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
5 unfavourable pre-treatment prognostic features in childhood ALL?
Unfavorable:
<1 or >10
WBC >50
T cell
Hypodiploidy <44, MLL, IKZF1 deletions or mutations, BCR-ABL “I kill zebra fish - but just 1 :)”
intrachromosomal amplification of 21 (iAMP21)
MRD after induction >1% (not pre-treatment prognostic marker)
KRAS, NRAS, PTEN = bad.
Homozygous, loss of function mutations in what gene result in ALL patients having severe hematologic toxicity to 6-MP unless the dose is reduced by 90% to 95% of normal?
TPMT (thiopurine methyl- transferase)
What are 3 indications and 3 treatments for T-LGL
- ANC <0.5
- ANC 0.5-1.0 with recurrent infections
- Transfusion dependent anemia
- Associated autoimmune condition requiring treatment
Tx
MTX
Cyclosporine
Cyclophosphamide
LGL = LMCC MTX Csa cyclophos
B-ALL with KMT2A rearrangement, what is the translocation?
t(v;11q23)
B-ALL with ETV6-RUNX1 rearrangement, what is the translocation?
t(12;21), good prognosis, almost always children.
High hyperdiploidy is associated with favourable outcome in ALL. How many chromosomes does this involve? What about low hypodiploidy?
51-67 chromosomes
32–39 chromosomes–a/w TP53 mutations
*hypodiploidy <44 chromosomes
*near haploidy (24–31 chromosomes)
A patient has an allergic reaction to asparginase. They are now recovered. What is one thing you should check in the patient that could affect their RR to treatment?
Asparginase activity. Often allergic reactions can be a/w antibody formation and inactivation of the drug. Must check that there is still activity on board, if not switch to peg-asp or Erwinia.
2 common molecular markers in ALL associated with down syndrome.
- JAK2
- CRLF2
CRying, Lonely and F*cked, you 2?
Tends to be megakaryoblastic
*T-cell and mature B-cell are quite rare.
What would be a single agent option for relapsed/refractory T-cell ALL? What toxicity must you monitor for?
- Nelaribine
- Peripheral neuropathy that can mimic Guillain-Barré syndrome (progressive, symmetric muscle weakness accompanied by absent or depressed deep tendon reflexes). Reduced consciousness, headache, and seizures have also been reported. Stop if any grade 2 toxicity or higher.
- now being used in the upfront setting in addition to chemotherapy for children.
