Patients with KMT2A-CBL rearrangement
| . | Patient 1 (Marseille) . | Patient 2 (Reims) . | Patient 3 (Barcelona) . | Patient 43 (Prague) . | Patient 512 (Taiwan) . | Patient 63 (Nantes) . | Patient 713 (London) . |
|---|---|---|---|---|---|---|---|
| Sex, age (y) | Male, 9 | Male, 11 | Male, 18 | Male, 3 | Female, 28 | Female, 59 | Female, 18 |
| Medical history | JMML - KRAS mut 6MP & CB-AlloSCT (Bu/Cy) | None | None | Development delay | None | Polycythemia vera JAK2+ Hydroxyurea and pipobroman | None |
| Hematologic diagnosis | T-ALL (EGIL T2) | T-ALL (EGIL T2) | T-ALL (EGIL T2) | B-ALL (EGIL B1) | AML (FAB M1) | sAML (FAB M5) | AML |
| White blood count (·109 /L) | 1.1 | 5.39 | 12.32 | 65.5 | 0.8 | 37.5 | 1.3 |
| Hemoglobin (g/L) | 90 | 97 | 83 | 107 | 44 | 107 | 74 |
| Platelets (·109 /L) | 109 | 69 | 24 | 71 | 15 | 45 | 55 |
| Blast count peripheral blood/bone marrow (%) | 0/97 | 33/99 | 85/99 | 80/93 | 47/96 | 65/83 | |
| Flow cytometry | cCD3+, sCD3−, TdT+, CD99+, CD7+, CD2+, CD5+ | cCD3+, sCD3−, CD7++, CD2++, CD5+/− (13%), CD34+dim, CD38++, CD13+ | cCD3+, sCD3+ dim, CD34−, TdT−, CD99+ dim, CD1a−, CD7++, CD38+ | CD34−, TdT+, CD19+, CD79a+, CD10+, CD7+ dim, CD38+ | CD34+, CD13+, CD33+ | CD34−, CD13+, CD33+, CD4+ | CD34+, cMPO+, CD33+, CD15+, CD38+, CD56+ |
| Cytogenetics | Pseudodiploid and monosomic with 3 clonal anomalies: del(2q),-16,r | 47,XY,?del(5)(q31),+8, del(9)(q13q34),del(11)(q21q23), del(12)(p11)[cp6]/46,XY[28] | 47, XY, der(7),+19[20] | NA | 50,XX,+22,+3 mar [5]/49,XX, −19, +22,+3mar [11]/46,XX,inv(9)[4] | 45∼46,XX,-5,add(6)(p21), -9,+i(9)(p10), add(11)(q23),-18,+mar[7], 47∼49,XX, +2,-5,-9,i(9q10),add(11)(q23), ?+13,-18,+19,+20,inc[9] | 46,XX[20] |
| KMT2A FISH | KMT2A 3' loss of signal | KMT2A 3' loss of signal | KMT2A 3' loss of signal | KMT2A 3' loss of signal | — | KMT2A 3' loss of signal | KMT2A 3' loss of signal |
| NGS | KRAS p.G13C (VAF 32%) ASXL1 p.G646Wfs12 (VAF 26%) STAT3 p.N481I (VAF 36%) | IL7R p.V253_A254insVA (VAF 13%) KMT2A p.N*2278fs (VAF 82%) NOTCH1 p.P2514fs (VAF 16%) NOTCH1 p.A1700D (VAF 10%) NOTCH1 p.L1678P (VAF 36%) ZFHX4 p.R2676Q (VAF 28%) | No mutations detected | KRAS p.A18D (VAF 44%) | CBL p.L380P (VAF 70%) | — | RUNX1 p.G372S (VAF 50%) |
| Method for KMT2A-CBL detection | RNAseq and targeted NGS | RNAseq and Targeted NGS | Targeted NGS | RNAseq and LDI-PCR | cDNA panhandle PCR Validated by RT-PCR + cloning and sequencing of the KMT2A fusion product. | RNAseq and LDI-PCR | Chromosomal microarray analysis |
