The Prognosis of Transformed DLBCL Were Superior to De Novo DLBL after the Relapsed/Refractory Status Related to the MYC Translocation
Authors: Mishima Yuko , Yokoyama Masahiro , Nishimura Noriko , Kusano Yoshiharu , Uryu Hideki , Inoue Norihito , Nishihara Anna , Fukuta Takanori , Shirouchi Yuko , Tsuyama Naoko , Takeuchi Kengo , Terui Yasuhito 
Published: October 2019

Abstract
Introduction; The prognosis of relapsed and refractory DLBCL (RR-DLBCL) after R-CHOP therapy is poor and the more than half of these cases had no cure. Autologous peripheral blood stem cell transplantation (auto-PBSCT) raises the survival rate about 20%, however many patients cannot reach the transplantation. The poor prognostic factors in RR-DLBCL have not been cleared yet. MYC/IgH translocations induced poor prognosis of DLBCL, especially double hit DLBCL is independent category in WHO 2016 criteria. However, in RR-DLBCL, the impact of MYC/IgH translocation had not been cleared yet. In this study, we studied the expression of MYC/IgH translocation in RR-DLBCL cases and analyzed the relationships with the prognosis by retrospectively.
Methods; We studied the translocations of MYC and BCL-2 by FISH analysis RR-DLBCL cases from 2006 to May 2017 in our institute. The cells were obtained from the biopsy samples at the first diagnosis and relapse or refractory status. The cells have been fixed by carnoy solution. After hybridizing with each probe, the 100 cells or more were analyzed by In Cell Analyzer 6000 and the positive levels were determined as 5% or more in both MYC and BCL-2. Additionally pathological review and clinical status were studied among these cases, retrospectively. All cases are treated by R-CHOP at diagnosis and followed by salvage therapy after relapse with or without auto-PBSCT. This study protocol was approved in our institutional ethical review board.
Results; Within 46 RR-DLBCL, 24 cases were negative for MYC translocation and 22 were positive. All MYC-positive cases were translocated with IgH except one case and the 9 cases (47.8%) were BCL2-positive. The median age was 62.4 (40-83) in MYC-negative and 62.6 (44-82) in MYC-positive cases. GC type was 11 (45%) and 9 (40.9%), and High IPI cases were 8 (33.3%) and 12 (54.5%) in MYC-negative and positive cases respectively. In these RR-DLBCL, the 5-year Overall survival (OS) was inferior in MYC-positive group (79.4%, 95% CI; 53.5-91.8%) compared to MYC-negative group (56.2%, 95%CI; 32.1-74.7%) (P=0.0414). There was no significant difference in progression free survival (PFS). There were no statistically significant differences in overall response rate (ORR), OS and PFS after second therapy between MYC-positive and negative group. The death cases were 6 (25%) and 11 (50%), respectively (P=0.079). By the pathological analysis, the transformed DLBCL cases from follicular or indolent lymphoma were significantly more in MYC negative group (12; 50%) than in MYC positive group (4; 18.1%) (P=0.024). In the transformed DLBCL, at the first relapse, 2nd biopsy detected heterogeneous pattern, such as the only indolent lymphoma, DLBCL or contamination of both type. In such cases, at the 2nd relapse, the pathological diagnoses had changed again. OS and PFS were significant superior in transformed DLBCL than de-novo DLBCL after second therapy. 2-year OS were 59.0%(95%CI 37.9-75.1%) and 92.9%(59.1-99.0%) (P=0.00474) and PFS were 16.13 and 49.43 moths (95% CI was 10.4 to 20.1 months and 16.1 to 63.7 months; P=0.00063), in transformed FL and de novo-DLBCL, respectively. The multivariate analysis identified transformed DLBCL as independent prognostic factor for both PFS and OS. Also, in MYC positive group, transformed DLBCL cases were superior to de-novo DLBCL for both OS (17.5 months vs. not yet reached, P=0.0353) and PFS (13.3 vs. 63.3moths, P= 0.0353) respectively.
Discussion and conclusion; From our results, it was suggested MYC-positive is still poor prognostic factor of overall survival in RR-DLBCL. However, RR-DLBCL contaminated transformed DLBCL especially in the MYC-negative group. After 2nd therapy, the transformed DLBCL were related to good prognoses compared to de-novo-DLBCL, in also MYC-positive group. We can consider that treatment strategy of transformed DLBCL were should be separated from de-novo DLBCL at the relapse, then MYC-positive transformed DLBCL still possesses for indolent character.

Disclosures
Mishima: Chugai pharmaceutical inc, Roche: Other: commissioned work. Yokoyama:Chugai pharmaceutical inc, Roche: Other: commissioned work. Nishimura:Chugai pharmaceutical inc, Roche: Other: commissioned work. Terui:Celgene: Honoraria; Janssen Pharmaceutical KK: Honoraria; Takeda pharmaceutical: Honoraria; Novartis pharma: Honoraria; Bristol myers Squib: Honoraria.