Leukemia

Question 1

Acute Myeloid Leukemia (AML)

Answer 1

• A heterogenous group of cancers of blood cells that arise from clonal expansion of malginant hematopoietic precursor cells (myeloid stem cells)
  
  • Leukemic cells proliferate in the marrow and interfere with production of normal blood cells, causing weakness, infection, bleeding, and other symptoms and complication.

Question 2

Pathogenesis of AML

Answer 2

• Aberrant hematopoiesis - AML occurs as a consequence of various genetic and epigenetic changes in hematopoietic precursor cells, resulting in a clone of abnormal cells that are able to proliferate but can’t mature into mature hematopoietic cells.
• Chromosomal and molecular genetic aspect - AML is associated with chromosomal abnormalities (nonrandom translocations, gain or loss of complete or parts of chromosomes, and other karyotype abnormalities).

Question 3

Epidemiology of AML

Answer 3

• AML is the most common acute leukemia in adults, but is relatively rare (~1% of adult cancers)
• Median age of diagnosis ~65 years and incidence increases with age

Question 4

Risk Factors AML

Answer 4

• Environment factors - exposure to chemicals, radiation, tobacco, chemotherapy, retroviruses
• May be preceeded by certain conditions - myelodysplastic syndrome, myeloproliferative neoplasmas, paroxysmal nocturnal hemoglobinuria aplastic anemia, or clonal hematopoiesis of indeterminate significance.
• Familial genetic abnormalities - trisomy 21; Fanconi anemia; Bloom’s syndrome; familial mutations of CEBPA, DDX41, RUNX1

Question 5

Clinical Presentaion AML

Answer 5

• Symptoms of anemia (SOB, weakness, dyspnea, on exertion), excess bleeding or bruising, and infection.
• Physical finding - pallor, bleeding/bruising, and occasionally hepatomegaly and/or splenomegaly (lymphadenopathy is uncommon).
• Otherwise unexplained headache or focal neurologic complaints
• Reduction in red cells, platelets, and mature neutrophils on a CBC with differential
• Accumulation of leukemic forms in peripheral blood, bone marrow, and/or other tissues.

Question 6

Diagnosis AML

Answer 6

• Criteria for diagnosis includes:
  
  • Blast forms must account for at least 20% of the total cellularity of the bone marrow biopsy sample or peripheral white blood cell count.
  • Blast forms must be identified as cells of the myeloid lineage, as distinct from the lymphoid lineage

Question 7

Treatment AML

Answer 7

• Induction therapy - treatment of AML in younger, medically fit adults begins with intensive remission induction chemotherapy with goal of obtaining complete remission.
• Post-remission therapy - relapse is very high without post-remission therapy. Goal is to eliminate any residual, undetectable disease and acheive a cure.
  
  • Consolidation therapy - one of more courses of chemotherapy, autologous hematopoietic cell transplantation, or allogeneic HCT
  • Maintence - non-myelosuppressive treatment with chemotherapy and/or targeted therapeutic agent that is administered over a period of months of years.

*Goal of induction therapy is to achieve complete remission in which the total body leukemic cell population is reduced from ~10¹² to below the cytologically detectable level of 10⁹ cells. It is assumed that many leukemia cells remains undetected, leading to relapse within weeks to months if no other post-remission therapy is given.

Question 8

Acute Lymphoblastic Leukemia (ALL)

Answer 8

• Acute leukemia is the most common form of cancer in children ~30% of all childhood malignancies, with ALL (Lymphoid stem cells) being 5 times more common than AML (myelod stem cells).
• Peak incidence occurs between two and five years of age
• More common among boys

Question 9

Risk Factors ALL

Answer 9

• Most cases are not associated with genetic or environment risk factors, but some genetic and immune deficiency syndrome put children at higher risk (ex. Downs, Bloom Syndrome, neurofibromatosis type 1, and ataxia telangiectasia).
• High birth weight
• Some polymorphic variants associated, but is generally not considered a famililar disease.

Question 10

Clinical Presentation ALL

Answer 10

• Most presenting symptoms are nonspecific
  
  • Palpable spleen
  • Palpable liver
  • Pallor
  • Fever
  • Bruising
  • Lymphadenopathy - nontender, firm, rubbery, matted
  • MSK pain
  • Headache - uncommon, but leukemia involving CNS on present with syndromes of increased intracranial pressure
  • Testicular enlargement (unilateral)
  • Mediastinal mass
  • Peripheral blood abnormalities - anemia, thrombocytopenia, normal or increased WBC count, and lymphoblasts on peripheral smear.

