Page 280 - 2021_02-Haematologica-web

Letters to the Editor
Table 1. Characteristics of 19 patients who developed late relapsed diffuse large B-cell lymphoma
At initial diagnosis At late relapse
Median age, years (range) 60 (32–77) 71 (45–84)
Sex, male : female, n 11 : 8
AnnArborclinicalstage,I/II/IIIorIV,n 13/6/0 5/1/13 Numberofextranodaldiseases,0/1/≥2,n 8/11/0 2/10/7 IPI risk, n
Low/ low-int
High-int/ high
Site of extranodal disease, n
Gingiva
Nasal or paranasal cavity Testis
Skin or subcutaneous Bone or bone marrow Intestine or colon
Liver
Other sites
19 9 0 10
3 0 3 2 3 3 0 6 0 4 0 3 0 2 2 6
594
Immunohistochemistry
Celloforigin 4/14/1/0 5/12/0/2 GCB / non–GCB / NA / non–DLBCL, n
PD–L1ontumorcells,+/- 0/19 2/17 BCL2,+/-/NA,n 9/7/3 11/5/3 MYC,+/-/NA,n 6/7/6 5/8/6
DLBCL: diffuse large B-cell lymphoma; IPI: International Prognostic Index; GCB: germinal–center B-cell–like; NA: not assessed; PD–L1: programmed death–ligand 1; int: inter- mediate.
defined by histology. Two of the 19 patients (#8 and #16) exhibited tumor expression of PD-L1 at LR, despite hav- ing negative expression at initial diagnosis. The FISH analysis revealed a 9p24.1 gain in patient #8 (Online Supplementary Figure S1). The expression of MYC was evaluated in 13 pairs; it turned positive at LR in four patients, one of whom gained an MYC translocation detected by FISH analysis. BCL2 expression was evaluat- ed in 15 pairs; seven pairs were positive, and three became positive at LR (Online Supplementary Table S6).
The summary of the results and representative exam- ples of the IgH clonality assays are shown in the Online Supplementary Table S7 and Online Supplementary Figure S2. Of the 12 pairs, 7 (58%) were judged to be clonally related, 2 (17%) clonally unrelated, while the clonal rela- tionship could not be determined in 3 (25%).
The summary of the target sequencing results is described in the Online Supplementary Table S8-9. Patient #9 was excluded from further analysis due to the poor specimen sequence quality at initial diagnosis.
The key results of the targeted sequencing, plus the clinicopathological information and IgH clonality find- ings are shown in Figure 2. Shared mutations were detected in 9 of the 11 patients. The most frequent shared mutation (n=7) was a CD79B missense mutation that involved a single substitution in the immunoreceptor tyrosine-based activation motif domain (Y196 [n=5] or L199 [n=2]). Next to this was an MYD88 missense muta- tion (L265P) (n=5). Four patients had shared mutations in both of the CD79B and MYD88 genes. Of the eight patients with shared mutations in the CD79B and/or MYD88 genes, all had non-GCB DLBCL. From the IgH clonality analysis, 6 of the 8 patients had a clonally relat-
ed relapse. All except 1 (patient #11) with tumor muta- tions in the CD79B and/or MYD88 genes had initially presented with an extranodal disease in the testis (n=3), nasal/paranasal cavity (n=2), or gingiva (n=2).
In our study, non-GCB types were more frequent in patients who developed LR, which is contrary to several previous studies.10,11 The difference in clinical characteris- tics of patients might explain this discrepancy. Our study focused only on the patients with limited-stage DLBCL and excluded those with transformed B-cell lymphoma at initial diagnosis, which might have lowered the number of patients with the GCB type.
Two recent large-scale studies, which examined the genetic characteristics of untreated DLBCL reported a similar genetic subtype of DLBCL, which typically involved comutations in the CD79B and MYD88 genes. These subtypes were described as the MCD type7 and cluster-5 type,6 which was associated with the activated B-cell type of COO and extranodal involvement.6,7 Our results suggest that tumors with CD79B and/or MYD88 mutations in eight patients may belong to this genetic subgroup; at least, tumors with both MYD88 and MYD88 mutations would belong to this subgroup. In the current study, patients with MYD88 and/or MYD88 tumor mutations all had the non-GCB type and extran- odal sites involvement (except for patient #11).
The survival curves of patients with the MCD type and cluster-5 type showed an acute decline within 12 months; after that, a gradual but continuous deteriora- tion.6,7 On the one hand, it can be speculated that most patients with these subtypes show aggressive clinical courses. However, limited-stage DLBCL, especially with low IPI risk of these subtypes, might respond to
haematologica | 2021; 106(2)