Early Stage Follicular Lymphoma Research Articles

Outcomes of stage I/II follicular lymphoma in the PET era: an international study from the Australian Lymphoma Alliance

AbstractManagement practices in early-stage (I/II) follicular lymphoma (FL) are variable and include radiation (RT), systemic therapy, or combined modality therapy (CMT). There is a paucity of data regarding maintenance rituximab in this cohort. We conducted an international retrospective study of patients with newly diagnosed early-stage FL staged with positron emission tomography (PET)–computed tomography and bone marrow biopsy. Three hundred sixty-five patients (stage I, n = 221), median age 63 years, treated from 2005-2017 were included, with a median follow-up of 45 months. Management included watchful waiting (WW; n = 85) and active treatment (n = 280). The latter consisted of RT alone (n = 171) or systemic therapy (immunochemotherapy [n = 63] or CMT [n = 46]). Forty-nine systemically treated patients received maintenance rituximab; 72.7% of stage I patients received RT alone, compared to 42.6% with stage II (P < .001). Active therapies yielded comparable overall response rates (P = .87). RT alone and systemic therapy without maintenance rituximab yielded similar progression-free survival (PFS) (hazard ratio [HR], 1.32; 95% confidence interval [CI], 0.77-2.34; P = .96). Maintenance rituximab improved PFS (HR, 0.24; 95% CI, 0.095-0.64; P = .017). The incidence of transformation was lower with systemic therapy compared to RT or WW (HR, 0.20; 95% CI, 0.070-0.61; P = .034). Overall survival was similar among all practices, including WW (P = .40). In the largest comparative assessment of management practices in the modern era, variable practices each resulted in similar excellent outcomes. Randomized studies are required to determine the optimal treatment in early-stage FL.

Therapy of nodal Follicular Lymphoma (WHO grade 1/2) in clinical stage I/II using response adapted Involved Site Radiotherapy in combination with Obinutuzumab (Gazyvaro) - GAZAI Trial (GAZyvaro and response adapted Involved-site Radiotherapy): a study protocol for a single-arm, non-randomized, open, national, multi-center phase II trial

BackgroundLarge field irradiation had been standard for early-stage follicular lymphoma (FL) for a long time. Although involved field radiotherapy (IF-RT) was recently favored because of the toxicity of large field irradiation, smaller irradiation fields have been accompanied with an increased risk of out-of-field recurrence. The MIR (MabThera® and Involved field Radiation) trial has shown that the combination of IF-RT at a dose of 30–40 Gy with the anti-CD20 antibody rituximab has led to similar efficacy compared with large field irradiation but with markedly reduced side effects. Immune modulating radiation therapy alone using low-dose radiotherapy (LDRT) of 2 × 2 Gy has been shown to be effective in FL. The GAZAI (GAZyvaro and response Adapted Involved-site Radiotherapy) trial aims to prove the efficacy of LDRT in combination with a novel anti-CD20 therapy.Methods/designThe GAZAI trial is a non-randomized, open, non-controlled, German, multi-center phase II trial that includes patients with early-stage (I and II) nodular FL (grades 1 and 2) confirmed by central histological review. A maximum of 93 patients will be included in the trial. Patients will receive a combined approach of immunotherapy with the fully humanized anti-CD20 antibody obinutuzumab (Gazyvaro®) and involved site radiotherapy (IS-RT) with 2 × 2 Gy. The primary endpoint of the trial is the rate of metabolic complete response (CR), based on fludeoxyglucose positron emission tomography/computed tomography, after obinutuzumab and 2 × 2 Gy IS-RT in week 18. Secondary endpoints are morphologic CR rate in weeks 7 and 18 and month 6, progression-free survival, toxicity, recurrence patterns, overall survival, and quality of life. Additionally, minimal residual disease response is assessed. The risk for a potentially higher recurrence rate after LDRT will be minimized by additional salvage radiation up to the “full dose” of 40 Gy for patients who have less than a metabolic CR and morphologic partial response/CR, which will be evaluated in week 18, offering a response-adapted approach.DiscussionThe goal of this trial is a further reduction of the radiation dose in patients with nodal early-stage FL showing a good response to a combination of LDRT and anti-CD20 immunotherapy and a comparison with the currently published MIR trial.Trial registrationEudraCT number: 2016-002059-89. ClinicalTrials.gov identifier: NCT03341520.