Question 11

Categories ALL

Answer 11

• Divided into 2 general categories:
  
  • Precursors B cells lymphoblastic leukemia/lymphoma
  • Precursors T cell lymphoma leukemia/lymphoma
    
    • There entities are morphologically indistinguishable
• Leukemia cells in ALL are classificed according to immunophenotype using panel of monoclonal antibodies to cell surface “cluster of differentiation” markers
  
  • 70-80% of childhood ALL are B-precursor lineage (CD10⁺, CD19⁺, and sometimes CD20⁺)
  • 15-17% of childhood ALL are T-precursor (CD 2, 3, 4, 5, 7, 8⁺)

Question 12

Cytogenetics ALL

Answer 12

• Chromosomal abnormalities are common in childhood ALL
• Not used for diagnosis, but essential part of risk group stratification and help to guide therapy
• Recognized abnormalities associated with poor outcome:
  
  • BCR/ABL 1 translocation
  • BCR/ABL 1-like ALL
  • Rearrangements involving the KMT2A/MLL
  • iAMP21
  • Extreme hyperdiploidy (59 to 84 chromosomes) or hypodiploid (fewer than 45 chromosomes)
• Abnormalities associated with favourable prognosis:
  
  • ETV6/RUNX1 rearrangement in B-precursor ALL
  • Hyperdiploidy (54 to 58 chromosomes) - present in 20-25% of childhood ALL. Childhood with hyperdiploidy have the best prognosis, especially if associated with combined trisomies of chromosomes 4 and 10.

Question 13

Diagnostic Evaluation ALL

Answer 13

• Diagnosis and classification of leukemia are best on tests that are performed on cells derived from a bone marrow aspirate or tissue biopsy specimens
• CNS involvment indicated by one of the following:
  
  • Cytologic confirmation of the presence of leukemic cells in CSF
  • Clinical signs of CNS leukemia such as facial nerve palsy, brain/eye involvement, or hypothalamic syndrome
  • Tumour mass involving CNS as determined by imaging studies

Question 14

Treatment ALL

Induction therapy

Answer 14

• Induction therapy - initial phase of treatment. Goal is to achieve complete remission (eradication of all detectable leukemic cells from bone marrow and blood and the restoration of normal hematopoiesis).

Question 15

Treatment ALL

CNS Preventive therapy

Answer 15

• CNS preventive therapy - CNS treatment usually begins during induction phase and contines throughout the remainder of the treatment regimen. Craniospinal radiotherapy has been replaced by intrathecal chemotherpy.
• Current protocols contain either no CNS radiotherapy or significantly reduced dose. Cranial radiotherapy was effective in preventing CNS leukemia, but was assoicated with significant toxicity such as cognitive impairment and decreases in white matter volume.

Question 16

Treatment ALL

Post-remission Therapy

Answer 16

• Post-remission therapy - consolidation or intensification therapy is the second phase of ALL treatment and started soon after attainment of complete remission. Need continuing treatment because small number of leukemic cells remain in bone marrow even if not detected on lab tests. Goal is to prevent leukemic re-growth, reduced residual tumour burden, and prevent emergence of drug-resistance in remaining leukemic cells.
  
  • Consolidation - usually lasts from 4-8 months. Involves use of several different drug combinations and drugs that differ from those used in induction phase.
  • Delayed intensification - follows consolidation therapy. Involves administration of 5-8 week “pulse” of intensive, multi-agent chemotherapy similar to that administered during induction and consolidation (associated with increased survival).
  • Allogeneic hematopoietic cell transplantation - some patients with highrisk disease have an increased incidence of relapse during delayed intensification chemotherapy (ex. hypodiploid ALL) - These patients are candidates for allogeneic hematopoietic cell transplanation during first remission. HLA - matched sibling donor is preferred and is associated with fewer severe infections and pulmonary complications.

Question 17

Maintenace Therapy ALL

Answer 17

• Treatment for most kids with ALL is 30-42 months
• After finishing consolidation or intensification phase pf therapy, patients often receive a less intensive continuation regimen (i.e., maintenance chemotherapy).
  
  • During maintenace therapy, patients are still at higher risk for infection.
• Patients are typically seen by their oncologist monthly for the first year after therapy completion and then less frequently for the next 2-4 years. After 3-5 years, patients are followed annually.

