scholarly journals Retrospective Analysis of Treatment Outcomes for Patients with Follicular Lymphoma and Comorbidities

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5082-5082
Author(s):  
Aya Watanabe ◽  
Yoichi Imai ◽  
Kenjiro Mitsuhashi ◽  
Akihito Shinohara ◽  
Norina Tanaka ◽  
...  
Keyword(s):  
Decision Making ◽  
Overall Survival ◽  
Liver Disease ◽  
Follicular Lymphoma ◽  
Charlson Comorbidity Index ◽  
Clinical Characteristics ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Chop Regimen ◽  
Comorbidity Index

Abstract Follicular lymphoma (FL) is a low-grade B-cell lymphoma, and the response of FL to treatment, as well as progression-free survival and overall survival (OS), are improved by the application of combined chemotherapy with rituximab (R). The cyclophosphamide, adriamycin, vincristine, and prednisolone with rituximab (R-CHOP) regimen is the standard first-line therapy for patients with FL. However, many patients have coexistent diseases (comorbidities), and it is believed that therapeutic decision-making is influenced by comorbidities. In this study, we retrospectively analyzed treatment decision-making and its outcome for patients with FL. Based on this analysis, we investigated how the presence of comorbidity affects the survival of patients with FL. We analyzed 113 patients who were diagnosed with FL at our institute between September 2001 and March 2014. The treatment strategy was classified as observation without treatment, chemotherapy, radiotherapy, and others. Chemotherapy was subclassified as R-CHOP, reduced R-CHOP (the chemotherapeutic dose was reduced), and other chemotherapy. The severity of the comorbidity present at the time of diagnosis of FL was estimated according to the Charlson Comorbidity Index (CCI) (Table 1). The clinical characteristics of the 113 patients are shown in Table 2. The median age of the patients was 60 years. Six patients were observed without treatment, and 8 patients underwent resection or localized radiation for lymphoma. R-CHOP and other chemotherapy regimens were utilized in 84, and 15 patients, respectively. The 5-year OS rates of patients treated with R-CHOP, reduced R-CHOP, and other chemotherapy regimens were 92.3%, 75.5%, and 74.1%, respectively. As shown in a previous study (Andre Wieringa, et al., Br J Haematol, 2014, 165, 489-496), the 5-year OS rate of patients with CCI score ≥2 was inferior to that of patients with CCI 0-1 (CCI ≥2 (n = 32); 76.5%, CCI 0-1(n=81); 92.4%, p = 0.0361, Figure 1a). When we analyze the patients treated with R-CHOP, the overall response rate was 92.4% (complete response [CR] = 77.2%, partial response [PR] = 15.1%) in patients with a CCI score of 0-1 and 94.4% (CR = 77.8%, PR = 16.7%) in those with CCI score ≥ 2. In addition, there was no significant difference in the 5-year OS rate between patients with a CCI score of 0-1 or ≥2 (91.0% vs. 85.0%, p = 0.779, Figure 1b). Although, the percentage of patients with CCI ≥2 is lower than that of the other therapies (CCI ≥2; R-CHOP 25%, other chemotherapy 67%), it is supposed that R-CHOP is effective even if the patients have severe comorbidities. In 6 patients among these, treatment was discontinued or the chemotherapeutic dose was reduced due to myelosuppression during the designated course of therapy .The 5-year OS rate of these patients was favorable, even among those with high CCI score(CCI 0,1; 94.1%, CCI ≥2; 100%). Thus, it appears that R-CHOP with appropriate dose modification during the designated course will improve patient survival. Our results indicate that patients with severe comorbidities can be treated effectively by adjusting R-CHOP. Table 1. The items used to estimate the Charlson comorbidity index in each patient Comorbidity Score No. of patients Cardiac disease 1 5 Peripheral vascular disease 1 1 Cerebrovascular disease 1 3 Chronic pulmonary disease 1 6 Connective tissue disease 1 8 Ulcers 1 3 Mild liver disease 1 4 Diabetes 1 16 Tumors 2 22 Moderate or severe liver disease 3 1 Metastatic solid tumors 6 2 Table 2. Clinical characteristics of the patients Characteristic No. of patients (n = 113) Percentage (%) Sex Male 53 47 Female 60 53 Age >60 years 56 50 ≤60 years 57 50 IPI Low 55 49 Low-intermediate 38 34 High-intermediate 17 15 High 3 2 FLIPI Low 41 36 Intermediate 36 32 High 36 32 Therapy None 6 4 Resection only 3 3 Radiotherapy only 3 3 Resection and radiotherapy 2 2 R-CHOP 71 63 Discontinued or dose was reduced 23 20 Reduced R-CHOP 13 12 Other chemotherapy 15 13 IPI, international prognostic index; FLIPI, follicular lymphoma international prognostic index; R-CHOP, cyclophosphamide, adriamycin, vincristine, and prednisolone with rituximab Figure 1. Overall survival of patients treated with the cyclophosphamide, adriamycin, vincristine, and prednisolone with rituximab (R-CHOP) regimen according to the Charlson Comorbidity Index (CCI) Figure 1. Overall survival of patients treated with the cyclophosphamide, adriamycin, vincristine, and prednisolone with rituximab (R-CHOP) regimen according to the Charlson Comorbidity Index (CCI) Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.

