Treatment Of Early Stage Follicular Lymphoma With Involved Field Radiotherapy and Rituximab. Role Of Bcl-2 Molecular Monitoring

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1813-1813
Author(s):  
Alessandro Pulsoni ◽  
Irene Della Starza ◽  
Pasqualina D'Urso ◽  
Gianna Maria D'Elia ◽  
Giorgia Annechini ◽  
...  

Abstract Background Stage I or II follicular lymphoma (FL) is an uncommon disease, representing only 20% of FL. Conventional treatment is represented by local radiotherapy (RT), which allows eradication of the disease in about 50% of patients. Despite the negative bone marrow biopsy in all cases, most patients present Bcl-2 rearranged cells in the bone marrow (BM) and/or peripheral blood (PB). The aim of this study was to analyze the prognostic role of Bcl-2 molecular monitoring in a series of stage I-II FL cases followed at a single center. Methods Fifty-seven consecutive patients with a confirmed diagnosis of stage I/II FL were investigated at presentation by PCR in order to identify the presence of Bcl-2 rearranged cells in the BM and/or PB. All patients were treated with involved field RT (30-36 Gy). Subsequently, minimal residual disease (MRD) was evaluated every 6 months after RT in patients positive at baseline; patients negative at baseline were not retested. In part of the patients (after 2005) Rituximab was administered in case of persistently positive Bcl-2 cells in the BM or PB after radiotherapy. The PCR analysis of the Bcl-2/IgH rearrangement was performed according to published methods. It consists in a nested PCR that uses in the first round a couple of primers for the major breakpoint region (MBR) or for the minor cluster region (mcr). After this first step, the amplification products were re-amplified using oligonucleotide primers internal to the original ones. An aliquot of the PCR products was analysed on 2% agarose gel containing ethidium bromide in Tris-borate electrophoresis buffer and visualized under UV light. For MBR and mcr, a reproducible sensitivity level of 10-5 and 10-4 respectively, was obtained. Results 1. Prognostic value of basal PCR in BM/PB: PCR analysis revealed Bcl-2 rearranged cells in the PB and/or BM in 38/57 patients (66.7%) at presentation. After a median follow-up of 55 months, 11 patients (19.3%) had a clinical relapse; of them, 10 belonged to the group with positive PCR at baseline, while only 1 patient with negative basal Bcl-2 (1.7%) experienced a clinical relapse (Pearson’s chi2= 0.058, Fisher exact test = 0.079). Among the 11 patients who showed a clinical relapse, 5 presented a positive Bcl-2 at relapse, 3 were negative (1 already at baseline),while in 3 this information is not evaluable. 2. Effect of local RT: After irradiation of the sole site of the disease, Bcl-2 rearranged cells disappeared in 19 of 38 patients positive at baseline (50%). In 17/38 (44.7%), MRD remained positive, while 2 patients refused to perform the analysis. A negative MRD after RT does not seem to correlate with a lower relapse probability. Only 1 patient died of breast cancer. 3. Effect of rituximab treatment in Bcl-2+ patients: Fourteen patients with persistently positive Bcl-2 after RT were treated with Rituximab 375 mg/m2 for 4 weekly administrations: 9 of them (64%) patients became negative. This result was only temporary in 4/9 cases (1 clinical relapse). Among persistently Bcl-2 positive patients after Rituximab, 1 clinical relapse was also observed. Conclusions In limited stage FL, despite a negative BM biopsy, Bcl-2/IgH rearranged cells can be found in the BM and/or PB, and they can disappear after local RT of the involved lymph node(s) in 50% of cases (19/38). The basal presence of Bcl-2+ cells in the BM/PB has a prognostic role: no clinical relapses were observed in Bcl-2 negative cases at baseline, except for 1 patient. Conversely, a negative MRD after radiotherapy does not seem to correlate with a better prognosis. -Rituximab therapy can induce a negativization of Bcl-2 in MRD-positive patients. Nevertheless, Rituximab treatment was only partially effective: negativization was observed in the majority of MRD-positive patients, but it was only temporary in a proportion of them. In Rituximab-treated patients, clinical relapses occurred only in the presence of MRD. -Not all clinical relapses were preceded by MRD positivity; further data are necessary to establish the usefullness of MRD monitoring over time. Prognosis of patients with early-stage FL treated with local RT + Rituximab in case of MRD persistence, is excellent: cause-specific survival=100%, EFS=70% projected at 10 years. Disclosures: No relevant conflicts of interest to declare.

