Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d'Etude des Lymphomes Folliculaires. Groupe d'Etude des Lymphomes de l'Adulte.

1997 ◽  
Vol 15 (3) ◽  
pp. 1110-1117 ◽  
Author(s):  
P Brice ◽  
Y Bastion ◽  
E Lepage ◽  
N Brousse ◽  
C Haïoun ◽  
...  
Keyword(s):  
Overall Survival ◽  
Follicular Lymphoma ◽  
Alkylating Agents ◽  
Intensive Therapy ◽  
Tumor Burden ◽  
Interferon Alfa ◽  
Response To Therapy ◽  
Response To Treatment ◽  
Survival Duration ◽  
Overall Response

PURPOSE To evaluate prospectively in patients with follicular lymphoma and a low tumor burden three therapeutic options: delay of any treatment until clinically meaningful progression, immediate treatment with an oral alkylating agent, or treatment with a biologic response modifier, interferon alfa-2b. PATIENTS AND METHODS Newly diagnosed follicular lymphoma patients with a low tumor burden (n = 193) were randomly assigned to one of three arms: arm 1, no initial treatment (n = 66); arm 2, prednimustine 200 mg/m2/d for 5 days per month for 18 months (n = 64); or arm 3, interferon alfa 5 MU/d for 3 months then 5 MU three times per week for 15 months (n = 63). Clinical characteristics were similar in the three arms. RESULTS Overall response rates with prednimustine and interferon alfa were 78% and 70%, respectively. The overall response to therapy, when deferred, was similar at 70%. With a median follow-up duration of 45 months after randomization, the median freedom-from-treatment (FFT) interval was 24 months in arm 1 and the interval of freedom from treatment failure (FFTF) was 40 months in arm 2 and 35 months in arm 3. The median overall survival time was not reached and the overall survival rate at 5 years was 78% in arm 1, 70% in arm 2, and 84% in arm 3. Therefore, deferred treatment does not adversely influence survival at 5 years. Patients who progressed within 1 year had a significantly shorter survival duration (median, 48 months). CONCLUSION Delayed treatment is feasible in patients with follicular lymphoma and a low tumor burden. For patients with early progression, more intensive therapy should be considered. For others, because delay of treatment until significant clinical progression does not seem to hamper the prognosis or subsequent response to treatment, the long-term toxicity of alkylating agents can be reduced.

Primary Extranodal Follicular Lymphoma: Clinicobiological Features and Outcome.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2456-2456
Author(s):  
Santiago Mercadal ◽  
Antonio Martinez-Pozo ◽  
Francesc Bosch ◽  
Eva Gine ◽  
Ana Muntanola ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Follicular Lymphoma ◽  
Histological Grade ◽  
Alkylating Agents ◽  
Stage Iv ◽  
Response To Therapy ◽  
Control Group ◽  
Significant Variable ◽  
Primary Origin

Abstract Follicular lymphoma (FL) is typically a nodal disease. Primary extranodal FLs, that represent less than 10% of the cases, might have differentiated clinicobiological features. The aim of the present study was to analyze the main clinicobiological characteristics, response to therapy and outcome of a series of patients with FL primarily extranodal in origin, and compare them with nodal FLs. Twenty two patients (12M/10F; median age, 59 years) with FL with primary origin in extranodal location diagnosed in a single institution during a 24-year period, with primary origin in extranodal location were the subject of the study. The control group was constituted by 212 patients with nodal FL diagnosed during the same period of time. Main clinicobiological features were recorded and analyzed. The sites of the primary disease were: skin, 5 cases; Waldeyer’s ring, 4; GI tract, 3; bone marrow, CNS and parotid (two cases each); and pancreas, thyroid, kidney and orbit (one case each). Main histological and clinical features are listed in the table. Treatment was given without considering the nodal or extranodal origin of the disease and consisted of: monotherapy with alkylating agents (38 cases), polychemotherapy (149), and fludarabine alone or with other drugs (14) and others, including surgery and observation (33). CR rate was higher in extranodal than in nodal FL (82% vs. 53%, respectively; p=0.02), but no differences were found in overall survival. FLIPI score was the most significant variable predicting overall survival in the global series as well as in either in nodal or extranodal FL. In conclusion, extranodal FL had some peculiar clinicobiological features with respect to nodal cases. Regarding the outcome, although patients with extranodal FL showed a higher CR rate, the overall survival was similar in both groups. Extranodal FL (N=22) Nodal FL (N=212) p Age (median, range) 59 (28–82) years 55 (24–93) years NS Sex (M/F) 12/10 100/112 NS Histological grade 3 (%) 12 10 NS CD10+(%) 85 90 NS Bcl2+ (%) 67 91 NS Bcl2/JH (%) 37 65 0.03 Stage IV (%) 50 64 NS Bone marrow + (%) 36 62 0.02 LDH > 450 IU/L (%) 15 24 NS B2-microglobulin > 2.3 mg/L (%) 7 41 0.058 High-risk FLIPI (%) 19 35 NS CR rate (%) 82 53 0.02 5-year OS (%) 75 74 NS 5-year FFS (%) 67 27 <0.02