High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma

Blood ◽  
2006 ◽  
Vol 108 (9) ◽  
pp. 2957-2964 ◽  
Author(s):  
Joaquim Carreras ◽  
Armando Lopez-Guillermo ◽  
Bridget C. Fox ◽  
Lluis Colomo ◽  
Antonio Martinez ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cells ◽  
Regulatory T Cells ◽  
Follicular Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Significance ◽  
Prognostic Index ◽  
Specific Cell ◽  
First Relapse ◽  
The Impact

Abstract The tumor microenvironment plays an important role in the biologic behavior of follicular lymphoma (FL), but the specific cell subsets involved in this regulation are unknown. To determine the impact of FOXP3-positive regulatory T cells (Tregs) in the progression and outcome of FL patients, we examined samples from 97 patients at diagnosis and 37 at first relapse with an anti-FOXP3 monoclonal antibody. Tregs were quantified using computerized image analysis. The median overall survival (OS) of the series was 9.9 years, and the FL International Prognostic Index (FLIPI) was prognostically significant. The median Treg percentage at diagnosis was 10.5%. Overall, 49 patients had more than 10% Tregs, 30 between 5% to 10%, and 19 less than 5%, with a 5-year OS of 80%, 74%, and 50%, respectively (P = .001). Patients with very low numbers of Tregs (< 5%) presented more frequently with refractory disease (P = .007). The prognostic significance of Treg numbers was independent of the FLIPI. Seven transformed diffuse large B-cell lymphomas (DLBCLs) had lower Treg percentages (mean: 3.3%) than FL grades 1,2 (mean: 12.1%) or 3 (mean: 9%) (P < .02). In conclusion, high Treg numbers predict improved survival of FL patients, while a marked reduction in Tregs is observed on transformation to DLBCL.

scholarly journals Follicular lymphoma patients with a high FLIPI score and a high tumor burden: A risk stratification model

2015 ◽  
Vol 72 (1) ◽  
pp. 26-32 ◽  
Author(s):  
Bosko Andjelic ◽  
Milena Todorovic-Balint ◽  
Darko Antic ◽  
Jelena Bila ◽  
Vladislava Djurasinovic ◽  
...  
Keyword(s):  
Risk Factors ◽  
Overall Survival ◽  
Prognostic Factors ◽  
Follicular Lymphoma ◽  
Histological Grade ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Tumor Burden ◽  
Cox Regression Analysis ◽  
High Tumor Burden

