Summary of studies on the prognostic impact of IKZF1 aberration in treatment trials of pediatric ALL
| Trial . | Ref. . | Country . | Trial period . | No. of patients . | Type of ALL . | Frequency of aberrant IKZF1 (method of detection) . | EFS (DFS) . | OS . | Cumulative incidence of relapse . | Comments . |
|---|---|---|---|---|---|---|---|---|---|---|
| COG P9906, St. Jude Total XI, XII, XIII, XIV, XV, and Interfant-99 | 10 | US | COG P9906: 2000-2003 | COG P9906: 221 | High-risk BCP | 28.6% (SNP array, Sanger sequencing) | 25% vs 73% (at 5 y), P < .0001 | 73% vs 25% (at 5 y), P < .0001 | Groundbreaking first study demonstrating prognostic impact of IKZF1 deletion; includes 5 patients with IKZF1 point mutation in the COG cohort and 21 BCR-ABL1–rearranged cases in the St. Jude cohort | |
| St. Jude and Interfant: 1986-2007 | St. Jude and Interfant: 258 | BCP | 18.6% (SNP array) | 40% vs 72% (at 10 y), P < .001 | 48% vs 26% (at 10 y), P = .004 | |||||
| DCOG ALL9 | 13, 48 | The Netherlands | 1997-2000 | 131 | BCP | 13.0% (MLPA, Sanger sequencing) | 39% vs 89% (at 8 y), P < .001 | 56.0% vs 91.0% (at 8 y), P < .001 | Exemplifies the importance of IKZF1 deletion as a prognostic factor, especially in non–high-risk patients; included 2 BCR-ABL1–rearranged cases; subsequent study in related population demonstrated the prognostic power of integrated use of aberrant IKZF1 and MRD levels | |
| TPOG-ALL-93, TPOG-97-VHR, TPOG-ALL-2002 | 14 | Taiwan | 1995-2009 | 242 | BCP | 10.7% (PCR) | 15% vs 76% (at 10 y), P < .0001 | 38% vs 78% (at 10 y), P = .0016 | First study indicating poor prognostic effect of IKZF1 deletion in an Asian population | |
| DCOG ALL8, ALL9, ALL10, UKALL 97, 97/99, 2003 | 30 | The Netherlands, UK | 1997-2006 | DCOG: 34 | Down syndrome ALL | DCOG: 35.3% (CGH array, MLPA, Sanger sequencing) | DCOG: 45% vs 95% (at 6 y), P = .002 | DCOG: 66% vs 95% (at 6 y), P = .02 | DCOG: 37% vs 5% (at 6 y), P = .044 | Strong prognostic effect of IKZF1 deletion in Down syndrome ALL |
| UKALL: 85 | UKALL: 27.1% (MLPA) | UKALL: 21% vs 58% (at 6 y), P = .002 | UKALL: 15% vs 71% (at 6 y), P = .002 | UKALL: 37% vs 18% (at 6 y), P = .06 | ||||||
| Japan Childhood Leukemia Study ALL02 | 31 | Japan | 2002-2008 | 202 | BCP | 9.4% (MLPA) | 63% vs 89% (at 5 y),P = ..001 | 72% vs 90% (at 5 y),P = ..02 | Particularly strong prognostic effect of IKZF1 deletion in the NCI high-risk group | |
| JCCLSG ALL 2004 | 32 | Japan | 2004-2008 | 177 | BCP | 12.0% (MLPA) | 68% vs 85% (at 4 y), P = .04 | Prognostic effect of IKZF1 deletion more pronounced in high-risk patients | ||
| ALL-REZ BFM 2002 | 33 | Germany, Austria, Switzerland | 2002-2009 | 204 | BCP relapse | 33.3% (MLPA) | 30% vs 51% (at 5 y), P = .002 | 36% vs 60% (at 5 y), P = .001 | 41% vs 23% (at 5 y), P = .006 | Prognostic impact of IKZF1 deletion also in second-line treatment of relapsed ALL; one-quarter of IKZF1 deletions was acquired at relapse |