The Prognostic Significance of the Absolute Lymphocyte to Monocyte Count Ratio (ALC/AMC-dx) at Diagnosis in Hodgkin´s Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2953-2953
Author(s):  
Brenda Lizeth Acosta-Maldonado ◽  
Ana Ramirez-Ibarguen ◽  
Flavio A Grimaldo-Gomez ◽  
Luis Oñate-Ocaña ◽  
Silvia Rivas-Vera
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Conflicts Of Interest ◽  
Independent Predictor ◽  
Prognostic Significance ◽  
Response To Therapy ◽  
Cutoff Point ◽  
Response To Treatment ◽  
Monocyte Count ◽  
Overall Response

Abstract Background. In Classic Hodgkin's lymphoma (cHL), malignant cells constitute only about 1% of the bulk of tumor tissue, the rest constitutes the microenvironment and is made up of a compound of inflammatory cells. Lymphocytopenia and increased CD68+ tumor-associated macrophages (TAMs) are adverse prognostic factors in cHL. TAMs are derived from circulating monocytes and are possibly related to absolute monocyte count (AMC). We have sought to investigate the relationship of circulating lymphocytes and monocytes with response and survival in patients. Recently, Porrata et al. reported that a low absolute lymphocyte count/absolute monocyte count at diagnosis [ALC/AMC-Dx] (<1.1) is an independent prognostic factor in cHL. Subsequent studies used different cutoffs for ALC/AMC (1.5 and 2.9). Currently, there are no studies that evaluate the usefulness of the index relative to the overall response. Aim To determine the prognostic value of ALC /AMC at diagnosis in patients with cHL and its impact on treatment response to therapy, progression and overall survival. Methods: We evaluated 262 consecutive individuals with cHL, referred and treated at the National Cancer Institute in Mexico between 2006 to 2013. The great majority of patients were treated with ABVD with or without radiotherapy, and all had available data for ALC/AMC determined at diagnosis. It was made a multivariate analysis and ROC curves for cutoff point of ALC/AMC. Results: Median age was 35 y (14-89), 59.2% of patients were male, 77% had B-symptoms, 36.3% had stage IV disease, 85% had advanced stage (IB,IIB,III,IV), 51.5% had IPS ≥3, 46.2% nodular sclerosing histology and 45.4% mixed cellularity. The overall response (CR + PR) was obtained in 188 patients (72%) and failure (stable disease or progressive disease) in 73 patients (28%). A new cutoff point, 1.77 in ALC/AMC-Dx ratio with area under the curve of 0.62. Multivariate analysis showed that the ALC/AMC-Dx index was an independent predictor for response to treatment, progression as well as overall survival (Table 1). Additionally the IPS≥3 showed to be an independent factor for response 68.8% vs 41.7% in low and high risk, respectively (p<0.0000). Conclusion: In our population ALC/AMC-Dx index was established with a cutoff of 1.77. The group of patient with < 1.77 had a less overall response and overall survival. It proves that ALM/AMC-Dx is an independent predictor of response, progression and overall survival in patients with classical cHL. That differs of other reviews where the cutoff was lower. Table 1. Multivariate analysis according to ALC/AMC-DX ratio ALC/AMC -Dx index p Low< 1.77 High >1.77 Overall Response 58.1% 79.8% OR 0.25-.0.84p 0.011 Overall Survival8 years 81% 94% p 0.004 Disclosures No relevant conflicts of interest to declare.

scholarly journals Drug resistance in multiple myeloma associated with high in vitro incorporation of 3H-thymidine

