ALL Flashcards
What are important factors in the pathogenesis of Leukemia?
Ionizing radiation
Chemicals
Drugs-ie alkylating agents
Genetics
-twins-in 1st 5yrs of life the risk of the second twin is 20%
-siblings the risk is 4x greater than general population
-chromosome abnormalities
What is the risk of developing leukaemia in a Down syndrome patient before the age of 10yrs?
1 in 95
What is the definition of CNS1 for ALL?
<5 WBC/mm3
No blasts on spin
What is the definition of CNS2?
<5 WBC/mm3 and blasts on cytospin
What is the definition of CNS3?
> 5 WBC/mm3 and blasts on the slide
For a traumatic LP Tap what equation should be used to determine if cns disease is present?
CNS disease is present if: CSF WBC/CSF RBC >2x blood WBC/blood rbc
ETV6-RUNX1 fusion gene involves which 2 chromosomes
t(12;21)
BCR-ABL fusion gene is associated with what features at diagnosis?
Older age
Higher WBC
Cns involvement
What translocations involving the MYC genes are seen in mature B-cell ALL
8;14 is most common
Then 2;8 and 8;22
What does the NOTCH1 gene code for?
Encodes a transmembrane receptor that regulates normal t-cell development
What are the 2 most NB predictors of outcome?
Age and WBC
List the prognostic factors for ALL
Age WBC Immunophenotype Cytogenetics DNA index Response to induction CNS status
What is an M1 marrow
What is an M2 marrow?
5-25% blasts
What is an M3 marrow?
> 25% blasts in marrow
What is the lowest level of MRD detection by morphology
5 leukaemia cells per 100 normal bone marrow cells
What is the level of detection of MRD by multicolour flow cytometry?
1 per 10,000
What is the level of detection of MRD by PCR?
1 per 1,000,000
What drugs are used in standard risk ALL therapy
Induction?
Dexamethasone Vincristine Asparaginase IT cytarabine IT MTX
What drugs are used in standard risk ALL therapy
Consolidation?
6-mp
Vincristine on day 1
IT MTX
What drugs are used in standard risk ALL therapy
Interim maintenance
Capizzi MTX
Vincristine
For capizzi MTX what is the dose escalation and when do you not escalate
Escalate by 50mg/m2/dose on days 11,21,31,41
Stop escalation and resume at 80% of last dose if there is a delay because of mucositis or myelosuppression
What drugs are used in standard risk ALL therapy
Delayed intensification?
Dexamethasone Vincristine Doxo day 1,8,15 25mg/m2 Cyclophosphamide day 29 1000mg/m2 6-TG IV cytarabine 2, 4 day courses IT MTX
What drugs are used in standard risk ALL therapy
Maintenance ?
Dexamethasone 5 day courses at beginning of each month Vincristine 6-MP Oral MTX, omit on IT days IT MTX
How long is maintenance therapy?
2 years for girls from start of IM1
3 years for boys from the start of IM1
For HR and VHR ALL treatment how is induction different from standard?
Daunomycin is added
Prednisone for those >10yrs, dexamethasone for those that are younger but only 14 days, however use 10mg/m2
For HR and VHR ALL treatment how is consolidation different from standard?
Lasts 9 weeks
Cyclo/AraC added
Peg-asp added
(SR has VCR, 6-MP, 3xIT)
For HR and VHR ALL treatment how is in
IM1 different from standard?
Lasts 63 days
Get high dose MTX 5g/m2 with leucovorin rescue at hour 42 after the start of HD MTX infusion
Oral 6-MP
For HR and VHR ALL treatment how is DI different from standard?
2 doses of Peg-asparaginase
What poor prognostic factors are associated with infant ALL?
High initial WBC Massive organomegaly Thrombocytopenia Cns leukaemia Failure to achieve complete remission by day 14
Where is the MLLgene located?
Band 11q23
What adverse independent prognostic features are associated with infant ALL?
Age less than 3 mth
High wbc
Slow response to induction
Presence of translocation at 11q23
ALL in trisomy 21 is associated with which cytogenetic subtypes?
Jak2 mutation
Fusion between P2RY8 and CRLF2
Absence of hyperdiploid, ETV6-RUNX1
ALL in trisomy 21 is rarely or almost never associated with this subtype?
T-cell ALL
Infant ALL negative risk factors
WBC > 300
Age < 3 months
MLL
ALL favourable prognostic factors
NCI - Age 1-10, WBC < 50 Immunophenotype - B>T (less so now) Hyperdiploid (DNA 1.16) (12;21) ETV6-RUNX1 MRD negative
ALL negative prognostic factors
NCI - Age < 1 or >10, WBC > 50 CNS positive Trisomy 21 Hypodiploid (<44 chrom) t(9;22) BCR-ABL1 Ph-like ALL t(v;11q23) MLL (KMT2A) - (4;11) is most common t(1;19) and t(17;19) - associated with hypercalcemia & DIC iAMP 21 IKZ mutations MRD positive
Genetic conditions associated with ALL
Congenital agammaglobulinemia Poland syndrome Shwachmann Diamond syndrome Ataxia telangiectasia Li-Fraumeni Neurofibromatosis Diamond-Blackfan Kostmann disease Bloom syndrome
Options for CNS directed therapy
Intrathecal chemotherapy
Irradiation
Systemic chemotherapy - dexamethasone, MTX
Systemic depletion of asparagine - L-asparaginase does not penetrate CNS
Indications for HSCT in CR1 for ALL
Hypodiploid ALL (<44 chromosomes)
End consolidation MRD > 0.01
Induction failure
MLL + Infant ALL (controversial)
What is the risk of developing ALL in identical twins less than 12 months old?
