Clinical and genomic characteristics of patients with PCNSL progression during the first 6 months of therapy
| Patient . | Age . | Sex . | KPS . | PFS days . | 6p CNA . | BTG1/ETV6/TP53 mutation . | Other genomic aberrations (mutations and CNA) . | Status . | Interventions after disease progression . |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 73 | F | 70 | 44 | CN-LOH 6p25.3-p11.2 | TP53 p.R273H | BRIP1 p.L43fs Loss: 2p15-p13.1, 6q, 12p, 20; gain: 12q; CN-LOH: none | Alive | Focal RT, EA, lenalidomide, M-R, pomalidomide, tafasitamab, ibrutinib |
| 2 | 72 | F | 60 | 35 | HD 6p22.3-p21.31 | CDKN2A p.S56fs, KMT2D p.R5179H, MCL1 p.Q221∗, MYD88 p.P258L, ROBO1 p.E1640K, ROS1 c.6233+3A>G, TBX3 p.P464L Loss: 1p (distal), 6q, 9p; gain: 1q, 18; CN-LOH: 9q | Alive | Ibrutinib | |
| 3 | 61 | M | 50 | 42 | Intact/diploid | BTG1 c.148+5G>A BTG1 p.Q36H | CD79B p.E197G, KMT2D p.R5282∗, MYD88 p.L265P, NFKBIE p.Y254fs Loss: 6q, 8q12.1, 9p21.3 (CDKN2A/2B); gain: 13; CN-LOH: none | Deceased | None |
| 4 | 87 | F | 60 | 60 | CN-LOH 6p25.3-p22.1 | BCOR p.C1363fs, CARD11 p.G123S, CDKN2A p.W110∗, GNA13 p.Q67∗, GNA13 c.511-1G>A, LZTR1 c.1260+1G>A, MYD88 p.S243N, NOTCH2 p.Q2409∗ Loss: 6q (interstitial); gain: 11q (distal), 12; CN-LOH: 9p | Deceased | None | |
| 5 | 77 | M | 60 | 60 | CN-LOH | CD79B p.Y196H, KMT2D p.Y2199fs, MYD88 p.L265P Loss: 6q22.32-q25.3, 9q21.32-q31.1; gain: 12; CN-LOH: 3p, 6p25.3-p21.1, 9p24.3-p13.2, 11q13.2-q25, 15q21.1-q26.3 | Deceased | Lenalidomide, focal RT, M-R, pomalidomide, ibrutinib | |
| 6 | 69 | M | 60 | 41 | HD 6p21.3-q21.1 | FBXW7 p.R479Q, JAK1 p.H421Y, MYD88 p.M232T Loss: 1p13.1, 1q41-q44, 4p15.31-p12, 5q35.2-p35.3, 9p21.3, Y, 21, 22, 17p; gain: 3p22.1-p26.3, 11q (distal), 18q; CN-LOH: 7q22.1-q36.1 | Deceased | Resection, focal RT, EA, ibrutinib, M-R, lenalidomide, pomalidomide | |
| 7 | 54 | M | 70 | 65 | Intact/diploid | TP53 p.T125 = | KMT2D p.S2039∗, MYD88 p.L265P, TET2 p.S894∗ Loss: 1, 2, 3p, 6, 7, 8, 9p21.3, 11, 14, 17p, 19p, 21; gain: 9q, 12, 16; CN-LOH: none | Alive | Ibrutinib, focal RT, EA, M-R, lenalidomide |
| 8 | 65 | F | 60 | 77 | CN-LOH 6p25.3-p21.31 | BTG1 p.R35∗ ETV6 c.33+2T>A | CASR p.A843E, CD79B c.68-1G>A, IKZF3 splice site deletion of exon 7, MEF2B p.E77K, NOTCH2 p.Q2367∗, XPO1 p.E571K Loss: 8q24; gain: 9p; CN-LOH: none | Alive | Lenalidomide, M-R, focal RT, pomalidomide, focal RT, ibrutinib |
| 9 | 42 | M | 70 | 93 | CN-LOH 6p25.3-p21.1 | ETV6 c.33+1G>A | BCL2 p.L86F, DUSP2 p.C143Y, IRF4 p.S114N, MYC c.30+8C>T, MYD88 p.L265P, PRDM1 c.1902+1G>A, STAT3 p.F752fs Loss: 6q16.1-q22.33, 13q; gain: 5p, 7, 9p, 21; CN-LOH: none | Deceased | EA, WBRT, ibrutinib, lenalidomide, pembrolizumab |