| Breakpoint | KMT2A intron 9 CBL intron 9 | KMT2A exon 10 CBL intron 15 | KMT2A intron 9 CBL intron 9 | KMT2A intron 10 CBL intron 9 | KMT2A intron 9 CBL intron 9 | KMT2A intron 9 CBL intron 9 | KMT2A intron 10 CBL exon 2 |
| Clinical outcome | Induction Chemotherapy (CALL-T protocol) – CR MRD+ Consolidation + Intensification – CR MRD-CB-AlloSCT Alive, CR 1 y after diagnosis | Induction chemotherapy (CAALL-F01 protocol) NR Consolidation + Intensification CR MRD- RD-AlloSCT Alive, CR 3 y after diagnosis | Induction chemotherapy (PETHEMA 2019) – PR Re-induction (FLAG-IDA) – CR MRD- Consolidation – CR MRD- MUD-AlloSCT Alive, CR 6 mo after diagnosis | AEIOP/BFM 2000 ALL protocol CR MRD- Relapse after 8 y IntReALL SR 2010 protocol CR-MRD+ Blinatumomab × 2 MUD-AlloSCT Alive, CR 13 y after diagnosis | Induction chemotherapy CR Consolidation – CR Relapse 2 y after diagnosis Reinduction CR MUD-AlloSCT Deceased due to alloSCT complications | Induction chemotherapy CR Consolidation CR RD-AlloSCT Relapse 11 mo after diagnosis Azacytidine: No response Deceased because of disease progression | Induction chemotherapy CR Loss of follow-up |
| . | Patient 1 (Marseille) . | Patient 2 (Reims) . | Patient 3 (Barcelona) . | Patient 43 (Prague) . | Patient 512 (Taiwan) . | Patient 63 (Nantes) . | Patient 713 (London) . |
|---|---|---|---|---|---|---|---|
| Sex, age (y) | Male, 9 | Male, 11 | Male, 18 | Male, 3 | Female, 28 | Female, 59 | Female, 18 |
| Medical history | JMML - KRAS mut 6MP & CB-AlloSCT (Bu/Cy) | None | None | Development delay | None | Polycythemia vera JAK2+ Hydroxyurea and pipobroman | None |
| Hematologic diagnosis | T-ALL (EGIL T2) | T-ALL (EGIL T2) | T-ALL (EGIL T2) | B-ALL (EGIL B1) | AML (FAB M1) | sAML (FAB M5) | AML |
| White blood count (·109 /L) | 1.1 | 5.39 | 12.32 | 65.5 | 0.8 | 37.5 | 1.3 |
| Hemoglobin (g/L) | 90 | 97 | 83 | 107 | 44 | 107 | 74 |
| Platelets (·109 /L) | 109 | 69 | 24 | 71 | 15 | 45 | 55 |
| Blast count peripheral blood/bone marrow (%) | 0/97 | 33/99 | 85/99 | 80/93 | 47/96 | 65/83 | |
| Flow cytometry | cCD3+, sCD3−, TdT+, CD99+, CD7+, CD2+, CD5+ | cCD3+, sCD3−, CD7++, CD2++, CD5+/− (13%), CD34+dim, CD38++, CD13+ | cCD3+, sCD3+ dim, CD34−, TdT−, CD99+ dim, CD1a−, CD7++, CD38+ | CD34−, TdT+, CD19+, CD79a+, CD10+, CD7+ dim, CD38+ | CD34+, CD13+, CD33+ | CD34−, CD13+, CD33+, CD4+ | CD34+, cMPO+, CD33+, CD15+, CD38+, CD56+ |
| Cytogenetics | Pseudodiploid and monosomic with 3 clonal anomalies: del(2q),-16,r | 47,XY,?del(5)(q31),+8, del(9)(q13q34),del(11)(q21q23), del(12)(p11)[cp6]/46,XY[28] | 47, XY, der(7),+19[20] | NA | 50,XX,+22,+3 mar [5]/49,XX, −19, +22,+3mar [11]/46,XX,inv(9)[4] | 45∼46,XX,-5,add(6)(p21), -9,+i(9)(p10), add(11)(q23),-18,+mar[7], 47∼49,XX, +2,-5,-9,i(9q10),add(11)(q23), ?+13,-18,+19,+20,inc[9] | 46,XX[20] |