Background/Aim. The widely accepted Follicular Lymphoma International Prognostic Index (FLIPI) divides patients into three risk groups based on the score of adverse prognostic factors. The estimated 5-year survival in patients with a high FLIPI score is around 50%. The aim of this study was to analyse the prognostic value of clinical and laboratory parameters that are not included in the FLIPI and the New Prognostic Index for Follicular Lymphoma developed by the International Follicular Lymphoma Prognostic Factor Project (FLIPI2) indices, in follicular lymphoma (FL) patients with a high FLIPI score and high tumor burden. Methods. The retrospective analysis included 57 newly diagnosed patients with FL, a high FLIPI score and a high tumor burden. All the patients were diagnosed and treated between April 2000 and June 2007 at the Clinic for Hematology, Clinical Center of Serbia, Belgrade. Results. The patients with a histological grade > 1, erythrocyte sedimentation rate (ESR) ? 45 mm/h and hypoalbuminemia had a significantly worse overall survival (p = 0.015; p = 0.001; p = 0.008, respectively), while there was a tendency toward worse overall survival in the patients with an Eastern Cooperative Oncology Group (ECOG) > 1 (p = 0.075). Multivariate Cox regression analysis identified a histological grade > 1, ESR ? 45 mm/h and hypoalbuminemia as independent risk factors for a poor outcome. Based on a cumulative score of unfavourable prognostic factors, patients who had 0 or 1 unfavourable factors had a significantly better 5-year overall survival compared to patients with 2 or 3 risk factors (75% vs 24.1%, p = 0.000). Conclusion. The obtained results suggest that from the examined prognostic parameters histological grade > 1, ESR ? 45 mm/h and hypoalbuminemia can contribute in defining patients who need more aggressive initial treatment approach, if two or three of these parameters are present on presentation.

scholarly journals BONE MARROW IN FOLLICULAR LYMPHOMA PROGNOSIS

2016 ◽  
Vol 15 (3) ◽  
pp. 99-102 ◽  
Author(s):  
N. N. Tupitsyn ◽  
N. A. Falaleeva ◽  
A. V. Mozhenkova ◽  
A. I. Pavlovskaya
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Follicular Lymphoma ◽  
Histological Study ◽  
Bone Marrow Involvement ◽  
International Prognostic Index ◽  
Prognostic Significance ◽  
Prognostic Index ◽  
Prognostic Role ◽  
Long Time

Background. Bone marrow is the mostfrequent metastatic site in follicular lymphoma, 40-70 % cases. It’s unfovourable prognostic role is stated in the index FLIPI-2 (Follicular Lymphoma International Prognostic Index-2). Objective. To study both prognostic role of bone marrow involvement and it’s relation to erythropoiesis peculiarities in follicular lymphoma was the purpose of this research. Materials and methods. Histological study was performed in 269 follicular lymphoma patients. Erythropoiesis peculiarities were studied in that patients according to standard myelogram analysis. Results. Bone marrow involvement was noted according to trephine biopsy section staining in 37,9 % of follicular lymphoma case (102 from 269). Bone marrow involvement did not influenced the prognosis (overall survival) in all period of observation (p = 0,18). Longterm survival (more than 48 months) was negatively influenced by bone marrow involvement (p = 0,04). Intertrabecular pattern of follicular lymphoma growth in bone marrow was negative prognostic factor (p = 0,02). We noted negative correlation between bone marrow involvement and the elevation of orthochromic normoblasts in bone marrow of patients with follicular lymphoma. In cause of bone marrow such elevation was noted in 67 %, and in the absense of involvement - in 78 % (p = 0,043). Elevation of orthochromic normoblasts did not influenced the overall survival of follicular lymphoma patients (p = 0,89). Conclusion. Bone marrow involvement in follicular lymphoma plays prognostically unfavourable role in long-time observation periods (later than 48 months). The most unfavourable are the intertrabecular patchy lesions. Involvement of bone marrow is in opposite relations to elevation of orthochromic normoblast, but the latter sign is of no prognostic significance.

scholarly journals Role of Bone Marrow Infiltration and POD 24 in Follicular Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5336-5336
Author(s):  
Silvia Rivas-Vera ◽  
Brenda Lizeth Acosta-Maldonado ◽  
Lizeth Elisua Estrada-Martínez
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Follicular Lymphoma ◽  
Conflicts Of Interest ◽  
Independent Predictor ◽  
Statistical Significance ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Bone Marrow Infiltration ◽  
Baseline Risk

