High-risk subtypes of acute lymphoblastic leukemia
| Disease entity . | Genetic testing . | Additional genetic changes . | Frequency . | Prognostic relevance . |
|---|---|---|---|---|
| Hypodiploid Near-haploid (24-31 chromosomes) Low-hypodiploid (32-39 chromosomes) High-hypodiploid (40-43 chromosomes) | Karyotyping/FISH | RTK and RAS pathway mutations (NF1), IKZF3 deletion in near-haploid. RB1, CDKN2A/B, IKZF2 deletions, TP53 mutations (up to 50% TP53 mutations are germline) in low-hypodiploidy | Approximately 2% of childhood, rare in adults are near-haploid; approximately 1% of childhood, 10% of adult are low hypodiploid | Unfavorable for near-haploid and low-hypodiploid |
| iAMP21 | FISH for ETV6::RUNX1 used to identify iAMP21 | Defined by 5 copies of RUNX1 per cell, with ≥3 copies on a single abnormal chromosome 21 | 1%–2% in children, rare in adults | Unfavorable; outcomes improve with intensive chemotherapy |
| BCR::ABL1rearranged | Karyotyping/FISH/ PCR/RNA-seq for detection of BCR::ABL1 fusion | IKZF1 deletions (80%) co-occurring with deletions of PAX5 and CDKN2A/B, EBF1 mutations in 14% | 2%–5% in children, 6% in adolescents and young adults, and >25% in adults | Unfavorable; incorporation of TKI targeted therapy has improved outcomes. IKZF1-rearranged unfavorable |
| BCR::ABL1-like (Ph-like) | Whole transcriptome or targeted RNA-seq. When unavailable, derivative methods like TaqMan low-density arrays, multiplex PCR, and FISH panels using break-apart probes may be used | a. ABL-class fusions: Fusions involving ABL1, ABL2, CSF1R, LYN, PDGFRA, PDGFRB b. JAK/STAT abnormalities: These include enhancer hijacking of promoter regions (IGH::CRLF2, P2RY8::CRLF2), fusions and mutations (eg, JAK2 R683G or JAK1 V658F) c. Miscellaneous fusions involving FGFR1, NTRK3, etc. in JAK1/JAK2/JAK3 genes and fusions/truncating deletions of EPOR (eg, EPOR::IGH) frequently associated with IKZF1 deletions and copy number alterations in B-lymphoid transcription factors. Activating mutations involving cytokine receptors (eg, IL7R and CRLF2) also constitute an underlying genetic abnormality | Frequency increases with age: 10%–15% of children, 20%–25% of adult, 50%–60% of patients with Down syndrome | Unfavorable; associated with high minimal residual disease positivity rates. Targeting the underlying genetic abnormality may improve survival rates |
| KMT2Arearranged | Karyotyping/FISH/ Global or targeted RNA sequencing | More than 90 partners of KMT2A described of which AF4, MLLT3, MLLT1, MLLT10, and MLLT6 are common | 70%–85% of infant, 2% of childhood and adult | Unfavorable |
| ETV6::RUNX1-like | Whole transcriptome or targeted RNA sequencing. Increased frequency of ETV6-like B-ALL may be seen in patients with germline ETV6 mutation | Fusions or copy number alterations involving ETV6, ERG, FLI1, IKZF, or TCF3 are common | 3% of childhood, uncommon in adults | Possibly unfavorable |
| TCF3::HLF | Global or targeted RNA sequencing for uncommon partners | Accompanying genetic lesions, including deletion of B-cell differentiation genes (PAX5, VPREB1, or BTG1), deletions of CDKN2A/B, and mutations in signaling pathways driving proliferation are frequently observed | <1% of childhood B-ALL; rare in adults | TCF3::HLF has a universally dismal prognosis |
| MEF2Drearranged | MEF2D::BCL9 can be detected by FISH. Whole transcriptome or targeted RNA sequencing is more reliable for diagnosis as it detects other MEF2D partners | BCL9 is the most common translocation partner. Others include HNRNPUL1, DAZAP1, CSF1R, SS18, FOXJ2, and DAZAP1 | 4% of childhood and 10% of adult | Unfavorable |
| ZNF384rearranged | FISH, whole transcriptome or targeted RNA sequencing | Numerous partners (EP300, EWSR1, TAF15, TCF3) were reported, either transcription partners or chromatin modifiers. FLT3 overexpression also described | 5% of childhood and 10% of adults B-ALL; 48% MPAL, B/Myeloid | EP300::ZNF384 favorable; TCF3::ZNF384 unfavorable |
| PAX5alt | FISH, whole transcriptome, GEP or targeted RNA sequencing | Numerous fusion partners, copy number alterations are common | 7% | Intermediate for PAX5alt in children and unfavorable in adults |
| PAX5p.P80R | Whole transcriptome or targeted RNA sequencing | PAX5 p.P80R, an inactivating mutation with distinct expression profile, is commonly associated with deletion of alternate allele or copy-neutral loss of heterozygosity | 3% | Favorable in adults; unfavorable in children |
| IG::MYCrearranged | Karyotyping/FISH. Genetic and epigenetic profile distinct from Burkitt lymphoma | Frequent mutations in genes involving RAS pathway, 1q gain | Rare in children; approximately 2% of adult | Unfavorable |
| Complex karyotype (≥5 alterations) | Karyotyping/FISH | TP53 mutations are common | 5% | Unfavorable |
| ETP-ALL | Flow cytometry immunophenotyping | Numerous alterations described. Lower incidence of NOTCH1, FBXW7 mutations than non-ETP-ALL. More frequent mutations in FLT3, DNMT3A, NRAS | 11%–16% of pediatric T-ALL; 7%–17% of adult T-ALL | Unfavorable |