| AIEOP-BFM ALL 2000 | 34 | Germany | 1999-2005 | 694 | BCP and T ALL | 12.0% (MLPA) | 69% vs 85% (at 5 y), P < .0001 | 82% vs 92% (at 5 y), P = .003 | 21% vs 10% (at 5 y), P = .001 | Pronounced prognostic effect of IKZF1 deletion in the intermediate-risk group |
| AIEOP-BFM ALL 2000 | 35 | Italy | 2003-2005 | 410 | BCP | 13.2% (MLPA) | 70% vs 85% (at 5 y), P = .007 | 87% vs 93% (at 5 y), P = .100 | 24% vs 13% (at 5 y), P = .049 | Due to the modest effect of IKZF1 deletion observed, the relevance of IKZF1 deletion as a clinically useful stratification factor is debated |
| DCOG ALL8, ALL9, ALL10, COALL-97, COALL-03 | 36 | The Netherlands, Germany | 1991-2012 | 857 | BCP | 15.9% (MLPA) | 34% vs 13% (at 5 y), P = <.001 | Confirms and extends the strong prognostic effect of IKZF1 deletion; IKZF1 deletion remained predictive in intermediate risk patients on the MRD-guided DCOG ALL10 trial | ||
| EsPhALL and I-BFM SG studies (for pre-TKI assessment) | 37 | Austria, Czech Republic, France, Germany, The Netherlands, UK | 1995-2005 | Pre-TKI cohort: 84 EsPh-ALL cohort: 107 | BCR-ABL1–rearranged BCP | 66.0% (MLPA, CGH array, SNP array) | DFS pre-TKI: 30% vs 58% (at 4 y), P = .013 | Pre-TKI: 49% vs 75% (at 4 y), P = .075 | Pre-TKI: 57% vs 21% (at 4 y), P = .026 | IKZF1 deletion is demonstrated to be a poor prognostic marker in BCR-ABL1–rearranged pediatric ALL independent of imatinib treatment |
| DFS EsPhALL: 54% vs 63% (at 4 y), P = .168 | EsPhALL: 58% vs 83% (at 4 y), P = .070 | EsPhALL: 28% vs 31% (at 4 y), P = .817 | ||||||||
| DFS EsPhALL TKI-treated good-risk patients: 56% vs 75% (at 4 y), P = .051 | EsPhALL TKI-treated good-risk patients: 66% vs 100% (at 4 y), P = .039 | EsPhALL TKI-treated good-risk patients: 29% vs 25% (at 4 y), P = .249 | ||||||||
| UKALL trials ALL 97/99 and ALL 2003 | 38 | UK, Ireland | UKALL 97/99: 1997-2002 | UKALL 97/99: 864 | BCP | 13.4% (MLPA) | 56% vs 80% (at 5 y), P = <.001 | 70% vs 89% (at 5 y), P = <.001 | 40% vs 18% (at 5 y), P = <.001 | Integration of cytogenetic with genomic data including IKZF1 deletion refines risk groups in a clinically meaningful way |
| UKALL 2003: 2003-2011 | UKALL 2003: 782 | BCP | 11.1% (MLPA) | 80% vs 92% (at 5 y), P = <.001 | 86% vs 95% (at 5 y), P = <.001 | 16% vs 6% (at 5 y), P = .002 | ||||
| NOPHO ALL-1992, NOPHO ALL-2000, NOPHO ALL-2008 | 39 | Denmark, Finland, Norway, Sweden | 1992-2013 | 334 | BCP | 15.0% (SNP array, MLPA) | 60% vs 83% (at 10 y), P < .001 | 73% vs 89% (at 10 y), P = .001 | 35% vs 12% (at 10 y), P < .001 | Prognostic impact independent of WBC count and MRD; co-occurrence of PAR1 deletion increased prognostic impact of IKZF1 deletion |
| EORTC Children’s Leukemia Group study 58951 | 40 | Belgium, France, Portugal | 1998-2008 | 1223 | BCP | 14.6% (PCR, MLPA) | 68% vs 87% (at 5 y), P = <.001 | 87% vs 92% (at 5 y), P = .035 | IKZF1-aberrant BCP ALL benefited from vincristine-steroid pulses during maintenance treatment | |
