In total, 1,434 LS DLBCL patients with known MYC-R status, diagnosed between 2014 and 2020, and treated with R-CHOP(-like) regimens, were identified in the NCR including 733 (51%) stage I patients and 701 (49%) stage II patients (Fig. 1).

Clinical characteristics of stage I DLBCL patients

In stage I patients, 83 (11%) had a MYC-R of whom 36 (43%) were DH/TH HGBL and 18 (22%) had unknown BCL2 and BCL6 status (Fig. 1 and Table 1). MYC-R patients were more often male (p < 0.01), but other baseline characteristics did not significantly differ between patients with and without a MYC-R (Table 1).

Table 1 Baseline characteristics of stage I DLBCL patients by MYC-R status.

Out of the 83 MYC-R stage I patients, 40 patients received 3 cycles of R-CHOP plus RT (49%), and 35 received 6–8 cycles of R-CHOP (42%, Supplementary Fig. 1A and Supplementary Table 2). Three patients received less intensive chemotherapy (4%) and five patients received more intensive chemotherapy regimens (6%). Among the 650 patients without an MYC-R, similar treatment distributions were observed: 326 received 3 cycles of R-CHOP plus RT (50%), 275 patients received 6–8 cycles of R-CHOP (42%), and the remaining patients received less intensive chemotherapy (48,7%), or a more intensive chemotherapy regimen (n = 1; 0.2%).

Outcome of stage I DLBCL patients

For stage I patients, CR rates were both 89% for patients with and without a MYC-R (p = 0.58).

Median follow-up was similar between patients with (41 months) and without a MYC-R (47 months, p = 0.24). The 2-year PFS in patients with stage I disease with and without a MYC-R was similar (89% (95% CI 82–96%) and 93% (95% CI 91–95%), respectively, p = 0.63; Fig. 2A). Two-year OS was 95% (95% CI 93–97%) for MYC-R patients as well as for patients without a MYC-R (95% CI 92-100%, p = 0.22; Fig. 2B).

Fig. 2: Survival analysis in stage I DLBCL patients stratified for MYC rearrangement status.

A, B Progression-free survival (A) and overall survival (B) analyses in stage I DLBCL patients with (blue, n = 83) or without (gray, n = 650) a MYC rearrangement (MYC-R), using Kaplan–Meier survival analysis.

In a multivariable analysis, where we assessed the impact of MYC and BCL2 and/or BCL6 rearrangements on the risk of mortality and relapse, SH and DH/TH were not associated with risk of mortality (Supplementary Table 3) or risk of relapse (Supplementary Table 4) compared to patients without a MYC-R.

Older age, elevated LDH, WHO performance score 2–4, and male gender were associated with a higher mortality risk (Supplementary Table 3) and relapse risk (Supplementary Table 4). Treatment with three cycles of R-CHOP plus RT was associated with a lower relapse risk as compared to 6–8 cycles of R-CHOP (Supplementary Table 4).

Clinical characteristics of stage II DLBCL patients

In stage II patients, 90 (13%) had a MYC-R of whom 39 (43%) were DH/TH HGBL and 15 (17%) had unknown BCL2 and BCL6 status (Fig. 1 and Table 2). Baseline characteristics did not differ between patients with and without MYC-R patients (Table 2).

Table 2 Baseline characteristics of stage II DLBCL patients by MYC-R status.

Out of the 90 MYC-R stage I patients, 57 patients received 6–8 cycles of R-CHOP (63%). The remaining MYC-R patients received 3 cycles of R-CHOP plus RT (n = 3; 3%), less intensive chemotherapy (n = 8; 9%), or more intensive chemotherapy regimens (n = 22; 24%, Supplementary Fig. 1B and Supplementary Table 2). Among the 611 patients without a MYC-R, similar treatment distributions were observed, with 543 patients (89%) receiving 6–8 cycles of R-CHOP, and the remaining patients R-CHOP plus RT (n = 22; 3%), less intensive chemotherapy (n = 43; 7%) or more intensive chemotherapy regimens (n = 3; 1%).

Outcome of stage II DLBCL patients

CR rate was lower in stage II patients with a MYC-R compared to patients without a MYC-R (81% vs. 89%, respectively; p = 0.02). Median follow-up was similar between patients with (42 months) and without (33 months, p = 0.12) a MYC-R.

The 2-year PFS was lower in MYC-R patients compared to patients without a MYC-R (70% (95% CI 60–81%) and 89% (95% CI 86–91%), respectively, p = 0.0012; Fig. 3A).

Fig. 3: Survival analysis in stage II DLBCL patients stratified for MYC rearrangement status.

A, B Progression-free survival (A) and overall survival (B) analyses in stage II DLBCL patients with (blue, n = 90) or without (gray, n = 611) a MYC rearrangement (MYC-R), using Kaplan–Meier survival analysis.

The 2-year OS was also lower in MYC-R patients compared to patients without a MYC-R (79% (95% CI 70–88%) vs. 94% (95% CI 92–96%), respectively, p < 0.0001; Fig. 3B).

Within MYC-R patients, SH and DH/TH patients had a comparable 2-year PFS (60% (95% CI 43–84%) and 70% (95% CI 56% and 87%), respectively, p = 0.83, Supplementary Fig. 2A) and OS (78% (95% CI 65–94%) and 73% (95% CI 60–89%), p = 0.57, Supplementary Fig. 2B).

In a multivariable analysis, SH and DH/TH were associated with a higher risk of mortality (HR 2.27, 95% CI 1.12–4.59, p = 0.02, and HR 3.55, 95% CI 1.90–6.65, p < 0.01, respectively, Supplementary Table 5) and risk of relapse (HR 2.20, 95% CI 1.17–4.14, p = 0.01, and HR 2.08, 95% CI 1.14–3.79, p = 0.02, respectively, Supplementary Table 6) compared to patients without a MYC-R.

Furthermore, involvement of ≥1 extranodal site was associated with a higher mortality risk and older age was associated with a higher mortality and relapse risk (Supplementary Tables 5 and 6).

Outcome of stage II DLBCL MYC-R patients treated with more intensive chemotherapy

Given the inferior outcomes of stage II MYC-R DLBCL patients, we aimed to investigate the potential benefit of intensive chemotherapy regimens in MYC-R patients in a sensitivity analysis. Survival outcomes in MYC-R patients treated with more intensive treatment regimens (n = 22) were compared to patients treated with 6–8 cycles of R-CHOP (n = 57). Median follow-up time was similar between the two groups (Table 3). The 2-year PFS and 2-year OS did not differ between the two treatment groups (p = 0.82, Fig. 4A, and p = 0.69, Fig. 4B, respectively). In DH/TH patients (n = 18 in both treatment groups, Table 4), the 2-year PFS and 2-year OS did not differ between the two treatment groups either (p = 0.96 Fig. 4C, and p = 0.88, Fig. 4D, respectively).

Table 3 Baseline characteristics of stage II MYC-R DLBCL patients by treatment.Fig. 4: Survival analysis in stage II MYC-R DLBCL patients stratified for treatment.

A, B Progression-free survival (A) and overall survival (B) analyses in stage II MYC-R DLBCL patients including single hit and double/triple hit lymphoma treated with R-CHOP (gray, n = 57) or more intensive chemotherapy regimens (red, n = 22), using Kaplan–Meier survival analysis. C, D Progression-free survival (C) and overall survival (D) analyses in stage II DLBCL double hit patients treated with R-CHOP (gray, n = 18) or more intensive chemotherapy regimens (red, n = 18), using Kaplan–Meier survival analysis.

Table 4 Baseline characteristics of stage II DH/TH DLBCL patients by treatment.