The impact of extra copies of MYC, BCL2, and BCL6 on outcome in patients with diffuse large B-cell lymphoma

High-grade B-cell lymphoma (HGBCL) with translocations in MYC, BCL2, and/or BCL6, termed double-hit lymphomas (DHL) and triple-hit lymphomas, are known to have inferior outcomes. The prognostic effect of extra copies (EC) of these genes, seen in some patients with diffuse large B-cell lymphoma (DLBCL), as opposed to gene translocations, is not known; optimal therapy for patients with these copy number alterations has not been established. In a study published in Blood Advances, David Sermer and colleagues investigated the impact of extra copies of MYC, BCL2, and BCL6 on the outcome of DLBCL.¹

Study design

This single-center, retrospective study included 144 patients (≥ 18 years) with DLBCL who had fluorescence in situ hybridization (FISH) reports, allowing separation into three categories: wild type (WT), EC, and DHL. The EC group was characterized by the presence of an EC of MYC with ≥ 1 gene anomaly (an EC or translocation), whereas the DHL group was defined as having MYC translocation plus BCL2, and/or BCL6 translocation. The WT group consisted of patients who had none of these genetic aberrations. In the EC group, 40% of cases had two gene abnormalities and the remaining 60% had three.

Out of the whole patient group, 53% received treatment with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP)-based therapy while 47% had intensive therapies, including

• dose adjusted etoposide, prednisone, vincristine, doxorubicin, and cyclophosphamide with rituximab (DA-EPOCH-R);
• cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate, ifosfamide, etoposide, and high-dose cytarabine (CODOX/M-IVAC);
• sequential R-CHOP/rituximab, ifosfamide, carboplatin, and etoposide (R-ICE); and
• upfront autologous stem cell transplant consolidation.

Most patients with DHL were in the group that received intensive therapy, while patients in the EC and WT categories were predominantly in the R-CHOP group.

Results

The characteristics of the patients are shown in Table 1. A total of 30% of patients were WT, with 38% and 32% belonging to the EC and DHL groups, respectively. The incidences of EC and DHL were slightly higher in male patients than female, at 62% and 59%, respectively, whereas the WT group showed an equal split. Germinal center B-subtype was the most predominant cell of origin in the DHL group at 87% and in the WT group at 67%, whereas the patients with EC showed a more equal distribution. Significantly more patients were diagnosed with de novo DLBCL than underwent transformation of indolent disease in all subtypes. The greatest incidence of elevated lactate dehydrogenase (75%) and high International Prognostic Index (IPI) score ≥ 3 (67%) occurred in the DHL group (Table 1).

Table 1. Patient and disease characteristics¹

The median follow-up time for survivors was 36 months (interquartile range, 16−88 months). The median overall survival (OS) and event-free survival (EFS) was not reached. The results for the three groups in terms of outcomes are shown in Table 2. Following induction therapy, the EC and WT groups achieved similar levels of complete response (CR; 93% and 86%, respectively), while only 67% of the DHL group reached CR (p = 0.01). In terms of progression after induction, the EC group again resembled the WT group more than the DHL group, with fewer refractory and relapsed patients (Table 2). The difference between the three groups in EFS at 2 years was approaching significance (p = 0.052), but not for 2-year OS.

Table 2. Outcomes by FISH group¹

Of the 77 patients treated with R-CHOP, the DHL group had the poorest outcome. Only 58% of these patients with DHL achieved CR, compared with 100% in the WT group and 95% in the EC group (p < 0.001). EFS after 2 years was 58% for the DHL group versus 89% and 84% for the WT and EC groups, respectively (p = 0.047). Although the differences were not statistically significant, a similar trend was identified with 2-year OS, with the DHL group achieving only 58% OS whereas the EC and WT groups reached 92% and 100%, respectively (Table 3).

When examining therapy choice alongside DHL, EC, and WT grouping, the worst outcome was seen for patients with DHL, regardless of the therapy used. The best result was in the WT group, followed by the EC group—both treated with R-CHOP. Patients in the WT group treated with intensive therapy also did poorly, however, when R-CHOP was used, patients in the EC and WT groups achieved similar outcomes. Using intensive therapy for the EC group did not improve outcomes in CR, 2-year OS, or EFS, as shown in Table 3.

Table 3. R-CHOP and intensive therapy subgroups and outcomes¹

Conclusion

Patients with EC tended to resemble the WT group more strongly in terms of prognosis than the DHL group, and patients in the EC and WT groups had better outcomes than patients with DHL. Increased intensity of treatment of EC did not improve outcome for this group; therefore, the presence of EC does not justify the use of intensive therapy in patients with no other risk factors.

However, several study limitations were highlighted by the authors. The EC group was a heterogeneous population, with some patients possessing two or three gene anomalies along with translocations in certain patients. Treatment subgroups were also heterogeneous, and the EC group and the WT group were both relatively small, which may have prevented statistically significant results being obtained.