Minimal residual disease monitoring in early stage follicular lymphoma can predict prognosis and drive treatment with rituximab after radiotherapy

Since 2000, we have investigated 67 consecutive patients with stage I/II follicular lymphoma (FL) for the presence of BCL2/IGH rearrangements by polymerase chain reaction (PCR), real time quantitative PCR (RQ-PCR) and digital droplet PCR (ddPCR). All patients were treated with involved-field radiotherapy (IF-RT) (24-30Gy). From 2005, patients with minimal residual disease (MRD) after IF-RT received rituximab (R) (375mg/m2 , 4 weekly administrations). The median follow-up is 82months (17-196). At diagnosis, 72% of patients were BCL2/IGH+. Progression-free survival (PFS) was significantly better in patients with undetectable/low levels (<10-5 ) of circulating BCL2/IGH+ cells at diagnosis and in those who were persistently MRD- during follow-up (P=0·0038). IF-RT induced an MRD- status in 50% of cases; 16/19 (84%) MRD+ patients after IF-RT became MRD- after R treatment. A significantly longer PFS was observed in MRD+ patients treated with R compared to untreated MRD+ patients (P=0·049). In early stage FL, both circulating levels of BCL2/IGH+ cells at diagnosis and MRD status during follow-up bear prognostic implications. Standard IF-RT fails to induce an MRD-negative status in half of patients. Most patients become MRD- following treatment with R and this is associated with a significantly better PFS.

Minimal residual disease - ready for prime time in follicular lymphoma?

The possible role of minimal residual disease (MRD) in the management of patients with follicular lymphoma (FL) has been a recurrent topic in this field for at least two decades. In this issue of the journal, Pulsoni et al (2019) report a study using MRD, determined in bone marrow (BM) and/or peripheral blood (PB), in patients with early stage FL treated with involved-field radiotherapy (IF-RT). MRD status after IF-RT was used to guide the decision of whether or not to administer systemic rituximab; this strategy resulted in longer progression-free survival (PFS). The study raises again the interest of MRD in FL, particularly in the setting of localized disease in which only few data are available. Although many of the published series have limitations, including the retrospective nature, small sample size, mixed DNA sources (BM vs. PB), and lack of prospective planning for MRD time points, nowadays considerable evidences suggest that persistence of polymerase chain reaction (PCR)-detectable residual tumour cells in BM, and to a lesser extent in PB, is an independent predictor of relapse and shorter PFS in patients with FL (Rambaldi et al, 2002; Rambaldi et al, 2005; Hirt et al, 2008; Goff et al, 2009; Morschhauser et al, 2012; Ladetto et al, 2013). However, no significant differences in terms of overall survival (OS) have been detected according to the MRD status, specifically in the only prospective study performed with this exploratory aim (Ladetto et al, 2013). Furthermore, besides its prognostic significance, the main issue in the clinical setting is whether or not MRD could be useful for making treatment decisions, as in acute lymphoblastic leukaemia or promyelocytic leukaemia. Unfortunately, no solid data that can be applied in the clinic have been published to date. On the other hand, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) scanning was shown to be a strong predictor of outcome (Trotman et al, 2014) and it is currently recommended for assessing response in FL (Cheson et al, 2014). The combination of MRD by PCR and FDG-PET has been suggested to be an excellent tool to define the prognosis of these patients (Luminari et al, 2016). Recently, the Fondazione Italiana Linfomi ran a phase 3 randomized trial that included MRD-based decision-making, with the objective of comparing standard maintenance with a tailored maintenance/consolidation programme based on MRD and FDG-PET in advanced stage FL. Unfortunately, preliminary data revealed no superiority of the tailored strategy (Federico et al, 2019). More recently, interest has been raised regarding the application of more modern techniques to detect MRD, including next generation sequencing (NGS), in the search for biomarkers that may help in adapting therapy to the disease risk. The sensitivity of NGS is substantially higher and, in addition, could be applied to a considerably higher number of patients with FL. Thus, the new tool might further improve MRD studies in FL. Follicular lymphoma usually presents in advanced stage, although up to 20% of newly diagnosed cases show localized disease. IF-RT with curative intent is limited to non-bulky stages I–II FL (Dreyling et al, 2016). Thus, patients with localized FL treated with IF-RT have an excellent outcome in terms of OS, although at least half of these individuals will eventually relapse. The detection of patients with higher risk of relapse who might be candidates for further systemic therapy, such as rituximab, as used by Pulsoni et al (2019), is an interesting challenge. With its limitations (heterogeneous series with a relatively small number of patients), this study is the first, to our knowledge, to address the impact of MRD in localized FL and adapting therapy to disease risk. Although the administration of rituximab to patients with MRD positivity after IF-RT could seem reasonable to many clinicians, the excellent prognosis of the whole series, irrespective the therapeutic approach, prevents any strong conclusions. In summary, the study by Pulsoni et al (2019) is interesting because it again centres the debate regarding the usefulness of MRD in FL and its probable role in strategies adapted to the risk of the disease. There is no doubt on the prognostic importance of MRD in FL; however, with the data currently available, it is still too early to integrate MRD into clinical practice. Future research could be useful to (i) refine our dynamic capacity for risk stratification; (ii) enable early termination or intensification of treatment based on MRD status and (iii) enable the discontinuation continuous therapy with targeted agents in those patients who become MRD-negative during treatment. The authors declare no conflict of interest regarding current manuscript. Both authors reviewed the bibliography and wrote the manuscript.