| ALLR3 | 41 | UK, Ireland, The Netherlands, Australia, New Zealand | 2002-2013 | 222 | BCP relapse | 23.0% (MLPA) | 48% vs 53% (at 5 y), P = .30 | No prognostic impact of IKZF1 deletion at relapse | ||
| ANZCHOG ALL8 | 42 | Australia, New Zealand | 2002-2011 | 475 | BCP standard and intermediate risk | 10.5% (MLPA) | 53% vs 83% (at 7 y), P < .0001 | 78% vs 94% (at 7 y), P < .0001 | 41% vs 15% (at 7 y), P < .0001 | Strong prognostic effect of IKZF1 deletion in non–high-risk BCP ALL |
| ALL-BFM 95 | 45 | Germany | 1995-2000 | 655 | BCP intermediate risk | 12.2% (PCR) | 66% vs 82% (at 5 y), P = .001 | Vincristine-dexamethasone pulses during maintenance were not of benefit to IKZF1-deleted intermediate-risk patients | ||
| DFCI ALL Consortium Protocol 05-001 | 43 | US | 2005-2010 | 385 | BCP | 16.0% (MLPA) | 63% vs 88% (at 5 y), P < .001 | 79% vs 94% (at 5 y), P < .001 | 29% vs 8% (at 5 y), P < .001 | IKZF1 deletion was confirmed as an independent predictor of inferior outcome |
| Malaysia-Singapore ALL 2003, 2010 | 44 | Malaysia, Singapore | 2002-2017 | 665 | BCP | 15.9% (MLPA) | Without IKZF1 as high-risk criterion: 30% vs 8% (at 5 y), P < .001 | Demonstrates that intensifying treatment of IKZF1-deleted BCP ALL patients reduces risk of relapse | ||
| With IKZF1 as high-risk criterion: 14% vs 5% (at 5 y), P = .030 | ||||||||||
| COG Trial AALL0622 | 46 | US, Canada | 2008-2012 | 44 | BCR-ABL1–rearranged BCP | 56.8% (SNP array) | 52% vs 82% (at 5 y), P = .040 | 80% vs 100% (at 5 y), P = .040 | Confirms poor outcome for IKZF1-deleted BCR-ABL1–rearranged ALL on dasatinib-containing treatment regimen | |
| AIEOP-BFM ALL 2000 | 61 | Germany, Italy | 1999-2009 | 1408 | BCP | 14.6% (MLPA) | IKZF1-deleted, but not IKZF1plus: 77% vs 86% (at 5 y), P = .0005 | IKZF1-deleted, but not IKZF1plus: 89% vs 94% (at 5 y), P = .023 | IKZF1-deleted, but not IKZF1plus: 16% vs 11% (at 5 y), P = .045 | Definition of a poor MRD-dependent prognostic pattern termed IKZF1plus with IKZF1 deletions co-occurring with deletions in CDKN2A, CDKN2B, PAX5, or PAR1 in the absence of ERG deletion |
| IKZF1plus: 51% vs 86% (at 5 y), P < .0001 | IKZF1plus: 75% vs 94% (at 5 y), P < .0001 | IKZF1plus: 44% vs 11% (at 5 y), P < .0001 |
| Trial . | Ref. . | Country . | Trial period . | No. of patients . | Type of ALL . | Frequency of aberrant IKZF1 (method of detection) . | EFS (DFS) . | OS . | Cumulative incidence of relapse . | Comments . |
|---|---|---|---|---|---|---|---|---|---|---|
| COG P9906, St. Jude Total XI, XII, XIII, XIV, XV, and Interfant-99 | 10 | US | COG P9906: 2000-2003 | COG P9906: 221 | High-risk BCP | 28.6% (SNP array, Sanger sequencing) | 25% vs 73% (at 5 y), P < .0001 | 73% vs 25% (at 5 y), P < .0001 | Groundbreaking first study demonstrating prognostic impact of IKZF1 deletion; includes 5 patients with IKZF1 point mutation in the COG cohort and 21 BCR-ABL1–rearranged cases in the St. Jude cohort | |
