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Prognostic markers of double-/triple-hit lymphomas
identified, and in other cases, the BCL6 rearrangement status was unknown. Cases with concurrent MYC and BCL2 rearrangements, concurrent MYC and BCL6 rearrangements, and concurrent MYC, BCL2, and BCL6 rearrangements are referred to as MYC/BCL2, MYC/BCL6, and MYC/BCL2/BCL6, respectively.
Clinical outcome analysis was limited to patients with DH/THL characteristics identified at initial diagnosis or at trans- formation from previously diagnosed low-grade lymphoma and who received an anthracycline-based chemotherapy regimen at DH/THL diagnosis. Previous therapies for the 11 patients with prior low-grade lymphoma are as follows: none (n=2); radiation therapy only (n=2); bendamustine and rituximab (B-R) only (n=2); single-agent rituximab (n=1); B-R followed by ibritu- momab consolidation (n=1); R-CHOP with maintenance ritux- imab (n=1); seven prior therapies, including rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP), CHOP, ifosfamide, carboplatin, and etoposide (ICE), and B-R (n=1); and four prior therapies, including R-CVP and B-R (n=1). Patients with recurrent B-cell lymphoma with high-grade or large-cell histological features were excluded from this analysis because the MYC/BCL2/BCL6 rearrangement status of the initial biopsy was unknown.
OS was defined as the time from DH/THL diagnosis to death of any cause or to last follow-up. Event-free survival (EFS) was defined as the time from diagnosis to progression, relapse, re- treatment after initial chemotherapy, or death of any cause. EFS12 was defined as event-free status at 12 months after diag- nosis. EFS12 was used as an endpoint because of limited follow- up and because progression or relapse occurred primarily in the first 12 months after diagnosis.39 OS and EFS were evaluated with Kaplan-Meier curves and Cox proportional hazards mod- els. All analyses were performed using statistical software (SAS version 9.4; SAS Institute Inc.) and R 3.3.1 (R Project for Statistical Computing). Statistical significance was defined by P values less than 0.05.
Results
Morphological and tumor characteristics
The study involved 100 patients (male to female ratio, 64:36) with the median (range) age at DH/THL diagnosis of 61 (29-87) years. Sixty-seven patients had DH/THL identified at initial diagnosis; 22, at the time of transfor- mation of previously diagnosed low-grade lymphoma; and 11, from a recurrent specimen in previously diag- nosed lymphoma with large-cell or high-grade morpho- logical features for which original diagnostic material was not studied (Table 1). Slides were available for consensus review in 72 cases, and in 65 cases a consensus diagnosis was reached. Of these, 39 patients (60%) had high-grade morphological features (Figure 1A) and 26 (40%) had large-cell morphological features (Figure 1B). According to the Hans classifier, the phenotype of 91 cases (91%) was germinal center B-cell (GCB); six (6%), non-GCB; and three (3%), unknown. In immunohistochemistry analysis, 37 of 43 cases (86%) met criteria for MYC posi- tivity, 76 of 84 (90%) expressed BCL2, and 30 of 37 (81%) expressed both (called double expressers).
MYC rearrangement partner (IG versus non-IG gene) and BCL2/BCL6 rearrangement status
The MYC rearrangement partner was an IG gene in 52 cases (39 IGH, 6 IGK, and 7 IGL), a non-IG gene in 35
cases, and unknown in 13 cases (Figure 2A). Fifty-nine cases were MYC/BCL2; 13, MYC/BCL6; 20, MYC/BCL2/BCL6; and 8, MYC/BCL2 (unknown BCL6) (Figure 2B). The MYC rearrangement partner (IG versus non-IG gene) was not associated with morphological fea- tures (P=0.96), cell of origin (P=0.18), or BCL2 rearrange- ment status (P=0.27) (Table 2). However, MYC expres- sion by immunohistochemistry was significantly more common in IG/MYC than in non-IG/MYC cases (95% versus 74%; P=0.049). GCB phenotype was present in 100% of the 85 cases with BCL2 rearrangements [MYC/BCL2, MYC/BCL2/BCL6, and MYC/BCL2 (unknown BCL6); collectively referred to as DH- BCL2/THL], and in six (50%) of the 12 MYC/BCL6 cases
Table 1. Clinicopathological features, genetic characteristics, and ther- apeutic regimens of all patients compared with those of the outcome analysis cohort.
Variable
All patientsa (n=100)
47 (47) 53 (53)
64 (64)
36 (36)
67 (67) 22 (22) 11 (11)
(n=65) 26 (40) 39 (60)
(n=97) 91 (94) 6 (6)
(n=43) 37 (86) 6 (14) 20-90 70
Outcome analysis cohorta (n=70)
34 (49) 36 (51)
41 (59)
29 (41)
59 (84) 11 (16) 0 (0)
(n=43) 19 (43) 24 (56)
(n=69) 64 (93) 5 (7)
(n=29) 26 (90) 3 (10) 0-90 50
(n=61) 35 (57) 26 (43)
39 (56) 11 (16) 14 (20) 6 (9)
32 (46) 17 (24) 15 (21) 6 (9)
0 (0)
0 (0)
Age, years <60
≥60
Sex Male Female
Timing of diagnosis
De novo
Transformation Recurrence
Morphologic review, central Large cell
High grade
COO per Hans classifier GCB
Non-GCB
MYC immunohistochemistry Positive
Negative
% MYC+, range
% MYC+, median
MYC FISH: rearrangement partner(n=87) IG gene 52 (60) Non-IG gene 35 (40)
BCL2 and BCL6 FISH: rearrangement status
MYC/BCL2
MYC/BCL6
MYC/BCL2/BCL6
MYC/BCL2 (BCL6 unknown)
Therapy
R-CHOP
R-EPOCH R-CODOX-M/IVAC R-hyper-CVAD Platinum-based salvage Other/none/unavailable
59 (59) 13 (13) 20 (20) 8 (8)
36 (36) 17 (17) 17 (17) 6 (6) 10 (10) 14 (14)
COO: cell of origin; FISH: fluorescence in situ hybridization; GCB: germinal center B cell; IG: immunoglobulin; hyper-CVAD: cyclophosphamide, vincristine: doxorubicin, and dexamethasone; R-CHOP: rituximab, cyclophosphamide, doxorubicin, and vin- cristine; R-CODOX-M/IVAC: rituximab, cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate alternating with rituximab, ifosfamide, etoposide, and high-dose cytarabine; R-EPOCH: rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin. aValues are presented as number (%) of patients unless specified otherwise.
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