Abstract Follicular lymphoma (FL) is the most common indolent lymphoma with a median survival approaching 20 years. However, there is significant clinical heterogeneity with subsets of patients experiencing transformation, early recurrence or refractory disease. Some authors found that progression of disease within 24 months of diagnosis, in patients treated with chemoimmunotherapy (POD24), is associated with poor overall survival (OS). OBJECTIVE Evaluate the POD24 as an early clinical endpoint in FL and evaluate FL international prognostic index (FLIPI), and other baseline risk factors at diagnosis for overall survival and relapse. METHODS We conducted a retrospective and observational study in which 160 patients with follicular lymphoma who received R-CHOP at National Institute of Cancerology, Mexico from 2011 to 2017. We analyze with Kaplan Meier curves, log rank test and logistic regression model. RESULTS We analyze 160 patients, median of age was 53 years (26- 88), with a female : male ratio of 1.17:1. In this group: 86% had hemoglobin >12 mg/dL, LDH was normal in 62%, 1-4 nodal areas were affected in 64%, 56% of patients had high FLIPI score, 27% had B symptoms and we found bone marrow infiltration in 30% of cases; grade 2 Follicular lymphoma was the most common histological subtype (40.5%). Most of patients achieved complete response (81%), 12% partial response after the first line therapy. Only 13 patients (8%) presents relapse. Sixty four percent received maintenance. Only 13 of patients relapsed, 10 after 24 months and only 3 in first 24 months from diagnostic (POD 24). Fig. 1 Overall survival in our population was 89% to 8 years, the factors with statistical significance in the bivariate analysis were the more nodal regions affected (1-4), high FLIPI score and POD 24 POD 24, adjusted to FLIPI score, was an independent predictor of survival in regression analysis (p<0.041, HR:35 IC 95% 1.15-1060.21). The bone marrow infiltration at diagnosis was the only independent predictor for relapse (p<0.007, HR: 6.9, IC 95% 1.7- 28.2). CONCLUSION: In our study group, POD 24, was an important predictor of overall survival, and bone marrow infiltration at diagnosis was the only predictor factor for relapse. Disclosures No relevant conflicts of interest to declare.

Rituximab Combined with Chemotherapy and Interferon in Follicular Lymphoma Patients: Final Analysis of the GELA-GOELAMS FL2000 Study with a 5-Year Follow-Up.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 792-792 ◽  
Author(s):  
Gilles Andre Salles ◽  
Nicolas Mounier ◽  
Sophie de Guibert ◽  
Franck Morschhauser ◽  
Chantal Doyen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Follicular Lymphoma ◽  
Chemotherapy Regimen ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Response To Therapy ◽  
Event Free Survival ◽  
Free Survival ◽  
Interferon Α2a

Abstract Background. The FL2000 study evaluated the combination of the anti-CD20 monoclonal antibody rituximab with chemotherapy plus interferon in the first line treatment of follicular lymphoma patients. Methods. Untreated follicular lymphoma patients (n=359) presenting with a high tumor burden were randomly assigned to receive either 12 courses of the chemotherapy regimen CHVP (cyclophosphamide, adriamycin, etoposide and prednisolone) plus interferon-α2a (CHVP+I arm) over 18 months or 6 courses of the same chemotherapy regimen combined with 6 infusions of 375 mg/m2 of rituximab and interferon for the same time period (R-CHVP+I arm). The primary endpoint of the study was event free survival and all results are shown as intent to treat. Results. Six months after treatment initiation, 156 out of 183 (85%) and 164 out of 175 (94%) patients had a response to therapy in the CHVP+I and R-CHVP+I study arm, respectively (P=.009). At the end of the 18 months treatment period, 59% and 75% of the patients were respectively in CR or CRu in the CHVP+I and R-CHVP+I arm (P<.05). After a median follow-up of five years, event-free survival (EFS) estimates were respectively 37% [95% C.I. 29 – 44] and 53% [95% C.I. 45 – 60] in the CHVP+I and R-CHVP+I arm (P=.0004). Response duration in CR/CRu or PR patients at the end of the 18 months treatment was also improved in the R-CHVP+I arm (P=.012). 5-year overall survival (OS) estimates were not statistically different in the CHVP+I (79%) [95% C.I. 72 – 84]) and R-CHVP+I (84% [95% C.I. 78 – 84]) arms. The Follicular Lymphoma International Prognostic Index (FLIPI) score allowed separation of the whole study population into 3 different risk categories with significantly different outcome for each group both for 5 year EFS and OS (P<.0001, respectively each). In a multivariate regression analysis, event free survival was significantly influenced by both the FLIPI score (HR=2.08; 95% C.I. [1.6 – 2.8]) and the treatment arm (HR=0.59; 95% C.I. [0.44 – 0.78]). In an exploratory analysis considering the 187 patients with a low/intermediate (<3) FLIPI score, the outcome according to each treatment arm was not statistically different while the benefit of the rituximab combination was highly significant in term of EFS (P=.0002) and OS (P=.025) in the 162 patients with a high (≥3) FLIPI score. Conclusions. These results extend our previous interim analyses and confirm that with a five year follow-up, the combination of rituximab with CHVP+I provides superior disease control in follicular lymphoma patients despite a shorter duration of chemotherapy. However, this combination appears to benefit essentially to high risk patients for whom overall survival is also significantly improved.

