AGE SPECIFIC INCIDENCE OF PARTNER GENE AND SECONDARY ABNORMALITIES IN MLL POSITIVE ACUTE LYMPHOBLASTIC LEUKAEMIA (ALL)
Author(s): ,
Alem S Gabriel
Affiliations:
Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research,Newcastle University,Newcastle upon Tyne,United Kingdom
,
Amir Enshaei
Affiliations:
Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research,Newcastle University,Newcastle upon Tyne,United Kingdom
,
Jennifer Taylor
Affiliations:
Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research,Newcastle University,Newcastle upon Tyne,United Kingdom
,
Amy Erhorn
Affiliations:
Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research,Newcastle University,Newcastle upon Tyne,United Kingdom
,
Claire Schwab
Affiliations:
Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research,Newcastle University,Newcastle upon Tyne,United Kingdom
,
Lena Rai
Affiliations:
Department of Haematology,Royal Free and UCMS,London,United Kingdom
,
Adele Fielding
Affiliations:
Department of Haematology,Royal Free and UCMS,London,United Kingdom
,
Nicholas Goulden
Affiliations:
Department of Haematology,Great Ormond Street Hospital,London,United Kingdom
,
Ajay Vora
Affiliations:
Department of Haematology,Sheffield Children's Hospital,Sheffield,United Kingdom
,
Christine J Harrison
Affiliations:
Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research,Newcastle University,Newcastle upon Tyne,United Kingdom
Anthony V Moorman
Affiliations:
Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research,Newcastle University,Newcastle upon Tyne,United Kingdom
EHA Library. Gabriel A. 06/13/15; 100937; P153 Disclosure(s): Newcastle University
Northern Institute for Cancer Research
Dr. Alem Gabriel
Dr. Alem Gabriel
Contributions
Abstract
Abstract: P153

Type: Poster Presentation + travel grant

Presentation during EHA20: From 12.06.2015 17:15 to 12.06.2015 18:45

Location: Poster area (Hall C)

Background

MLL gene rearrangements (MLL-t) define a unique subgroup in 5-10% patients with ALL. However, there is still heterogeneity in clinical outcomes and genetic composition. The incidence of MLL-t varies by age accounting for 80% infant, 3% children and 10% adults. Patients harbouring MLL-t have a poor outcome relative to their age-matched counterparts and are typically assigned to high risk treatment protocols. The frequency and clinical relevance of the partner gene and cooperating lesions is unclear.



Aims

We investigated the age-specific frequency of partner genes and the spectrum of additional abnormalities in 368 MLL-t cases treated on UK clinical trials over a 20 year period.



Methods

Cytogenetic and FISH analysis was performed on pre-treatment bone marrow samples using the Vysis MLL break apart probe, Kreatech Poseidon MLL fusion probes [t(4;11)(q21;q23), t(11;19)(q23;p13), t(9;11)(p21;q23) and t(6;11)(q27;q23)] and a home-grown AF10 break-apart probe. Copy number alterations (CNA) were assessed by high resolution Affymetrix arrays: SNP6 (n=14) or CytoscanHD (n=12).



Results
Among the 368 patients the most prevalent translocations were t(4;11) n=225 (64%), t(11;19) n=61 (17%), t(9;11) n=28 (8%), t(10;11) n=12 (3%) and t(6;11) n=10 (3%). Seventeen patients harboured other rare partners while the partner gene could not be determined in 15 patients. The presence of t(4;11) was age-dependent: infant (<1 year) 78/137 (57%);  young children (1-9 years) 35/77 (48%); older children (10-14 years) 19/33 (58%);  young adults (15-24 years) 27/30 (90%); and adults 66/76 (87%). The majority of MLL-t cases had B-cell precursor ALL (93%) but 24 (7%) patients had T-ALL and these were commonly older children and younger adults (11/24, 46%) and included 11 (46%) cases with t(11;19). In order to address the question of outcome heterogeneity by partner gene, we examined the outcome data for 47 patients (1-24 years) treated on UKALL2003 where patients with MLL-t were treated on the high risk arm. There was no evidence that the t(4;11) conveyed an inferior outcome compared with other MLL-t: 5 year event-free and overall survival rates were 74% v 70%, p=0.7 and 74% v 83%, p=0.5, respectively. Among 347 cases with successful cytogenetics, 116 (33%) cases had at least one additional chromosomal abnormality (ACA) whilst in the remaining 225 cases only the 11q23 abnormality was observed. A total of 299 ACA were counted, averaging 0.8 per case but with some variation by age (0.43, 0.70, 0.51, 0.83 and 0.32 in infants, young children, older children, young adults and adults, respectively) as well as partner gene (0.48 in t(4;11) and 1.34 in non-t(4;11)). The most common ACA were gain of chromosomes X, 6, and 8 as well as loss of 17p and i(7q). CNA analysis of 14 children and 12 adults with t(4;11) (n=22) and t(11;19) (n=4) revealed a total of 87 CNA, mostly gains (n=58). SNP array analysis of 24 patients revealed at least one CNA per case and an average of 3.3 per case. This average is fewer than that reported in other cytogenetic subgroups using lower resolution arrays (6-7 per case). Although the number of CNA was low and many were private, the increased resolution offered by the CytoscanHD array identified several regions of the genome which were recurrently affected by CNA and warrant further investigation, including 2q26~31 and 15q26.

