Advanced Topics Block
CBI-2: “3-year-old female with pallor”
Initial case presentation
Initial case presentation:
Sonia Armenta is a 3-year-old Mexican-American girl who is brought to her primary physician with a 1 week history of pallor
and listlessness.
Differential Dx:

Anemia (spherocytosis, autoimmune, etc)

Hypothermia

Leukemia (ALL/Burkitt’s)

Hypercalcemia

Infection

Hypothyroidism

Nutritional Deficiency

Renal dysfunction

Lead poisoning

Accidental Ingestion/poisoning

Celiac Disease/Malabsorption

Hemorrhage (Meckel’s Diverticulum)
History:

Previously healthy

Marked pallor

Decreased activity and energy

Intermittent leg pain several times in the past week

No change in growth velocity in past 6 mos

No bruising/bleeding
Physical

Tachycardia

Pale bulbar conjunctivae/oral mucosae/faintly yellow skin

III/VI systolic ejection murmur loudest at pulmonic area +S3. (Pulmonary stenosis? Flow murmur?)

Hepatosplenomegaly

Scattered petechiae on arms and abdomen (thrombocytopenia)
Labs

Lymphocytosis

Hyperuricemia

Thrombocytopenia

Elevated LDH

Low Hb (2.2)

Retic Index: Retic Count x (Pt Hct/Normal Hct)

Hypocalcemia

Smear: Blasts seen
Learning Objectives:

Hematopoesis (Martin)

Reticulocyte count and RI corrections, LDH/uric acid/other labs, petechiae VS ecchymosesreasons they would be
elevated (Michelle)

ALL (Steve)
o Clinical presentation, blood/marrow analysis, epidemiology, genetics

AML (Raj)
o Clinical presentation, blood/marrow analysis, epidemiology, genetics

Lead Poisoning (Karen)

Leukemia Treatments and drug side effects in ALL (Nick)

Leukemia Treatments and drug side effects in AML (Mike)
Friday Session-Presentations
Hematopoiesis
 Formation of all blood cellular components.
 Components: Erythroid (RBC), lymphocyte (B, plasma, T, NK cells), myelocytes (PMN, eos, basos,
MKC’s, monos).
 PMN>lymphos>monos>eos>basos (Neutrophils Like Making Everything Better)
ALL

Malignant aggressive neoplasm of immature undifferentiated lymphoid precursor cells with abnormal
hematopoiesis. (B cell>T cell). Most common pediatric hematologic neoplasm.
 B-cell ALL presents as leukemia, T-cell ALL presents as a lymphoma.
 Presentation: Anemia, thrombocytopenia, neutropenia, B symptoms, HSM (invasion), lymphadenopathy,
CNS symptoms (invasion), mediastinal masses (in T-cell). Due to overwhelming of the bone marrow by
hyperplastic blasts.
 Bone marrow analysis: Infiltration of blasts (dark condensed chromatin with little cytoplasm)
 Cytogenetics: Hyperdiploidy, hypodiploidy, Philadelphia chromosome (t(9:22), TEL/AML (t(12:21) most
common), MLL, translocations involving chromosome 14 (T-cell).
 Risk Stratification:
o Low Risk: 1-10 yrs, WBC <50x10^9, hyperdiploid, TEL-AML. (>85% survival)
o High Risk: <1 or >10, WBC>50X10^9, BCR-ABL, MLL, hypodiploid, failure of induction, CNS Dz.
(>75% survival)
ALL Treatment
 Supportive: antibiotics, transfusions, metabolic, electrolyte.
 Induction: Vincristine + corticosteroids + asparaginase (90% enter CR). 3-6 cycles, short term.
o Response monitored by bone marrow assessment
o



