What is the stem cell problem in the following conditions:
- Aplastic anemia:
- Myeloproliferative Syndromes:
- Acute Leukemia:
- Aplastic anemia: stems are gone
- Myeloproliferative Syndromes: SCs lead to progenitros with increased proliferation, normal maturation
- Myelodysplasia: SCs support ineffective hematopoiesis (seems to mature, but ineffective; low counts but cellular marrow)
- Acute Leukemia: SCs proliferate but do not mature
What does this show?
Blasts (probably lymphoid)
- Not as distinct nucleoli as myeloblast
- Little cytoplasm
Thyroid mass suggests what?
TdT(+) is a marker of what?
Very young cells
What is CD34(+) a marker of?
Stem cells (very young)
What is t(11;19) associated with?
- Prevalent in childhood and infant ALL
- Associated with CNS involvement and a poor prognosis
What is the genetic alteration common in childhood/infant ALL and associated with CNS involvement/poor prognosis?
What are some characteristics of ALL?
Acute Lymphocytic Leukemia (ALL):
- Bone marrow > 30% lymphoblasts
- May present as mediastinal or LN only: lymphoblastic lymphoma
- Acquired somatic mutations in a single lymphoid progenitor cell
- The blast shares many features of normal lymphoid progenitors-- "arrested development"
Clinical presentations of ALL?
- Arthralgias, arthritis
- Fever, Infection
What is this?
Acute Lymphoblastic Leukemia
Epidemiology of ALL?
Most common type of leukemia in children
- Children > adults
- Males > females
- Whites > blacks
85% B cell; 15% T cell
T/F: Pts with ALL commonly present in a characteristic way? How?
False; there is variable presentation
What are the variable presentations of ALL?
- Completely asymptomatic: 1-2% (CBC may be wnl or very closely to nl)
- Significant HSM in 2/3
- Clinically significant adenopathy in 1/2
- Fever in 60% (life threatening sepsis at Dx is rare but not impossible)
- Bone pain in 1/4
- Some bleeding manifestation (petechiae, purpura) in 1/2
Variable prodromal period:
- Vague hx of not feeling well for days-weeks (THIS IS AN ACUTE PROCESS)
- Occassionally several months (BEWARE PRE-TREATMENT, e.g .steroids)
What causes ALL?
- Don't know; idiopathic
- In utero events (1, 2, vs. 10,000 "hits")
- Environmental exposure/drug-toxin metabolizing genes
- Blasts vs. the immune system (stochastic?)
ALL is associated with what other conditions?
- Unstable genes: ataxia telangiectasia, Bloom, Fanconi
- Wiskott Aldrich, congenital Hypogammaglobulinemia
- In utero: high risk for twin if one twin has ALL
DDx of ALL?
- Juvenile rheumatoid arthritis
- infectious mononucleosis
- Pertussis and Parapertussis
- Aplastic anemia
- Other viral illnesses
When should a pediatrician consider Dx of ALL?
- Unexplained adenopathy or marked HSM
- Bone pain
- Bleeding symptoms/pallor
Meets the threshold of obtaining a CBC:
- 2+ more cell lines "down" or WBC up and one other line down
Incidence of acute lymphoid leukemia by age?
More in KIDS
- Peak at 4 yo
- 75% of childhood leukemia
- Most common pediatric cancer
What is this?
Lymphoblasts in CSF from ALL patient
What is a big difference between ALL and AML?
ALL commonly includes CNS involvement
- Like meningitis, with headache and CN palsies
What is the typical presentation of T cell ALL?
Young boy with a mediastinal mass
- If there is no bone marrow involvement, we call this "lymphoblastic lymphoma" (can be B or T cell disease)
- If you wait long enough, you will have bone marrow and peripheral blood involvement
- Same treatment as ALL, just lymphoblastic lymphoma is the lymph node version
Types/characteristics of ALL in terms of cell types involved and presentation?