| St. Jude and Interfant: 1986-2007 | St. Jude and Interfant: 258 | BCP | 18.6% (SNP array) | 40% vs 72% (at 10 y), P < .001 | 48% vs 26% (at 10 y), P = .004 | |||||
| DCOG ALL9 | 13, 48 | The Netherlands | 1997-2000 | 131 | BCP | 13.0% (MLPA, Sanger sequencing) | 39% vs 89% (at 8 y), P < .001 | 56.0% vs 91.0% (at 8 y), P < .001 | Exemplifies the importance of IKZF1 deletion as a prognostic factor, especially in non–high-risk patients; included 2 BCR-ABL1–rearranged cases; subsequent study in related population demonstrated the prognostic power of integrated use of aberrant IKZF1 and MRD levels | |
| TPOG-ALL-93, TPOG-97-VHR, TPOG-ALL-2002 | 14 | Taiwan | 1995-2009 | 242 | BCP | 10.7% (PCR) | 15% vs 76% (at 10 y), P < .0001 | 38% vs 78% (at 10 y), P = .0016 | First study indicating poor prognostic effect of IKZF1 deletion in an Asian population | |
| DCOG ALL8, ALL9, ALL10, UKALL 97, 97/99, 2003 | 30 | The Netherlands, UK | 1997-2006 | DCOG: 34 | Down syndrome ALL | DCOG: 35.3% (CGH array, MLPA, Sanger sequencing) | DCOG: 45% vs 95% (at 6 y), P = .002 | DCOG: 66% vs 95% (at 6 y), P = .02 | DCOG: 37% vs 5% (at 6 y), P = .044 | Strong prognostic effect of IKZF1 deletion in Down syndrome ALL |
| UKALL: 85 | UKALL: 27.1% (MLPA) | UKALL: 21% vs 58% (at 6 y), P = .002 | UKALL: 15% vs 71% (at 6 y), P = .002 | UKALL: 37% vs 18% (at 6 y), P = .06 | ||||||
| Japan Childhood Leukemia Study ALL02 | 31 | Japan | 2002-2008 | 202 | BCP | 9.4% (MLPA) | 63% vs 89% (at 5 y),P = ..001 | 72% vs 90% (at 5 y),P = ..02 | Particularly strong prognostic effect of IKZF1 deletion in the NCI high-risk group | |
| JCCLSG ALL 2004 | 32 | Japan | 2004-2008 | 177 | BCP | 12.0% (MLPA) | 68% vs 85% (at 4 y), P = .04 | Prognostic effect of IKZF1 deletion more pronounced in high-risk patients | ||
| ALL-REZ BFM 2002 | 33 | Germany, Austria, Switzerland | 2002-2009 | 204 | BCP relapse | 33.3% (MLPA) | 30% vs 51% (at 5 y), P = .002 | 36% vs 60% (at 5 y), P = .001 | 41% vs 23% (at 5 y), P = .006 | Prognostic impact of IKZF1 deletion also in second-line treatment of relapsed ALL; one-quarter of IKZF1 deletions was acquired at relapse |
| AIEOP-BFM ALL 2000 | 34 | Germany | 1999-2005 | 694 | BCP and T ALL | 12.0% (MLPA) | 69% vs 85% (at 5 y), P < .0001 | 82% vs 92% (at 5 y), P = .003 | 21% vs 10% (at 5 y), P = .001 | Pronounced prognostic effect of IKZF1 deletion in the intermediate-risk group |
| AIEOP-BFM ALL 2000 | 35 | Italy | 2003-2005 | 410 | BCP | 13.2% (MLPA) | 70% vs 85% (at 5 y), P = .007 | 87% vs 93% (at 5 y), P = .100 | 24% vs 13% (at 5 y), P = .049 | Due to the modest effect of IKZF1 deletion observed, the relevance of IKZF1 deletion as a clinically useful stratification factor is debated |
| DCOG ALL8, ALL9, ALL10, COALL-97, COALL-03 | 36 | The Netherlands, Germany | 1991-2012 | 857 | BCP | 15.9% (MLPA) | 34% vs 13% (at 5 y), P = <.001 | Confirms and extends the strong prognostic effect of IKZF1 deletion; IKZF1 deletion remained predictive in intermediate risk patients on the MRD-guided DCOG ALL10 trial | ||
