BCL-2/IgH PCR Values at the End of Induction Treatment Are Not Predictive for Progression Free Survival in Relapsed/Resistant Follicular Lymphoma: Results of a Prospective Randomized Phase III Intergroup Trial.
Authors: van der Reijden Bert A. , Van Oers Marinus H.J , Tonissen Evelyn , Van Glabbeke Martine , Giurgia Livia , Klasa Richard , Marcus Robert E. , Wolf Max , Van t Veer Mars , Vranovsky Andrej , Holte Harald , Kimby Eva , Hagenbeek Anton 
Published: October 2019

Background. The predictive value of assessment of minimal residual disease after induction treatment in follicular lymphoma (FL) is still controversial. Last year we published the results of a prospective randomized phase III intergroup trial evaluating the role of rituximab (R) both in remission induction and maintenance treatment of 465 relapsed /resistant FL patients. Major conclusions were that addition of R to CHOP induction yielded an increased ORR and CR rate, and that R maintenance strongly improved median progression free survival (PFS; both after induction with CHOP and R-CHOP) and overall survival when compared to observation (van Oers et al Blood2006;108:3295). We now report on the Bcl-2/IgH PCR analysis in this study. Study design. Peripheral blood (PB) and bone marrow (BM) samples where obtained before the start of the induction therapy, at the end of the induction therapy and at the end of the 2 years maintenance/ observation period. The percentage of Bcl-2/IgH MBR+ cells was quantified by genomic qPCR with a sensitivity of at least one Bcl-2/IgH MBR+ cell among 10,000 normal cells (primer and probe sequences are available on request. The main question of our analysis was whether the primary endpoints of the study (response rate /quality for the induction phase and PFS for the maintenance phase) were correlated with results of the Bcl-2/IgH PCR in PB or BM.

Results. Molecular biology data were available from 250 patients, evenly distributed amongst the therapeutic arms, both for induction and maintenance. Before treatment 48.5% and 42.0% of assessable patients had a positive Bcl-2/IgH PCR in BM and PB respectively. At the end of induction this had decreased to 28.6% and 17.3% respectively, and at the end of maintenance/observation to 10.5% and 10.6%. Conversion of positive to negative values were more frequent with R-CHOP induction (BM: P=0.026 and PB: P=0.003), and with R maintenance (BM: P=0.005). Percentages and levels of Bcl-2/IgH positivity in PB and BM correlated well at the three sampling time points. Bcl-2/IgH PCR results at diagnosis did not predict for overall response or complete remission rates after induction treatment, but BM results predicted PFS (P=0.04). Rather surprisingly, Bcl-2/IgH PCR results of BM and PB at the end of induction treatment were not predictive for PFS: 3 years PFS was 46% and 38% in the BM− and BM+ group respectively (p=0.4), and 51% and 42% in the PB-and PB+ group respectively (p=0.4).The highly significant improvement of PFS by R maintenance versus observation was observed in both Bcl-2/IgH PCR PB/BM positive and negative groups. Finally, patients who still had a positive Bcl-2/IgH PCR in PB or BM at the end of the 2 years of R maintenance/observation had a significantly shorter PFS (from end of maintenance/observation) than those who were Bcl-2/IgH PCR negative.

Conclusion: Bcl-2/IgH PCR results in BM or PB at the end of CHOP or R-CHOP induction treatment are not useful for decisions on subsequent therapy in patients with relapsed/resistant follicular lymphoma.