Molecular characteristics of the r/r T-ALL patients used for the randomized phase 2–like preclinical study
| Patient . | Age at diagnosis (y) . | Sex . | WBC count (initial)/µL . | Blast (PB) initial (%) . | Blast (BM) initial (%) . | Immuno phenotype . | Karyotype . | Transcription factors (qPCR)* . | Mutations . | Copy number alterations (MLPA, probe set P383 MRC Holland) . | Treatment protocol† . | Pred response . | Final risk group‡ . | Blasts (BM) day 15 (%) . | MRD day +33 . | MRD day +78 . | Relapse . |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Patient 1r/r | 4 | M | 10 230 | 0 | 27.5 | Pre-T | 46,XY, del(1)(q32)[10] | TLX3, HOXA9, LMO1, LMO2, LYL1, MYB | n.o. | n.o. | Euro-LB 02 | Good | MR | 0 | 1.00E-3 | 1.00E-8 | Yes |
| Patient 2r/r | 4 | M | 15 800 | 49.5 | 47 | Mature T-ALL | 46,XY+(i9)(q10), +19[10] / 46,XY[20] | TLX3, HOXA9, LMO1, LMO2, LYL1, MYB | None | n.o. | 2000 | Poor | MR (Pred) | n.o. | 1.00E-2 | 1.00E-2 | Yes |
| Patient 3r/r | 3 | M | 77 100 | 78.5 | 96.5 | Cortical T | 46,XY del(10)(q24) | TLX3, HOXA9, LMO1, LMO2 | Notch1 | Deletions: MTAP, CDKN2A, CDKN2B, PTPN2 | 2000 | Good | SR-2 (Pred) | 1.5 | 1.00E-8 | 1.00E-8 | Yes |
| Patient 4r/r | 3 | M | 131 300 | 67 | 83 | Pre-T | 47,XX t(1;8)(q21;q24), +7,+8,t(11;14), (p13;q11)[5], [TRD/LMO2] | TLX3, HOXA9, LMO1, LMO2 | Notch1 | Deletions: LEF1, CDKN2A | 2000 | Good | MR-1 (Pred) | 2 | 1.00E-4 | 1.00E-4 | Yes |
| Patient 5r/r | 14 | M | 14 100 | 27.5 | 57 | Pre-T | 46, XY | TLX3, HOXA9, HOXA10,LMO1, LMO2 | None | n.o. | 2000 | Good | MR-1 (Pred) | 1.5 | 1.00E-3 | 1.00E-4 | Yes |
| Patient 6r/r | 8 | F | 170 900 | 73 | 86.5 | Cortical T | No MP | TLX3, HOXA9, LMO1, LMO2 | Notch1 | Deletions: SIL-TAL, CDKN2A, CDKN2B | 2000 | Good | MR-2 (Pred) | 0 | 1.00E-3 | 1.00E-4 | Yes |
| Patient 7r/r | 2 | F | 550 000 | 90 | 96 | Cortical T | No MP | None | None | None | 2000 | Poor | HR-2 (Dexa) | 26.5 | n.o. | 1.00E-2 | Yes |
| Patient 8r/r | 2 | M | 14 400 | 86.5 | n.o. | Cortical T | 46,XY[5] | TLX3, HOXA9, LMO1 | Notch1 | Deletions: MTAP, CDKN2A, CDKN2B, PTPN2 | 2000 | Poor | HR-2 (Pred) | 4.5 | 1.00E-4 | 1.00E-8 | Yes |
| Patient 9r/r | 11 | M | 226 500 | 87.5 | n.o. | Mature T-ALL | 46,XY,del(6) (q1?5q2?3) [8] / 46,XY[6] | TLX3, LMO1 | n.o. | n.o. | 2000 | Poor | HR-2 (Pred) | 59 | 1.00E-1 | 1.00E-4 | Yes |
| Patient 10r/r | 9 | M | 36 300 | 27.5 | 84.5 | Cortical T | 46,XY,t(11;14) (p13;q11)[12] | None | n.o. | n.o. | 2000 | Good | MR | 1 | 1.00E-3 | 1.00E-4 | Yes |
| Patient 11r/r | 12 | F | 33 100 | 13.5 | 82 | Cortical T | 46,XX,i(7)(q10)[10] | TLX3, HOXA9, LMO1, LMO2 | None | Deletions: LEF1, MTAP, CDKN2A | 2009 | Good | MR | 0 | 1.00E-3 | 1.00E-5 | Yes |
| Patient . | Age at diagnosis (y) . | Sex . | WBC count (initial)/µL . | Blast (PB) initial (%) . | Blast (BM) initial (%) . | Immuno phenotype . | Karyotype . | Transcription factors (qPCR)* . | Mutations . | Copy number alterations (MLPA, probe set P383 MRC Holland) . | Treatment protocol† . | Pred response . | Final risk group‡ . | Blasts (BM) day 15 (%) . | MRD day +33 . | MRD day +78 . | Relapse . |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Patient 1r/r | 4 | M | 10 230 | 0 | 27.5 | Pre-T | 46,XY, del(1)(q32)[10] | TLX3, HOXA9, LMO1, LMO2, LYL1, MYB | n.o. | n.o. | Euro-LB 02 | Good | MR | 0 | 1.00E-3 | 1.00E-8 | Yes |
| Patient 2r/r | 4 | M | 15 800 | 49.5 | 47 | Mature T-ALL | 46,XY+(i9)(q10), +19[10] / 46,XY[20] | TLX3, HOXA9, LMO1, LMO2, LYL1, MYB | None | n.o. | 2000 | Poor | MR (Pred) | n.o. | 1.00E-2 | 1.00E-2 | Yes |