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2959-2959 ◽  
Author(s):  
Alessandro Pulsoni ◽  
Irene Della Starza ◽  
Maria Elena Tosti ◽  
Luca Vincenzo Cappelli ◽  
Giorgia Annechini ◽  
...  

Abstract 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. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.


2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7216-7216
Author(s):  
C. Lu ◽  
I. Wistuba ◽  
X. Zhou ◽  
B. N. Bekele ◽  
J. B. Putnam ◽  
...  

7216 Background: Promoter hypermethylation is an epigenetic mechanism of gene silencing commonly observed in malignancies. Prior studies suggest that hypermethylation of DAP kinase and p16, genes involved in apoptosis and cell cycle regulation, respectively, are associated with poorer survival in NSCLC patients. In this study we investigate the prognostic role of DAP kinase and p16 promoter hypermethylation in a large cohort of early-stage NSCLC patients. Methods: Pathologic stage I and II NSCLC patients who underwent complete surgical resection between 1/97 and 12/01 at our institution and did not receive adjuvant therapy were identified. Formalin-fixed, paraffin-embedded tissue blocks were retrieved, and p16 and DAP kinase promoter methylation status was determined by methylation specific PCR. Two-sided statistical analyses were performed to determine associations between methylation status, clinicopathologic characteristics, and survival. Results: DAP kinase and p16 methylation status was observed in 36.3% (97 of 267) and 36.4% (95 of 261) cases, respectively. Subject characteristics: 55% female, 77% former/current smokers, 81% stage I, 19% stage II, 61% adenocarcinoma, 29% squamous carcinoma, 63% performance status (PS) 0, 37% PS 1,93% < 5% weight loss. Recurrent NSCLC and death occurred in 21.3% and 38% of cases, respectively. No significant associations were observed between DAP kinase methylation status and subject characteristics. P16 methylation was associated with moderate/high grade (p = 0.03). A higher frequency of p16 methylation was observed in ever vs never smokers (39% vs 28%, p = 0.17). Preliminary analyses do not demonstrate significant associations between methylation status and overall survival (p16 p = 0.13; DAP kinase p = 0.56) or disease-free survival (p16 p = 0.36; DAP kinase p = 0.71). Conclusions: In this relatively large cohort of early-stage NSCLC patients, we did not detect significant associations between p16 and DAP kinase promoter methylation and clinical outcome. Further subset analyses stratified by gender and histology will be performed. The prognostic role of these biomarkers in NSCLC remains unclear. No significant financial relationships to disclose.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4901-4901
Author(s):  
Arlene Dawravoo ◽  
Neel B. Shah ◽  
Teresa O'Brien ◽  
Stephanie A. Gregory ◽  
Parmeswaran Venugopal