100%
Believe that there is transplacental transfer of cells with a chromosomal translocation leading to ALL
Patients with Ataxia Telangiectasia are at risk for which type of ALL?
T-ALL
and also T-NHL
Are patients with Neurofibromatosis more likely to develop AML or ALL?
AML»>ALL
CD45 characterizes which type of cell?
Hematopoietic cells
What is the most common immunophenotype for pre-B ALL?
CD10+ CD19+ CD22+ CD79a+ Can express myeloid markers CD13+ or CD33+
Is it common for pre-B ALL to be HLA-DR+
Yes almost all are positive
compared to to T-ALL where most are HLA-DR negative
What is a common immunophenotype for T-ALL
cytoplasmic CD3+, often surface CD3+, CD7+, Tdt+
Can express CD2,4,8
CD10 expression is variable
Is pre-B ALL surface Ig positive or negative
Negative!
Being positive is a mature B cell marker, ie Burkitts leukemia is surface Ig positive
Which translocation is associated with ALL and hypereosinophilia?
t(5;14)
eosinophilia is reactive and not part of the leukemic clone
List a differential diagnosis for pancytopenia in childhood
Leukemia Metastatic solid tumour Aplastic anemia HLH MDS/myelofibrosis Infectious or post-infectious Lupus hypersplenism B12 or folate deficiency
What prognostic factors are important for ALL relapse?
site- marrow worse than extramedullary
timing-early worse than late
age at initial dx-older worse than younger
immunophenotype- T-ALL tough to cure
When can isolated CNS relapse patient be treated with systemic therapy and radiation alone?
If the relapse is longer than 18 months from the first remission. If relapse is earlier than the first remission they should be put into remission and then undergo HSCT
What is blinatumomab
A bi-specific T-cell engager monoclonal antibody against CD19
What pre-disposition syndrome is associated with low hypodiploid ALL?
p53/Li Fraumeni
What surface and cytoplasmic Ig are expressed in pro-B ALL?
CD19+ CD10- cIg- sIg- Often M-R
What surface and cytoplasmic Ig are expressed in Pre-pre-B ALL?
CD19+
CD10+
cIg-
sIg-
What surface and cytoplasmic Ig are expressed in pre-B ALL?
CD19+
CD10-
cIg+
sIg-
What surface and cytoplasmic Ig are expressed in nature B (Burkett) ALL?
CD19+
CD10+ or -
cIg + or -
sIg+
What is lack of CD10 expression commonly lined with?
MLL rearrangement
What are 4 findings on X-ray that you might expect to see on a patient with ALL?
Osteolytic lesions involving medullary cavity and cortex.
Transverse metaphysical radiolucent bands.
Transverse metaphysical lines of increased density (growth arrest lines).
Subperiosteal née bone formation.
What is the Steinherz-Breyer equation used for? And what is it?
Used to determine significance of a bloody tap.
CSF WBC/CSF RBC > 2x Blood WBC/Blood RBC
What is the genetic polymorphism that catalyzes the inactivation of mercaptopurine?
Gene polymorphism for thiopurine methyltransferase.
10% of the population carries at least one variant allele. Results in high levels of the active 6MP metabolite, and increases side effects. Requires decreased doses.
AALL0331 - LR trial: main outcomes?
Intensified Consolidation did not improve SR-Avg pts
AALL0232 - HR trial: main outcomes?
- Interim analysis showed HD MTX better than capizzi. 5yr EFS 82%vs 75%.
- Pts <10yrs had better outcome with dex.
- Pts >10yrs dex showed no benefit, associated with more osteonecrosis, should receive prednisone
AALL0434 - T-ALL trial : main outcome?
Capizzi-Style Methotrexate with Pegasparagase (C-MTX) Is Superior to High-Dose Methotrexate (HDMTX) in T-Lineage Acute Lymphoblastic Leukemia (T-ALL):
Interfant 99 - main outcomes?
- Efficacy of a hybrid protocol demonstrated MLL rearrangement, age <6 months at diagnosis and poor day 8 prednisone response identified as independent adverse prognostic factors
- No benefit from adding a late intensification course
- Prognostic impact of MRD following induction and consolidation identified
- Risk of relapse significantly higher for congenital ALL
- HSCT beneficial for MLL-rearranged infants aged <6 months and poor day 8 prednisone response or WBC ≥300 g/l at diagnosis
List 3 modifications to therapy or management in Down syndrome ALL
- limit dose of HD mtx
- Leucovorin with IT chemo
- prophylactic IVig replacement
- remain hospitalized until count recovery
- prophylactic anti-fungal therapy
- conservative F&N management
What additional therapy do HR B-ALL patients receive compared to standard risk?
1) Dauno in induction
2) Intensified consolidation
3) IM#1 has HD-MTX
4) DI part 2 has additional VCR/Peg
5) IM#2 for VHR with 2 more Peg
6) Extra IT therapy in maintenance (even for CNS1)
ETP immunophenotype
cCD3 +,
Positive for immature markers: TdT, CD117, or HLA-DR
CD1a, CD5, CD 8 negative
Positive for one or more myeloid marker
