Acute Lymphoblastic Leukemia

Front 1

Least common type of leukemi in children

Back 1

CLL

Front 2

Acute Lymphoblastic Leukemia accounts for what percentage of Leukemias in children?

Back 2

80%

Front 3

Leukemias in children vs adults

Back 3

CLL most common in adults, ALL most common in children

Front 4

ALL epidemiology

Back 4

ALL is the most common childhood malignancy
In the U.S., ~3,000 children per year are diagnosed with leukemia; ~80% of these are ALL
peak incidence at age 2-5 years
whites > blacks
males > females
< 5% cases associated with ionizing radiation (pre- and post-natal) or a genetic syndrome such as Down syndrome, neurofibromatosis, Shwachman syndrome, Bloom syndrome, Ataxia telangectasia, Klinefelter syndrome
Evidence exists suggesting some cases have prenatal origins

Front 5

Clinical manifestations

Back 5

fatigue
pallor
bruising, bleeding
fever
lymphadenopathy
hepatosplenomegaly
mediastinal mass
pain (musculoskeletal)

Front 6

Laboratory findings in ALL

Back 6

Blood
leukocytosis or leukopenia (high or low white blood cell count, respectively); may see “blasts” on the blood smear
anemia (low hemoglobin/hematocrit)
thrombocytopenia (low platelets)
may see chemical abnormalities consistent with “tumor lysis” (increased uric acid, phosphorus, potassium, creatinine)

Front 7

Diagnosis

Back 7

>25% lymphoblasts in bone marrow
Lumbar puncutr also required for eval of CNS disease

Front 8

ALL Diagnosis and Classification

Back 8

Morphology (L1, L2, L3 – based on FAB criteria)
cytochemical stains (ALL vs. AML)
immunophenotyping - monoclonal antibodies reacting with cell surface antigens (ALL vs. AML, T vs. B lineage)

Front 9

ALL favorabe prognosis in cytogenetics

Back 9

Findings associated with a favorable prognosis
Hyperdiploidy (>50 chromosomes per leukemia cell)
t(12;21) translocation (TEL-AML1 fusion gene, aka ETV6-RUNX1)
Trisomies of chromosomes 4, 10, and 17

Front 10

ALL unfavroable prognosis in cytogenetics

Back 10

Findings associated with an unfavorable prognosis
Hypodiploidy (<44 chromosomes per leukemia cell)
t(4;11) translocation (MLL-AF4 fusion)
t(9;22) translocation (BCR-ABL fusion or Philadelphia chromosome)

Front 11

ALL L1 L2 morphology

Back 11

Precursor B cell (B-lineage, pre-B, early pre-B)
Precursor T cell (T cell)

Front 12

ALL Bcell L3 morphology

Back 12

mature B-cell, Burkitt cell leukemia)

Front 13

Precursor T cell (T cell) ALL

Back 13

associated with:
Males > Females
older age (5-12 years)
high WBC count
bulky adenopathy, mediastinal mass, hepatosplenomegaly
CNS disease

Front 14

ALL emergencies

Back 14

Sepsis (infection)
Bleeding (from thrombocytopenia)
Tumor lysis syndrome
Hyperleukocytosis (very high WBC count)
Tracheal compression/SVC syndrome

Front 15

Emergency ABC's

Back 15

ABC’s!
Airway
Breathing
Circulation
D-stick (check blood sugar level)
Exposure (undress to rule out penetrating injury)

Front 16

ALL treatment

Back 16

Combination chemotherapy
4 components of therapy:
1. Remission induction (~1 month)
2. Intensification (consolidation) (~6 months)
3. CNS treatment (throughout all phases)
4. Continuation (“maintenance”) (2-3 years)
Treatment generally lasts 2.5 - 3 years (exception is B-cell (Burkitt’s) ALL, which is treated intensively for only about 5 months)
stem cell/bone marrow transplants generally reserved for refractory disease or very high risk patients

Front 17

Commonly used drugs for ALL

Back 17

Steroids (prednisone, dexamethasone)
Vincristine
Asparaginase
Doxorubicin/daunorubicin (antharcyclines)
Methotrexate
Mercaptopurine
Cytarabine
Cyclophosphamide

Front 18

Newer Drugs for ALL

Back 18

Imatinib- BCR-ABL positive
Nelarabine- Tcell
Rituximab- CD20 positive
Clofarabine all subtypes

Front 19

ALL CNS treatment

Back 19

Intrathecal chemotherapy (delivered by lumbar puncture (LP)) – start on first day of therapy and continue throughout treatment duration (18-20 LPs over ~3 years)
radiation therapy (e.g. CNS positive at diagnosis or relapse, T-ALL)
Only 5-20% patients currently get CNS radiation
Can it be omitted for all patients?
high dose IV methotrexate - penetrates CNS

Front 20

Genetic Variability

Back 20

Host
Drug metabolism (affects efficacy and toxicity)
Leukemia cells
Intracellular drug levels

Front 21

Pediatric ALL prognosis

Back 21

Depends on multiple factors (age, WBC at diagnosis, etc. – see next slide) but prognosis is generally GOOD, with ~80% overall event-free survival (Unlike adult ALL, where prognosis is relatively poor - only 30-50% of adults are cured)

Front 22

Precursor B ALL- Favorable Prognostic Factors

Back 22

Age 1-10yrs, WBC <50K, no CNS disease, >50 chromosomes ( hyperploidy), Cytogenetics: t(12;21), rapid response to Tx

Front 23

Precursor B ALL unfavorable prognostic factors

Back 23

less than 1 y/o or >10. >50K WBC, CNS disease present, hypoploidy (<44 chromosomes), cytpgenetics: t (4;11), t(9;22), sloww response to treatment

Front 24

ALL risk Assessment

Back 24

Best done by combining the following data for each patient:
presenting clinical features (age, WBC count)
blast cell immunophenotype (T-cell vs. B-cell) and genotype (cytogenetics, other DNA tests)
early responsiveness to treatment
Patients are currently classified as low, standard, high, or very high risk

Front 25

Late effects of ALL therapy (and primary culprits

Back 25

Neurocognitive delay (CNS therapy)
Endocrinopathies (CNS therapy and steroids)
Gonadal failure/sterility (alkylating agents)
Cardiac dysfunction (antharcyclines)
Musculoskeletal disease (steroids)
Second malignancies (chemotherapy and radiation therapy)

Front 26

Relapsed ALL

Back 26

Longer first remissions are better than shorter first remissions
In general, prognosis for relapsed ALL is 30-50%
if long first remission - chemotherapy alone
if short first remission - stem cell transplant
CNS, testicles (“sanctuaries”) are a relatively common sites of extramedullary relapse