| 10 | 58 | F | 70 | 116 | Intact/diploid | ETV6 p.S9T | CCND2 p.R57K, CD79B p.Y196F, DUSP2 p.G121fs, FOXO1 p.P16S, IKZF3 p.A260P, IRF4 p.L70V, KMT2D p.G3015fs, MED12 p.E709∗, MEF2B p.Y144∗, MYC p.E243del, NFKBIE c.782+5G>A/C, ROBO1 p.A620V, RUNX1 p.A34fs, SMAD4 c.1140-2A>C, SOCS1 p.E152Q, SOCS1 p.L150V, ZMYM3 p.R625Q Loss: none; gain: 5, 12; CN-LOH: 1p36.31-p34.3, 19p13.3-p13.11 | Alive | Ibrutinib, focal RT, ASCT, lenalidomide |
| 11 | 80 | F | 70 | 122 | Intact/diploid | BTG1 c.148+6C>T ETV6 c.33+1G>A ETV6 p.A6T | CDK8 p.S62L, KMT2D p.T4629fs, MYD88 p.L265P Loss: 1p21.1-p11.2, focal CDKN2A/2B; gain: 11q13.5-q25; CN-LOH: 3p26.3-p12.3 | Deceased | HD-MTX, lenalidomide |
| 12 | 75 | F | 70 | 129 | Intact/diploid | BTG1 c.148+5G>A | CD79A c.568-2_610del, MYD88 p.L265P Loss: 6q, 17p (proximal, distal); gain: none; CN-LOH: 9p, 15q, 18 | Alive | Focal RT, lenalidomide, focal RT, ibrutinib |
| 13 | 81 | F | 70 | 129 | Hemizygous deletion 6p21.33-p21.31 | BTG1 c.148+1G>A BTG1 c.148+1_ 148+5 delGTGAG insATAAA | BCL2 c.-4_14del, BCL2 p.F49L, BCL2 p.G27T, BCL2 p.S161N, CD79B p.Y196F, EPHB1 c.-4_18del, IRF4 p.Y62∗, MYD88 p.L265P, PRDM1 c.291+1G>A, STAG2 p.E979∗ Loss: 6q, 9p, 20q, 21q; gain: 12, 1q (distal), 19q (distal); CN-LOH: 1p | Deceased | Lenalidomide, M-R, pomalidomide |
| 14 | 32 | M | 60 | 147 | Intact/diploid | BTG1 p.L47V | CD79B c.549+1G>T, MYD88 p.M232T Loss: 6q, 9p23-p21.3, 9p24.3-p23 (CD274, PDCD1LG2), 10q25.3-q26.13, 11p13-p11.12, 16q11.2-q23.1; gain: 18, 21; CN-LOH: none | Deceased | Focal RT, ASCT, IT Ara-C, ibrutinib, lenalidomide, nivolumab, pomalidomide, tafasitamab |
| 15 | 80 | F | 50 | 157 | CN-LOH 6p25.3-p21.33 | CD79B p.Y196C, MYD88 p.L265P Loss: 6p (proximal), 6q, 9p21.3; gain: 7, 9p, 9q, 11q, 18p, 20p; CN-LOH: 20q | Deceased | Focal RT, M-R, pomalidomide | |
| 16 | 78 | F | 40 | 48 | Intact/diploid | TP53 p.R248Q | CD79B p.Y196C, MYD88 p.S243N, PRDM1 p.S469∗ Loss: 6q, 12p (interstitial), 18p; gain: 6p, 7, 11, 18q, 19q; CN-LOH: 3, 17p (distal), 17q (distal), 20q | Deceased | None |
| 17 | 75 | F | 90 | 102 | Intact/diploid | BTG1 p.L37V | MYD88 p.L265P, SOCS1 p.H129Y Loss: 6q (proximal), 9p21.3; gain: 1q, 7q, 16, 19q; CN-LOH: 2, 9p | Alive | Focal RT, EA |
| Patient . | Age . | Sex . | KPS . | PFS days . | 6p CNA . | BTG1/ETV6/TP53 mutation . | Other genomic aberrations (mutations and CNA) . | Status . | Interventions after disease progression . |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 73 | F | 70 | 44 | CN-LOH 6p25.3-p11.2 | TP53 p.R273H | BRIP1 p.L43fs Loss: 2p15-p13.1, 6q, 12p, 20; gain: 12q; CN-LOH: none | Alive | Focal RT, EA, lenalidomide, M-R, pomalidomide, tafasitamab, ibrutinib |
