The Rituximab Treament for Relapsed Follicular Lymphomas Changes the Duration of Subsequent Responses. the Analysis on Behalf of CLSG

Follicular lymphoma is considered to be incurable disease, although rituximab introduction into the first line therapy has changed the outcome of the patients. Repeated relapses are observed and  it is accepted, that each subsequent remission in the same patient  has significantly shorter duration compared to the  previous one (Gallagher, JCO 1986). We have addressed this question in the group of patients diagnosed and treated in the rituximab era. The interval 1999 till 2002 was chosen because in this time rituximab was already labeled for relapse treatment, but not for the first line treatment.
Patients and method: Patients diagnosed as FL gr I,II, IIIa (central pathology review) and reported  in the 6 centers during the period 1999-2002 were included into the analysis. The cohort consisted out of 176 pts.  Median age  at the 57.5 y(22-93), B symptoms were observed in  40 pts (2 missing),  clinical stage (CS) I  had 16 pts, II 32 pts,  III 28 pts and IV 95 pts,  PS WHO ≥ 2 in 25 pts(four missing), elevated LDH >n 60 pts (8 missing). FLIPI  was estimated as poor risk in 52, intermediate risk in 46 and good risk  in 66 pts. (13 missing). Median follow up is 7.5 years.
Results: Ninety eight (55%) pts experienced 1^st  progression and 9 deaths without progression,  36 pts 2^nd progression and 14 deaths w/o progression, 15 pts 3 rd progression and 6 death w/o progression and 9 pts 4^th progression, therefore 176 were evaluable for 1^st response, 98 pts were evaluable for duration of 2^nd  response, 36 for 3^rd resp, 15 for 4^th response.
Median age was 57.5y at dg, 59y at 1^st, 64y at 2 ^nd, 66y at 3^rd and 77y at 4^th progression. The treatment data for the first line: 175 pts evaluable, 3 pts watch and wait (WW), anthracyclin based chemotherapy  (A-th) 76%, fludarabine based chemotherapy (F-th) 5.2%, rituximab (R) 28.5%,  radiotherapy (RT) 19.1%,  ASCT  9.3%. 2^nd line therapy:  93 pts available, WW 5pts, A-th  26%, F-th 13.6%, R 70.5%, RT 8.0%, ASCT  20.5%, AlloSCT  2.3%, 3^rd line therapy: 35 pts evaluable, WW 3 pts, A-th 9.4%, F-th 28%, R 65.6%, RT 31.3%,  ASCT and AlloSCT both 3.1%,  4^th line therapy: 10 pts evaluable, WW 1 pt,  A-th 1 pt, F-th 3 pts, R 7 pts, RT 3 pts. The significant increase in the relative number of rituximab treated pts in the subsequent treatment lines was observed.  Median survival for the all pts PFS was 40 months, median OS not reached (79 month at 7 y).  The medians of the time to progression (TTP) in subsequent responses (deaths w/o progression were excluded)  were as follows: TTP1  49m, TTP2  43 m, TTP3  52m and TTP4  11m. There was no signifiant difference  observed between TTP1, TTP2 and TTP3, but due the the very short TTP4 the overall significance was 0.05.  Comparison of the PFS of  subsequent lines revealed median PFS1 40 months, PFS2 30 months, PFS3 14 m and PFS4 11m. The difference between PFS1 and PFS2 was not significant, the subsequent PFS were significantly shorter for PFS3 and PFS 4 compared to the previous ones (p<0.05). 
Conclusion: The present analysis demonstrates that introduction of rituximab in the treatment of relapses led to the same TTP after 1^st, 2^nd or 3^rd line of treatment, and the same  PFS after the first and  2^nd line therapy.  The introduction of the efficient treatment modality - rituximab -  into the relapse treatment  has changed the concept, that each subsequent response have to have significantly shorter duration. This is important for  understanding of natural history of the  indolent disease such as follicular lymphoma. The reanalysis however needs to be done on the cohort of patients treated with rituximab as part of the first line treatment in the future with  the sufficient follow up
Supported by grant IGA MZ CR number NR/9453-3.