| Patient 3r/r | 3 | M | 77 100 | 78.5 | 96.5 | Cortical T | 46,XY del(10)(q24) | TLX3, HOXA9, LMO1, LMO2 | Notch1 | Deletions: MTAP, CDKN2A, CDKN2B, PTPN2 | 2000 | Good | SR-2 (Pred) | 1.5 | 1.00E-8 | 1.00E-8 | Yes |
| Patient 4r/r | 3 | M | 131 300 | 67 | 83 | Pre-T | 47,XX t(1;8)(q21;q24), +7,+8,t(11;14), (p13;q11)[5], [TRD/LMO2] | TLX3, HOXA9, LMO1, LMO2 | Notch1 | Deletions: LEF1, CDKN2A | 2000 | Good | MR-1 (Pred) | 2 | 1.00E-4 | 1.00E-4 | Yes |
| Patient 5r/r | 14 | M | 14 100 | 27.5 | 57 | Pre-T | 46, XY | TLX3, HOXA9, HOXA10,LMO1, LMO2 | None | n.o. | 2000 | Good | MR-1 (Pred) | 1.5 | 1.00E-3 | 1.00E-4 | Yes |
| Patient 6r/r | 8 | F | 170 900 | 73 | 86.5 | Cortical T | No MP | TLX3, HOXA9, LMO1, LMO2 | Notch1 | Deletions: SIL-TAL, CDKN2A, CDKN2B | 2000 | Good | MR-2 (Pred) | 0 | 1.00E-3 | 1.00E-4 | Yes |
| Patient 7r/r | 2 | F | 550 000 | 90 | 96 | Cortical T | No MP | None | None | None | 2000 | Poor | HR-2 (Dexa) | 26.5 | n.o. | 1.00E-2 | Yes |
| Patient 8r/r | 2 | M | 14 400 | 86.5 | n.o. | Cortical T | 46,XY[5] | TLX3, HOXA9, LMO1 | Notch1 | Deletions: MTAP, CDKN2A, CDKN2B, PTPN2 | 2000 | Poor | HR-2 (Pred) | 4.5 | 1.00E-4 | 1.00E-8 | Yes |
| Patient 9r/r | 11 | M | 226 500 | 87.5 | n.o. | Mature T-ALL | 46,XY,del(6) (q1?5q2?3) [8] / 46,XY[6] | TLX3, LMO1 | n.o. | n.o. | 2000 | Poor | HR-2 (Pred) | 59 | 1.00E-1 | 1.00E-4 | Yes |
| Patient 10r/r | 9 | M | 36 300 | 27.5 | 84.5 | Cortical T | 46,XY,t(11;14) (p13;q11)[12] | None | n.o. | n.o. | 2000 | Good | MR | 1 | 1.00E-3 | 1.00E-4 | Yes |
| Patient 11r/r | 12 | F | 33 100 | 13.5 | 82 | Cortical T | 46,XX,i(7)(q10)[10] | TLX3, HOXA9, LMO1, LMO2 | None | Deletions: LEF1, MTAP, CDKN2A | 2009 | Good | MR | 0 | 1.00E-3 | 1.00E-5 | Yes |
| . | Relapse . | Time initial diagnosis relapse (mo) . | Time point of relapse§ . | Site of relapse . | Immunophenotype . | Risk group at relapseǁ . | Morphologic response . | SCT . | Event . | Death . | Cause of death . |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Patient 1r/r | Yes | 19 | Early | BM/other site | Pre-T | S4 | Early (during induction) | Yes | Second relapse | Yes | n.o. |
| Patient 2r/r | Yes | 13 | Very early | BM isolated | T-ALL no further subtype | S4 | Nonresponse | No | Nonresponse | Yes | n.o. |
| Patient 3r/r | Yes | 14 | Very early | BM isolated | T-ALL no further subtype | S4 | Early (during induction) | Yes | Second relapse | Yes | Progressive disease |
| Patient 4r/r | Yes | 21 | Early | BM/Testis | Cortical T | S4 | Early (during induction) | Yes | Secondary Malignancy | No | |
| Patient 5r/r | Yes | 33 | Late | BM/other site | Pre-T | S4 | Early (during induction) | Yes | Second relapse | Yes | Renal insufficiency |
| Patient 6r/r | Yes | 15 | Very early | BM isolated | Cortical T | S4 | Early (during induction) | No | Second relapse | Yes | Progressive disease |
| Patient 7r/r | Yes | 14 | Very early | BM isolated | T-ALL no further subtype | S4 | Early (during induction) | Yes | CCR | No | |
| Patient 8r/r | Yes | 47 | Late | BM isolated | T-ALL no further subtype | S4 | Normal (after induction) | Yes | CCR | No | |
| Patient 9r/r | Yes | 17 | Very early | BM isolated | T-ALL no further subtype | S4 | Normal (after induction) | No | Second relapse | Yes | Progressive disease |
| Patient 10r/r | Yes | 18 | Very early | BM isolated | T-ALL no further subtype | S4 | Normal (after induction) | Yes | CCR | No | |