scholarly journals Cause of Death in Follicular Lymphoma in the First Decade of the Rituximab Era: A Pooled Analysis of French and US Cohorts

2019 ◽  
Vol 37 (2) ◽  
pp. 144-152 ◽  
Author(s):  
Clémentine Sarkozy ◽  
Matthew J. Maurer ◽  
Brian K. Link ◽  
Hervé Ghesquieres ◽  
Emmanuelle Nicolas ◽  
...  
Keyword(s):  
Overall Survival ◽  
Follicular Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Event Free Survival ◽  
Free Survival ◽  
International Prognostic Index Score ◽  
Treatment Related Mortality ◽  
Related Mortality

Purpose Although the life expectancy of patients with follicular lymphoma (FL) has increased, little is known of their causes of death (CODs) in the rituximab era. Patients and Methods We pooled two cohorts of newly diagnosed patients with FL grade 1-3A. Patients were enrolled between 2001 and 2013 in two French referral institutions (N = 734; median follow-up 89 months) and 2002 and 2012 in the University of Iowa and Mayo Clinic Specialized Program of Research Excellence (SPORE; N = 920; median follow-up 84 months). COD was classified as being a result of lymphoma, other malignancy, treatment related, or all other causes. Results Ten-year overall survival was comparable in the French (80%) and US (77%) cohorts. We were able to classify COD in 248 (88%) of 283 decedents. In the overall cohort, lymphoma was the most common COD, with a cumulative incidence of 10.3% at 10 years, followed by treatment-related mortality (3.0%), other malignancy (2.9%), other causes (2.2%), and unknown (3.0%). The 10-year cumulative incidence of death as a result of lymphoma or treatment was higher than death as a result of all other causes for each age group (including patients ≥ 70 years of age at diagnosis [25.4% v 16.6%]) Follicular Lymphoma International Prognostic Index score 3 to 5 (27.4% v 5.2%), but not Follicular Lymphoma International Prognostic Index score 0 to 1 (4.0% v 3.7%); for patients who failed to achieve event-free survival within 24 months from diagnosis (36.1% v 7.0%), but not for patients who achieved event-free survival within 24 months of diagnosis (6.7% v 5.7%); and for patients with a history of transformed FL (45.9% v 4.7%), but not among patients without (8.1% v 6.2%). Overall, 77 of 140 deaths as a result of lymphoma occurred in patients whose FL transformed after diagnosis. Conclusion Despite the improvement in overall survival in patients with FL in the rituximab era, their leading COD remains lymphoma, especially after disease transformation. Treatment-related mortality also represents a concern, which supports the need for less-toxic therapies.

Numbers of Lymphoma Associated Macrophages (LAMS) and Regulatory T-Cells (Tregs) in Follicular Lymphoma (FL) Patients (pts) Treated with and without Monoclonal Antibody (MoAb)-Containing Therapy Do Not Correlate with Overall Survival (OS): A Study from the Southwest Oncology Group (SWOG).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2602-2602
Author(s):  
John William Sweetenham ◽  
Eric Hsi ◽  
Bryan Goldman ◽  
Michael LeBlanc ◽  
Raymond R. Tubbs ◽  
...  
Keyword(s):  
Overall Survival ◽  
Follicular Lymphoma ◽  
Prognostic Value ◽  
Cox Regression ◽  
International Prognostic Index ◽  
Prognostic Significance ◽  
Prognostic Index ◽  
Continuous Variables ◽  
Hazard Ratios ◽  
Anti Cd20

