Follicular lymphoma : clinical and biological factors associated with response to therapy and overall prognosis

Follicular lymphoma (FL) is a heterogeneous group of malignancies within the adaptive immune system. The clinical course is highly variable. Treatment includes different chemotherapy regimens as well as the anti-CD20 monoclonal antibody rituximab which has significantly improved the prognosis for patients with all types of B cell lymphomas. The majority of patients with FL respond well to therapy but eventually relapse and generalized disease is still considered incurable. On the other hand, a substantial number appear to have such an indolent disease that the benefit from treatment is unclear. In the clinical setting one challenge is to identiy FL patients in need of therapy upfront as opposed to those who can be managed with active expectancy. Seemingly of importance in addition to the clinical status of the host are characteristics of the tumour cells as well as of the immune cells in the surrounding microenvironment. A greater understanding of the complex intra- and intercellular signaling provides new potential targets for therapeutical intervention. The aim of this thesis was to gain increased insight in clinical and immunological factors of prognostic importance, in indolent lymphoma in general and in FL in particular. This was done by investigation of the long-term outcome in patients treated with rituximab-based immunotherapy and of the validity of the prognostic tools developed in patients receiving standard chemotherapy-based treatment. We also made a study on the interaction of rituximab and the immunomodulator lenalidomide with the healthy immune system during therapy. In paper I we evaluated the late effects of rituximab monotherapy and rituximab with interferon-α2a in 321 previously untreated symptomatic indolent lymphoma patients. After a median follow-up of 10 years more than one third had never required chemotherapy and 73% were still alive. In papers II and III we investigated the two prognostic models m7-FLIPI and PRIMA-PI, both recently developed on cohorts of FL patients treated with a combination of rituximab and CHOP/CVP. The clinicogenetic m7-FLIPI model was not valid in our cohort treated with rituximab with or without interferon. The PRIMA-PI on the other hand, although based on only two parameters – beta2-microglobulin and bone marrow involvement, was a useful tool in differentiating a small group of patients with very poor prognosis, that should be considered for a new or more intensive and hopefully more effective therapeutic approach. In paper IV we followed the changing composition of immune cells in blood in FL patients randomized to therapy with rituximab with or without lenalidomide. Cells were sampled at baseline, after 2 weeks of lenalidomide (combination arm), 24 hours after first rituximab dose and at follow-up weeks 10 and 23 and analysed by flow cytometry. With lenalidomide alone a transient increase in monocyte and NK cell fractions appeared, the latter decreasing again after first rituximab infusion. Post-treatment effects included an increased fraction of T cells as a group and an increased CD4/CD8 ratio. A high proportion of monocytes at baseline was associated with clinical response at week 10 as were a larger fraction of naïve T cells in the rituximab monotherapy treatment arm. Possibly lenalidomide may help overcome the negative impact of few naïve cells, by a beneficial effect on their activity

The simplified follicular lymphoma PRIMA-prognostic index is useful in patients with first-line chemo-free rituximab-based therapy

Follicular lymphoma (FL) is a heterogeneous disease; therefore, reliable prognostic tools are needed to plan treatment strategies. The FL International Prognostic Index (FLIPI) was developed before the rituximab era, while the PRIMA-PI was built on rituximab chemotherapy. Our objective was to evaluate these two prognostic tools in a cohort of 291 patients with FL treated in two prospective randomised Nordic Lymphoma Group trials with rituximab +/- interferon. All patients had symptomatic/progressive disease and were previously untreated. The PRIMA-PI was prognostic for both time to treatment failure (TTF) and overall survival (OS) (log-rank P = 0 center dot 003 and P < 0 center dot 001, respectively). The PRIMA-PI high-risk identified a small group of patients with a very short TTF and OS compared to the low-risk group, with a hazard ratio (HR) of 1 center dot 90 (95% confidence interval [CI] 1 center dot 30-2 center dot 78, P = 0 center dot 001) and HR of 3 center dot 19 (95% CI 1 center dot 75-5 center dot 83, P < 0 center dot 001), respectively. The FLIPI risk groups were prognostic only for OS (log-rank P = 0 center dot 018). The simplified PRIMA-PI was valid in our FL cohort with first-line rituximab-containing chemo-free therapy and shows an improved risk stratification compared to the FLIPI, especially in patients aged >60 years. Patients in the PRIMA-PI high-risk group should be considered for alternative therapies