Lymphoblasts in bone marrow and blood
- FAB L1, L2
- Mediastinal or lymph node T-cell blasts
- Rare Patients have a B-cell phenotype
FAB L3 leukemia
- Burkitt’s lymphoma
Molecular markers of B cell development
Molecular makers of T cell development
Which antigen markers do we care about the most?
- "Stem cell":
What are current classification methods of ALL?
- FAB classification on Wright Stain (L1-3)
- Other morphological and special stain criteria (PAS stain)
- Cytogenetics (ploidy/DI;standard G-banding, FISH, RT-PCR)
- Molecular/Experimental: cDNA microarray
What is the breakdown of immunophenotypes in ALL?
B-cell precursor ALL: 85%
T-cell precursor ALL :13-15%
B-cell ALL: 1-2%
*Cytogenically, adults are not just big children
What are some chromosomal findings with poor prognostic significance in ALL?
- t(4;11): AFP and MLL/ALL-1/HTRX
- t(1;19): E2Aa and PBX1
- t(9;22): Bcr/ABL (Philadelphia chrom)
- Extreme hyperdiploidy (i.e. tetraploidy)
What are some chromosomal findings with good prognostic significance in ALL?
- t(12;21): TEL and AML1 (RT-PCR or FISH)
- Trisomy 4 and 10 (17 but not 5)
What are some good clinical prognostic factors in ALL?
- female sex
- age 3-8
- low WBC
- Pre-B phenotype
- C10 (CALLA +)
- low LDH
- hyperdiploid cytogenetics
What are some poor clinical prognostic factors in ALL?
- male sex
- age above 8
- high WBC
- L3, T-cell
- CNS presentation
- high LDH
- Ph chromosome
What are some accepted principles of therapy in ALL?
One drug is NEVER enough
- Duration of therapy should be > 18 months (130 weeks on POG protocols, COG 2.5 years for girls and 3.5 years for boys)
- Sanctuary sites need special consideration—primarily CNS
- Intensity is scaled to risk, but variation in intensity is important
Emerging principles of therapy in ALL?
Early Response and Degree of that response may be the most important prognostic indicator
- Minimal Residual Disease (MRD) is probably important
- Relapse is the worst prognostic sign and salvage rate will depend on timing of the relapse and the intensity of the initial therapy
Active Agents to use (chemo) for ALL?
- L-Asp (Ecoli, Erwinia,Peg)
- Daunomycin (all anthra)
- Cytoxan (other alkylators)
- Ara C
- 6 mercaptopurine (6MP), MTX
Common Approaches to ALL Therapy?
(Don't need to know details)
- CNS as a sanctuary is a worry
- Bone marrow transplant used in first remission for high risk disease or in 2nd remission
What is BiTE? CAR?
Bispecific T cell engager
- Targets malignant T cells??
Chimeric Antigen Receptor (CAR) involved in harnessing your T cells
- Anti B19 CAR T used in ALL with 70-90% response rates
- Often durable but at least allow segue to transplant
- Cytokine release syndrome
- B cell depletion
What does this show?
Burkitt cells in the blood and marrow
- Characteristic appearance in peripheral blood with medium sized cells with open nuclei and nucleoli visible; cytoplasm is very blue with vacuoles
- Can be a leukemia-- L3 in FAB classification
Important genetics in Burkitt lymphoma?
What is Burkitt lymphoma?
- African variety: jaw tumor, strongly linked to Epstein-Barr Virus infection (50% BL due to EBV in US)
- May present as abdominal mass
- Most rapidly growing human tumor
- Treated with multidrug regimen similar to pediatric leukemia/lymphoma regimens
What is shown here?
Jaw tumor characteristic in presentation of Burkitt lymphoma (African variety)
What is this?
Burkitt lymphoma (Starry Night cells)
What is Tumor Lysis Syndrome? When does it occur?
Occurs in ALL L3 and Burkitt's Lymphoma
- High grade lymphomas
- AML less often
Massive tumor death results in:
- High LDH
- Increased Uric Acid
- Increased Phosphate
- Renal Failure (urate nephropathy, CaPO4 crystals)
How can Tumor Lysis Syndrome be prevented?
- Recombinant uricase