Abstract Introduction: Conflicting results have been reported for the prognostic value of LAMs and Tregs in FL. A recent study from the SWOG suggested that survival for pts with FL has improved in the last 30 years, possibly due to the introduction of MoAb-based therapy. We examined the prognostic significance of LAMs and FOX-P3-positive Tregs using tissue microarrays (TMAs) from pts entered onto SWOG studies 8809 (no MoAb) and 9911chemotherapy followed by (including 131I-tositumomab). Pts & methods: Adequate tissue samples were identified from 87 pts on SWOG 8809 and 47 on 9911. Pt characteristics were as follows: 8809: median age - 47.4 yrs (26.1 – 69.4), male 53%, Follicular Lymphoma International Prognostic Index (FLIPI) score: 1–36%, 2–39%, 3–21%. 9911: median age - 49.9 (22.9 – 66.8), male-60%, FLIPI score: 1–36%, 2–45%, 9–19%. The pts with available tissue were comparable with those who did not have available tissue for clinical prognostic factors. Archival blocks were reviewed to confirm FL and to assess for preparation of TMAs containing two 1mm diameter cores per case. Automated immunostaining for CD68 (PGM1) and FOXP3 (236A/E7) was performed. Intrafollicular (IF) and extra follicular (EF) LAMs were quantitated by manual count (5 1000x high power fields [hpf]). FOXP3 was scored for pattern (follicular/perfollicular vs. other) and number/5 hpf .LAM and Treg numbers/patterns were correlated with OS Marker levels were categorized by medians, 3rd quartiles and as continuous variables. Survival differences by marker level/pattern were assessed within each study population by Cox regression. Results: Pt characteristics did not differ by SWOG study. Hazard ratios with 95% confidence intervals for OS according to FOX-P3 and CD68 staining are shown in table 1. LAMS were not associated with OS, except for IF LAMS in S9911. Levels or pattern of FOX-P3 staining were not associated with OS. Conclusion: Levels of LAMs and Tregs were not predictive of overall survival in FL pts on SWOG trials before and after the introduction of anti-CD20 radio-immunotherapy (RIT). While IF LAMs in pts receiving RIT may be associated with shorter OS, the number of cases/events is too small for firm conclusions. Further studies are required to determine the prognostic value of these biomarkers in FL patients receiving anti-CD20 MoAb-containing therapies. Hazard ratios (95% CI) for OS for biomarker levels S8809 S9911 Overall * p&lt;0.05 FOX-P3 (follicular vs other) 0.66 (0.29, 1.46) 0.95 (0.11, 8.10) 0.69 (0.33, 1.46) FOX-P3 (above median vs below) 1.30 (0.66, 2.58) 0.60 (0.11, 3.26) 1.16 (0.62, 2.17) EF LAM (above median vs below) 1.24 (0.59, 2.61) 0.70 (0.16, 3.11) 1.11 (0.56, 2.18) EF LAM (above 3rd quartile vs below) 1.12 (0.42, 2.94) 0.64 (0.13, 3.32) 0.96 (0.41, 2.23) IF LAM (above median vs below) 0.79 (0.35, 1.76) 5.33 (1.03, 27.51)* 1.22 (0.58, 2.57) IF LAM (above 3rd quartile vs below) 1.38 (0.62, 3.06) 2.24 (0.43, 11.56) 1.50 (0.72, 3.11)

MUM1 Expression in Follicular Lymphoma Is a Poor Prognostic Marker in Patients Treated with Immunochemotherapy (SWOG 9800/9911) but Not Chemotherapy Alone (SWOG 8809): A Southwest Oncology Group Correlative Science Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 376-376
Author(s):  
Eric D Hsi ◽  
Lisa Rimsza ◽  
Bryan H Goldman ◽  
James R. Cook ◽  
Raymond R. Tubbs ◽  
...  
Keyword(s):  
Immune Response ◽  
Overall Survival ◽  
Follicular Lymphoma ◽  
Tumor Cells ◽  
Prognostic Markers ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
The United States ◽  
Chemotherapeutic Agents ◽  
Rapid Progression