| KMT2A FISH | KMT2A 3' loss of signal | KMT2A 3' loss of signal | KMT2A 3' loss of signal | KMT2A 3' loss of signal | — | KMT2A 3' loss of signal | KMT2A 3' loss of signal |
| NGS | KRAS p.G13C (VAF 32%) ASXL1 p.G646Wfs12 (VAF 26%) STAT3 p.N481I (VAF 36%) | IL7R p.V253_A254insVA (VAF 13%) KMT2A p.N*2278fs (VAF 82%) NOTCH1 p.P2514fs (VAF 16%) NOTCH1 p.A1700D (VAF 10%) NOTCH1 p.L1678P (VAF 36%) ZFHX4 p.R2676Q (VAF 28%) | No mutations detected | KRAS p.A18D (VAF 44%) | CBL p.L380P (VAF 70%) | — | RUNX1 p.G372S (VAF 50%) |
| Method for KMT2A-CBL detection | RNAseq and targeted NGS | RNAseq and Targeted NGS | Targeted NGS | RNAseq and LDI-PCR | cDNA panhandle PCR Validated by RT-PCR + cloning and sequencing of the KMT2A fusion product. | RNAseq and LDI-PCR | Chromosomal microarray analysis |
| Breakpoint | KMT2A intron 9 CBL intron 9 | KMT2A exon 10 CBL intron 15 | KMT2A intron 9 CBL intron 9 | KMT2A intron 10 CBL intron 9 | KMT2A intron 9 CBL intron 9 | KMT2A intron 9 CBL intron 9 | KMT2A intron 10 CBL exon 2 |
| Clinical outcome | Induction Chemotherapy (CALL-T protocol) – CR MRD+ Consolidation + Intensification – CR MRD-CB-AlloSCT Alive, CR 1 y after diagnosis | Induction chemotherapy (CAALL-F01 protocol) NR Consolidation + Intensification CR MRD- RD-AlloSCT Alive, CR 3 y after diagnosis | Induction chemotherapy (PETHEMA 2019) – PR Re-induction (FLAG-IDA) – CR MRD- Consolidation – CR MRD- MUD-AlloSCT Alive, CR 6 mo after diagnosis | AEIOP/BFM 2000 ALL protocol CR MRD- Relapse after 8 y IntReALL SR 2010 protocol CR-MRD+ Blinatumomab × 2 MUD-AlloSCT Alive, CR 13 y after diagnosis | Induction chemotherapy CR Consolidation – CR Relapse 2 y after diagnosis Reinduction CR MUD-AlloSCT Deceased due to alloSCT complications | Induction chemotherapy CR Consolidation CR RD-AlloSCT Relapse 11 mo after diagnosis Azacytidine: No response Deceased because of disease progression | Induction chemotherapy CR Loss of follow-up |
In cytogenetic studies, number of metaphases studied is represented in brackets. 6MP, mercaptopurine; AlloSCT, allogeneic stem cell transplantation; CB, cord blood; CR: complete response; EGIL, European Group for the Immunological Classification of Leukemia; FAB, French-American-British classification; LDI-PCR, long-distance-inverse PCR; MRD, minimal residual disease; MUD, matched unrelated donor; NR, no response; PR, partial response; RD, related donor; VAF, variant allele frequency.