Cytogenetic and Molecular Genetic Characterization Of MLL-PTD Positive AML In Comparison To MLL-Translocated AML
Authors: Haferlach Claudia , Kohlmann Alexander , Kern Wolfgang , Haferlach Torsten , Schnittger Susanne 
Published: October 2019

Background

Partial tandem duplications within the MLL gene (MLL-PTD) are a recurrent molecular alteration in acute myeloid leukemia (AML). MLL-PTD occurs with a frequency of 6-8% in de novo AML. Data on additional cytogenetic and molecular alterations in MLL-PTD+ AML is scarce. Beside partial tandem duplications within the MLL gene, the MLL gene is also a target of balanced translocations leading to the fusion of MLL with a large variety of partner genes.

Aims

1. Evaluate the spectrum of additional cytogenetic and molecular genetic alterations. 2. Analyze whether additional aberrations impact prognosis. 3. Compare the spectrum of additional abnormalities between MLL-PTD+ AML and AML with MLL-translocations.

Patients and Methods

We selected a cohort of 225 de novo AML patients harboring a MLL-PTD. These were compared to a cohort of 130 de novo AML with MLL-translocation (MLL-t). Mutation screening for the following genes was performed in pts with MLL-PTD and MLL-t, respectively: ASXL1 (132; 85), CEBPA (184; 67), FLT3-ITD (225; 125), FLT3-TKD (208; 112), IDH1R132 (145; 88), IDH2R140 (141; 63), IDH2R172 (137; 73), KRAS (59; 82), NRAS (98; 82), RUNX1 (213; 97), NPM1 (221; 123), TP53 (104; 89), and WT1 (159; 86). EVI1 expression was assessed in 55 MLL-PTD+ pts and in 77 pts with MLL-t.

Results

The frequency of MLL-PTD and MLL-translocations differed significantly with respect to age. While MLL-PTD were more frequent in elderly pts, MLL-t were more frequent in younger pts (<10 yrs: 0%/2.3%; 10-19 yrs: 0%/3.8%, 20-29 yrs: 0.9%/13.1%, 30-39 yrs: 3.1%/9.2%, 40-49 yrs: 8.9%/23.1%; 50-59 yrs: 11.1%/13.1%; 60-69 yrs: 35.1%/13.8%; 70-79 yrs: 29.3%/13.8%; ≥80 yrs: 11.6%/7.7%; p<0.001). FAB subtype distribution differed significantly between of MLL-PTD+ and MLL-t AML. While in MLL-PTD+ AML most frequently subtypes M1 (33.8%) and M2 (43.6%) were observed, AML with MLL-t most frequently showed M4 (30%) and M5a (23.1%). The most frequent cytogenetic abnormalities in MLL-PTD+ cases were gains of 11q (n=37), followed by 8q (n=14), and 13q (n=7) and losses of 5q (n=14), 7q (n=14) and 17p (n=5). In contrast, in MLL-t patients the most frequent gains were trisomies 6 (n=7) and 8 (n=33), as well as gains of 1q (n=10), 19p (n=10), 19q (n=8) and 21q (n=21). There were many significant differences in co-occurring mutations between MLL-PTD+ and MLL-t: DNMT3Amut: 44.7% vs 0% (p<0.001), FLT3-ITD: 33.3% vs 3.2% (p<0.001), IDH1R132 14.5% vs 0% (p<0.001), IDH2R140: 19.9% vs 0% (p<0.001), IDH2R172 9.5% vs 0% (p=0.005), and RUNX1 25.8% vs 2.1% (p<0.001). On the other hand KRASmut (3.4% vs 23.2%, p=0.001) and NRASmut (8.2% vs 25.6%, p=0.002) were less frequent in MLL-PTD+ as compared to MLL-t AML. TP53 mutations were observed in comparable frequencies (3.8% vs 5.6%). NPM1 mutations were not detected in either entity. The mean EVI1 expression was significantly higher in MLL-t pts compared to MLL-PTD+ pts (167.1+/-259.1vs 0.4 +/- 0.47, p<0.001). Overall, chromosome abnormalities in addition to the MLL alteration were more frequent in MLL-t AML as compared to MLL-PTD+ AML (mean number of alterations: 1.2 vs 0.7, p=0.004). This goes along with more additional molecular mutations in MLL-PTD+ AML as compared to MLL-t AML (mean number of molecular mutations: 1.5 vs 0.6, p=0.004). Overall survival at 5 yrs was comparable in both subgroups (MLL-PTD+: 27.9% vs MLL-t: 39.8%). In both subgroups age was significantly associated with OS (<60 yrs vs ≥60 yrs: MLL-PTD+: 56.9 vs 16.3 months, MLL-t: 47.8 vs 9.7 months, for both p<0.001). Neither in MLL-PTD+ AML nor in MLL-t AML the presence of additional chromosome aberration had an impact on outcome. With respect to molecular mutations only IDH2R140 was significantly associated with shorter OS (HR: 2.2, p=0.007) and IDH2R172 with longer OS (HR: 0.2, p=0.04) in MLL-PTD+ AML.

Conclusions

Although both MLL-PTD+ and MLL-translocations disrupt the same gene AML harboring one or the other MLL abnormality differ significantly with respect to age distribution, the pattern of additional cytogenetic abnormalities and the frequency of accompanying molecular mutations. MLL-PTD is more frequent in older patients, presents most frequently as FAB M1 and M2, and harbors more additional molecular genetic events and less additional cytogenetic events. However, both AML subtypes are associated with adverse outcome, particularly in elderly patients.

Disclosures:

Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.