Blood ◽  
1981 ◽  
Vol 58 (3) ◽  
pp. 471-476
Author(s):  
V Hofmann ◽  
SE Salmon ◽  
BG Durie
Keyword(s):  
Multiple Myeloma ◽  
Tumor Regression ◽  
Alkylating Agents ◽  
Cell Mass ◽  
Bone Marrow Aspiration ◽  
Labeling Index ◽  
Response To Treatment ◽  
Survival Duration ◽  
Thymidine Uptake

In multiple myeloma, tumor cell mass and labeling index correlate with subsequent survival duration, but do not predict for response to treatment. In the present study was have autoradiographically measured the incorporation of 3H-thymidine as determined by the number of grains over the myeloma nuclei in bone marrow aspiration samples. In 33/37 patients with less than 50% tumor regression or progressive disease, the pretreatment grain count was greater than or equal to 20/myeloma nucleus. Conversely, values of less than 20 were found in 27/29 patients who had greater than or equal to 50% cell mass reduction. Survival duration was significantly better than (p less than 0.001) in patients with grain counts less than 20. Sixty percent of the patients with both a low labeling index (less than or equal to 3%) and grain count (less than 20) were alive at 48 mo, whereas 15/17 patients with a high labeling index and grain count had a median survival of less than 6 mo. In a subset of 22 patients, there as a significant correlation between in vitro resistance to melphalan, adriamycin, and vincristine as tested in the myeloma stem cell colony assay system and a grain count of greater than 20. We can only speculate as to the reasons for the increased 3H-thymidine uptake by myeloma cells resistant to treatment, however, it could be associated with accumulation of excess DNA and /or increased unscheduled DNA synthesis following injury from alkylating agents.

scholarly journals Drug resistance in multiple myeloma associated with high in vitro incorporation of 3H-thymidine

Blood ◽  
1981 ◽  
Vol 58 (3) ◽  
pp. 471-476 ◽  
Author(s):  
V Hofmann ◽  
SE Salmon ◽  
BG Durie
Keyword(s):  
Multiple Myeloma ◽  
Tumor Regression ◽  
Alkylating Agents ◽  
Cell Mass ◽  
Bone Marrow Aspiration ◽  
Labeling Index ◽  
Response To Treatment ◽  
Survival Duration ◽  
Thymidine Uptake

Abstract In multiple myeloma, tumor cell mass and labeling index correlate with subsequent survival duration, but do not predict for response to treatment. In the present study was have autoradiographically measured the incorporation of 3H-thymidine as determined by the number of grains over the myeloma nuclei in bone marrow aspiration samples. In 33/37 patients with less than 50% tumor regression or progressive disease, the pretreatment grain count was greater than or equal to 20/myeloma nucleus. Conversely, values of less than 20 were found in 27/29 patients who had greater than or equal to 50% cell mass reduction. Survival duration was significantly better than (p less than 0.001) in patients with grain counts less than 20. Sixty percent of the patients with both a low labeling index (less than or equal to 3%) and grain count (less than 20) were alive at 48 mo, whereas 15/17 patients with a high labeling index and grain count had a median survival of less than 6 mo. In a subset of 22 patients, there as a significant correlation between in vitro resistance to melphalan, adriamycin, and vincristine as tested in the myeloma stem cell colony assay system and a grain count of greater than 20. We can only speculate as to the reasons for the increased 3H-thymidine uptake by myeloma cells resistant to treatment, however, it could be associated with accumulation of excess DNA and /or increased unscheduled DNA synthesis following injury from alkylating agents.

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.

Has the Incidence of Extramedullary Disease Changed with the New Therapeutic Approaches? Analysis of a Cohort of 965 Multiple Myeloma (MM) Patients (pts).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4749-4749
Author(s):  
Marzia Varettoni ◽  
Alessandro Corso ◽  
Gianmatteo Pica ◽  
Patrizia Zappasodi ◽  
Silvia Mangiacavalli ◽  
...  
Keyword(s):  
Overall Survival ◽  
Median Time ◽  
Response To Therapy ◽  
Response To Treatment ◽  
High Dose ◽  
Solitary Plasmacytoma ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches ◽  
Over Time