Additional therapy improves outcomes in completely resected, limited-stage follicular lymphoma

Patients with early-stage nodal follicular lymphoma (FL) may be rendered free of detectable disease by a diagnostic excisional biopsy. We reviewed the management and outcomes of 48 patients with FL, diagnosed from 2003–2013, treated at a single institution. The primary endpoints were local control (LC) and progression-free survival (PFS).Median age at diagnosis was 54.5 years (range 15–74 years). Forty-seven patients were stage I (97.9%); 15 patients (31.3%) had grade 3 disease. Initial management consisted of observation (12 patients; 25.0%), radiation therapy (RT) alone (12 patients; 25.0%), systemic therapy alone (9 cases; 18.8%), or both (15 patients; 31.3%). Median follow-up was 4.92 years (range 0.5–13.83 years). 4-year PFS and OS were 80.9% and 97.1%, respectively. Patients treated with additional therapy experienced significantly better 4-year LC (100% vs. 81.8%; p = .012) and 4-year PFS (86.7% vs. 63.6%; p = .006).Patients with completely resected limited-stage FL would benefit from therapy beyond excisional biopsy alone.

Rituximab With Involved Field Irradiation for Early-stage Nodal Follicular Lymphoma: Results of the MIR Study.

The MabThera and Involved field Radiotherapy study investigated efficacy and safety of involved field (IF) radiotherapy in combination with the anti-CD20 antibody Rituximab for early-stage follicular lymphoma (FL) in a prospective, single-arm multicenter phase 2 design. Eighty-five stage I–II FL patients received 8 cycles of Rituximab (375 mg/m2) and IF irradiation (30/40 Gy). The primary endpoint was progression-free survival (PFS) 2 years from treatment start. Secondary endpoints were overall survival (OS), complete response rates, toxicity, quality of life, and minimal residual disease (MRD) response with protocol defined visits up to month 30. For the primary endpoint, PFS at 2 years was 85% for the intention-to-treat set. Long-term data were captured in selected sites and evaluated as post hoc analysis in the per protocol (PP) set: PFS and OS were 78% and 96% at 5 years with a median follow-up of 66 or 78 months, respectively. There were 17/76 recurrences in the PP set, of which 14 were outside the radiation volume only. MRD analyses revealed a clonal marker in 36% of patients at diagnosis. All but 1 marker positive patients experienced a molecular treatment response. There were 13 serious adverse events (4 related to the therapy) during the first 30 months. IF radiotherapy combined with Rituximab is well tolerated and highly efficient with low rates of recurrence in the first years in early-stage FL. The efficacy is comparable with more aggressive therapy approaches without compromising the quality of life and maintains for an extended follow-up of more than 5 years.