Abstract Abstract 4901 Early stage Hodgkin Lymphoma (HL) has been conventionally treated with radiotherapy alone or abbreviated chemotherapy along with involved field radiation therapy. The role of combined modality therapy was investigated to study the favorable effects of lower doses of radiation on acute and long term toxicities without compromising response and cure rates. The goal of this study was to evaluate the role of combined chemotherapy, which incorporated mitoxantrone in place of doxorubicin and dexamethasone in place of dacarbazine, and involved field radiation therapy in patients with early stage, non-bulky (I and II) HL. The patients enrolled in this trial were originally enrolled in 1997–2002 and treated with 4 cycles of chemotherapy with mitoxantrone 6 mg/m2 IV, vinblastine 5 mg/m2 IV, bleomycin 5 units/m2 on day 1 and day 15, and dexamethasone 6 mg/m2 PO on days 1–5 and days 15–19 on a 28 day cycle (MBVD). Restaging was done following 4 cycles of chemotherapy. Subsequently patients received involved field radiation with total dose of 30 Gy at 150 cGy per fraction. Patients were followed for response, duration, toxicity and survival. Results: 15 patients were enrolled, 10 were evaluable. All completed treatment. 7 patients were stage II and 3 were stage I at diagnosis. 4 were males and 6 were females between the ages of 20 to 52 years with a median age 33.5 years. Following completion of treatment with chemotherapy and radiation, 8 patients achieved a complete response and 2 patients remained in partial remission. Duration of response in patients in follow up ranged between 9 and 149 months with a median of 75 months. 2 relapses occurred at 8 and 23 months with increase in size of the mediastinal lymph nodes. 7/10 patients experienced grade 1 toxicities which included anemia, leukopenia, neutropenia, thrombocytopenia, GI upset or cardiomyopathy. 4/10 patients experienced grade 2 toxicities. 2/10 patients had grade 3 toxicities with severe neutropenia. All patients experienced grade 1 skin changes following radiation. One patient's left ventricle ejection fraction decreased from 65% to 52% following therapy. At last follow up, 9/10 patients were alive with 9/10 patients still in remission. 1 patient underwent bone marrow transplant after relapse at 8 months and was lost to follow up. 1 patient experienced recurrence of disease at 23 months and underwent bone marrow transplant at 29 months and was in remission at 73 month follow up. Although the number of patients in this study is small, treatment appears to be well tolerated and acute toxicities less compared to standard therapy with ABVD chemotherapy followed by radiotherapy. At last follow up 9/10 are in remission, with 2 patients in remission for 12 years. No patients have experienced MDS or other long term sequelae. Confirmatory studies should be done to determine the safety of the MBVD regimen compared to standard ABVD. Disclosures: No relevant conflicts of interest to declare.


2018 ◽  
Vol 36 (29) ◽  
pp. 2918-2925 ◽  
Author(s):  
Michael MacManus ◽  
Richard Fisher ◽  
Daniel Roos ◽  
Peter O’Brien ◽  
Andrew Macann ◽  
...  

Purpose Follicular lymphoma (FL) is curable by involved-field radiotherapy (IFRT) in < 50% of patients with stage I to II disease. We hypothesized that adding systemic therapy to IFRT would improve long-term progression-free survival (PFS). Patients and Methods A multicenter randomized controlled trial enrolled patients with stage I to II low-grade FL after staging computed tomography scans and bone marrow biopsies. 18F-labeled fluorodeoxyglucose–positron emission tomography (PET) was not mandatory. Patients were randomly assigned to either arm A (30 Gy IFRT alone) or arm B (IFRT plus six cycles of cyclophosphamide, vincristine, and prednisolone [CVP]). From 2006, rituximab was added to arm B (R-CVP). Results Between 2000 and 2012, 150 patients were enrolled, 75 per arm. In arm B, 44 patients were allocated to receive CVP and 31 were allocated to receive R-CVP. At randomization, 75% had stage I, the median age was 57 years, 52% were male, and 48% were PET staged. With a median follow-up of 9.6 years (range, 3.1 to 15.8 years), PFS was superior in arm B (hazard ratio, 0.57; 95% CI, 0.34 to 0.95; P = .033). Ten-year PFS rates were 59% (95% CI, 46% to 74%) and 41% (95% CI, 30% to 57%) for arms B and A, respectively. Patients in arm B who received R-CVP had markedly superior PFS compared with contemporaneous patients in arm A (hazard ratio, 0.26; 95% CI, 0.07 to 0.97; P = .045). Fewer involved regions ( P = .047) and PET staging ( P = .056) were associated with better PFS. Histologic transformation occurred in four and 10 patients in arms B and A, respectively ( P = .1). Ten deaths occurred in arm A versus five in arm B, but overall survival was not significantly different ( P = .40; 87% and 95% at 10 years, respectively). Conclusion Systemic therapy with R-CVP after IFRT reduced relapse outside radiation fields and significantly improved PFS. IFRT followed by immunochemotherapy is more effective than IFRT in early-stage FL.


Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5988
Author(s):  
Annika Ålgars ◽  
Lotta Kemppinen ◽  
Ruth Fair-Mäkelä ◽  
Harri Mustonen ◽  
Caj Haglund ◽  
...  

Macrophages, which are key players in the tumor microenvironment and affect the prognosis of many cancers, interact with lymphatic vessels in tumor tissue. However, the prognostic role of tumor-associated macrophages (TAM) and lymphatic vessels in human colorectal cancer (CRC) remains controversial. We investigated the prognostic role of CD68+ and CLEVER-1+ (common lymphatic endothelial and vascular endothelial receptor 1) TAMs in addition to CLEVER-1+ lymphatic vessels in 498 stage I–IV CRC patients. The molecular markers were detected by immunohistochemical (IHC) analysis. The results showed that, in early stage I CRC and in young patients (age below median, ≤67.4 years), a high number of CD68+ and CLEVER-1+ TAMs was associated with longer disease-specific survival (DSS). In early stage I CRC, high intratumoral CLEVER-1+ lymphatic vessel density (LVD) predicted a favorable prognosis, whereas the opposite pattern was observed in stage II CRC. The highest density of CLEVER-1+ lymphatic vessels was found in metastatic disease. The combination of intratumoral CLEVER-1+ lymphatic vesselhigh + CD68+ TAMlow was associated with poor DSS in stage I–IV rectal cancer. The present results indicate that the prognostic significance of intratumoral macrophages and CLEVER-1+ lymphatic vessels differs according to disease stage, reflecting the dynamic changes occurring in the tumor microenvironment during disease progression.


1993 ◽  
Vol 11 (7) ◽  
pp. 1344-1352 ◽  
Author(s):  
N L Berinstein ◽  
M D Reis ◽  
B Y Ngan ◽  
C A Sawka ◽  
H H Jamal ◽  
...  

PURPOSE The object of this study was to compare the relative sensitivities of morphologic, immunophenotypic, gene rearrangement, cytogenetic, and polymerase chain reaction (PCR) analyses in the detection of lymphoma cells in the bone marrow and peripheral blood of patients with follicular lymphoma. PATIENTS AND METHODS Bone marrow and peripheral-blood samples from 28 newly diagnosed patients with follicular lymphoma referred from several different medical centers were assessed. Routine morphologic assessment was performed initially and the remainder of the sample was aliquoted for DNA extraction to be used for gene rearrangement and PCR analyses and for immunophenotypic and cytogenetic analyses where a sufficient amount of sample remained. RESULTS Morphologic assessment of the bone marrow was positive for lymphoma cells in 11 of 28 patients. PCR amplification of t(14;18) breakpoint DNA detected lymphoma cells in 17 of 24 patients assessed. Morphologic assessment detected lymphoma cells in three bone marrow samples that were negative by PCR. PCR analysis was the only method able to detect circulating lymphoma cells in peripheral blood at diagnosis and was positive in 15 of 24 samples. The other methods of assessment did not show lymphoma in any samples in which lymphoma was not detected by morphologic or PCR analysis. Lymphoma cells were found in the bone marrow and/or peripheral blood as frequently in early-stage patients as in advanced-stage patients. CONCLUSION PCR amplification of t(14;18) breakpoint DNA together with morphologic assessment had the highest yield of detecting lymphoma cells in the bone marrow and/or peripheral blood of our population of newly diagnosed patients with follicular lymphoma. The clinical significance and prognostic importance of lymphoma cells detected by PCR in the bone marrow and/or peripheral blood of newly diagnosed follicular lymphoma patients awaits long-term follow-up data of these and additional patients.


