Classification and risk stratification in T-lineage acute lymphoblastic leukemia Flashcards
What have cure rates for patients with acute lymphoblastic leukemia (ALL) improved due to?
Risk stratification incorporating leukemia genomics, response to treatment, and clinical features.
What are the key prognostic factors validated in T-lineage acute lymphoblastic leukemia (T-ALL)?
- Age
- Central nervous system involvement
- Measurable residual disease (MRD) response
How is immunophenotype used in T-ALL classification?
It is widely used but not consistently associated with outcome in multivariable risk models.
What has recent genomic profiling identified in T-ALL?
Multiple genetic subtypes and alterations associated with outcome independent of MRD.
What is the purpose of risk stratification in acute lymphoblastic leukemia?
To group patients based on expected prognosis by integrating biologic biomarkers with demographics, clinical features, and therapy response.
What is the common treatment approach for high-risk patients with ALL?
They receive more intensive or alternate therapies, including immunotherapies and precision medicines.
What distinguishes low-risk patients with ALL?
They may be eligible for clinical trials exploring therapy reduction to mitigate toxicity.
What are some of the validated prognostic features in B-lineage ALL (B-ALL)?
- White blood cell count (WBC)
- Age
- CNS disease at diagnosis
- MRD response
- Subtype-defining genomic alterations (e.g., BCR::ABL1, ETV6::RUNX1)
What percentage of T-ALL patients who relapse are classified as ‘low-risk’ at diagnosis?
A large percentage.
What is the most common childhood tumor?
Acute lymphoblastic leukemia (ALL).
What percentage of childhood and adult ALL cases does T-ALL account for?
- Childhood: 10% to 15%
- Adult: 10% to 25%
In which demographic is T-ALL more commonly observed?
Males (~70% of cases).
What is a contributing factor to the increased frequency of T-ALL in males?
Frequent alterations of genes located on the X chromosome.
How does the prevalence of B-ALL and T-ALL differ based on self-identified race in the United States?
- B-ALL is more common in children self-identifying as White.
- T-ALL is more prevalent in patients self-identifying as Black or African American.
What disparity was found in outcome for children and AYAs with B-ALL based on race?
Substantial outcome disparities were found for those self-reporting as Black or African American and Hispanic.
Was there a difference in survival for T-ALL based on self-reported race or ethnicity?
No difference in survival was seen.
What is suggested about the timing of therapy for T-ALL compared to B-ALL?
Earlier courses of more intensive therapy may be more important for cure in T-ALL.
What may earlier relapses in T-ALL be linked to?
Resistance to antimetabolite-based maintenance chemotherapy.
What is the mechanism of relapse in T-ALL?
The clonal selection of blasts with genetic alterations in chemotherapy resistance genes, such as NT5C2.
Disparities related to adherence during maintenance may not affect outcomes to the same degree in T-ALL as in B-ALL.
What clinical features have historically been used for T-ALL risk stratification?
Mediastinal mass, CNS involvement, peripheral blood WBC, hemoglobin, platelet count, age, and splenomegaly at diagnosis.
Modern T-ALL risk stratification now includes MRD response.
Which factors remain independently prognostic in modern T-ALL risk stratification?
Age and CNS involvement.
Age at diagnosis is a strong predictor of outcome in both B- and T-ALL.
What is the prognosis for infants aged <1 year diagnosed with T-ALL?
Poor outcomes regardless of type of leukemia.
T-ALL is rare in infants and data are limited.
How does age affect prognosis in B-ALL?
Patients aged ≥10 years have a worse prognosis, with survival rates declining almost linearly with increasing age beyond 10 years.
What recent change has been made in B-ALL risk stratification algorithms regarding age?
Age is treated as a continuous variable rather than dividing patients into discrete groups.
What is the correlation between peripheral blood leukocyte count at diagnosis (WBC) and outcome in ALL?
WBC is correlated with outcome, often dichotomized in risk stratification.
In T-ALL, the prognostic impact of WBC is less robust.
What WBC count is often used as a cutoff for high- and low-risk groups in B-ALL?
