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F. Schieppati et al.
   OS 32% vs. 70%, P=0.04) (Figure 5), whereas BCL6-ICN and BCL6-T did not significantly impact on patient out- come compared to WT BCL6 (data not shown). Of note, among patients with MYC-ICN and BCL2-T, the group with ≥4 MYC copies had a significantly worse prognosis than patients with <4 copies (median OS of 11 months compared to a 2.5-year OS of 75%, P=0.004) (data not shown). Only one patient with MYC-AMP was positive for BCL2 translocation; survival was seven months.
Discussion
MYC rearrangement is considered to confer a poor prognosis to DLBCL patients and to represent an adverse prognostic factor in patients treated with R-CHOP. In our study, the prevalence of MYC translocations was 8.8%, in accordance with data from the literature.10 A single-hit MYC aberration was present in 26% of patients, while 74% had classical DH/TH aberrations. Although a worse prognosis of patients with DH/TH compared to SH DLBCL has been described,24,25 we could not confirm a sig- nificant difference in the outcome of SH versus DH/TH patients, as reported also by Copie-Bergman.16 Among patients with MYC-T eligible for curative chemotherapy, 65% were treated with an intensified regimen, obtaining a slight advantage in terms of response rate but no signif- icant advantage in survival compared to standard dose chemo-immunotherapy, confirming data reported by Petrich et al.26
In addition to MYC gene rearrangements, an increase in MYC copy number was observed in 16% of patients, a nearly 2-fold more than that of MYC translocations. The presence of MYC-ICN has been analyzed in several stud- ies; frequency ranged from 7% to 21%,18,20,27-29 but its prog- nostic significance is still controversial. Yoon reported ICN in 7% of 156 DLBCL patients,18 with an adverse prognos- tic significance, while Testoni et al. found an ICN of no more than 4 gene copies in 10% of 166 patients, and the negative prognostic impact was limited to patients with a concomitant del (8p) chromosomal aberration.28 Valera et al. found 3-4 MYC ICN in 19% and >4 MYC-ICN in 2% of 176 patients, with a negative impact on outcome in the few patients with >4 MYC-ICN.20 In the group of 22 patients with >4 MYC ICN analyzed by Landsburg et al., neither the 2-year PFS (48%) or OS (71%) were signifi- cantly lower than those of patients with normal MYC.29 More recently, in a large study reported by Quesada on 663 DLBCL patients, 76 (12%) had MYC-ICN, and 16% of them had >4 extra-copies. The CR and OS of patients with MYC-ICN were significantly worse compared to patients with normal MYC gene, irrespective of the num- ber of MYC extra-copies.27
A number of MYC copies >4 has been defined in some studies as MYC amplification.20,30 In the present study, we have analyzed the 61 patients with MYC-ICN by exactly enumerating the number of MYC extra-copies, defining as amplified those cases with an uncountable number of MYC-copies. The same criteria and terminology have been adopted in a recent study by Pophali et al.31 We, like other authors,20,31 did not systematically use a chromo- some 8 centromeric probe for this study. Nevertheless, we analyzed chromosome 8 in 11 cases with MYC-ICN, and no abnormal copies of chromosome 8 were detected, thus excluding polysomy as cause of MYC-ICN.
Our patients with 3 or 4 gene copies, accounting for
more than 60% of MYC-ICN, had a more favorable out- come than patients with MYC-ICN >4, and their ORR and CRR were higher compared to the other FISH groups, and were not influenced by the type of treatment received as first-line. There was no difference in OS between patients with 3 or 4 MYC gene copies. On the other hand, by stratifying them according to the exact number of MYC extra-copies, a negative correlation between an increasing number of MYC copies and survival was observed. Patients with MYC-ICN >7 had the worst prog- nosis, and patients with an amplification of MYC at FISH had a particularly aggressive disease and a dismal progno- sis. Of note, the single MYC-AMP patient who did not show MYC protein positivity by immunohistochemistry was also the only patient who responded to treatment. Notably, a correlation between an excess of MYC copies, MYC protein overexpression and poor outcome has been previously described.32 In our study, patients with MYC- ICN >4 seemed to have a more favourable outcome com- pared to MYC-T patients, whereas Quesada and col- leagues observed the opposite result, although this out- come was not statistically significant in both studies.27
Taken together, our results show a prognostic role of the number of MYC extra-copies. In accordance with other studies, results underline that, among MYC-ICN, the pres- ence of >4 MYC gene copies, and particularly of countless numbers of MYC as in MYC-AMP, is associated with a worse prognosis and does identify a category of patients with a prognosis similar to double-hit lymphoma. Of note, the 24 patients with >4 MYC copies represented 6.6% of our entire series, further supporting the potential usefulness of a routine use of FISH at diagnosis in DLBCL.12,13,33 We did not identify specific clinical character- istic of patients associated with the presence of different FISH patterns, except that a significant higher percentage of patients with BCLU histology clustered in the MYC-T group. Notably, 7 of 8 patients with BCLU carried MYC- T and one patient MYC-AMP. Since 5 patients with BCLU and MYC-T had a double- or triple-hit lymphoma, they would now be defined as high grade B-cell lymphoma (HGBCL) with MYC and BCL2 and/or BCL6 transloca- tions according to the updated 2016 WHO classification of lymphoid neoplasms.1
Although there have been no published prospective tri- als in double-hit lymphoma, retrospective studies seem to suggest that aggressive induction regimens may confer a superior outcome.34 In a large retrospective series, patients receiving a Burkitt-like regimen (cyclophosphamide, vin- cristine, doxorubicin, methotrexate, ifosfamide, etopo- side, cytarabine, CODOX-M/IVAC) and consolidation with ASCT appeared to have favorable outcomes over historical controls; however, the 2-year PFS was only 44%, with early progressions precluding ASCT in 41% of patients.35 In another non-randomized retrospective study comparing R-CHOP with R-DA-EPOCH and other inten- sified regimens, response rates were higher for dose- adjusted R-EPOCH.26,36
In addition to its retrospective nature, a major limitation of our study in evaluating the impact of different treat- ment strategies on lymphoma outcome was the hetero- geneity of the regimens used, including ASCT, and the small number of patients in each subgroup with different MYC abnormalities. Moreover, the exclusion of patients not treated with curative intent does not allow the fre- quency of MYC abnormalities in these patients or their
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