ALL Flashcards
Bad cytogenetics in children with ALL
-Ph+ t(9;22)
-MLL translocations (involving 11q23)
-Hypodiploidy (<44 chromosomes, <40 even worse, near haploidy <24)
-intrachromosomal amplification of 21 (iAMP21)
-Abnormal 17p, loss of 13q have been shown to be poor in some reports
NOTCH1/FBXW7 mutations and RAS/PTEN germ line status, MRD, and white blood cell count were the 3 most discriminating variables independently predictive of relapse
Good cytogenetics with pediatric ALL
High hyperdiploidy (may not be considered a translocation technically) (23-30%)
Translocation = t(12;21) – ETV6-RUNX1 (20-25%)
NOTCH1 mutations, favourable in T-ALL (molecular).
Describe the pathobiology and prognosis of Mature B cell ALL in children
-Almost all cases of mature B cell ALL are associated with the t(8;14) MYC/IGH translocation
-mature B cell ALL may represent a disseminated form of Burkitt’s lymphoma
-mature B cell ALL responds poorly to conventional ALL treatment but has a better response to therapy designed for Burkitt’s lymphoma (ex: CODOX-M/IVAC)
Name long-term sequelae for pediatric survivors of ALL
- Secondary malignancies
2.Cardiomyopathy from anthracyclines - Psychosocial difficulties, depression, anxiety, chronic fatigue
- Dental disease (cranial radiation)
- Cataracts (radiation and IT chemo)
- CNS
-neurocognitive problems (radiation and IT chemo)
-stroke (cranial radiation) - Endocrine
-Gh deficiency: sexual delay, growth retardation
-Hypothyroidism (craniospinal irradiation)
-Obesity/Metabolic syndrome (irradiation/glucocorticoids)
-Decreased BMD (glucocorticoids /irradiation)
-Infertility (less so with current regimens)
*We don’t routinely use RT anymore, so the RT ones are less relevant
Bad cytogenetics in adults with ALL
t(9;22)
t(4;11) -KMT2A (MLL)
11q23-KMT2A (MLL)
Low hypodiploidy (esp <40 chrom)
BCR-ABL-like CRLF2
Complex karyotype
t(8,14)
Molecular:
IKZF1 (IKAROS) and TP53 gene mutations, early TPLL on flow
Non-cytogenetics poor prognostic features in ALL
- Age
-18-35 (5y OS 50%), 35 – 60 (5y OS 35%), >60 (5y OS 10%) - WBC
-poor prognosis if > 30 (B-ALL) vs. >100 (T-ALL) - Failure to achieve CR after first induction
- MRD status (more than 0.01 percent post-induction)
What chromosomal abnormality is usually associated with mature B-cell ALL?
Burkitt’s
t(8;14) = IgH - c-myc
t(2;8) = K-light chain – c-myc
t(8;22) = L-light chain – c-myc
CD19+, HLA-DR+, CD34+, CD10-, CD15, CD33. Name the most likely cytogenetic abnormality in child with B-ALL
t(4;11) [MLL- AF4+}
Germline MLL (also known as KMT2A) on chromosome 11q23
-CD10- is the key!
-aberrant myeloid markers such as CD15, CD33, CD68 (not mixed pheno)
-frequently seen in infants (<1 year of age), often associated w/ WBC >100
-poor prognosis
What % of childhood ALL has MLL abnormalities & significance? What does MLL do?
-5% of paediatric and 60% of infant ALL
-MLL = mixed lineage leukemia gene, now called KMT2A
-KMT2A = lysine [K]-specific methyltransferase 2A
this is a histone (H3K4) methyltransferase, involved in epigenetic regulation
-poor prognostic factor, poor response to therapy
Pui et al NEJM 2003–>extended follow-up of long-term survivors of childhood ALL. 3 long-term sequela of CNS radiation?
- Secondary malignancies
-Incidence of 21% vs. 0.9% at 20 years
-BCC, meningioma, brain tumor, sarcoma, lymphoma - Slightly increased mortality compared to general pop
- Increased unemployment rate (men: 15 vs. 5%; F 35% vs. 5%)
- Women in irradiated group were less likely to be married
Management of CN palsies in pt with pre-cursor B-ALL
IT chemo +/- CNI
MTX 12 mg, ara-C 40 mg / hydrocortisone 50 mg
If initial CSF+, continue IT chemo twice weekly CSF clear x 3.
MOA of Ondansetron and Aprepitant
a. Ondansetron: Serotonin 5’HT3 inhibitor
b. Aprepitant: Neurokinin 1 (NK1) inhibitor that binds to substance P
Major side effects of asparginase?
Hypersensitivity / anaphylaxis (common); erwinase/peg-asparaginase have lower risk of this
Thrombosis
Hyperglycemia (can reduce serum insulin levels)
Acute pancreatitis (2-5%)
Headache/lethargy
Hepatic toxicity
Decreased fibrinogen
4 methods to determine MRD status in ALL in order of sensitivity.
From most sensitive to least:
1. NGS
2. PCR for specific genes (BCR-ABL, KMT2A)
3. PCR for TCR/ IG gene rearrangements
4. Flow cytometry to detect LAIP (leukemia associated aberrant immunophenotype)
5. Cytogenetics, to determine chromosomal abnormalities.
5 favourable pre-treatment prognostic features in childhood ALL?
Favorable:
Age 1-9
WBC <50
B >T
Genotype: Hyperdiploidy >50, ETV6-RUNX1
MRD after induction <0.01% (not pre-treatment prognostic marker)
NOTCH1 (T cell ALL), FBCW7 = good