50,000 cells per mL.
What WBC count is associated with inferior survival in children with non-ETP T-ALL?
> 200,000 cells per L.
What are the CNS status classifications used to predict outcomes?
- CNS-1 (no blasts)
- CNS-2 (blasts present with <5 cells per mL)
- CNS-3 (blasts present with ≥25 cells per mL).
What is the prognostic significance of CNS status in T-ALL?
CNS-3 predicts poorer outcomes despite intensive CNS-directed therapy.
How does the EGIL classify T-ALL?
Into 4 groups: pro-T ALL, pre-T/immature ALL, cortical T-ALL, and ETP ALL.
What immunophenotype defines ETP ALL?
Positivity for T-cell markers (CD2, cCD3, CD7), absence of CD1a, and positivity for at least one myeloid or stem cell marker.
How do survival rates compare between ETP ALL and non-ETP T-ALL?
Survival rates for ETP ALL are now comparable with those of non-ETP T-ALL.
What is the strongest predictor of outcome in T-ALL?
Therapy response.
What is the significance of early treatment response in T-ALL?
It correlates with outcomes but does not retain independent prognostic significance in all studies.
What are ‘prednisone good responders’ and ‘prednisone poor responders’ in T-ALL?
‘Prednisone good responders’ have <1.0 x 10^9 per liter blasts after prephase; ‘prednisone poor responders’ have higher levels.
What outcomes are associated with prednisone good responders in T-ALL?
Improved event-free survival (EFS) and overall survival compared to prednisone poor responders.
What was the prognostic value of early peripheral blood MRD response at day 8 of induction?
It had prognostic value in univariable analysis but not in multivariable analysis when end-of-induction BM MRD was considered.
Which time point is considered the best predictor of outcome in B-ALL according to the majority of data?
End-of-induction MRD assessment (time point 1).
What is a better predictor of adverse outcomes in T-ALL according to the AlEOP-BFM ALL 2000 study?
End-of-consolidation (EOC) MRD (time point 2).
What does EOC MRD assess?
MRD levels after completing the consolidation phase.
What percentage of patients were MRD positive on the AALL1231 clinical trial using a 0.1% threshold?
<5% of patients.
What is the definition of induction failure (IF) in T-ALL?
Varies across cooperative groups; some use BM blast percentage, others MRD, and some both.
What is the common threshold for defining induction failure in some cooperative groups?
≥25% BM blasts after induction.
What is the World Health Organization’s distinction in T-ALL?
Distinguishes ETP ALL and more differentiated T-ALL.
How many entities does the International Consensus Classification recognize in T-ALL?
3 entities and 8 provisional entities.
What are some identified oncogenes in T-ALL?
TAL1, LMO1, LMO2, TLX1, NKX2-1, HOXA9, TLX3.
What mechanisms commonly activate T-ALL transcription factor oncogenes?
Chromosomal translocations or enhancer alterations.
What study improved T-ALL classification using genetic alterations?
A study of 1309 pediatric and young adult cases subjected to whole-genome sequencing.
What percentage of disease-classifying driver alterations were found in noncoding regions?
59%.
What is a hallmark of ETP-like ALL?
Driver alterations of genes encoding known or putative regulators of hematopoietic stem cells.
What conclusion was drawn regarding immunophenotypic classification in T-ALL?
It is suboptimal.
Fill in the blank: The ETP-like subtype is distinct from the more differentiated _______ and HOXA9 TCR subtypes.
MLLT10/KMT2A.
What did early studies define as immature leukemia?
High expression of LYL1, LMO2, CD34.
What is the five-year event-free survival (EFS) percentage for T-ALL?
86%
Based on a cohort of 889 patients.
What is the five-year event-free survival (EFS) percentage for ETP ALL?
81%
Based on a cohort of 102 patients.
What does EFS stand for?
Event-Free Survival
List three genes associated with T-ALL classification.
- NKX2-1
- TLX1
- TAL1 DP-like
What is the survival probability (EFS) for Low-Risk T-ALL with NKX2-R?
93%
Based on a cohort of 84 patients.