AML

Adverse effects: tumor lysis syndrome (high uric acid, PO4, and K), thrombosis, bleeding,
infection
Consolidation: Methotrexate/cytarabine/anthracyclines/alkylating agents for 4-6 months.
o Goal: Prevent leukemic re-growth and reduce residual tumor burden.
o Levels based on risk
Maintenance: Daily 6-mercaptopurine with weekly methotrexate for 2-3 years.
Stem Cell Transplant:
o 1st remission high risk
o 2nd remission normal risk
Malignant aggressive neoplasm of immature undifferentiated myeloid precursor cells with abnormal
hematopoiesis.
 Clinical Presentation: Anemia, thrombocytopenia, neutropenia, headache, B symptoms, coagulopathies
(think DIC), HSM.
 Bone Marrow: Replacement of the normal marrow by myeloblasts with AUER RODS in the cytoplasm.
(Auer rods: composed of fused lysosomes with cytoperoxidase +. (Also seen in APL).)
 + Elevated circulating blasts.
 Cytogenetics: Multiple translocations are causative, t(15:17) most common.
AML Treatment
 Considerations: Patient age, past medical history, cytogenetics, functional capacity (Karnofsky/ECOG
score).
 Induction: Reduce tumor burden.
o 7+3 (7 cytarabine + 3 anthracycline)
 Consolidation: Eliminate leukemic cells.
o Good prognosis: Cytarabine (3 courses).
o Bad prognosis/2nd remission: Stem cell transplant.
o Anti CD33 Monoclonal Antibody (Gemtuzimab). Experimental.
 Relapse Therapy:
 Prophylaxis
o Hydroxyurea (lowering WBC counts), antibiotics.
 PML (M3 Leukemia): Treated with ATRA (VITAMIN A).
Lab Values
 Reticulocyte: Immature RBC. EPO stimulates marrow in response to low blood O2.
 Reticulocyte count: Measure of bone marrow response to anemia
 Corrections: Reticulocyte Index: (Retic%)(Pt Hct/45)(RMT)
o <1 indicates failure of the bone marrow response
o 4-5 considered good response
 LDH: Present in many tissues throughout the body. Nonspecific indicator of tissue destruction/cell
turnover.
 Uric Acid: Byproduct of purine nucleotide metabolism. Nonspecific indicator of cell turnover.
Lead Poisoning
 Cause: Repeated exposure to lead (ammunition factories, radiator repairs, lead paint, pica (in children),
lead plumbing, and gunshot wounds).
 Pathogenesis: Lead denatures enzymes involved in heme synthesis and ribosomal degradation.
 Clinical Presentation:
o Mental deterioration & slow growth in children
o Peripheral neuropathy (foot and wrist drop) and renal failure in adults
o Lead Lines (gums and long bones)
o Abdominal colic
 Lab:
o Microcytic sideroblastic anemia.
o Basophilic stipling of RBC’s