Summary

In conclusion, although the number of secondary abnormalities in MLL-t is low there is evidence that it is related to both the partner gene and the age of the patient. In addition, when treated as high risk on a contemporary protocol all children and young adults with a MLL-t can achieve good OS rates.



Keyword(s): 11q23, Acute lymphoblastic leukemia, MLL, SNP
Abstract: P153

Type: Poster Presentation + travel grant

Presentation during EHA20: From 12.06.2015 17:15 to 12.06.2015 18:45

Location: Poster area (Hall C)

Background

MLL gene rearrangements (MLL-t) define a unique subgroup in 5-10% patients with ALL. However, there is still heterogeneity in clinical outcomes and genetic composition. The incidence of MLL-t varies by age accounting for 80% infant, 3% children and 10% adults. Patients harbouring MLL-t have a poor outcome relative to their age-matched counterparts and are typically assigned to high risk treatment protocols. The frequency and clinical relevance of the partner gene and cooperating lesions is unclear.



Aims

We investigated the age-specific frequency of partner genes and the spectrum of additional abnormalities in 368 MLL-t cases treated on UK clinical trials over a 20 year period.



Methods

Cytogenetic and FISH analysis was performed on pre-treatment bone marrow samples using the Vysis MLL break apart probe, Kreatech Poseidon MLL fusion probes [t(4;11)(q21;q23), t(11;19)(q23;p13), t(9;11)(p21;q23) and t(6;11)(q27;q23)] and a home-grown AF10 break-apart probe. Copy number alterations (CNA) were assessed by high resolution Affymetrix arrays: SNP6 (n=14) or CytoscanHD (n=12).



Results
Among the 368 patients the most prevalent translocations were t(4;11) n=225 (64%), t(11;19) n=61 (17%), t(9;11) n=28 (8%), t(10;11) n=12 (3%) and t(6;11) n=10 (3%). Seventeen patients harboured other rare partners while the partner gene could not be determined in 15 patients. The presence of t(4;11) was age-dependent: infant (<1 year) 78/137 (57%);  young children (1-9 years) 35/77 (48%); older children (10-14 years) 19/33 (58%);  young adults (15-24 years) 27/30 (90%); and adults 66/76 (87%). The majority of MLL-t cases had B-cell precursor ALL (93%) but 24 (7%) patients had T-ALL and these were commonly older children and younger adults (11/24, 46%) and included 11 (46%) cases with t(11;19). In order to address the question of outcome heterogeneity by partner gene, we examined the outcome data for 47 patients (1-24 years) treated on UKALL2003 where patients with MLL-t were treated on the high risk arm. There was no evidence that the t(4;11) conveyed an inferior outcome compared with other MLL-t: 5 year event-free and overall survival rates were 74% v 70%, p=0.7 and 74% v 83%, p=0.5, respectively. Among 347 cases with successful cytogenetics, 116 (33%) cases had at least one additional chromosomal abnormality (ACA) whilst in the remaining 225 cases only the 11q23 abnormality was observed. A total of 299 ACA were counted, averaging 0.8 per case but with some variation by age (0.43, 0.70, 0.51, 0.83 and 0.32 in infants, young children, older children, young adults and adults, respectively) as well as partner gene (0.48 in t(4;11) and 1.34 in non-t(4;11)). The most common ACA were gain of chromosomes X, 6, and 8 as well as loss of 17p and i(7q). CNA analysis of 14 children and 12 adults with t(4;11) (n=22) and t(11;19) (n=4) revealed a total of 87 CNA, mostly gains (n=58). SNP array analysis of 24 patients revealed at least one CNA per case and an average of 3.3 per case. This average is fewer than that reported in other cytogenetic subgroups using lower resolution arrays (6-7 per case). Although the number of CNA was low and many were private, the increased resolution offered by the CytoscanHD array identified several regions of the genome which were recurrently affected by CNA and warrant further investigation, including 2q26~31 and 15q26.

Summary

In conclusion, although the number of secondary abnormalities in MLL-t is low there is evidence that it is related to both the partner gene and the age of the patient. In addition, when treated as high risk on a contemporary protocol all children and young adults with a MLL-t can achieve good OS rates.



Keyword(s): 11q23, Acute lymphoblastic leukemia, MLL, SNP

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