What is the survival probability (EFS) for High-Risk T-ALL with SPI1-R?
34%
Based on a cohort of 11 patients.
Fill in the blank: The five-year EFS for Moderate-Risk T-ALL with LMO1/2-R is _____
88%
True or False: ETP-like T-ALL has a five-year EFS of 75% in the High-Risk category.
True
What is the five-year event-free survival (EFS) percentage for T-ALL NOS?
80%
Based on a cohort of 225 patients.
What does the term ‘ETP’ refer to in the context of T-ALL?
Early T-cell Precursor
Identify two pathways that are altered in T-ALL subtypes.
- JAK/STAT
- RAS
What is the significance of the log-rank test in this context?
It is used to compare survival distributions.
What is the five-year EFS for patients with KMT2A?
100%
Based on a cohort of 39 patients.
List two genetic subgroups that are separated from the ETP-like subtype.
- HOXA9
- MLLT10
Fill in the blank: The five-year EFS for patients with TLX3 is _____
89%
What is the five-year EFS for patients with NKX2-5?
62%
Based on a cohort of 8 patients.
What does the term ‘TME-enriched’ indicate in T-ALL classifications?
A subtype with specific genetic markers.
What percentage of patients with ETP-like T-ALL have a five-year EFS of 75%?
75%
Based on a cohort of 235 patients.
True or False: The five-year EFS of HOXA9 TCR is 100%.
True
What is the five-year EFS for patients with MLLT10?
79%
Based on a cohort of 31 patients.
What defines ETP-like T-ALL?
Defined by genomics and variable immunophenotype
What are the three subtypes of ETP-like T-ALL?
- ETP (38%)
- Near-ETP (34%)
- Non-ETP (28%)
What is the prognosis for ETP-like T-ALL?
Worse outcome and poor event/disease-free survival (EFS/DFS)
What is a common characteristic of ETP-like T-ALL regarding induction?
High end of induction MRD and high rates of induction failure
What percentage of ETP cases are ETP-like?
71% of ETP cases are ETP-like
What genomic subtypes are included in ETP-like T-ALL?
- ETP-like (70%)
- BCL11B (14%)
- TLX3 Immature (8%)
- Other (7%)
Do immunophenotypes impact EFS/DFS in ETP-like T-ALL?
No impact on EFS/DFS
What defines Non-ETP in T-ALL?
Defined by immunophenotype and variable genomic subtypes
What is the percentage of ETP-like cases in Non-ETP?
7% ETP-like cases in Non-ETP
What are some key genetic alterations associated with T-ALL?
- PIK3CD
- PIK3R1
- PTEN
- MTOR
- NRAS
- KRAS
What is the significance of NOTCH1 activation in T-ALL?
NOTCH1 activation has been associated with favorable outcomes
What was found regarding intronic NOTCH1 variants?
Worse outcomes for intronic NOTCH1 single-nucleotide variants and intragenic deletions
What do recent studies suggest about relapse in T-ALL?
Lack of a unifying genetic driver of relapse
What percentage of relapse cases in T-ALL had ETP immunophenotype?
~50% of cases were of ETP immunophenotype
What is the most prevalent mutation driving T-ALL relapse?
Activation of nucleosidase NTSC2, facilitating chemotherapy resistance
What other mutations are commonly enriched in T-ALL relapse?
- RAS-activating mutations in ~23%
- TP53 in ~8%
What is a hypermutator phenotype in T-ALL relapse?
Observed in ~8% of relapses and indicative of defective DNA mismatch repair
What does the emergence of dominant clones at relapse indicate?
Expansion of minor clones with NOTCH1, KRAS/NRAS, and CREBBP mutations
What age is considered a high-risk feature for T-ALL?
Age ≥30 y or Age <1 y
What is the WBC threshold for high-risk T-ALL?
WBC ≥200 000 cells per pL
What indicates a positive MRD at the end of induction?
End-of-induction MRD positive
What is a characteristic of the immunophenotype in high-risk T-ALL?
y T-ALL
What is the significance of the ETP ALL subtype?