| 2 | 72 | F | 60 | 35 | HD 6p22.3-p21.31 | CDKN2A p.S56fs, KMT2D p.R5179H, MCL1 p.Q221∗, MYD88 p.P258L, ROBO1 p.E1640K, ROS1 c.6233+3A>G, TBX3 p.P464L Loss: 1p (distal), 6q, 9p; gain: 1q, 18; CN-LOH: 9q | Alive | Ibrutinib | |
| 3 | 61 | M | 50 | 42 | Intact/diploid | BTG1 c.148+5G>A BTG1 p.Q36H | CD79B p.E197G, KMT2D p.R5282∗, MYD88 p.L265P, NFKBIE p.Y254fs Loss: 6q, 8q12.1, 9p21.3 (CDKN2A/2B); gain: 13; CN-LOH: none | Deceased | None |
| 4 | 87 | F | 60 | 60 | CN-LOH 6p25.3-p22.1 | BCOR p.C1363fs, CARD11 p.G123S, CDKN2A p.W110∗, GNA13 p.Q67∗, GNA13 c.511-1G>A, LZTR1 c.1260+1G>A, MYD88 p.S243N, NOTCH2 p.Q2409∗ Loss: 6q (interstitial); gain: 11q (distal), 12; CN-LOH: 9p | Deceased | None | |
| 5 | 77 | M | 60 | 60 | CN-LOH | CD79B p.Y196H, KMT2D p.Y2199fs, MYD88 p.L265P Loss: 6q22.32-q25.3, 9q21.32-q31.1; gain: 12; CN-LOH: 3p, 6p25.3-p21.1, 9p24.3-p13.2, 11q13.2-q25, 15q21.1-q26.3 | Deceased | Lenalidomide, focal RT, M-R, pomalidomide, ibrutinib | |
| 6 | 69 | M | 60 | 41 | HD 6p21.3-q21.1 | FBXW7 p.R479Q, JAK1 p.H421Y, MYD88 p.M232T Loss: 1p13.1, 1q41-q44, 4p15.31-p12, 5q35.2-p35.3, 9p21.3, Y, 21, 22, 17p; gain: 3p22.1-p26.3, 11q (distal), 18q; CN-LOH: 7q22.1-q36.1 | Deceased | Resection, focal RT, EA, ibrutinib, M-R, lenalidomide, pomalidomide | |
| 7 | 54 | M | 70 | 65 | Intact/diploid | TP53 p.T125 = | KMT2D p.S2039∗, MYD88 p.L265P, TET2 p.S894∗ Loss: 1, 2, 3p, 6, 7, 8, 9p21.3, 11, 14, 17p, 19p, 21; gain: 9q, 12, 16; CN-LOH: none | Alive | Ibrutinib, focal RT, EA, M-R, lenalidomide |
| 8 | 65 | F | 60 | 77 | CN-LOH 6p25.3-p21.31 | BTG1 p.R35∗ ETV6 c.33+2T>A | CASR p.A843E, CD79B c.68-1G>A, IKZF3 splice site deletion of exon 7, MEF2B p.E77K, NOTCH2 p.Q2367∗, XPO1 p.E571K Loss: 8q24; gain: 9p; CN-LOH: none | Alive | Lenalidomide, M-R, focal RT, pomalidomide, focal RT, ibrutinib |
| 9 | 42 | M | 70 | 93 | CN-LOH 6p25.3-p21.1 | ETV6 c.33+1G>A | BCL2 p.L86F, DUSP2 p.C143Y, IRF4 p.S114N, MYC c.30+8C>T, MYD88 p.L265P, PRDM1 c.1902+1G>A, STAT3 p.F752fs Loss: 6q16.1-q22.33, 13q; gain: 5p, 7, 9p, 21; CN-LOH: none | Deceased | EA, WBRT, ibrutinib, lenalidomide, pembrolizumab |
| 10 | 58 | F | 70 | 116 | Intact/diploid | ETV6 p.S9T | CCND2 p.R57K, CD79B p.Y196F, DUSP2 p.G121fs, FOXO1 p.P16S, IKZF3 p.A260P, IRF4 p.L70V, KMT2D p.G3015fs, MED12 p.E709∗, MEF2B p.Y144∗, MYC p.E243del, NFKBIE c.782+5G>A/C, ROBO1 p.A620V, RUNX1 p.A34fs, SMAD4 c.1140-2A>C, SOCS1 p.E152Q, SOCS1 p.L150V, ZMYM3 p.R625Q Loss: none; gain: 5, 12; CN-LOH: 1p36.31-p34.3, 19p13.3-p13.11 | Alive | Ibrutinib, focal RT, ASCT, lenalidomide |
| 11 | 80 | F | 70 | 122 | Intact/diploid | BTG1 c.148+6C>T ETV6 c.33+1G>A ETV6 p.A6T | CDK8 p.S62L, KMT2D p.T4629fs, MYD88 p.L265P Loss: 1p21.1-p11.2, focal CDKN2A/2B; gain: 11q13.5-q25; CN-LOH: 3p26.3-p12.3 | Deceased | HD-MTX, lenalidomide |
