In a Lunenburg Lymphoma Biomarker Consortium study reported in the Journal of Clinical Oncology, Rosenwald et al found that MYC rearrangement was associated with poorer outcomes in diffuse large B-cell lymphoma (DLBCL) when accompanied by rearrangement of BCL2 and/or BCL6 and an immunoglobulin translocation partner gene.

Study Details

The study involved 2,383 patients (47%) with biopsy material available to test for MYC rearrangement from a cohort of 5,117 patients with DLBCL derived from large prospective trials and patient registries in Europe and North America. All patients were treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, or similar therapy. Fluorescence in situ hybridization was used for identification of alterations in MYC, BCL2, BCL6, and immunoglobulin heavy and light chain loci. The aim was to identify prognostic significance of MYC translocation alone (single-hit) and BCL2 and/or BCL6 (double-hit/triple-hit) translocations in the context of the MYC translocation partner gene (immunoglobulin or nonimmunoglobulin).

“The negative prognostic impact of MYC rearrangement in DLBCL is largely observed in patients with MYC double-hit/triple-hit disease in which MYC is translocated to an immunoglobulin partner, and this effect is restricted to the first 2 years after diagnosis. Our results suggest that diagnostic strategies should be adopted to identify this high-risk cohort, and risk-adjusted therapeutic approaches should be refined further.”

— Rosenwald et al

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Effects of MYC Rearrangement and Translocation Partner

MYC rearrangement was identified in 264 of the 2,383 patients (11%). Among patients with MYC rearrangement and available data, 40 had single-hit disease with an immunoglobulin translocation partner; 54 had double-hit/triple-hit disease with an immunoglobulin translocation partner; 17 had single-hit disease with a nonimmunoglobulin partner; and 53 had double-hit/triple-hit disease with a nonimmunoglobulin partner.

Overall, the presence vs absence of MYC rearrangement was associated with poorer progression-free (hazard ratio [HR] = 1.7, 95% confidence interval [CI] = 1.4–2.1) and overall survival (HR =  2.1, 95% CI = 1.7–2.7), with the effect being significant for these outcomes within the first 2 years of diagnosis (HR = 0.7, 95% CI = 0.4–1.2) but not after 24 months (HR = 0.8, 95% CI = 0.5–1.4). MYC double-hit/triple-hit disease was associated with significantly poorer progression-free (HR = 1.8, 95% CI = 1.3–2.4) and overall survival (HR = 2.4, 95% CI = 1.8–3.3) vs no MYC rearrangement—again, only within the first 2 years of diagnosis; MYC single-hit disease was not associated with significantly poorer outcomes (HRs = 1.2, 95% CI = 0.8–1.7 for progression-free survival, and 1.3, 95% CI = 0.9–2.0 for overall survival).

In analysis by translocation partner, just those patients with double-hit/triple-hit disease with an immunoglobulin translocation partner had significantly poorer progression-free survival (HR = 2.9, 95% CI = 2.0–4.3) and overall survival (HR = 3.6, 95% CI = 2.5–5.4) within 24 months after diagnosis. Outcomes in patients with MYC single-hit disease (with either immunoglobulin or nonimmunoglobulin partner) and those with double-hit/triple-hit disease with a nonimmunoglobulin partner were similar to those in patients without MYC rearrangement.

The investigators concluded, “The negative prognostic impact of MYC rearrangement in DLBCL is largely observed in patients with MYC double-hit/triple-hit disease in which MYC is translocated to an immunoglobulin partner, and this effect is restricted to the first 2 years after diagnosis. Our results suggest that diagnostic strategies should be adopted to identify this high-risk cohort, and risk-adjusted therapeutic approaches should be refined further.”

Andreas Rosenwald, MD, of the Institute of Pathology, University of Würzburg, Germany, is the corresponding author of the Journal of Clinical Oncology article.

Disclosure: The study was supported by grants from Genentech, Roche, Gilead Sciences, Servier, Seattle Genetics, TG Therapeutics, Takeda Oncology, AbbVie, Pharmacyclics, Celgene, and Bloodwise. For full disclosures of the study authors, visit jco.ascopubs.org.