Question 18

Monitoring for Relapse ALL

Answer 18

• Signs and symptoms of ALL relapse are similar to those of initial presentation - fever, malaise, bleeding, and bone pain
• Usually occurs in bone marrow and presents with persistent peripheral blood cytopenias
• CNS relapse (rates are reduced with prophylactic intrathecal therapy) - may present with increased intracranial pressure, nuchal rigidity rigidity, focal neurologic findings, papilledema.
• Testicular relapse (uncommon)

Question 19

Tumour Lysis Syndrome (TLS)

Answer 19

• TLS is an oncologic emergency that is caused by massive tumour cell lysis with the release of large amounts of potassium, phosphate, and nucleic acids into the systmic circulation.
• Caused by rapid leukemic cell death following the onset of chemotherapy.
• Characterized by hyperphosphatemia, hypocalcemia, hyperuricemia, and renal insufficiency.

Question 20

Pathogenesis Tumour Lysis Syndrome

Answer 20

• Malignancy with a high proliferative rate, large tumour burden, and/or high sensitivity to treatment, initiation of cytotoxic chemotherapy, cytolytic antibody therapy radiation therapy, or glucocortocoid therapy can result in rapid lysis of tumour cells.
• Ultimately results in massive amounts of intracellular material (i.e., potassium, phostphate, and nucleic acids) into systemic circulation.
• Results in hyperkalemia, hyperphosphatemia, secondary hypocalcmia, and AKI.

Question 21

Hyperuricemia in TLS

Answer 21

• Occurs as a result of the nucleic acids being metabolized into uric acid. Uric acid is poorly soluble in water, especially in the acid envivronment of the distal tubules and collecting system of the kidney
• Thus, overproduction and overexcretion of uric acid can lead to precipitatn and deposition in the renal tubules leading to AKI.

Question 22

Hyperphosphatemia in AKI

Answer 22

• Phosphorus content in malignant cells is higher than in normal cells and thus cell breakdown results in hyperphosphatemic and secondary hypocalcemia.
• Futhermore, calcium phostphate percipation in renal tubules can lead to AKI and precipiation in the heart may lead to cardiac arrhythmias.

Question 23

Clinical Manifestations TLS

Answer 23

• Symptoms are asociated with the metabolic abnormalities (hyperkalemia, hyerphosphatemic, and hypocalcemia)
• Nausea, vomiting, diarrhea, anorexia, lethargy, hematuria, heart failure, cardiac dysrhythmias, seizsures, muscle crams, tetany (intermittent muscular spasma), syncope, and possible suddent death.

Question 24

Diagnosis TLS

Answer 24

• 2 or more abnormal lab values present:
  
  • Uric acid 25% increase from baseline
  • Potassium 25% increase from baseline
  • Phosphorus 25% increase from baseline
  • Calcium 25% decrease from baseline

Question 25

Risk Factors TLS

Answer 25

• High tumour cell proliferation rate
• Large tumour burden
• Pretreatment hyperuricemia or hyperphosphatemia
• A pre-exisiting nephropathy or exposure to nephrotoxins
• Oliguria and/or acidic urine
• Dehydration, volume deplation, or inadequate hydration during treatment.

Question 26

Pneumocystis Pneumonia (PCP)

Answer 26

• A potentially life-threatening infection (fungal) that occurs in immunocompormised individuals (i.e., HIV, hematopoietic stem cell, and solid organ transplant recipient, those with cancer, and those receiving glucocorticoids, chemotherapeutic agents, and other immunosuppressive meds).
• Recommended to treat prophylaxically in transplant recipients, patients with acute lymphocytic leukemia, and patients receiving certain immunosuppressive drugs
• Medication = Trimethoprim - sulfamethoxazole (TMP-SMX)

Question 27

Febrile Neutropenia

Answer 27

• Cancer patietns receiving cytotoxic antineoplastic therapy sufficient to adversely affect myelopoiesis and the developmental integrity of the GI mucosa are at risk for invasive infections due to colonizing bacteria and/or fungi that move across intestinal mucosal surface
• In neutropenic patients the inflammatory response may be mutated and thus fever may be the earliest and only sign of infection. It is important to recognize neutropenic fever early and initiate empiric systemic antibacterial therapy to avoid progression to sepsis and death

Question 28

Categories of Neutropenic Fever Syndromes

Answer 28

1. Microbiologically documented infection - neutropenic fever with clinical focus of infection and an associated pathogen
2. Clinically documented infection - neutropenic fever with clinical focus (ex. cellulitis, pneumonia) but without the isolated of an associated pathogen
3. Unexplained fever - neutropenic fever with neither a clinical focus of infection nor an identified pathogen

• First neutropenic fever - first febrile episode occuring during a given period of chemo-induced neutropenia
• Persistent neutropenic fever - a febrile episode that persists after at least 5 days of initial empiric broad-spectrum antibacterial therapy in high-risk neutropenic patietns or after at least 2 days in low-risk neutropenic patients.