Abstract Extramedullary myeloma (EMM) at diagnosis or during the course of the disease is rare and often anecdotal. We reviewed the records of 965 consecutive MM pts diagnosed and followed from 1969 to July 2007 in order to evaluate: the overall incidence of EMMs and the changes over time clinical presentation, response to treatment and outcome of EMM pts divided into two subgroups according to the time of appearance, at diagnosis or during the course of the disease. We considered three periods: 1969–1989 (conventional chemotherapy, CCT); 1990–1999 (introduction of high-dose therapy, HDT); 2000–2007, (era of novel agents). The overall incidence of EMM was of 13% (129/965 pts), 87/42 M/F, median age 58 (31–80) years. A prior MGUS was present in 24 pts and a solitary plasmacytoma in 10 (8%). Characteristics at the time of EMM were: 77 pts IgG (60%), 23 IgA (18%), 2 IgM (2%), 16 light chain (12%), 11 not secretory (8%); 29 pts were in stage I, 14 in stage II, 86 in stage III; 30/129 pts (23%) were asymptomatic. More frequently involved sites were: paravertebral (40%), rib cage (32%), pelvis (10%). Multiple localizations were present in 27 pts (21%). A plasmacytic leukemia was observed during the follow-up in 9 pts (7%). The overall median follow-up was 24.4 (2.5–148) months. Seventy-three pts presented EMM at the time of diagnosis with different incidences in the 3 periods: 1969–1989 4.5%, 1990–99 4.3%, 2000–07 12.7%. These pts were treated with HDT in 43 cases (59%) and CCT in 30 (41%). Radiotherapy (RT) was associated in 38 pts (52%). A partial response (PR) was achieved in 49 pts (67%). Progression or relapse were observed in 46 pts (63%) and the median time to progression (TTP) and overall survival (OS) in this subgroup of pts were 17.3 and 21.5 months respectively. The other 56 pts showed an EMM during the course of the disease after a median time of 20 (2–144) months from diagnosis. EMM incidence varied as follows: 1969–1989 2.7%, 1990–99 7.2%, 2000–07 7.4%. Median number of previous lines of therapy was 1 (range: 1–7), including HDT in 22 pts (39%), thalidomide or lenalidomide in 18 (32%), bortezomib in 5 (9%). The median time from HDT to EMM was 17 (2–125) months. Treatment of these pts consisted of CCT in 36 cases (64%), thalidomide in 3 (5%) and bortezomib in 8 (14%). RT was given in 29 cases (52%). Response rate in this subgroup was low, only 30% of pts obtained a PR. The median TTP and OS from the time of appearance of EMM were 4.7 and 6.5 months respectively and the overall survival from the diagnosis was 29.9 months. The two groups of EMM pts were also compared for all the clinical characteristics, response to therapy and outcome. EMM pts at diagnosis showed higher levels of monoclonal component and haemoglobin, and lower bone marrow plasmacytosis with respect to the others. OS from diagnosis was similar in the two groups. In conclusion, our study shows an increased incidence of EMM over time. The more recent increase of EMM at diagnosis might be due to the wider use of more sensitive imaging techniques as CT scan and magnetic resonance, while during the course of the disease after 1990 could be related to the longer survival of pts thanks to the new therapeutic approaches. Anyway, the presence of EMM whether at diagnosis or at progression seems to negatively affect the outcome of pts since the OS is shorter than MM pts without EMM.

Patterns of survival in patients with recurrent follicular lymphoma: a 20-year study from a single center.

1995 ◽  
Vol 13 (1) ◽  
pp. 140-147 ◽  
Author(s):  
P W Johnson ◽  
A Z Rohatiner ◽  
J S Whelan ◽  
C G Price ◽  
S Love ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Median Survival ◽  
Alkylating Agents ◽  
Disease Stage ◽  
Survival Duration ◽  
Median Survival Duration ◽  
Kaplan Meier ◽  
First Recurrence ◽  
New Treatments