Considered to be high risk
What genomic alterations are associated with ETP ALL?
NOTCHIWT, FBXW/WT, KRAS/NRAS, PTEN, KMTA-FO
What does CNS-3 indicate in T-ALL risk features?
CNS-3
What does a WBC count of ≥50 000 cells per L indicate?
CNS-2
Fill in the blank: The MRD threshold(s) used to distinguish favorable vs unfavorable risk T-ALL vary based on the treatment _______.
backbone
True or False: The study of Pölönen et al identified multiple genomic subtypes to be prognostic independent of MRD.
True
What is the significance of KMT2A rearrangement in T-ALL?
Associated with poor MRD response at end of induction
What subgroup displayed higher rates of MRD yet achieved favorable outcomes?
ZFP36L2 ETP-like subgroup
What is one reason for limited progress in identifying genomic alterations in T-ALL?
Few cases subjected to WGS
What is the impact of treatment response on identifying prognostic genetic alterations in T-ALL?
No study has been large enough for independent identification
What does the term ‘self-reported race: Black or African American’ indicate?
Needs validation
Fill in the blank: Immunophenotype-defined ETP ALL has been considered high risk and is considered in risk _______.
stratification
What is a common characteristic of ETP-like subgroups?
Often associated with worse outcomes
What is the outcome of BCL11B-activated subtype despite being highly enriched for ETP immunophenotype?
Relatively favorable outcome
What is the significance of the bone-marrow progenitor-like signature in T-ALL?
It serves as a tool for T-ALL risk stratification and is significantly enriched in the ETP-like subtype.
How are TAL1 subtypes classified?
By differentiation stage into aß-like and double positive (DP)-like subtypes, and further into genetic subgroups with varying clinical outcomes.
What characterizes the TAL1 DP-like subtype?
High expression of CD4, CD8, RAG1, and RAG2.
What are the four groups within the TAL1 DP-like subtype?
- RPL10 mutations (TAL1 DP-like RPL10)
- LEF1 SVs and deletions or LYL1 alterations (TAL1 DP-like LEF1/LYL1)
- Mutations activating JAK signaling (TAL1 DP-like JAK)
- Heterogenous additional lesions (TAL1 DP-like Other).
Which TAL1 DP-like groups have worse outcomes?
The TAL1 DP-like ‘LEF1/LYL1’ and ‘Other’ groups.
What defines the TAL1 aß-like subtype?
TCRaß rearrangements and high expression of the TCRa constant (TRAC) gene.
What are the three groups within the TAL1 aß-like subtype?
- PTEN deletions, PI3K pathway alterations, and NOTCH1 wild type (TAL1 aß-like NOTCH WT)
- Loss of 6q (TAL1 aß-like loss 6q)
- Other alterations including NOTCH1 mutations without 6q loss (TAL1 aß-like other).
Which TAL1 aß-like group had inferior outcomes?
The TAL1 aß-like ‘Other’ group.
What are the two subtypes of TLX3?
- TLX3 immature
- DP-like.
What is associated with the TLX3 immature subtype?
Worse prognosis and various colesions that deregulate kinase signaling.
What type of cancers frequently develop from the SPl1 subtype?
Secondary cancers related to dendritic cell-derived Langerhans cell histiocytosis and myeloid sarcomas.
What is the significance of the BRAF mutation in the SPl1 subtype?
It is related to clonal changes during the transformation from T-ALL to histiocytosis.
What demographic showed a higher risk for y T-ALL according to Kimura et al’s study?
Children aged <3 years and those with the STAG2/LMO2 subtype.
What characterizes the LMO2 yo-like T-ALL subtype?
Most cases harbor BCL11B::LMO2 rearrangements and frequently have poor response to induction therapy.
What has been reported about DNA CpG methylation in T-ALL?
Associations between DNA CpG methylation and outcome have been reported, but it is unclear if these are independent of genomic subtype.
What is the ‘CpG island methylator phenotype’ associated with?
Favorable prognosis in hypermethylated cancers.
What common alterations are seen in adult T-ALL regarding methylation?
