Silva, María Gomes da

Abstract Introduction: The immunoglobulin (Ig) is one of the most diverse molecules in nature, and its therapeutic potential, by stimulation of the immune system, has been widely studied/used. Its effect is manifest at the cellular and humoral compartments. However it is still to clarify the specific effect of each fraction of the molecule in the observed immune stimulation. Aims: To develop a murine model of ASCT that mimics the autologous transplant in humans To study the independent effect of the various fractions of the immunoglobulin in the reconstitution of the immune system after ASCT. Methods: In this study, we developed, de novo, a murine model of ASCT. Four groups of transplanted animals were established (weekly injections of: Ig (n=8) or Fab fragment (n=7) or Fc fragment (n=6) or saline (control, n=7)). The evolution of the immune reconstitution was monitored weekly and compared among groups by characterization of cellular fractions by flow cytometry, serum levels of Igs by ELISA and thymic function by quantification of TRECs (“T cell receptor excision circles”). The statistical analysis of the longitudinal data was performed by a linear-mixed effects model. Results: We determined that a regimen of daily injections of G-CSF for 4 consecutive days produces a degree of mobilization of hematopoietic stem cells adequate for a donors/recipient ratio of 9 to 7, and to a standard engraftment extent. Regarding the recovery of cellular sub-populations among groups, the major differences occur up to the 6th week (w) after ASCT. As soon as 2 w after ASCT the treated groups show higher counts of CD4+ T cells compared with control mice (p<0.05). The maximum number of CD4+ T lymphocytes was attained at 2 w after ASCT for mice treated with Fab and Fc and at 9 w for mice treated with polyclonal Ig and PBS. The recovery of CD4+ T lymphocytes in the treated groups was higher compared to control (p<0.001 for Fab, p<0.001 for Fc and p=0.001 for polyclonal Ig). For CD8+ T cells, the mice treated with Fc show, during all the follow up, superior values, being statistically significant when compared to PBS treated mice (p=0.003). The differences with the other groups vary with time. Regarding the recovery of CD19+ lymphocytes, the mice treated with Fab reveal, after the 7th w, superior counts compared to all the other groups (p<0.05). Treated groups (Fab and Fc) show higher values of serum IgM compared to control, as well as an earlier recovery of levels (p<0.05). In what concerns CD4+ naïve T cells, the group treated with polyclonal Ig shows an increased recovery during the first weeks of treatment compared with the other groups (p<0.05). Conclusions and Discussion: The early treatment with polyclonal Ig or its fragments is highly beneficial for the recovery of CD4 and CD8 T lymphocytes (earlier recovery and higher cell counts). After the 6th week after transplant there is a tendency for homeostasis. The increase of CD4+ naïve T cells with Ig treatment may well correspond to an increased thymopoiesis, as suggested by our previous studies.

Abstract Background Rituximab in combination with chemotherapy has been shown to improve overall survival (OS) in pts with FL compared with chemotherapy alone. The effect of MR was evaluated in randomized clinical trials (RCTs) with conflicting results regarding OS. In a previous systematic review and meta-analysis of summary (aggregate) data we demonstrated an OS benefit of MR treatment in pts with relapsed or refractory FL and an improved progression free survival (PFS) in both untreated and relapsed refractory FL. However, pts' disease and treatment characteristics may interact with the effect of MR. To improve identification of sub-groups of pts who may benefit from MR treatment, and to evaluate factors that interact with the effect of MR we conducted an international IPD (raw data) meta-analysis of RCTs of MR for pts with FL. We present the first analysis of this meta-database. Methods In June 2014, we updated an electronic search in Pubmed and the Cochrane Library, conference proceedings and database of clinical trials for randomized trials comparing MR to observation. The investigators of eleven trials that fulfilled inclusion criteria were invited to cooperate. Results of one trial were not reported and this trial could not be included in the meta-analysis. Seven study groups participated in this collaborative project and contributed data on individual pts, including disease characteristics, past treatment, response, survival and adverse events. We examined the effect of pt, disease and treatment characteristics by performing a series of Cox regression analyses stratified by trial. In a sensitivity analysis we combined the assessed log hazard ratios (HR) using a log-rank test for each study and combined the results using a fixed effect meta-analysis. Results We obtained data for 2323 patients randomized in 7 trials of MR compared to observation after induction therapy. The median follow up ranged from 28-114 months. The median age was 57 years (23 - 85 years), and 41% were older than 60 years. 50% of pts were women, 97% had WHO performance status 0-1; 1195 (53%) pts received CHOP/RCHOP, 453 (20%) CVP/R CVP; 1755 (77%) received rituximab containing induction; 33% of pts received 1st induction, 67% ≥2nd. Overall, pts less than 60 years of age (vs. ≥60 years) (p < 0.0001), and women (p = 0.001) had a better prognosis. There was no interaction between sex and the effect of MR (p = 0.65). Pts treated with MR had an improved OS compared to observation (HR 0.76, 95% CI 0.62-0.93, p=0.008, Figure). This was demonstrated also in a sensitivity analysis of 10 studies fulfilling inclusion criteria. There was no statistically significant heterogeneity of treatment effect between trials (p=0.15). In an analysis by treatment line (1st vs. ≥2nd), the estimated effect of MR among patients who received ≥2nd induction was HR of 0.70 (95% CI 0.55 - 0.91), compared to 0.90 (95% CI 0.65 - 1.25) among patients who received 1st induction. However, this difference was not statistically significant (p=0.25). Analysis by the inclusion of rituximab in induction demonstrated among patients who received rituximab in induction a HR of 0.82 (95% CI 0.63 – 1.06), and among those who received induction without rituximab a HR of 0.68 (95% CI 0.49 – 0.93). This difference was not statistically significant (p= 0.35). Analysis by chemotherapy regimen demonstrated an estimated effect for MR among patients who received RCHOP/CHOP of 0.79, 95% CI 0.58 – 1.06, and after RCVP/CVP of 0.65, 95% CI 0.42 – 1.02, with no statistically significant difference between these sub-groups (p = 0.50). Conclusions This is the first report of the collaborative group of maintenance therapy for FL patients. Based on individual patient data, this study demonstrated an improved OS with MR therapy for patients with FL. A sensitivity analysis with all 10 eligible trials supported these results. Results support the effectiveness of MR among patients after their 1st induction as well as after ≥2nd induction, and irrespective of inclusion of rituximab in induction, and the chemotherapy regimen. These results are consistent with those of the summary data meta-analysis that was previously published. The wider CI and lack of statistical significance within sub-groups could be attributed to the sample size. Figure: Pooled HR of death of MR compared to observation in patients with follicular lymphoma. In one study there were no events in one group and it is not represented in the forest plot. Figure:. Pooled HR of death of MR compared to observation in patients with follicular lymphoma. In one study there were no events in one group and it is not represented in the forest plot. Disclosures Vidal: Roche: unrestricted grant Other. Shpilberg:Roche: Consultancy, Research Funding.

Key Points In FL, no prognostic index has been built based solely on a large cohort of patients treated with initial immunochemotherapy. The PRIMA-PI is a simplified index based on β2m and bone marrow involvement for patients treated with immunochemotherapy.