Electronic supplementary material
Integration of genetic markers into risk stratification algorithms
Adverse outcome with advancing age
Presenting WBC count
Adverse for B-ALL > 30
Adverse for T-ALL >100
Poor PS at diagnosis were an independent predictor of inferior outcomes
Adverse: t(9;22), t(4;11), t(8;14), complex (≥ 5 abnormalities), hypodiploidy, triploidy, -7, del(7p), +8, MLL translocations, t(1;19), t(17;19), t(5;14)]
In response to therapy
Time to initial response
Adverse: failure to attain complete remission within 4 weeks of induction
Detection of MRD
Adverse: detection at various time-specific points in several studies
IKZF1 deletions and sequence mutations
15% of pediatric B-ALL cases; 70% of BCR-ABL1 + lymphoid leukemia, and 30% of high-risk BCR-ABL1-like B-ALL
IKZF1 alterations are associated with poor outcome in both BCR-ABL1–positive and negative ALL cases, and triple the risk of treatment failure. IKZF1 status is an independent risk factor at a multivariable analysis of established prognostic factors.
CRLF2 rearrangement (as IGH@-CRLF2 or P2RY8-CRLF2)
Up to 16% of pediatric and adult B-ALL; >50% Down syndrome (DS) ALL
Concomitant JAK1/2 mutations in >50% of cases; associated with IKZF1 alteration and poor outcome, particularly in non-DS-ALL.
Up to 10% of high-risk BCR ABL1-like B-ALL; 18–35% of DS ALL
Almost all cases of B-ALL with JAK1/2 mutations harbor concomitant CRLF2 rearrangement, associated with poor outcome; may be responsive to JAK inhibitors.
CREBBP deletions and sequence mutations
19% of relapsed B-ALL
Associated with glucocorticoid resistance; Resulted in impaired acetylation of histone targets; histone deacetylase inhibitors may be useful.
~30% of B-ALL; 47% of relapsed BCR-ABL1-ALL;
Associated with poor outcome in terms of overall survival, and incidence of relapse in adult BCR-ABL1-positive ALL; controversial prognosis in other B-ALL subtypes.
TP53 deletions and sequence mutations
Up to 12% of B-ALL;
Enriched at relapse and associated with non-response to chemotherapy and poor event-free survival and overall survival.
PHF6 deletions and sequence mutations
38% of adult T-ALL cases
Associated with reduced overall survival.
PTEN deletions and sequence mutations
6–8% of T-ALL
Associated with poor response to chemotherapy and resistance to pharmacological inhibition of NOTCH1
10% of adult T-ALL
N/K-RASmutations demonstrated trends to a worse outcome.
~50% of T-ALL
Associated with favorable outcome
12-24% of adult T-ALL
Associated with favorable prognosis due to enhanced glucocorticoid receptor α levels and steroid sensitivity
19% of relapse T cell ALL and 3% of relapse B-precursor ALL
NT5C2 mutant proteins increase nucleotidase activity in vitro and drive resistance to treatment with nucleoside analog therapies