Abstract Background: Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma in the United States and is typically an indolent lymphoma with a relapsing/remitting course. The FL international prognostic index (FLIPI) predicts outcome in FL. However, some patients with a favorable FLIPI experience unexpectedly rapid progression and short survival. Biologic prognostic markers are needed for better stratification and markers of immune response predict outcome in patients treated with chemotherapy (CT). Therapy has evolved in recent years, with the routine addition of monoclonal antibody therapy to chemotherapeutic agents (immunochemotherapy, ICT). Because biologic prognostic markers may vary by treatment regimen, we evaluated biologic markers of the immune response (FOXP3, CD68) and tumor cells (MUM1) in patients treated with either CT (SWOG 8809) or ICT (SWOG 9800/9911). Methods: We constructed tissue microarrays with 181 available tissue blocks from SWOG 8809 (CHOP + interferon alpha; n=103) and SWOG 9800/9911 (CHOP+ rituximab/131I-tositumomab; n=30 and 48 respectively). Immunostains to enumerate regulatory T-cells (Tregs, FOXP3) and lymphoma associated macrophages (LAMs, CD68) were performed. FOXP3 was scored as positive cells/5 high power field (hpf) and by pattern (follicular/perifollicular vs evenly distributed). LAMs were scored as intrafollicular (IF) LAMs/5 hpf and extrafollicular (EF) LAMs/5 hpf. We also evaluated MUM1 expression in tumor cells based on single institution data suggesting MUM1/IRF4 expressing FL demonstrated an aggressive course (Kelley T et al 2007), using 20% positive cells as the cutoff. Associations between potential biomarkers and outcome were assessed using stratified Cox proportional hazards regression. Results: The median ages were 47.4, 54.8 and 49.8 yrs for S8809, S9800, and S9911, respectively. FLIPI score distributions for S8809 and S9911 were 0 (36%, 35%), 1(38%, 44%), and 2 (26%, 21%); FLIPI score was not available for S9800. S9800 patients were slightly older and S9911 patients were less likely to have elevated LDH than the other studies; otherwise, baseline clinical characteristics were similar across the study populations. The median and interquartile ranges for FOXP3+ cells, CD68 IF LAM, CD68 EF LAM were 169 (106–253), 68 (55–84), and 146 (120–188) respectively. 19.3% of cases showed a follicular/perifollicular pattern of FOXP3. MUM1 expression was seen in 14.4% of cases. Of the clinical variables available for all study populations, age &gt;60 years and LDH&gt;ULN were both associated with worse overall survival (OS, P&lt;.0001). As continuous or dichotomized values (above/below the mean values), LAMs or FOXP3+ cells were not associated with overall survival (OS) in either the entire cohort or in patients receiving IC. Likewise, FOXP3 pattern was also not associated with OS. However, MUM1 expression was associated with poor OS (hazard ratio [HR] 1.91, 95% confidence interval [CI] 1.06–3.46, P=.03). Interestingly, this effect was due entirely to the poor OS of MUM1+ FL in the ICT S9800/S9911group (HR 5.53, 95% CI 2.07–14.75, P=.0006). Conclusions: MUM1 is expressed in a subset (approximately 15%) of FL. In this series, MUM1 expression appears to identify a group of FL patients with shorter OS in the context of ICT. The biologic basis for this more aggressive behavior is unknown; however, because MUM1 controls expression of cytokines/chemokines involved in both B-cell proliferation and T-cell responses, it may have direct effects on tumor cells as well as tumor immune microenvironment.

Neither CD68+ Nor CD163+ Macrophages Are Associated with Decreased Survival in Follicular Lymphoma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3747-3747
Author(s):  
Di ta Gratzinger ◽  
Weiyun Ai ◽  
Robert Tibshirani ◽  
R. Levy ◽  
Y. Natkunam
Keyword(s):  
Overall Survival ◽  
Follicular Lymphoma ◽  
Cancer Progression ◽  
Initial Treatment ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Gene Expression Signature ◽  
Small Subset ◽  
Interval Time ◽  
Free Interval

