Picking a Partner: As in Life, it Matters for MYC

It has become apparent throughout the past 10 years that “double-hit” diffuse large B cell lymphoma (DLBCL) is a unique entity within DLBCL. It is so unique, that the World Health Organization renamed it in 2016 using the term “high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements.” That’s a mouthful, and in clinic we still just call it “double-hit DLBCL.” Naming issues aside, what was not in dispute was the universally bad outcomes for these patients when treated with standard R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. In desperation, treating clinicians have resorted to more intensive strategies such as the dose-adjusted EPOCH-R (etoposide plus R-CHOP) regimen, R-hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) with alternation R-methotrexate/cytarabine, or adding a consolidation strategy with high-dose chemotherapy and autologous stem cell transplantation. Retrospective analysis has suggested that outcomes are improved with these approaches but still relatively poor. Additionally, double-hit DLBCL is more common in older patients, who are often not candidates for the more intensive strategies. Therefore, the unmet need is large.

Much work has been devoted to characterizing the biology and natural history of double-hit DLBCL. This entity is defined by the presence of a MYC rearrangement at chromosome 8q24 and a rearrangement in BCL2 at chromosome 18q21 or in BCL6 at chromosome 3q27. If MYC and both BCL2 and BCL6 are rearranged, it has been called “triple-hit” DLBCL. These rearrangements are detected by use of fluorescent in situ hybridization techniques (FISH), which are both sensitive and specific for the chromosomal abnormalities they are designed to detect. Of note, the FISH probe commonly used to detect MYC rearrangements is a “break-apart” probe, meaning it detects breakpoints in the MYC loci but does not tell us which gene MYC has partnered with in the DNA rearrangement process. Previous small studies have suggested the partner matters. Specifically, MYC partnered with an immunoglobulin gene (IG) was hypothesized to carry a worse outcome than if MYC was partnered with a non-IG gene. A recent large study by Dr. Andreas Rosenwald and colleagues from the Lunenburg Lymphoma Biomarker Consortium has confirmed and refined this observation in a larger cohort of patients.

The investigators had access to more than 2,000 DLBCL biopsy specimens with annotated clinical data. Using the break-apart probe, they found a MYC rearrangement in 264 patients (11% of the patient population). They then further interrogated these cases by using FISH probes for a MYC/IG gene fusion and by using three different FISH probes that could test for IG heavy chain, IG κ light chain, and IG λ light chain. The panel of FISH tests allowed patients to be categorized into one of the following five categories:

1. DLBCL without MYC rearrangement

2. DLBCL, double hit with IG partner;

3. DLBCL, double hit with non-IG partner

4. DLBCL, single-hit MYC rearrangement with IG partner 

5. DLBCL, single-hit MYC rearrangement with non-IG partner.

The Figure shows the progression-free and overall survival Kaplan-Meier estimates for each of the five groups of patients. The only subgroup with a clearly inferior outcome compared to “ordinary” DLBCL is that of patients with double-hit (or triple-hit) DLBCL with an IG partner for the MYC rearrangement. All other groups experienced outcomes similar to ordinary DLBCL.