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Prognostic markers of double-/triple-hit lymphomas
sensus pathology review (n=24) showed a nonsignificant tendency to inferior outcome (median OS, 13.5 months; HR, 2.32; 95% CI: 0.88-6.12; EFS12, 37%) compared with that of patients with large-cell morphological features (n=19) (median OS, unreached; P=0.09; EFS12, 57%) (Figure 4B). Patients with MYC/BCL6 (BCL2 rearrange- ment-negative) tumors showed a nonsignificant tendency to better outcomes (n=11) (median OS, unreached; HR, 0.42; 95% CI: 0.13-1.40; EFS12, 64%) than those of patients with BCL2 rearrangement (DH-BCL2/THL; n=59; median OS, 21.7 months; P=0.16; EFS12, 42%) (Figure 4C). There was no association between MYC partner (IG gene versus non-IG gene) and OS (for IG, HR, 1.00; 95% CI: 0.48-2.09; P=0.99) (Figure 4D).
Compared with patients receiving all other therapies, patients treated with R-CODOX-M/IVAC had superior EFS12 (72% versus 39%, P=0.04) and showed a nonsignif- icant tendency to improved OS (HR, 0.37; 95% CI, 0.11- 1.23; P=0.10) (Figure 5). However, patient selection bias may confound this outcome because the patients were significantly younger (P<0.001) than the patients who received other anthracycline-based regimens. Nevertheless, outcomes stayed consistent although not significant for EFS12 (HR, 0.27; 95% CI: 0.07-1.16; P=0.08) and for OS (HR, 0.40; 95% CI: 0.11-1.51; P=0.18), after adjustment for age in multivariable logistic and Cox models, respectively.
Discussion
The diagnosis of ‘high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements’ (DH/THL) was established in the 2016 revision of the WHO classifi- cation of lymphoid neoplasms, in part to acknowledge the prognostic significance of the MYC and BCL2 or MYC and BCL6 rearrangements, or both, in B-cell lym- phomas with large-cell or high-grade morphological fea- tures. However, our study shows that within this umbrel-
la category, several subgroups have distinctive features and varying clinical outcomes. Strengths of this single- institution study include thorough pathology review, comprehensive analyses of genetic features and cell of origin, and availability of key clinical, treatment, and out- come data. The main limitations of this retrospective study include missing MYC rearrangement data for some cases, potential for selection bias in treatment choice given to the patient, inclusion of cases over an 11-year time frame during which clinical management evolved rapidly, and small sample size for some analyses. Although there is likely some bias toward selection of cases with high-grade cytological features in the early specimens, this bias should not have been present in the 57 cases that were identified after our institution began performing interphase FISH to identify DH/THL in all B- cell lymphomas with either large-cell or high-grade histo- logical features. Of the specimens with histological con- sensus re-review, 16/20 (80%) of the early cases but only 23/45 (51%) of the later cases had a morphological diag- nosis of high-grade B-cell lymphoma, suggesting that the selection bias present in the early cases had been mitigat- ed in the later group.
Our data suggest several important observations. First, patients with DH/THL at transformation of previously diagnosed low-grade lymphoma had a dismal outcome with a median OS of 10.8 months and EFS12 of 10%. In light of the small number of cases and potential con- founding effect of the prior immunochemotherapy for some patients, this observation should be interpreted with caution. However, it raises an interesting biological question that may warrant investigation in future studies. Few previous studies have addressed this, although a report of two cases of transformation of low-grade follic- ular lymphoma to DH/THL described an aggressive clini- cal course.34 In DH/THL, induction failure occurs early and is worse among patients aged 60 years or older. Nevertheless, the OS for the entire cohort at 5 years was 49%, suggestive of long-term cure in a subset of patients.
Table 2. Correlations between clinicopathological and genetic characteristics in de novo, transformed, and recurrent double-hit/triple-hit lymphoma.a
Morphological evaluation
Cell of origin
MYC
Double BCL2 expresserb
All High Large
Characteristic patients grade cell GCB Non-GCB IGgene gene Rearranged Rearranged Yes No
All patients
Timing of diagnosis
De novo
Transformed
Recurrent
Morphological evaluation High grade
Large cell
Cell of origin GCB
Non-GCB
MYC partner IG gene Non-IG gene
BCL2
Rearranged
Not rearranged
67 (67) 22 (22) 11 (11)
39 (60) 26 (40)
91 (94)
6 (6)
52 (60) 35 (40)
39 (60)
20 (51) 10 (63) 9 (90)
26 (40)
19 (49) 6 (38) 1 (10)d
91 (94)
59 (91) 21 (100) 11 (100)
36 (95) 22 (88)
6 (6)
6 (9) 0 (0)c 0 (0)
2 (5) 3 (12)
52 (60)
34 (60) 12 (60) 6 (60)
20 (53) 13 (52)
48 (62)
2 (33)
35 (40)
23 (40) 8 (40) 4 (40)
18 (48) 12 (48)
30 (38)
4 (67)
87 (87)
54 (81) 22 (100) 11 (100)
35 (90) 20 (77)
85 (93)
0 (0)
46 (88) 28 (80)
Not
13 (13)
13 (19) 0 (0)c 0 (0)
4 (10) 6 (23)
6 (7)
6 (100)e
4 (12) 7 (20)
30 (81)
20 (87) 8 (73) 2 (67)
16 (80) 10 (83)
28 (82)
2 (67)
18 (84) 12 (75)
28 (85)
2 (50)
7 (19)
3 (13) 3 (27) 1 (33)
4 (20) 2 (17)
6 (18)
1 (33)
3 (16) 4 (25)
5 (15)
2 (50)
partner Non-IG
GCB:germinalcenterBcell;IG:immunoglobulin.aValuesarepresentedasnumber(%)ofpatients. bExpressionofbothMYCandBCL2.cP=0.01to<0.05.dP=0.05to0.10.eP≤0.001.
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