2007 ◽  
Vol 137 (3) ◽  
pp. 216-220 ◽  
Author(s):  
Alessandro Pulsoni ◽  
Irene Della Starza ◽  
Natalia Frattarelli ◽  
Emanuela Ghia ◽  
Emanuela Carlotti ◽  
...  

2021 ◽  
Vol 39 (S2) ◽  
Author(s):  
F. Sha ◽  
M. Okwali ◽  
A. Alperovich ◽  
P. C. Caron ◽  
L. Falchi ◽  
...  

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2876
Author(s):  
Giovanni Manfredi Assanto ◽  
Giulia Ciotti ◽  
Mattia Brescini ◽  
Maria Lucia De Luca ◽  
Giorgia Annechini ◽  
...  

Background: Despite that the unfavorable prognostic role of a high Total Metabolic Tumor Volume (TMTV) in Follicular Lymphoma has been demonstrated, the role of SUVmax alone at baseline PET/CT could have a different prognostic role. Patients and Methods: We performed a retrospective observational monocentric cohort study. All patients affected by FL who underwent a basal PET/CT were included. Two subgroups were identified and compared in terms of PFS and OS: (A) Basal SUVmax ≤ 6; and (B) Basal SUVmax > 6. Results: Ninety-four patients were included, 34 in group A (36.2%) and 60 in group B (63.8%). The PFS at two years was comparable in the two groups (97%). The five-year PFS was 73.5% for group A and 95% for group B (p 0.005). The five-year PFS in the whole cohort was 87.5%. A clear advantage was confirmed in group A in the absence of other risk factors. Patients with SUVmax ≤ 6 and no risk factors showed a 5-year PFS of 73% against 83% for patients with SUVmax > 6 and at least two risk factors. Conclusion: A high FDG uptake favorably correlated with PFS. A low basal SUVmax reflected a higher rate of late relapse requiring a prolonged follow-up. The basal SUVmax is an approachable parameter with prognostic implications.


2020 ◽  
Author(s):  
Zaoxiu Hu ◽  
Yonghe Zhao ◽  
Yanlong Yang ◽  
Zhenghai Shen ◽  
Yunchao Huang

Abstract Objective: Recent studies indicated sputum miRNAs may provide a promising approach for non-small cell lung cancer (NSCLC) diagnosis. But some results were still inconsistent. So, we performed meta-analysis to evaluate the diagnostic role of sputum miRNAs for the detection of NSCLC.Methods: Eligible studies that estimated the diagnostic accuracy of sputum miRNAs in NSCLC were searched in Pubmed, Embase and Web of Science and Chinese National Knowledge Infrastructure (CNKI). Data from the eligible studies were collected and pooled; sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratios, weighted symmetric summary ROC curve and the area under the curve (AUC) were calculated by bi-variate random effects model. The between-study heterogeneity was evaluated by Q test and I2 statistics.Results: 30 studies from 16 articles were included for analysis. The overall analysis yielded the sensitivity of 0.77 (95% CI: 0.73–0.81) and specificity of 0.87 (95% CI: 0.83–0.90), with an area under the SROC curve (AUC) of 0.89 (95% CI: 0.86–0.91). Subgroup analysis revealed the diagnostic accuracy in multiple miRNAs studies was higher than single miRNA (the sensitivity, specifcity and an AUC of multiple miRNAs were 0.76, 0.88 and 0.90; and for single miRNA, it was 0.74, 0.74, and 0.80). The diagnostic performance in early stage NSCLC was also very high (the sensitivity, specifcity and an AUC of stage I/II was 0.76, 0.88 and 0.91; and for stage I, it was 0.79, 0.85, and 0.87). We also found miR-210, miR-21, miR-31 and miR-126-3p might serve as potential biomarkers for lung cancer.Conclusion: Sputum miRNAs was useful noninvasive biomarkers for NSCLC diagnosis.


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