Question 29

Approaches to Management

Febrile Neutropenia

Answer 29

• Primary prophylaxis - Administration of antimicrobial drug to prevent infection in patient at increased risk
• Secondary prophylaxis - Administration of prophylactic doses of an antimicrobial drug to prevent recurrent infection
• Empiric therapy - initiation of therapy at time of onset of neutropenic fever but before firm diagnosis of infection
• Preemptive therapy - initiation of therapy based on screening with a sensitive microbiology assay

Question 30

Diagnosis of Neutropenic Fever

Answer 30

• Neutropenia - absolute neutrophil count < 1500 cells/microL
  
  • Severe - absolute neutrophil count < 500 cells/microL (higher risk)
• Fever in neutropenic patients is a single oral temperature of ≥ 38.8 ^oC or a temperature of ≥ 38.0 ^oC sustained over aone-hour period.
• Febrile neutropenia = neutropenia (<1500) + fever

Question 31

Pathogensis Febrile Neutropenia

Answer 31

• Contributory factors:
  
  • Effects of chemotherapy on mucosal barriers and the immune system - mucositis can result in seeding of the bloodstream from endogenous flora in the GI tract
  • Breeches in host defense related to the underlying malignancy
• Common Pathogens:
  
  • Bacterial - Gram- positive bacteria (Staphylococcus epidermidis, staphylococcus aureus, streptococci)
  • Fungal - common in high risk patients (Candida spp, aspergillus spp)
• Viral Pathogens:
  
  • Certain virus (HSV) are common in high risk patients

Question 32

Management Neutropenic Fever

Answer 32

• Important to recongize early and initiate antibacterial therapy quickly to avoid progression to sepsis.
• Antibiotics should be started within 60mins of presentaiton and blood cultures should be obtained right before starting therapy
• Even when pathogen in known, antiboitics should be provide broad spectrum coverage due to possibility of other pathogens in the immunocompromised host

Question 33

Chronic Leukemia

Answer 33

• Caused by chromosomal abnormalities - deletions, translocation, trisomy.
• Cells only mature partially (vs. acture leukemia where they don’t mature at all).
  
  • These cells don’t work effectively and thus result in a weakened immune system.

Question 34

Chronic Myeloid Leukemia (CML)

Answer 34

• Affects granulocytes (neutrophils, basophils, eosinphils)
• Chromosomal changes alter normal cell cycle - cells divide too quickly (results in too many premature cells)
  
  • Philadelphia chromosome - translocation between chromosome 9 and 22. Results in a BCR-ABL gene codes for a BCR-ABL proteins that activates tyrosine kinases, this causes myeloid cells dividing faster than they should.
• Leukocytes accumulate in the bone marrow and eventually spill into the blood
  
  • Some cells settle into organs and tissues and others continue into circulation. Healty cells in the blood get “crowded out” and can’t compete for nutrients resulting in cytopneia (ex. anemia, thromobocytopenia, and leukopenia)
  • Premature leukocytes can accumulate in the liver and spleen resulting in hepto-or-spleno-megaly.
  • Since myelodi cells are diving so quickly they have the potential to progress to a acute leukemia known as a “blast crisis”.

Question 35

Chronic Lymphocytic Leukemia (CLL)

Answer 35

• Affects lymphocutes, especially B cells
• Chromosomal changes alter normal cell cycle - cells don’t die as they should - results in too many premature cells
  
  • Unknown which mutations cause CLL
• Leukocytes accumulate in the bone marrow and eventually spill into the blood
  
  • Some cells settle into organs and tissues and other continue circulation. Healthy cells in the blood get “crowded out” and can’t compete for nutrients resulting in cytopenia (ex. anemia, thrombocytopenia, and leukopenia)
  • B cells start to interfere with the pathways of B cells receptors that should only be signalled during inflammation to acticate specific tyrosine kinases. Interference with tyrosine kinases prevents maturation and prooper cell death
  • Immature B cells spill out into the blood and may accumulate in the lymphatic system (especially lymph nodes) resulting in lymphadenopathy and may result in lymphoma.

Question 36

Symptoms of Chronic Leukemia

Answer 36

• Fatigue - anemia
• Easy bleeding - thromobocyopenia
• Infections - Leukopenia
• Hepatoplenomegaly (CML)
• Lymphadenopathy (CLL)