Outcomes of Stage I and II Follicular Lymphoma in the Era of 18F-FDG PET-CT Staging: An International Collaborative Study from the Australian Lymphoma Alliance

Outcomes of Stage I and II Follicular Lymphoma in the Era of 18F-FDG PET-CT Staging: An International Collaborative Study from the Australian Lymphoma Alliance

Difference of Relapse Pattern Between Nodal and Gastrointestinal Follicular Lymphomas

The characteristics and treatment result of localized nodal follicular lymphoma (FL) is relatively well recognized, while those of extranodal follicular lymphomas have not been fully elucidated. The purpose of this study is to compare the relapse patterns between patients with localized nodal FL and extranodal FL, focusing on gastro-intestinal (GI) FL, treated with radiation therapy (RT) in modern era. We reviewed consecutive 70 patients with early stage FLs treated by RT with/without pharmaceutical therapy between 2005 and 2015 at single institution. All patients were histologically proven with low grade FL by expert hemato-pathologists. Information of patient characteristics, detailed RT, toxicities, relapses and salvages treatment, and outcomes were collected with chart review. The characteristics of all patients were following; median age 60 years (range, 33-79 years old), male/female: 32/38, clinical stage I: 50 II: 20, nodal 36 and extranodal 34 (Gastro-Intestinal tract 30, H&N 4). As an initial treatment, 65 patients with grade 1/2 FL were treated with radiation therapy alone and 5 patients with grade 3a FL + high tumor burden were treated with RC(H)OP+IFRT. The median radiation dose was 30.6 Gy (range, 24-40). The IFRT was delivered to the patients with nodal FL and ISRT was delivered to the patients with extranodal FL. The median follow-up time was 53 months (range 14-132). None of all patients died with FL, 2 died of other disorder, and 54 patients are alive without any evidence of relapse. The local control was achieved in 69/70 patients. One patient developed local gastric relapse. Of 36 nodal FL, 8 (22%) patients developed relapses (all of 8 relapse were systemic), while 34 extranodal FL, 6 (11%) patients developed relapse. Of extranodal FL, all relapse were patients with GI-FL, only 1 (4%) systemic relapse was recorded, and the other 5 cases were classified into local or regional relapse. The 5 loco-regional relapse sites were recognized as the organs presenting the homing receptor of GI-FL. No toxicities greater than grade 2 were observed during treatment and over follow-up time. The RT for localized follicular lymphomas provides excellent local control with low toxicities. The extranodal FL patient, especially GI-FL, has significantly lower incidence of systemic relapse than nodal FL. The RT plays more important role on the management of GI-FL than nodal FL, because of the relapse of GI-FL were few but limited within the homing sites.

Adjuvant Therapy Improves Outcomes in Completely Resected, Limited-Stage Follicular Lymphoma

Early-stage nodal follicular lymphoma (FL) patients may be rendered disease-free by a diagnostic excisional biopsy. The optimal subsequent therapy in this setting is not well established. We reviewed the management and outcomes of such patients treated at a single institution. The study cohort consisted of 39 FL patients, diagnosed from 2003-2013, who presented after complete excision of all involved lymph nodes. Complete resection was confirmed by a post-operative 18F-fluorodeoxyglucose-positron emission tomography-computed tomography (PET-CT) or CT scan. The primary endpoints were local control (LC), progression-free survival (PFS) and overall survival (OS). Survival outcomes were calculated using Kaplan-Meier methods and compared using the log-rank test. Median age at diagnosis was 55 years (range 15-74 years). Thirty-eight patients had stage I disease (97.4%) and 33 (86.8%) had disease limited to 1 lymph node. The resected nodes had a median diameter of 2.5 cm (range 1.0-7.0 cm). Eleven patients (28.2%) had grade 3 disease. Post-operative imaging, confirming no evidence of disease, consisted of a PET-CT in 74% of patients and a CT in 26%. A bone marrow biopsy was negative in all cases. The FL International Prognostic Index (FLIPI)-2 score was 0 in 50%, 1 in 29%, 2 in 18%, and 3 in 4%. The initial management strategy consisted of observation (9 patients; 23%), radiation therapy (RT) alone (11 patients; 28%), chemotherapy alone (6 cases; 15%), or both (13 patients; 33%). The systemic therapy regimens included: R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; n = 11; 58%), R-COP (rituximab, cyclophosphamide, vincristine, and prednisone; n = 4; 21%), R-CVP (rituximab, cyclophosphamide, vincristine, prednisolone; n = 2; 11%), and rituximab alone (n = 2; 11%). At a median follow-up of 4.5 years (range 0.5-12.8), 4-year PFS and OS were 82.0% and 96.3%, respectively. The only baseline patient or tumor characteristic that was significantly associated with PFS was FLIPI-2 score (P = .002). Compared to patients who were observed, those treated with adjuvant therapy experienced significantly better LC (100% vs. 76.2% at 4 years; P = .001) and PFS (87.3% vs. 66.7% at 4 years; P = .01), with a trend toward improved OS (100% vs. 83.3% at 4 years; P = .06). No local relapse occurred in any patient treated with adjuvant therapy; however, the risk of distant progression was higher in patients treated with RT vs. chemotherapy (4-year PFS: 61% for RT alone, 100% for chemotherapy alone, 100% for chemotherapy and RT; P = 0.03). This difference in PFS did not affect OS: no death was observed in any patient treated with adjuvant therapy of any type. Patients with early-stage FL who undergo complete resection of disease experience significantly better outcomes with adjuvant therapy compared to observation. Our findings suggest that patients with completely resected, limited-stage FL should be offered therapy beyond excisional biopsy alone.