| Patient 11r/r | Yes | 32 | Late | BM isolated | Cortical T | S4 | Early (during induction) | Yes | Second relapse | Yes | Progressive disease |
| . | Relapse . | Time initial diagnosis relapse (mo) . | Time point of relapse§ . | Site of relapse . | Immunophenotype . | Risk group at relapseǁ . | Morphologic response . | SCT . | Event . | Death . | Cause of death . |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Patient 1r/r | Yes | 19 | Early | BM/other site | Pre-T | S4 | Early (during induction) | Yes | Second relapse | Yes | n.o. |
| Patient 2r/r | Yes | 13 | Very early | BM isolated | T-ALL no further subtype | S4 | Nonresponse | No | Nonresponse | Yes | n.o. |
| Patient 3r/r | Yes | 14 | Very early | BM isolated | T-ALL no further subtype | S4 | Early (during induction) | Yes | Second relapse | Yes | Progressive disease |
| Patient 4r/r | Yes | 21 | Early | BM/Testis | Cortical T | S4 | Early (during induction) | Yes | Secondary Malignancy | No | |
| Patient 5r/r | Yes | 33 | Late | BM/other site | Pre-T | S4 | Early (during induction) | Yes | Second relapse | Yes | Renal insufficiency |
| Patient 6r/r | Yes | 15 | Very early | BM isolated | Cortical T | S4 | Early (during induction) | No | Second relapse | Yes | Progressive disease |
| Patient 7r/r | Yes | 14 | Very early | BM isolated | T-ALL no further subtype | S4 | Early (during induction) | Yes | CCR | No | |
| Patient 8r/r | Yes | 47 | Late | BM isolated | T-ALL no further subtype | S4 | Normal (after induction) | Yes | CCR | No | |
| Patient 9r/r | Yes | 17 | Very early | BM isolated | T-ALL no further subtype | S4 | Normal (after induction) | No | Second relapse | Yes | Progressive disease |
| Patient 10r/r | Yes | 18 | Very early | BM isolated | T-ALL no further subtype | S4 | Normal (after induction) | Yes | CCR | No | |
| Patient 11r/r | Yes | 32 | Late | BM isolated | Cortical T | S4 | Early (during induction) | Yes | Second relapse | Yes | Progressive disease |
BM, bone marrow; CCR, complete clinical remission; CDKN2A/B, cyclin-dependent kinase inhibitor 2A/B; F, female; HOXA9/10, homeobox A9/10; HR, high risk; LEF1, lymphoid enhancer–binding factor 1; LMO1/2, LIM domain only 1/2; LYL1, LYL1 basic helix-loop-helix family member; M, male; MLPA, multiplex ligation-dependent probe amplification; MP, meta-phase; MR, medium risk; MRD, Minimal Residual Disease; MTAP, methylthioadenosine; MYB, MYB proto-oncogene; n.o., not obtainable; Notch1, Notch homolog 1, translocation-associated; PB, peripheral blood; Pred, prednisone; PTPN2, protein tyrosine phosphatase non-receptor type 2; qPCR, quantitative real-time polymerase chain reaction; SCT, stem cell transplant; SIL-TAL, STIL centriolar assembly protein-TAL BHLH transcription factor; SR, standard risk; TAL1, T-cell ALL 1; TLX1/3, T-cell leukemia homeobox 1/3; WBC, white blood cell.
Relative expression values >10-fold beyond control (normal human T cells). Patients #7 r/r and #10 r/r were analyzed; no value above >10-fold increase, and TAL1 was below cutoff in all samples.
Treatment protocol: AIEOP-BFM ALL.
Stratification according to AIEOP-BFM ALL 2000/2009 treatment protocol.
Definition of time point of relapse according to ALL-REZ BFM 2012.
Stratification according to observational study of ALL-REZ BFM 2012. Detailed information regarding stratification in corresponding studies is provided in the supplemental Methods.