Sequential Brief Chemo-Immunotherapy FND + Rituximab in Elderly Patients with Advanced Stage Follicular Lymphoma (FL): High Clinical and Molecular Remission Rate Associated with a Prolonged Failure-Free Survival.

Abstract

Introduction: Elderly patients (pts) with FL do worse than younger ones and the aim of the treatment is usually palliation rather than cure. In order to outline a treatment plan specifically devised for elderly pts with a reduced amount of chemotherapy, we investigated the efficacy and safety of a brief chemo-immunotherapy FND plus Rituximab. Patients and methods: from March 1999 to March 2003, 80 elderly pts (age >60) with advanced stage FL at diagnosis were enrolled. Treatment plan was: 4 courses of FND (Fludarabine 25 mg/m2 days 1–3, Mitoxantrone 10 mg/m2 day 1 and Dexamethasone 20 mg days 1–3) followed by 4 Rituximab infusions at 375 mg/m2/week; pts in partial remission received 2 further FND and 2 Rituximab infusions. PCR molecular monitoring for the presence of IgH/Bcl2 and/or Ig heavy chain gene rearrangement was performed at the beginning of the treatment, after FND, after Rituximab and during follow-up time on bone marrow (BM) samples. Results: median age was 66 (range 60–78); 42 males and 38 females; 16% had stage II, 12% stage III and 72% stage IV disease; 61% had BM involvement; 41% had bulky disease and 24% were at high risk according to IPI score. PCR molecular analysis was performed in 46 pts at diagnosis: 63% were Bcl2 rearranged and 37% were not; IgH rearrangement was detected in 24% of Bcl2 negative pts. Up to date, 70 pts are evaluable. Overall response at the end of treatment was achieved in 63 pts (90%) with 58 pts (83%) in complete remission (CR) and 5 pts (7%) in partial remission (PR). Six pts (9%) did not respond and one patient (1%) died of neutropenic sepsis during a FND course. The addition of Rituximab allowed to increase CR rate from 44% (31 pts) after FND to 83% (58 pts); 73% of responding pts did so with a brief treatment program (4 FND + 4 Rituximab). Patients with adverse prognostic features at diagnosis responded as well as those with more favorable ones with no significant differences in CR rates: BM+ 89%, BM- 79%; low IPI 83%, high IPI 82%; Bulky+ 85%, Bulky- 79%; stage II 90%, III 87%, IV 84%. A thorough molecular analysis is ongoing; to date a molecular marker was detectable in 26 pts. After FND 9/26 pts (35%) did not show anymore BM molecular disease, while PCR negativity was achieved in 23/26 pts (88%) after Rituximab treatment. With a median follow-up of 30 months, 3-yr failure free survival was 50% for the whole series of pts. Failures were observed more frequently in PCR+ pts: all 3 PCR+ pts failed compared to only 7/23 PCR- pts (p=.01). The toxicity was mild with grade 3–4 neutropenia reported in 22% of FND courses, but only 3 pts developed grade 3–4 infections. The whole program was performed in an outpatient setting. Rituximab toxicity was as expected. Conclusions: a brief course of chemo-immunotherapy is able to achieve high clinical and molecular response rates in elderly pts with low toxicity. The sequential use of FND and Rituximab induces a CR rate >80% also in unfavorable subsets of pts. The achievement of PCR negative status correlates with a lower risk of failure.

Determinants of the optimal first‐line therapy for follicular lymphoma: A decision analysis

“…Details of the findings from the included studies are provided in Table II. Nine studies were available for RCHOP in first-line therapy [26][27][28][29][30][31][32][33][34], two for RCHOP in the relapsed/refractory setting [10,35], five for RFlu in first-line therapy [36][37][38][39][40], and five for RFlu in the relapsed/refractory setting [40][41][42][43][44]. Only one study evaluating first-line RCVP met criteria for inclusion in the analysis [45].…”

“…To determine the relative contribution of PFS and QOL in our model, we performed a number of sensitivity analyses. We first varied the point estimates [26] Peer-reviewed 222 0.96 0.01 3-year PFS 75% Huang et al [27] Abstract only 102 0.86 0.01 -Hensel et al [28] Abstract only 69 0.90 0.01 -Ladetto et al [29] Peer-reviewed 68 0.62 0.03 4-year PFS 28% Ogura et al arm C [30] Peer-reviewed 32 0.94 0 Median 34.2 months Jager et al [31] Peer-reviewed 30 1.00 0 5-year PFS 59.4% Tomita et al [32] Peer-reviewed 21 0.76 0 2-year PFS 82% Niitsu et al [34] Peer-reviewed 15 1.00 0 2-year PFS 68.1% Economopoulos et al [33] Peer-reviewed 12 a 1.00 0 3-year PFS 60% RCHOP second-line therapy van Oers et al [10] Peer-reviewed 234 0.85 0.004 Median 33.1 months Domingo-Domenech et al [35] Peer-reviewed 16 0.88 0 18-month PFS 53% RFlu first-line therapy Vitolo et al [36] Abstract only 95 0.84 0 -Vitolo et al [37] Abstract only 80 0.90 0.01 3-year PFS 50% McLaughlin et al [38] Abstract only 76 1.00 0 3-year PFS 77% Tomas et al [39] Abstract only 69 0.97 0.03 -Tam et al [40] Peer-reviewed 7 1.00 0 3-year PFS 100% RFlu second-line therapy Forstpointner et al [41] Peer-reviewed 67 a 0.96 0.03 Median 3.9 years Sacchi et al [42] Peer-reviewed 54 0.90 0 4-year PFS 60% Hagemeister et al [43] Abstract only 39 0.95 0 2-year PFS 66% Leo et al [44] Peer-reviewed 17 0.88 0 -Tam et al [40] Peer-reviewed of treatment-related parameters over the broad range of values from heterogeneous individual studies reported in the literature. We observed that variation in the first-line PFS for RCHOP or RFlu within the range of published values did alter the optimal strategy of the model.…”