Sites of extranodal involvement are prognostic in patients with stage 1 follicular lymphoma.

ObjectivesFollicular lymphoma (FL) is the most common indolent B cell lymphoma in the United States and a quarter of patients present with stage I disease. The objective of this study was to examine if primary site of disease influences survival in early stage lymphoma.ResultsThe most common extranodal primary sites were the integumentary system (8%), followed by the GI tract (6.4%) and head & neck (5.6%). We stratified patients into a pre-rituximab era (1983-1998) and the rituximab era (1999-2011). In multivariable analysis, integumentary disease was associated with better overall survival (Hazard Ratio [HR], 0.77; Confidence Interval [CI], 0.66-0.9) while primary site FL of the nervous system (HR, 2.40; CI, 1.72-3.38) and the musculoskeletal system (HR, 2.14; CI, 1.44-3.18) were associated with worse overall survival when compared to primary nodal FL. Treatment in the pre-rituximab era, male gender and older age at diagnosis were associated with worse survival.MethodsWe queried the SEER database from 1983 to 2011. We included all adult patients (>18 years) with histologically confirmed stage I FL, active follow-up, and a single primary tumor. A total of 9,865 patients met eligibility criteria, with 2520 (25%) having an extranodal primary site. We classified the primary sites by organ or anatomic location into 11 sites.ConclusionPrimary site of disease is a prognostic factor for patients with early stage FL and may help identify subsets of patients that could benefit from early, aggressive treatment.

MINIMAL RESIDUAL DISEASE (MRD) IN EARLY STAGE FOLLICULAR LYMPHOMA CAN PREDICT PROGNOSIS AND DRIVE RITUXIMAB TREATMENT AFTER RADIOTHERAPY