| 12 | 75 | F | 70 | 129 | Intact/diploid | BTG1 c.148+5G>A | CD79A c.568-2_610del, MYD88 p.L265P Loss: 6q, 17p (proximal, distal); gain: none; CN-LOH: 9p, 15q, 18 | Alive | Focal RT, lenalidomide, focal RT, ibrutinib |
| 13 | 81 | F | 70 | 129 | Hemizygous deletion 6p21.33-p21.31 | BTG1 c.148+1G>A BTG1 c.148+1_ 148+5 delGTGAG insATAAA | BCL2 c.-4_14del, BCL2 p.F49L, BCL2 p.G27T, BCL2 p.S161N, CD79B p.Y196F, EPHB1 c.-4_18del, IRF4 p.Y62∗, MYD88 p.L265P, PRDM1 c.291+1G>A, STAG2 p.E979∗ Loss: 6q, 9p, 20q, 21q; gain: 12, 1q (distal), 19q (distal); CN-LOH: 1p | Deceased | Lenalidomide, M-R, pomalidomide |
| 14 | 32 | M | 60 | 147 | Intact/diploid | BTG1 p.L47V | CD79B c.549+1G>T, MYD88 p.M232T Loss: 6q, 9p23-p21.3, 9p24.3-p23 (CD274, PDCD1LG2), 10q25.3-q26.13, 11p13-p11.12, 16q11.2-q23.1; gain: 18, 21; CN-LOH: none | Deceased | Focal RT, ASCT, IT Ara-C, ibrutinib, lenalidomide, nivolumab, pomalidomide, tafasitamab |
| 15 | 80 | F | 50 | 157 | CN-LOH 6p25.3-p21.33 | CD79B p.Y196C, MYD88 p.L265P Loss: 6p (proximal), 6q, 9p21.3; gain: 7, 9p, 9q, 11q, 18p, 20p; CN-LOH: 20q | Deceased | Focal RT, M-R, pomalidomide | |
| 16 | 78 | F | 40 | 48 | Intact/diploid | TP53 p.R248Q | CD79B p.Y196C, MYD88 p.S243N, PRDM1 p.S469∗ Loss: 6q, 12p (interstitial), 18p; gain: 6p, 7, 11, 18q, 19q; CN-LOH: 3, 17p (distal), 17q (distal), 20q | Deceased | None |
| 17 | 75 | F | 90 | 102 | Intact/diploid | BTG1 p.L37V | MYD88 p.L265P, SOCS1 p.H129Y Loss: 6q (proximal), 9p21.3; gain: 1q, 7q, 16, 19q; CN-LOH: 2, 9p | Alive | Focal RT, EA |
The median PFS for this cohort of 17 patients was 77 days (range, 35-157), the median age at diagnosis was 73 years (range, 32-87), and the median KPS was 60 (range, 50-70). Each had at least 1 of the high-risk aberrations at the 4 loci: 6p CN-LOH/6p21.3 HD, and mutations in BTG1, ETV6, or TP53. Six patients had tumors that contained 6p CN-LOH, 2 had 6p21.3 HD, 7 had BTG1 mutations, 4 had ETV6 mutations, and 3 had TP53 mutations. Co-occurrence of 6p CN-LOH, BTG1, and/or ETV6 mutations was detected in 2 cases. Only 2 tumors from this cohort lacked an aberration at 6p21.3, BTG1, and ETV6; these tumors contained both a TP53 mutation as well as deletion or CN-LOH involving 17p. Patients 1, 2, 5, 8, 10, and 11 have had extended response durations exceeding 1 year with ibrutinib and lenalidomide.
Ara-C, cytarabine; ASCT, autologous stem cell transplantation; F, female; HD-MTX, high-dose methotrexate; IT, intrathecal; M, male; M-R, high-dose methotrexate plus rituximab; RT, radiotherapy; WBRT, whole brain radiotherapy.