Alterations in DNA methyltransferases (e.g., DNMT3A, DNMT3B) and in demethylase inhibitors (e.g., IDH1, IDH2).
What does the aberrant methylation profile reflect according to Roels et al?
The epigenetic history of T-ALL established in preleukemic thymocytes.
What is the goal of developing prognostic models for T-ALL?
To enable optimal risk stratification incorporating clinical and genomic information.
What is the only classifier applied across multiple cohorts for T-ALL?
A 5-gene risk classifier (NOTCH1, FBXW7, NRAS/KRAS, and PTEN).
What novel classification algorithm was proposed by Simonin et al?
An NGS-based risk classification algorithm for T-ALL that stratifies both adult and pediatric cohorts.
What genes are associated with favorable outcomes in the novel classification algorithm?
- NOTCH1
- FBXW7
- PHF6
- EP300.
What alterations are associated with higher relapse rates?
- NRAS
- KRAS
- PI3K pathway genes
- TP53
- DNMT3A
- IDH1
- IDH2
- IKZF1.
What are the two accurate risk frameworks developed by Pölönen et al?
- A penalized Cox regression model
- A survival tree.
What does the penalized Cox regression model incorporate?
Clinical variables, 5 subtypes, and 18 genomic alterations selected in a data-driven way.
What does the survival tree divide groups based on?
Subtype or genetic subgroup and MRD of ≤0.1% vs >0.1%.
What is essential for advancing the understanding of T-ALL?
Integrated analysis of WGS and WTS data to identify genomic alterations defining disease subtypes.
What is pivotal for accurate T-ALL classification and prognostication?
Identification of 15 subtypes of T-ALL and drivers by genomic analysis
Validation of findings in independent cohorts is essential.
What has proven valuable in the prognostic classification of acute myeloid leukemia?
Assessing the allelic fraction of FLT3 internal tandem duplication
Screening for similar biomarkers in T-ALL could offer significant prognostic insights.
What factors require evaluation in T-ALL outcomes?
Germ line predisposition and genetic ancestry
These factors can influence prognosis and treatment responses.
What is necessary for understanding different T-ALL subtypes?
Mechanistic studies and assessing targetability to precision medicines
This understanding is crucial for developing effective treatments.
What percentage of childhood T-ALL cases are predicted to be sensitive to dasatinib?
~40%
Sensitivity is based on pre-TCR-LCK activation, enriched in cases with TAL1, TAL2, or LMO1/2 overexpression.
What are the two TAL1 subtypes mentioned?
- TAL1 aß-like subtype
- TAL1 DP-like subtype
These subtypes correspond to specific T-cell maturational stages.
What vulnerability was identified in the STAG2/LMO2 subtype?
DNA repair pathway vulnerability from STAG2 inactivation
This can be targeted by poly(adenosine 5’-diphosphate-ribose) polymerase inhibitors.
What is the goal of genomic profiling in T-ALL?
To identify patients more likely to benefit from targeted therapies
This is an important area for future investigation.
What relationship requires further investigation in T-ALL?
Mechanisms of relapse and their relationship to specific subtypes
Current analyses have focused predominantly on genetic drivers of relapse.
What emerging area presents a promising opportunity for research on relapse?
Nongenetic mechanisms of relapse and treatment resistance
Noncoding alterations in relapse have been previously underexplored.
What have TAL1 enhancer indels and hijacking of enhancers been linked to?
A higher cumulative incidence of relapse
This includes alterations involving LMO2 and NOTCH1 intragenic deletions.
What does the latest research provide for T-ALL disease biology?
A roadmap for mechanistic understanding of T-ALL disease biology and progression
This includes advancements in classification and discovery of key relapse mechanisms.
What is the next key phase in T-ALL research?
Benchmark disease classification and risk stratification approaches in independent cohorts
Translating genomic knowledge into improved treatment strategies is crucial.
What are the potential outcomes of improved T-ALL treatment strategies?
- Higher remission rates
- Lower relapse rates
- Increased survival rates
These outcomes are essential for enhancing patient care.