| Disease entity . | Genetic testing . | Additional genetic changes . | Frequency . | Prognostic relevance . |
|---|---|---|---|---|
| Hypodiploid Near-haploid (24-31 chromosomes) Low-hypodiploid (32-39 chromosomes) High-hypodiploid (40-43 chromosomes) | Karyotyping/FISH | RTK and RAS pathway mutations (NF1), IKZF3 deletion in near-haploid. RB1, CDKN2A/B, IKZF2 deletions, TP53 mutations (up to 50% TP53 mutations are germline) in low-hypodiploidy | Approximately 2% of childhood, rare in adults are near-haploid; approximately 1% of childhood, 10% of adult are low hypodiploid | Unfavorable for near-haploid and low-hypodiploid |
| iAMP21 | FISH for ETV6::RUNX1 used to identify iAMP21 | Defined by 5 copies of RUNX1 per cell, with ≥3 copies on a single abnormal chromosome 21 | 1%–2% in children, rare in adults | Unfavorable; outcomes improve with intensive chemotherapy |
| BCR::ABL1rearranged | Karyotyping/FISH/ PCR/RNA-seq for detection of BCR::ABL1 fusion | IKZF1 deletions (80%) co-occurring with deletions of PAX5 and CDKN2A/B, EBF1 mutations in 14% | 2%–5% in children, 6% in adolescents and young adults, and >25% in adults | Unfavorable; incorporation of TKI targeted therapy has improved outcomes. IKZF1-rearranged unfavorable |
| BCR::ABL1-like (Ph-like) | Whole transcriptome or targeted RNA-seq. When unavailable, derivative methods like TaqMan low-density arrays, multiplex PCR, and FISH panels using break-apart probes may be used | a. ABL-class fusions: Fusions involving ABL1, ABL2, CSF1R, LYN, PDGFRA, PDGFRB b. JAK/STAT abnormalities: These include enhancer hijacking of promoter regions (IGH::CRLF2, P2RY8::CRLF2), fusions and mutations (eg, JAK2 R683G or JAK1 V658F) c. Miscellaneous fusions involving FGFR1, NTRK3, etc. in JAK1/JAK2/JAK3 genes and fusions/truncating deletions of EPOR (eg, EPOR::IGH) frequently associated with IKZF1 deletions and copy number alterations in B-lymphoid transcription factors. Activating mutations involving cytokine receptors (eg, IL7R and CRLF2) also constitute an underlying genetic abnormality | Frequency increases with age: 10%–15% of children, 20%–25% of adult, 50%–60% of patients with Down syndrome | Unfavorable; associated with high minimal residual disease positivity rates. Targeting the underlying genetic abnormality may improve survival rates |
| KMT2Arearranged | Karyotyping/FISH/ Global or targeted RNA sequencing | More than 90 partners of KMT2A described of which AF4, MLLT3, MLLT1, MLLT10, and MLLT6 are common | 70%–85% of infant, 2% of childhood and adult | Unfavorable |
| ETV6::RUNX1-like | Whole transcriptome or targeted RNA sequencing. Increased frequency of ETV6-like B-ALL may be seen in patients with germline ETV6 mutation | Fusions or copy number alterations involving ETV6, ERG, FLI1, IKZF, or TCF3 are common | 3% of childhood, uncommon in adults | Possibly unfavorable |
| TCF3::HLF | Global or targeted RNA sequencing for uncommon partners | Accompanying genetic lesions, including deletion of B-cell differentiation genes (PAX5, VPREB1, or BTG1), deletions of CDKN2A/B, and mutations in signaling pathways driving proliferation are frequently observed | <1% of childhood B-ALL; rare in adults | TCF3::HLF has a universally dismal prognosis |
| MEF2Drearranged | MEF2D::BCL9 can be detected by FISH. Whole transcriptome or targeted RNA sequencing is more reliable for diagnosis as it detects other MEF2D partners | BCL9 is the most common translocation partner. Others include HNRNPUL1, DAZAP1, CSF1R, SS18, FOXJ2, and DAZAP1 | 4% of childhood and 10% of adult | Unfavorable |
| ZNF384rearranged | FISH, whole transcriptome or targeted RNA sequencing | Numerous partners (EP300, EWSR1, TAF15, TCF3) were reported, either transcription partners or chromatin modifiers. FLT3 overexpression also described | 5% of childhood and 10% of adults B-ALL; 48% MPAL, B/Myeloid | EP300::ZNF384 favorable; TCF3::ZNF384 unfavorable |
| PAX5alt | FISH, whole transcriptome, GEP or targeted RNA sequencing | Numerous fusion partners, copy number alterations are common | 7% | Intermediate for PAX5alt in children and unfavorable in adults |
| PAX5p.P80R | Whole transcriptome or targeted RNA sequencing | PAX5 p.P80R, an inactivating mutation with distinct expression profile, is commonly associated with deletion of alternate allele or copy-neutral loss of heterozygosity | 3% | Favorable in adults; unfavorable in children |
| IG::MYCrearranged | Karyotyping/FISH. Genetic and epigenetic profile distinct from Burkitt lymphoma | Frequent mutations in genes involving RAS pathway, 1q gain | Rare in children; approximately 2% of adult | Unfavorable |
| Complex karyotype (≥5 alterations) | Karyotyping/FISH | TP53 mutations are common | 5% | Unfavorable |
| ETP-ALL | Flow cytometry immunophenotyping | Numerous alterations described. Lower incidence of NOTCH1, FBXW7 mutations than non-ETP-ALL. More frequent mutations in FLT3, DNMT3A, NRAS | 11%–16% of pediatric T-ALL; 7%–17% of adult T-ALL | Unfavorable |
Table modified from Choi et al.1