| EsPhALL and I-BFM SG studies (for pre-TKI assessment) | 37 | Austria, Czech Republic, France, Germany, The Netherlands, UK | 1995-2005 | Pre-TKI cohort: 84 EsPh-ALL cohort: 107 | BCR-ABL1–rearranged BCP | 66.0% (MLPA, CGH array, SNP array) | DFS pre-TKI: 30% vs 58% (at 4 y), P = .013 | Pre-TKI: 49% vs 75% (at 4 y), P = .075 | Pre-TKI: 57% vs 21% (at 4 y), P = .026 | IKZF1 deletion is demonstrated to be a poor prognostic marker in BCR-ABL1–rearranged pediatric ALL independent of imatinib treatment |
| DFS EsPhALL: 54% vs 63% (at 4 y), P = .168 | EsPhALL: 58% vs 83% (at 4 y), P = .070 | EsPhALL: 28% vs 31% (at 4 y), P = .817 | ||||||||
| DFS EsPhALL TKI-treated good-risk patients: 56% vs 75% (at 4 y), P = .051 | EsPhALL TKI-treated good-risk patients: 66% vs 100% (at 4 y), P = .039 | EsPhALL TKI-treated good-risk patients: 29% vs 25% (at 4 y), P = .249 | ||||||||
| UKALL trials ALL 97/99 and ALL 2003 | 38 | UK, Ireland | UKALL 97/99: 1997-2002 | UKALL 97/99: 864 | BCP | 13.4% (MLPA) | 56% vs 80% (at 5 y), P = <.001 | 70% vs 89% (at 5 y), P = <.001 | 40% vs 18% (at 5 y), P = <.001 | Integration of cytogenetic with genomic data including IKZF1 deletion refines risk groups in a clinically meaningful way |
| UKALL 2003: 2003-2011 | UKALL 2003: 782 | BCP | 11.1% (MLPA) | 80% vs 92% (at 5 y), P = <.001 | 86% vs 95% (at 5 y), P = <.001 | 16% vs 6% (at 5 y), P = .002 | ||||
| NOPHO ALL-1992, NOPHO ALL-2000, NOPHO ALL-2008 | 39 | Denmark, Finland, Norway, Sweden | 1992-2013 | 334 | BCP | 15.0% (SNP array, MLPA) | 60% vs 83% (at 10 y), P < .001 | 73% vs 89% (at 10 y), P = .001 | 35% vs 12% (at 10 y), P < .001 | Prognostic impact independent of WBC count and MRD; co-occurrence of PAR1 deletion increased prognostic impact of IKZF1 deletion |
| EORTC Children’s Leukemia Group study 58951 | 40 | Belgium, France, Portugal | 1998-2008 | 1223 | BCP | 14.6% (PCR, MLPA) | 68% vs 87% (at 5 y), P = <.001 | 87% vs 92% (at 5 y), P = .035 | IKZF1-aberrant BCP ALL benefited from vincristine-steroid pulses during maintenance treatment | |
| ALLR3 | 41 | UK, Ireland, The Netherlands, Australia, New Zealand | 2002-2013 | 222 | BCP relapse | 23.0% (MLPA) | 48% vs 53% (at 5 y), P = .30 | No prognostic impact of IKZF1 deletion at relapse | ||
| ANZCHOG ALL8 | 42 | Australia, New Zealand | 2002-2011 | 475 | BCP standard and intermediate risk | 10.5% (MLPA) | 53% vs 83% (at 7 y), P < .0001 | 78% vs 94% (at 7 y), P < .0001 | 41% vs 15% (at 7 y), P < .0001 | Strong prognostic effect of IKZF1 deletion in non–high-risk BCP ALL |
| ALL-BFM 95 | 45 | Germany | 1995-2000 | 655 | BCP intermediate risk | 12.2% (PCR) | 66% vs 82% (at 5 y), P = .001 | Vincristine-dexamethasone pulses during maintenance were not of benefit to IKZF1-deleted intermediate-risk patients | ||