Introduction: In stage I–II follicular lymphoma (FL), BCL2/IGH+ cells can be detected in the peripheral blood (PB) and/or bone marrow (BM) in a high proportion of cases. We analyzed the prognostic impact of MRD in localized FL and explored the possibility of a MRD-guided rituximab therapeutic approach after standard involved field-radiotherapy (IF-RT). Methods: Between 2000 and 2016, 67 consecutive patients with stage I/II FL were investigated for the BCL2/IGHrearrangement by qualitative PCR in the PB and BM, and (when available) in lymph nodes (LN). MRD was monitored every 6 months in patients positive at baseline. RQ-PCR and droplet digital PCR (ddPCR) were retrospectively performed in 30 MBR+ cases. All patients were treated with IF-RT (24-30 Gy); from 2005, patients who were MRD+ after IF-RT received rituximab (R) (375 mg/m2 x 4). The median follow-up is 67 months (17–183). Results: At baseline, 72% of patients were BCL2/IGH+: 54% MBR+, 9% mcr+, 9% minor BCL2 rearrangement+. Of the 13 evaluable LNs, 11 showed the same molecular marker identified in the PB/BM; 2 cases, negative in the PB/BM, showed a rearrangement in the LN. IF-RT induced an MRD negativity in 50% of baseline positive cases. R was administered to 19 MRD+ patients after IF-RT and an MRD− status was achieved in 16 (84%); 9/16 patients (56.3%) remain persistently MRD−, and none has so far relapsed (p = 0.02). Eight MRD+ patients did not receive R (pre-2005) and 6 (75%) have relapsed (p = 0.025). Progression-free survival (PFS) was significantly longer for MRD+ patients treated with R compared to untreated MRD+ patients (p = 0.0412) (Figure 1). Overall, of the 39 patients with molecular follow-up, 18 were persistently MRD+ and 21 MRD−. Ten of the 18 (55.5%) MRD+ patients relapsed, while this occurred only in 3/21 (14.3%) of the MRD− patients (p = 0.015). PFS was significantly better for MRD− patients (p = 0.0163). RQ-PCR-defined tumor burden at diagnosis predicted the MRD clearance after IF-RT (p = 0.0027), whilst it predicted PFS only when assessed by ddPCR (p = 0.026). The 10-year PFS and OS are 66% (95% CI: 51%–77%) and 96% (95% CI: 76%–99%), respectively. Conclusions: Early stage FL has a heterogeneous disease extension profile: 2 of our cases were truly localized, with a molecular marker only in the LN. On the contrary, when BCL2/IGH+ circulating cells are detectable at diagnosis, ddPCR is a powerful tool to quantify tumor circulating levels and to predict prognosis. IF-RT in localized FL is the undisputed first-line treatment, but alone it often does not clear circulating FL cells. R administration in MRD+ patients decreased significantly the risk of a subsequent relapse and improved PFS. We strongly suggest treating patients suffering from early stage FL through an MRD-guided treatment with R after IF-RT. Keywords: follicular lymphoma (FL); minimal residual disease (MRD); rituximab.

Effect of Rigorous Staging at the First Diagnosis on Prognosis of Patients with Follicular Lymphoma

A survey of early stage follicular lymphoma(FL) revealed that the rigorously staged FL patients at first diagnosis had a better outcome as compared with non-rigorous staged FL patients, but there were no similar reports in China. To explore the relationship between the rigorous staging at first diagnosis and the prognosis of FL patients at different stages. The clinical data of 111 patients with newly diagnosed FL from 2008 to 2014 year were collected and analyzed. The rigorous staging included: (1) bone marrow aspiration and biopsy, (2) imaging examination of whole body including CT and ultrasounic scan, or PET/CT, either or both is defined as rigorous staging, or else as non-rigorous staging. The FL patients at I-II stages by rigorous staging showed a superior progression-free survival(PFS) compared with non-rigorous staging patients(P=0.048). For all the patients, the age, serum LDH, bone marrow lesion and more than 3 foci of diameter larger than 3 cm correlated with prognosis in univariate analysis, and multivariate analysis revealed that the age, serum LDH and bone marrow imolvement were the independent prognostic factors. Rigorous staging leads to better outcomes, suggesting that accurate and appropriate testing is important for the patients at the first treatment. The close correlation of bone marrow with prognosis indicates that the evaluation of bone marrow is very important for the daily clinical practice.

Early Stage Follicular Lymphoma. Predictive Role of Minimal Residual Disease (MRD) and Impact of MRD-Driven Treatment with Radiotherapy and Rituximab on Clinical Outcome

