Clinical Relevance of MYC, BCL2 and BCL6 Rearrangements

and Amplification in Diffuse Large B-cell Lymphoma

GC Caponetti1, BJ Dave2, L Smith2, M Bast2, P Meyer2, P Bierman2, G Bociek2, J Vose2, J Armitage2, K Fu2, P Aoun3, TC Greiner2, WC Chan2 and DD Weisenburger3.
Creighton University Medical Center, Omaha, NE, USA; 2University of Nebraska Medical Center, Omaha, NE, USA; 3City of Hope National Medical Center, Duarte, CA, USA.

Objectives: The highly-variable clinical outcome seen in patients with diffuse large B-cell lymphoma (DLBCL) may be
due, at least in part, to various genetic abnormalities. BCL2 and BCL6 are often rearranged in DLBCL, and about 10% of
cases have rearrangement of MYC. These oncogenes play an important pathogenic role in DLBCL, and simultaneous
rearrangement or amplification of MYC, along with BCL2 and/or BCL6 (double hit) may have a synergistic effect leading
to poor survival. To test this hypothesis, we performed a retrospective analysis of DLBCL cases tested for translocations
and amplifications involving MYC, BCL2 and BCL6, and treated with CHOP- or R-CHOP-like therapies.

Methods:

We searched the database of the Nebraska Lymphoma Study Group for cases of de novo DLBCL with
available clinical data, patient consent, no prior treatment, and available conventional cytogenetics (CC) and/or FISH
results. Patients with a history of HIV infection or organ transplantation were excluded. CC and/or FISH reports were
reviewed to identify rearrangements of MYC, BCL2, and BCL6. Cases were classified into three groups according to the
rearrangement or amplification status of these three genes: 1) MYC- (with or without BCL2 or BCL6 rearrangement or
amplification); 2) MYC+/BCL2-/BCL6- or BCL6 unknown; and 3) MYC+/BCL2+ or BCL6+. A gene was considered
amplified if four or more copies were identified by FISH. The 5-year overall survival (OS) and event-free survival (EFS)
of the three groups were then compared.

1.0

0.9

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MYCMYC+/BCL2-/BCL6MYC+/BCL2+ or BCL6+

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Event-free Survival(%)

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Test: p=0.023
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Test: p=0.0059

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MYC+/BCL2-/BCL6MYC+/BCL2+ or BCL6+

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0.9

MYC+/BCL2-/BCL6MYC+/BCL2+ or BCL6+

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Test: p=0.010
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MYCMYC+/BCL2-/BCL6MYC+/BCL2+ or BCL6+

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Test: p=0.094

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Overall Survival (%)

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Event-free Survival(%)

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Overall Survival (%)

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Years

Figure 1 . Overall survival (A and C) and event-free survival (B and D) of patients with DLBCL according to the presence
or absence of rearrangement or amplification of the MYC, BCL2 and BCL6 genes.

Results: We identified 212 cases of DLBCL that met the study criteria, with a male to female ratio of 1:1 and a median
age of 67 years at diagnosis (range, 20-90 years). Based on the rearrangement and amplification status of the three
genes, 178 cases (85%) were classified as MYC- and had a 5-year OS of 47% and EFS of 38%; 17 cases (8%) were
MYC+/BCL2-/BCL6- or BCL6 unknown and had a 5-year OS of 76% and EFS of 71%; and 17 cases (8%) had a double
hit (MYC+/BCL2+ or BCL6+) with a 5-year OS of only 29% and EFS of 12%. No significant differences in clinical
characteristics were identified among these groups. However, a decreased complete remission rate (p=0.091) and
worse OS (p=0.064) and EFS (p=0.011) were found among double hit cases with MYC+/BCL2+ or BCL6+.

Conclusions:

MYC+ DLBCL cases without BCL2 or BCL6 rearrangements or amplification do not have a worse
survival when compared to cases without MYC abnormalities. However, MYC+ DLBCL cases with either BCL2 or BCL6
abnormalities have a poor clinical outcome and should be treated with aggressive or novel therapies.

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