Minimal residual disease status is the prognostic determinant following high-dose treatment for patients with multiple myeloma

Background: The presence of minimal residual disease (MRD+) following autologous stem cell transplantation (ASCT) in multiple myeloma represents a poor prognostic factor for progression-free survival (PFS) and overall survival (OS).Methods: At our department, we recommend lenalidomide maintenance for patients who are MRD+ after ASCT, while MRD-negative (MRD-) patients, after information about the national guidelines, were not advised to follow this regimen.Results: Out of the total 228 patients, 175 received ASCT following first-line induction (MRD- 92 (53%), MRD+ 83 (47%), at 2 months post-ASCT), while 53 underwent ASCT after second-line treatment (MRD- 27 (51%), MRD+ 26 (49%), at the same time point). Comparatively, MRD- patients who did not receive maintenance demonstrated better OS than MRD+ patients who received upfront ASCT and maintenance treatment (96% vs. 86%, p = 0.030, at 3 years). However, nonsignificant difference was found in PFS (76% vs. 62%, at 3 years). Furthermore, second-line ASCT, MRD- non-maintained patients exhibited significantly better PFS than MRD+ (71% vs. 27%, p &amp;gt; 0.001, at 3 years). However, OS was better but nonsignificant (96% vs. 76%, at 3 years). Fluorescence in situ hybridization (FISH) analysis was performed on 141 out of the 228 patients. Of these, 85 (60%) patients were deemed standard risk (SR), and 56 (40%) were classified as high risk (HR). In the SR cohort, MRD- patients exhibited better PFS and OS than MRD+ patients (71% vs. 59% and 100% vs. 85%, respectively). In the HR cohort, the MRD- patients showed superior PFS but similar OS compared to MRD+ patients (66% vs. 42% and 81% vs. 80%, respectively).Conclusions: Our results indicate that being MRD- is a more crucial prognostic factor for the 3-year PFS and OS than the presence of high-risk cytogenetic markers or undergoing maintenance treatment. The latter appears insufficient, particularly for MRD+ patients following ASCT in the second-line setting, suggesting that these patients may require a more intensive treatment approach.Funding Agencies|We would like to extend our gratitude to all patients and their families who participated in this study. Their willingness to contribute has been crucial for the continuation of our research. We would also like to acknowledge the invaluable work of our col</p

Survival by First-line Treatment Type and Timing of Progression Among Follicular Lymphoma Patients : A National Population-based Study in Sweden

In follicular lymphoma (FL), progression of disease &lt;= 24 months (POD24) has emerged as an important prognostic marker for overall survival (OS). We aimed to investigate survival more broadly by timing of progression and treatment in a national population-based setting. We identified 948 stage II-IV indolent FL patients in the Swedish Lymphoma Register diagnosed 2007-2014 who received first-line systemic therapy, followed through 2020. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated by first POD at any time during follow-up using Cox regression. OS was predicted by POD using an illness-death model. During a median follow-up of 6.1 years (IQR: 3.5-8.4), 414 patients experienced POD (44%), of which 270 (65%) occurred &lt;= 24 months. POD was represented by a transformation in 15% of cases. Compared to progression-free patients, POD increased all-cause mortality across treatments, but less so among patients treated with rituximab(R)-single (HR = 4.54, 95% CI: 2.76-7.47) than R-chemotherapy (HR = 8.17, 95% CI: 6.09-10.94). The effect of POD was similar following R-CHOP (HR = 8.97, 95% CI: 6.14-13.10) and BR (HR = 10.29, 95% CI: 5.60-18.91). The negative impact of POD on survival remained for progressions up to 5 years after R-chemotherapy, but was restricted to 2 years after R-single. After R-chemotherapy, the 5-year OS conditional on POD occurring at 12, 24, and 60 months was 34%, 46%, and 57% respectively, versus 78%, 82%, and 83% if progression-free. To conclude, POD before but also beyond 24 months is associated with worse survival, illustrating the need for individualized management for optimal care of FL patients

Primary refractory follicular lymphoma: a poor outcome entity with high risk of transformation to aggressive B cell lymphoma