Background. In localized follicular lymphoma (FL, stage I-II), BCL2/IGH+ cells can be detected in the peripheral blood (PB) and/or bone marrow (BM) in 66.7% of cases (Pulsoni et al, BJH 2007). We hereby analyzed the prognostic impact of MRD in localized FL and explored the possibility of a MRD-guided therapeutic approach on a series of patients with a long follow-up.Methods. Between April 2000 and February 2015, 67 consecutive patients with a confirmed histologic diagnosis of stage I/II FL followed at our Center were enrolled in the study. PB and BM samples were collected at enrollment in all patients and investigated by qualitative PCR to identify the presence of a BCL2/IGH rearrangement. Paraffin-embedded lymph nodes (LN) were studied when available. Patients who proved positive at baseline were studied for MRD every 6 months. Real-Time Quantitative PCR (RQ-PCR) was retrospectively performed according to material availability. All patients were treated with involved field radiotherapy (RT) (24-30 Gy); from 2005, patients who were MRD+ after RT received rituximab (R) (375 mg/m2, 4 weekly administration). The median follow-up is 67 months (17-183); 21 patients (31%) have relapsed after a median of 37 months (17-165) from diagnosis.Results. At baseline, a clonal marker was found by qualitative PCR in 48/67 cases (72%): 36 were MBR+ (54%), 6 mcr+ (9%), 6 showed a minor BCL2 rearrangement (9%), while 19 (28%) were negative. Fifteen of the latter 19 were analyzed by RQ-PCR and 4 proved MBR+. Of the 13 available LNs, 11 showed the same molecular marker identified in the PB/BM; 2 cases, negative in the PB/BM, showed a rearrangement in the LN only. After RT, 40/42 MBR+/mcr+ patients were analyzed: 20 resulted MRD-, while 20 persisted MRD+. Regardless of the post-RT MRD status, an equal number of relapses was recorded in both groups (7 each). R treatment was administered to the 20 MRD+ patients after RT. Sixteen (80%) achieved a MRD- status after R: over time, 7/16 patients converted to MRD+ and 4 relapsed, whilst 9/16 patients (56.2%) remain persistently MRD- and none has relapsed so far.To evaluate the impact of R, we considered a series of 27 patients MRD+ after RT or who were MRD- and became MRD+ during the follow-up. Of the 19 patients who received R (1 could not be studied), 15 (79%) did not relapse, while of the 8 untreated patients (pre-2005), 6 (75%) relapsed (p=0.025). Progression-free survival (PFS) was significantly longer for R-treated patients (p=0.0412) (Fig. 1).To define the predictive role of MRD in the entire cohort regardless of post-RT treatment, we considered the 39 patients with molecular follow-up. Thirteen have relapsed: 10/13 (77%) were MRD+ in the follow-up, including the pre-relapse time point, while 3 resulted persistently MRD-. Contrariwise, of the 26/39 patients in continuous remission, 18 (69%) were persistently MRD- while 8 were MRD+ (p=0.015). PFS was significantly better for MRD- patients (p=0.0163) (Fig. 2).RQ-PCR was performed in 30 MBR+ patients: 17 (57%) showed a tumor burden ≥10-5 and 13 <10-5. Tumor burden at diagnosis predicted the MRD clearance following RT: 9/13 (69%) cases with low tumor burden resulted MRD- after RT compared to 2/17 (12%) cases with high tumor burden (p=0.0027). Contrariwise, tumor burden did not predict the occurrence of relapse.Conclusions. Early stage FL at diagnosis can have a heterogenous disease extension: 2 of our cases were truly localized, showing a molecular marker only in the LN. However, in most cases the use of combined qualitative approaches, including canonical MBR/mcr and minor rearrangements, together with RQ-PCR has allowed to identify circulating BCL2/IGH+ cells (52/67 cases: 77.6%), despite a negative BM biopsy. RT induced a MRD negativity in 50% of BCL2/IGH+ patients, but this did not impact on clinical outcome. The administration of R in MRD+ patients decreased significantly the risk of a subsequent relapse and improved PFS. Regardless of treatment, MRD positivity during the follow-up is a predictor of relapse and PFS. Tumor burden at diagnosis is associated with MRD clearance after RT. We support the use of a MRD-driven treatment with anti-CD20 monoclonal antibodies in patients with localized FL after RT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Comparative Analysis Between RQ-PCR and Digital Droplet PCR of BCL2/IGH Rearrangement in the Peripheral Blood and Bone Marrow of Early Stage Follicular Lymphoma

[Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Limited Stage Follicular Lymphoma: Current Role of Radiation Therapy.

Radiation therapy (RT) alone has been considered for a long time as the standard therapeutic option for limited stage FL, due to its high efficacy in terms of local disease control with a quite significant proportion of “cured” patients (without further relapses at 10–15 years). Multiple therapeutic choices are currently accepted for the management of early stage FL at diagnosis, and better staging procedures as well as better systemic therapy partially modified the role of RT in this setting. RT has also changed in terms of prescribed dose as well as treatment volumes. In this review, we present and discuss the current role of RT for limited stage FL in light of the historical data and the modern RT concepts along with the possible combination with systemic therapy.