| DFCI ALL Consortium Protocol 05-001 | 43 | US | 2005-2010 | 385 | BCP | 16.0% (MLPA) | 63% vs 88% (at 5 y), P < .001 | 79% vs 94% (at 5 y), P < .001 | 29% vs 8% (at 5 y), P < .001 | IKZF1 deletion was confirmed as an independent predictor of inferior outcome |
| Malaysia-Singapore ALL 2003, 2010 | 44 | Malaysia, Singapore | 2002-2017 | 665 | BCP | 15.9% (MLPA) | Without IKZF1 as high-risk criterion: 30% vs 8% (at 5 y), P < .001 | Demonstrates that intensifying treatment of IKZF1-deleted BCP ALL patients reduces risk of relapse | ||
| With IKZF1 as high-risk criterion: 14% vs 5% (at 5 y), P = .030 | ||||||||||
| COG Trial AALL0622 | 46 | US, Canada | 2008-2012 | 44 | BCR-ABL1–rearranged BCP | 56.8% (SNP array) | 52% vs 82% (at 5 y), P = .040 | 80% vs 100% (at 5 y), P = .040 | Confirms poor outcome for IKZF1-deleted BCR-ABL1–rearranged ALL on dasatinib-containing treatment regimen | |
| AIEOP-BFM ALL 2000 | 61 | Germany, Italy | 1999-2009 | 1408 | BCP | 14.6% (MLPA) | IKZF1-deleted, but not IKZF1plus: 77% vs 86% (at 5 y), P = .0005 | IKZF1-deleted, but not IKZF1plus: 89% vs 94% (at 5 y), P = .023 | IKZF1-deleted, but not IKZF1plus: 16% vs 11% (at 5 y), P = .045 | Definition of a poor MRD-dependent prognostic pattern termed IKZF1plus with IKZF1 deletions co-occurring with deletions in CDKN2A, CDKN2B, PAX5, or PAR1 in the absence of ERG deletion |
| IKZF1plus: 51% vs 86% (at 5 y), P < .0001 | IKZF1plus: 75% vs 94% (at 5 y), P < .0001 | IKZF1plus: 44% vs 11% (at 5 y), P < .0001 |
AIEOP, Associazione Italiana di Ematologia e Oncologia Pediatrica; ALL-REZ, Acute Lymphoblastic Leukemia-Relapse Study; BFM, Berlin-Frankfurt-Münster; ALLR3, An International Collaborative Trial for Relapsed and Refractory Acute Lymphoblastic Leukaemia Combination Chemotherapy in Treating Young Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia; ANZCHOG, Australian & New Zealand Children’s Haematology/Oncology Group; CGH, comparative genomic hybridization; COG, Children’s Oncology Group; DCOG, Dutch Childhood Oncology Group; DFCI, Dana-Farber Cancer Institute; DFS, disease-free survival; EFS, event-free survival; EORTC, European Organisation for Research and Treatment of Cancer; EsPHALL, Safety and Efficacy of Imatinib Added to Chemotherapy in Treatment of Ph+ Acute Lymphoblastic Leukemia in Children; I-BFM SG, International Berlin-Frankfurt-Münster Study Group; JCCLSG, Japanese Children's Cancer and Leukemia Study Group; MLPA, multiplex ligation probe-dependent amplification; MRD, minimal residual disease; NCI, National Cancer Institute; NOPHO, Nordic Society of Pediatric Hematology and Oncology; OS, overall survival; PCR, polymerase chain reaction; Ref., reference(s); Sanger sequencing, dye-terminator sequencing; SNP, single-nucleotide polymorphism; TKI, tyrosine kinase inhibitor; TPOG, Taiwan Pediatric Oncology Group; UK, United Kingdom; US, United States; VHR, very high risk; WBC, white blood cell.