Modified r-bfm immunochemotherpy results higher frequency of complete remission than r-daepoch/ r-chop in patients with high-grade b-cell lymphoma double-hit transformed from follicular lymphoma
Authors: A. Misyurina, S. Kravchenko, F. Babaeva, K. Sychevskaya, V. Misyurin, A. Magomedova, A. Kovrigina, T. Obukhova
Journal: HemaSphere (2021)

Background: High-grade B-cell lymphoma double-hit (HGBL DH) can arise from follicular lymphoma (FL). In the case of transformation of FL it accumulates a large number of additional mutations and secondary c-MYC gene rearrangement, which can make it resistant to standard immunochemotherapy. Aims: To evaluate an efficacy of induction regimen R-CHOP/R-DAEPOCH and modified BFM chemotherapy with rituximab in treatment of HGBL DH raised from FL. Methods: We studied13 FL pts with double- (9 - with c-MYC/8q24 and BCL2/18q21;4 - with c-MYC/8q24 and BCL6/3q27) and one pt with triple translocations involving c-MYC/8q24, BCL2/18q21 and BCL6/3q27 genes and deletion of17p13.10 pts had morphological signs of transformation into aggressive lymphoma;4 pts had FL 3A. There was 8 women and 6 men aged from 30 to 60 y. o. (median 47 y.o.). Lymph node with the highest FDG-accumulation according to PET-CT was chosen for biopsy and consequent immunohistochemistry and cytogenetics. The majority of pts had high12/14 and 2/14 - high-intermediate FLIPI score. All pts had advanced (III-IV) stage according to Ann-Arbor classification. 3 out of14 pt had a history of low-grade FL (16-96 months) without c-MYC rearrangement in primary biopsy samples, in other11 cases - anamnesis varied from 0,5 to 4,0 months. Lymphoma manifested by rapidly spread aggressive tumor with bulky disease: 2 pts had leukemic presentation of FL;1 pt had FL cells in cerebrospinal fluid;12/14 out of pts had several extranodal sites of involvement such as ovaries (2/8), kidneys or adrenals (6/14), paranasal sinuses (1/14);bones (3/14);soft tissues (4/14);lungs (3/14);stomach or intestine (4/14);spleen (4/14);liver (1/14). Ki-67 varied from 40 to 90%. An expression of c-MYC protein higher than 40% in11/13 of FL pts. We didn't revealed TP53 mutation within 7 out of 7 analyzed pts. Results: None of pts had previous therapy. 4 pts were treated with R-CHOP-21. 3/4 (75%) out of pts died due to progressive disease (PD),1/4 (25%) had partial remission (PR) after consequent therapy including obinutuzumab. 7 pts underwent modified BFM-protocol with Rituximab. 6/7 (86%) out of pts achieved complete remission (CR) after first-line treatment,1 pt died due COVID-19 in PD status (14%). Autologous stem cell transplantation (auto-SCT) was performed in 4 out of 7 pts. 3 pts underwent R-DA-EPOCH.1 pt achieved a CR after 6 courses,1 pt - after second-line 2 R-DHAP;auto-SCT was performed for consolidation.1 pt (33%) had PD after R-DA-EPOCH and another therapy. Rituximab supportive treatment was administrated only in 4 cases due to epidemiological situation. Median of observation was 9 months (1,0-59,5). We couldn't study TP53 mutation status in pts with PD, but we observed PD in one case with deletion of17p13. Summary/Conclusion: For better diagnostics of FL transformation into HGBL DH we should perform biopsy of lymph node with the most active FDG accumulation according to PET-CT. We observed a higher rate of CR in this pts cohort when treated with intensive induction immunochemotherapy (modified BFM chemotherapy with rituximab) in comparison with R-CHOP/R-DA-EPOCH (86% vs 25% and 33%, respectively), and lower rate of primary resistance/PD (14% vs 75% and 33%). Our data needs consequent confirmation or consideration within metanalysis due to rare diagnostics of FL with double translocations of c-MYC and BCL2/BCL6. We should initiate a randomized study to estimate if auto-SCT had any benefits in comparison with a new immunotherapy modalities in FL transformed into HGBL DH.