Impact of 18-Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) Stage on Outcomes Among Patients With Early-Stage Follicular Lymphoma

Impact of 18-Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) Stage on Outcomes Among Patients With Early-Stage Follicular Lymphoma

Radiotherapy Compared to Other Strategies in the Treatment of Stage I/II Follicular Lymphoma: A Study of 404 Patients with a Median Follow-Up of 15 Years.

PurposeTo investigate outcome for patients with follicular lymphoma (FL) stage I-II treated at a population-based referral institution with a median follow-up of 15 years. Overall and cause-specific survival was compared to that of a sex, age and residency matched individuals from normal population.Material and Methods404 patients with early stage FL treated between 1980 and 2005 were retrospectively analyzed. Two of three patients had stage I disease. Based on clinical characteristics, first line treatments were radiotherapy (RT) (48% of patients), chemotherapy (CT) (16%), combined chemo-and radiotherapy (CRT) (16%) or observation (OBS) (15%). Survival was modeled with Kaplan-Meier methodology. Multivariate analyses were performed with the Cox model.ResultsFifteen years overall survival (OS), progression free survival (PFS) and time to next treatment (TNT) were 50% (95% confidence interval [CI]: 45–55), 42% (95% CI: 36–47) and 48% (95% CI, 42–54), respectively. For patients treated with RT 97% achieved a complete remission, and 15 year OS, PFS and TNT were 57% (95% CI, 50–64), 46% (95% CI, 39–54) and 49% (95% CI, 42–57), respectively. Relapse rate after RT and CRT was 49% and 36%, respectively. Only 2% of patients who received RT or CRT relapsed inside the radiation field and 5% had isolated near-field relapse. No statistical differences were found between treatment groups regarding death from cardiovascular disease or incidence of second cancer. Compared to a matched normal population, non-lymphoma cancer mortality was higher among patients given RT, hazard ratio 1.66 (95% CI: 1.14–2.42; P<0.01). Compared to other treatment modalities, patients selected for observation without treatment did not have inferior outcome.ConclusionsA differentiated treatment strategy in early stage FL results in long term survival for the majority of patients. OBS is a valid initial choice for selected patients without lymphoma-related symptoms.

Radiotherapy in early stage follicular lymphoma: is it really the gold standard?

"Radiotherapy in early stage follicular lymphoma: is it really the gold standard?." Leukemia & Lymphoma, 56(10), pp. 2999–3000

What is the optimal management of early-stage low-grade follicular lymphoma in the modern era?

Despite international practice guidelines endorsing radiotherapy (RT) as the preferred initial therapy, treatment approaches vary for patients with early-stage follicular lymphoma. The authors engaged the National Cancer Data Base to analyze patterns of care and survival outcomes for patients with early-stage follicular lymphoma in the era of modern therapy. A National Cancer Data Base retrospective cohort study was conducted of 35,961 patients with lymph node and extranodal, American Joint Committee on Cancer stage I to II, WHO grade 1 to 2 follicular lymphoma who were diagnosed between 1998 and 2012. Univariate and multivariable analyses were performed to identify sociodemographic, treatment, and tumor characteristics that were predictive of overall survival (OS) and treatment use. Propensity score-adjusted Cox proportional hazards ratios for survival in patients treated for follicular lymphoma were used. Of the 35,961 patients with follicular lymphoma included in the current study, 63% had stage I disease, 79% were without extranodal disease, and 61% were aged >60 years. RT use decreased from 37% in 1999 to 24% in 2012 (P<.0001), with corresponding significant increases in observation and single-agent chemotherapy. Patients who received RT had 5-year and 10-year OS rates of 86% and 68%, respectively, compared with 74% and 54%, respectively, for those who did not receive RT (P<.0001). On multivariable survival analysis, including a propensity score to account for potential uncaptured confounding variables due to a lack of randomization, upfront RT remained independently associated with improved OS (hazard ratio of death, 0.54; 95% confidence interval, 0.47-0.63 [P<.0001]). RT is an increasingly underused treatment approach in the era of modern therapy for patients with early-stage follicular lymphoma. The use of RT appears to improve OS and should remain standard practice as encouraged by clinical practice guidelines.

XV. Clinical aspects of transformed lymphoma.

XV. Clinical aspects of transformed lymphoma.