Abstract Introduction: Tumor-infiltrating immune cells are thought to be important in the biology and clinical course of follicular lymphoma. Recently a gene expression signature associated with monocyte/macrophages was identified in follicular lymphoma patients with poor overall survival. One hypothesis is that macrophages may act to suppress the immune response to the lymphoma and thus decrease survival. A number of groups have assessed the prognostic value of enumerating tumor-associated macrophages (TAM) using immunohistochemistry for the macrophage marker CD68, with mixed results: some have shown poorer survival with increased CD68+ TAM, others have shown no effect, and others have shown poorer survival only in patients not treated with rituximab. CD68 is a sensitive marker of tissue macrophages which also shows reactivity with other cell types. CD163, by contrast, shows high specificity for the monocyte/macrophage lineage and is thought to be a marker for immunosuppressive M2-polarized macrophages. Methods: 187 follicular lymphoma patients underwent excisional lymph node biopsy prior to treatment. We enumerated extrafollicular and follicular CD163+ and CD68+ TAM in two high power fields (hpf) each of duplicate tissue microarray cores. The median age at diagnosis was 45 yrs, with a median follow-up of 8.8 yrs and 51 deaths. All but 6 patients had stage III/IV disease, 3 had stage I/II, and 3 were unknown. The histological grades are as follows: 112 grade 1, 65 grade 2, and 10 grade 3. FLIPI (follicular-lymphoma specific international prognostic index) scores are as follows: 33 low, 95 intermediate, 19 high, 40 unavailable. For their initial treatment regimen 120 patients received CVP +/− fludarabine; 42 received a variety of other chemotherapeutic regimens; and 9 patients received rituximab. Results: CD163 marks a subset of TAMs that is preferentially enriched in the extrafollicular compartment and that does not covary with numbers of CD68+ TAMs overall. CD163+ TAMs are significantly less frequent than CD68+ TAMs: 32 vs 88 TAM/hpf in the extrafollicular compartment (p = 5.89E-62) and 2.5 vs 29 TAM/hpf in the follicular compartment (p = 2.05E-62). Both CD163+ and CD68+ TAMs are enriched in the extrafollicular compartment (p = 5.39E-46 for CD163, p = 2.17E-81 for CD68); however this gradient is more marked for CD163+ than for CD68+ TAMs (7.6% of CD163+ TAM vs 24% of CD68+ TAM are follicular, p = 6.53E-43). There is no correlation between numbers of CD68+ and CD163+ TAM in the follicular (r2 = 0.05) or extrafollicular (r2 = 0.12) compartments. Furthermore, while CD68+ TAM content within follicles increases with grade (26/hpf in grade 1 vs 33/hpf in grade 2 follicular lymphoma, p = 0.01) there is no corresponding increase in CD163+ TAM within follicles (2.8/hpf in grade 1 vs 2.0 per hpf in grade 2 FL, p = 0.15). There was no association between TAM content and FLIPI. We found no statistical difference in overall survival with respect to either CD163+ or CD68+ TAM within follicles or in the extrafollicular compartment. Higher numbers of extrafollicular CD68+ macrophages are associated with longer initial treatment-free interval (time from diagnosis to initial treatment; z = −2.23, p = 0.026). This association is independent of FLIPI and grade (z = −2.94, p =0.0033). Higher numbers of extrafollicular CD163+ macrophages are associated with a longer second treatment-free interval (interval from first treatment to second treatment; z = −2.151, p = 0.031); this association is independent of FLIPI and grade (z = −2.151, p = 0.031). Conclusions: It has been suggested that CD68+ TAM are associated with poorer prognosis in follicular lymphoma; however we found no association with overall survival, and indeed a longer initial treatment-free interval, with increased CD68+ extrafollicular macrophages. CD163 is highly expressed in immunosuppressive M2-polarized macrophages, which are thought to provide an environment permissive to cancer progression. We found that CD163+ macrophages are a small subset of the total CD68+ macrophage count, are distributed differentially, and vary independently of CD68+ macrophage content, suggesting that CD163 highlights a functionally distinct macrophage subpopulation. However CD163+ macrophages, like CD68+ macrophages, were not associated with poorer overall survival and indeed were associated with a longer second treatment-free interval (time from first to second treatment).

Sign in / Sign up

Export Citation Format

Share Document