o Blood lead levels: >10 children, >15 adults (>70 MEDICAL EMERGENCY use chelation therapy)
Treatment: Chelation therapy (dimercaprol, CaEDTA, succimer-pediatric)
CBI-2: “3-year-old female with pallor”
RELEASE 4: Conclusion
Session #2 (Friday)
Sonia had early B-lineage ALL (Acute Lymphoblastic Leukemia). Her flow cytometry revealed an early (precursor) Bcell leukemia with the following pattern of reactivity: CD19 (for B cells), CD34 and Tdt (early lineage), CD10 (B –cell
associated) and HLA-DR (HLA Class II). Her cells do not express myeloid (CD13, CD33) or lymphoid linage markers
(CD2, CD3, CD7). Additionally, her cells are not mature enough to express surface immunoglobulins. She had
standard risk disease based on clinical and molecular features. She responded well to induction therapy and went
promptly into remission. She tolerated consolidation and maintenance well. She never required radiotherapy or
bone marrow transplantation. She is cured.
The majority of children diagnosed with ALL in the United States are treated on clinical trials, and it is through
these trials that improvements in treatment come about. ALL is the most common cancer in children, so a large
portion of the improvement in outcome shown in the figure below can be attributed to improvements in ALL
therapy.
Induction, consolidation and maintenance regimens are revised in an iterative fashion as clinical trials are
developed in order to improve outcomes for those with the poorest prognoses and decrease toxicity for those with
the most favorable prognoses.
Looking to the future for Sonia:
It is now 5 years later and you are seeing Sonia for a well child check. She is 8 years old but is one year behind in
school. Her mother explains that she had difficulty concentrating in school and did not catch on to math and
reading the way the other children in her class did. You find out that S. A.’s father had had learning disabilities, as
did her older brother.
Learning Objectives:
1.
2.
3.
4.
Integrate pathophysiologic and morphologic approaches to the classification of anemia in children.
 Pathophysiologic Classification:
o Increased Destruction: Hemolytic Anemia
 Intrinsic (IE spherocytosis, HbS) VS Extrinsic (IE WAIHA, CAIHA)
 Intravascular VS Extravascular
 Mechanical Hemolysis
o Decreased Production of RBC (IE aplastic anemia, renal failure w/low EPO, B12/folate
deficiency)
o Increased Loss
 Chronic hemorrhage
 Acute hemorrhage
 Morphologic Classification:
o Macrocytic: B12/folate deficiency
o Microcytic: Fe deficiency, anemia of chronic disease, hemosiderosis, thalassemia
o Normocytic: Aplastic anemia
o Hemolytic: Spherocytosis, G6PD deficiency, HbS, WAIHA, CAIHA, etc
Identify the 2 most common types of leukemia in children and explain the specific diagnostic procedures
needed to make a correct diagnosis.
 ALL: Bone marrow biopsy showing >20% blasts with immunohistochemical staining showing B-cell
markers (CD19, CD20, CD34 [general blast marker] TdT. Blasts may or may not be seen on peripheral
smears, but neutropenia, anemia, and thrombocytopenia are common.
 AML: Bone marrow biopsy showing <20% blasts with immunohistochemical staining showing myeloid
markers (CD13, 14, 15, and CD34). Blasts may or may not be seen on peripheral smears, but
neutropenia, anemia, and thrombocytopenia are common.
Analyze the concept of risk stratification in pediatric leukemia and identify the key determinants of risk in
childhood.
 High Risk:
o Philadelphia Chromosome
o MLL Karyotype
o Complex karyotypes
o Hypodiploid
o <1 or >10y/o
o >50x10^9 WBC’s
o Induction Failure
 Low Risk:
o TEL/AML
o 1-10 Y/o
o <50x10^9 WBC’s
o Hyperdiploid
Define the term “remission” and identify major components of therapy used to induce and sustain remission
in children with leukemia.
 Remission: Absence of disease activity in individuals with a chronic disease that cannot be cured.
Usually indicates complete absence of symptoms of disease, absence of serum biomarkers, and
cessation of growth in the case of cancer remission.
 Components of Therapy:
o Induction: Consists of vincristine, prednisone, and L aspariginase. Designed to get the patient
into remission. 90% of children attain remission after induction. Those that do not are
considered high risk cases.
o Consolidation: Consists of approximately 4-6 months of methotrexate (or another selected
chemotherapeutic drug). Designed to reduce residual tumor burden (it can never be
completely cleared), prevent drug resistance from occurring, and prevent regrowth of the
tumor.
o Maintenance: Maintenance can last up to 2 years and consists of weekly treatments of oral
methotrexate and daily oral vincristine. Designed to keep the patient in remission.
o CNS Prophylaxis: Intrathecal administration of methotrexate is often given to prevent spread
of the cancer into the CNS.
5. Explain the concept of “late effects” of therapy in the context of curable malignancies and connect late effects
to specific therapies.
Agents thought to be associated with long-term cognitive impairment are methotrexate, corticosteroids, and
possibly cytarabine. Two thirds of the studies of patients who received chemotherapy alone for ALL have indicated
that survivors experience some degree of cognitive decline. It has been postulated that CNS prophylaxis with
intrathecal chemotherapy may contribute to neural sequelae (ie chronic demyelinating encephalopathy), but
studies to date have not been conclusive. Learning disabilities are often multifactorial, and many children with ALL
are diagnosed during their preschool and early primary years. Therefore, in addition to having been exposed to
both systemic and intrathecal chemotherapy, these children have also been absent from preschool, kindergarten,
and the early grades to a greater extent than most of their peers. Whether effects of therapy are based on
pharmacology or early educational experiences, it does appear that young children surviving ALL therapy face
specific challenges that require attention from parents, health care providers, and educators.