Background: Primary refractory (PREF) follicular lymphoma (FL) has a completely different clinical course from that of FL that responds to front-line treatments. In addition to having poor responses to salvage therapies, it seems that patients with PREF are at increased risk of histological transformation (HT). The Aristotle consortium presented the opportunity of investigating the risk of HT in a very large series of cases. Thus, we investigated the risk of HT in patients with PREF FL compared with that of responding patients or in stable disease and ultimately their outcome. Methods: Six thousand three hundred thirty-nine patients from the Aristotle database were included in the analysis. These patients had a histologically confirmed grade 1, 2 or 3a FL diagnosed between 1997 and 2013. The primary end-points were the cumulative incidence (CI) of HT at the first progression or relapse and the survival after transformation. Findings.: The 5-year CI of HT among patients with PREF was 34% (95% confidence interval (CI): 27–43), whilst it was 7.1% (95% CI: 6.0–8.5) in the group of patients with partial response (PR) or stable disease (SD) (PR + SD) and 3.5% (95% CI: 3.0–4.2) in the group of patients achieving complete response (CR). The 5-year survival after relapse (SAR) was 33% (95% CI: 28–39) for the PREF group, 57% (95% CI 54–61) in patients with PR, 51% (95% CI 43–58) in the SD group after first-line therapy and 63% (95% CI: 66–72) in patients with CR after initial treatment (p-value <0.001). The 5-year SAR for those patients with PREF who developed HT was 21% (95% CI: 12–31), clearly diminished when compared with those patients with PREF who did not experience HT (38% [95% CI: 31–44]) (p-value = 0.001). Interpretation.: Patients with PREF FL have a dismal outcome and an associated very high rate of HT that further worsens their poor prognosis

Rituximab and the risk of transformation of follicular lymphoma: a retrospective pooled analysis

Background: Histological transformation of follicular lymphoma to aggressive lymphoma is a serious event with a substantial effect on patient outcome. The aim of the Aristotle study was to assess the effect of rituximab on the risk of histological transformation and its outcome. Methods: 11 cooperative groups or institutions across Europe contributed data to this study. Eligible patients (≥18 years) had histologically confirmed follicular lymphoma grade 1, 2, or 3a, diagnosed between Jan 2, 1997, and Dec 20, 2013. Histological transformation was defined as a biopsy-proven aggressive lymphoma that occurred as a first event after first-line therapy. The primary endpoints were the cumulative hazard of histological transformation and survival after transformation. Findings: Information was available for 10 001 patients with follicular lymphoma, 8116 of whom were eligible for analysis. 509 histological transformations were reported. After a median follow-up of 87 months (range 1–221; 2·5–97·5th percentile 5–160), the 10-year cumulative hazard of histological transformation was 7·7% (95% CI 6·9–8·5). The 10-year cumulative hazard of histological transformation was 5·2% (95% CI 4·5–6·2) in patients who received rituximab and 8·7% (7·2–10·6) in those who did not (hazard ratio [HR] 0·73, 95% CI 0·58–0·90; p=0·004). The 10-year cumulative hazard of histological transformation was 5·9% (95% CI 5·0–7·0) for patients who received induction rituximab only and 3·6% (95% CI 2·3–5·5) for those treated with induction and maintenance rituximab (HR 0·55, 95% CI 0·37–0·81; p=0·003). This finding was confirmed in a multivariate analysis (p=0·016). 287 deaths were recorded in 509 patients with histological transformation, resulting in a 10-year survival after transformation of 32% (95% CI 26–38). Survival after transformation did not differ between patients not exposed to rituximab and those who received rituximab in induction only (HR 0·94, 95% CI 0·69–1·28; p=0·70), and those who received rituximab in induction and maintenance (0·96, 0·58–1·61; p=0·88). Interpretation: The risk of histological transformation as a first event can be significantly reduced by the use of rituximab. These findings support the need to inform patients using rituximab nowadays that the risk of transformation is lower than it was before the introduction of rituxumab. Funding: Associazione Angela Serra per la Ricerca sul Cancro, European Lymphoma Institute, European Hematology Association Lymphoma Group, Fondazione Italiana Linfomi, Spanish Group of Lymphoma and Bone Marrow Transplantation

Genetic and Microenvironment Features Do Not Distinguish Follicular Lymphoma Patients Requiring Immediate or Deferred Treatment

International audienc