Rituximab Combined Therapy and Maintenance Eliminate the Follicular Lymphoma with MYC Translocation

Introduction : The WHO classification published in 2016 shows that lymphoma with BCL2 and MYC rearrangement is mostly classified as high-grade B-cell lymphomas. On the other hand, follicular lymphoma with BCL2 and MYC rearrangement (double-hit follicular lymphoma, DH-FL) is rare. In some case-reports described that DH-FL patients frequently transformed to aggressive disease and had resistance to the treatment. However, there is no large study with regard to the rate of DH-FL and the comparison of the prognosis between DH-FL and FL without MYC translocation. In this study, we assessed the frequency of DH-FL and the prognosis of DH-FL.

Methods : We retrospectively studied 99 patients diagnosed as FL from 2005 to 2015 in our institution. The pathological diagnosis was performed based on histopathological and cytogenetic analyses. The clinical stage of patients and evaluation of the effect of the therapy were performed using PET-CT scan. The statistical analyses of characteristics of patients were performed by Fisher's exact test. The survivals were calculated by the Kaplan Meier method, and statistical analysis were performed by log rank test using EZR software. The samples for FISH analysis were derived from tumor biopsy or bone marrow aspiration. All cells fixed by carnoy solution, then collected cells by cytospin. The cells prepared to slide, then hybridized with the probe of BCL2 or MYC . After hybridization with each probe, the cells were taken the photo and analyzed using In Cell Analyzer 6000. The cells were counted 100 cells in each sample. By the peripheral blood of five healthy volunteers, we calculated the standard deviation of false positive and evaluated each sample's data. This protocol approved by our institute ethical committee.

Results : The averages of positive percentage within five healthy volunteer samples were 0.8% (0-2%) and 1.2% (0-3%), and the standard deviations were 0.74 and 1.3 for BCL2 and MYC, respectively. From these data, we decided to set the cutoff points of ≥3% and ≥5% for BCL2 - and MYC -positive, respectively. Within 98 samples from FL patients, BCL2 -positive were 75 (77%). In these 75 BCL2 -positive FL patients, we assessed the frequency of DH-FL and the prognosis of DH-FL. The characteristics of 75 FL patients were as follows: the median age was 61 years old (range 36-79), and a median follow up was 71 months (range 18-132). FL Grade1 was 45 (60%), Grade2 was 26 (35%) and Grade 3A was 4 (5%). Men was 33 (44%), stages III-IV was 60 (80%), IPI high and high intermediate was 20 (27%) and ECOG PS 0 was 72 (96%) and 1 was 3 (4%). The first treatments were as follows: 52 (69%) were Rituximab(R)-CHOP or R-COP, 6 (8%) were CHOP or COP like regimen without rituximab, 3 (4%) were rituximab monotherapy, 3 (4%) were clinical trial, 5 (7%) were radiation only, 3 (4%) were others (bendamustine with or without rituximab 2, R-fludarabine 1). 3 patients (4%) were watch and waiting. Within 75 FL patients, MYC -positive cases were 6 (8%). MYC-positive level was 6-17% within each 100 cell counts. The median age of DH-FL patients was 61 years old (range 40-75), Men was 2 (33%), all DH-FL patients were stages III-IV, IPI high was 1 (16%). There was no difference in CR rate after first treatment between DH-FL and FL without MYC translocation (83% vs 72%, p=0.581, DH-FL vs FL without MYC translocation, respectively.). Furthermore, there were no differences in OS and PFS between DH-FL patients and the FL patients without MYC translocation (4-year OS: 100% vs 92.8%, p=0.416, 4-year PFS: 55.6% vs 78.0%, p=0.832, DH-FL vs FL without MYC translocation, respectively.). There were also no differences in relapse rate within 2 years (17% vs 11%, p=1.0, DH-FL vs FL without MYC translocation, respectively).

In DH-FL patients, five patients got CR after the first chemotherapy. In the 4 patients still maintain CR; they were treated with R-COP and rituximab maintenance. The one patient relapsed after first treatment without rituximab. The other one patient with bulky disease got CR after R-CHOP plus radiation and relapsed after rituximab maintenance.

Conclusion and Discussion: In the previous reports, it is considered that patients with DH-FL showed poor prognosis, however, our data suggested that the prognosis of DH-FL patients treated by R-CHOP with rituximab maintenance were not inferior to the FL patients without MYC translocation. Rituximab maintenance therapy might overcome the progression of tumor with MYC translocation in FL.