostic factor indicating likely treatment failure
  • Early precursor T-cell ALL: CD1a-, CD8- (13% of cases, poorer prognosis)

Cytogenetic Prognostic Indicators:

Common translocations not previously mentioned:

  • ETV6/RUNX1 t(12;21): 25% of B-ALL, carries favorable prognosis
  • BCR/ABL t(9;22): Treatable with Imatinib, generally good prognosis
  • MLL gene t(4;11) or t(11;19): commonly infants with CNS involvement with high rate of treatment failure
  • E2A/PBX1 t(1;19): more common in black children than white children

Other cytogenetic prognostic indicators:

  • High hyperdiploidy: 51-65 chromosomes, 20-25% of precursor B-cell ALL; favorable prognostic factor
  • Hypodiploidy: <44 chromosomes; poor prognostic indicator, worsens as number of chromosomes decreases

Treatment

Treatment is typically with 2-3 years of chemotherapy given with stepwise goals.  Initial therapy is aimed at achieving remission while also treating the sanctuary sites (CNS, testes). 

Induction chemotherapy is given with vincristine, corticosteroids, and L-asparaginase with or without anthracycline.  Approximately 95% achieve complete remission in the first 4 weeks (<5% bone marrow involvement with evidence of hematopoietic recovery). 

A significant adverse outcome during induction chemotherapy is the tumor lysis syndrome, when the leukemic cell contents are released into the system in massive quantities sometimes resulting in acute renal failure.  Patients with ALL are at high risk for tumor lysis and need to have levels of uric acid, phosphate and potassium followed closely.  

Tumor lysis prevention and treatment centers on proper IV hydration, initiation of hypouricemic agents such as allopurinol and rasburicase, and correction of electrolyte abnormalities (hyperkalemia, hyperphosphatemia, hypocalcemia) in order to prevent renal failure. 

Patients with persistent disease at 4 weeks may benefit from a stem cell transplant.  Post induction treatment for those who achieve remission involves consolidation/intensification followed by maintenance phases stratified based on risk factors. 

In addition to the immunophenotype and cytogenetics, age at diagnosis, response to induction therapy, and WBC count at diagnosis impact the future treatment decisions and prognosis.  Patients older at time of diagnosis with higher WBC counts unfortunately have poorer prognosis in general. 

Ongoing research

nci_0.jpg

CLICK ON THE NCI LINK ABOVE to access information for patients, families and physicians regarding current clinical trials.  The website also has LiveHelp Online Chat and a hotline (1-800-4-CANCER) to assist with clinical trial questions. 

References

  1. “Cellular Classification and Prognostic Variables”. Childhood Acute Lymphoblastic Leukemia Treatment; National Cancer Institute: National Institutes of Health (NIH). Web-site last modified January 23, 2013. http://www.cancer.gov/cancertopics/pdq/treatment/childALL/HealthProfessional/page2
  2. Hutter J, Childhood Leukemias.  Pediatrics in Review.  June 2010
  3. Pui HC et al. Extended Follow-up of Long Term Survivors of Childhood Acute Lymphobalstic Leukemia NEJM 2003; 349: 640-649
  4. Howard S. et.al. The Tumor Lysis Syndrome.  New England Journal of Medicine May 12, 2011
  5. Onciu, Mihaela. Acute lymphoblastic leukemia. Hematology/oncology clinics of North America 23.4 (2009): 655-674.