PURPOSE To examine outcome of treatment for patients with recurrent follicular lymphoma. PATIENTS AND METHODS Two hundred twelve newly diagnosed follicular lymphoma patients were studied. One hundred seventy-nine were initially treated successfully. Recurrent or progressive lymphoma developed in 116. Treatment was given according to disease stage and current protocols, mostly with single alkylating agents. A policy of repeated lymph node and bone marrow biopsy was pursued. RESULTS The overall median survival duration was 9 years, with a median follow-up duration of 12 years. Following recurrence, the median survival duration was 4 1/2 years. Only eight of 116 patients with recurrent disease died of causes unrelated to lymphoma. The overall response rate to first re-treatment was 78% and showed slight decline with successive recurrences, reaching 48% after the fourth treatment. The median duration of second remission was 13 months, (v 31 months for first remission), with the only significant predictive factor being quality of remission. Multivariate analysis showed only age at recurrence and number of prior treatments to correlate with survival after first recurrence. Survival after second remission was only correlated with age and quality of response: Kaplan-Meier estimates gave 53% of patients reaching second complete remission alive 10 years later, compared with 28% in partial remission. CONCLUSION Age and previous and continuing responsiveness of follicular lymphoma to therapy are the principal determinants of survival following recurrence. Improvement in survival with new treatments will be demonstrated most readily in older patients, while more intensive approaches should be tested in younger patients in whom remission is achieved with difficulty.

Rituximab Added αIFN+CHVP Improves the Outcome of Follicular Lymphoma Patients with a High Tumor Burden: to First Analysis of the GELA-GOELAMS FL-2000 Randomized Trial in 359 Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 160-160 ◽  
Author(s):  
Gilles Andre Salles ◽  
Charles Foussard ◽  
Mounier Nicolas ◽  
Morschhauser Franck ◽  
Doyen Chantal ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Response Rate ◽  
Bone Marrow Involvement ◽  
Tumor Burden ◽  
High Response Rate ◽  
Response To Therapy ◽  
High Tumor Burden ◽  
Classical Association ◽  
Anti Cd20 ◽  
Ecog Ps

Abstract The monoclonal anti-CD20 antibody rituximab has been shown to induce a high response rate in follicular lymphoma patients and to improve the outcome when associated with CVP or CHOP in newly diagnosed patients. Rituximab synergy with αIFN has also been established in experimental and clinical studies. In order to investigate the benefit of rituximab when added to the classical association of αIFN with CHVP (cyclophosphamide 600 mg/m2, doxorubicin 25 mg/m2, etoposide 100 mg/m2 on day 1 and prednisone 40 mg/m2 day 1–5), the intergroup GELA-GOELAMS FL-2000 trial was initiated. Inclusion criteria consisted in untreated histologically proven stage II-IV follicular lymphoma (any grade) patients (18–75 years) with a high tumor burden consisting in the presence of at least one of the following criteria: B symptoms presence; ECOG PS≥1; LDH>normal value; β2-microglobulin≥3 mg/L; largest tumor≥7cm; three distinct nodes≥3cm; serous effusion, compression or symptomatic splenomegaly). Treatment in arm A consisted in CHVP (6 monthly courses + 6 courses every 2 months) associated with αIFN-2a (4.5 MU [reduced at 3 MU > 70 years] 3 times a week) for 18 months and in arm B in 6 monthly courses of CHVP associated with 18 months of αIFN-2a combined with 6 infusions of 375 mg/m2 rituximab (Day 1 and 8 course 3 & 4 ; day 1 courses 5 & 6). Patients were evaluated for response at 6 months and 18 months and followed every 3 months. From 05/2000 until 05/2002, 359 eligible patients were included (Arm A 175 pts and Arm B 184 pts) with the following characteristics: M/F =1; median age =60 years [25–75]; ECOG>1 =8%; B symptoms =27%; AA stage>II =87%; bone marrow involvement =58%; β2−m≥3mg/L =31%; LDH>N =37%; Hb≤12g/dL =18%; the FLIPI score was ≥3 in 56% of patients. This first analysis of all patients demonstrated a significant improvement of response to therapy in arm B as compared to arm A, both at 6 months [CR+CRru 49% vs. 76%; PR 36% vs. 18%; stable, progression or death 15% vs. 6%; respectively (P<.0001)] and at 18 months [CR+CRu 79% vs. 63%; PR 5% vs. 10%; stable, progression or death 17% vs. 27%; respectively (P=.004)]. With a median follow-up of 30 months, the median EFS was not reached in both arms and 104 patients presented an event. In the control arm, estimated 2.5 years EFS is of 62% versus 78% in arm B (P=.003). In conclusion, this first analysis indicate that 1) the control arm reproduces earlier results with the same regimen 2) rituximab associated with α-IFN+CHVP induces a higher response rate in high tumor burden FL patients; 3) rituximab addition to αIFN+CHVP allows to reduce the number of CHVP chemotherapy cycles and 4) this rituximab association with αIFN+CHVP results in a marked improvement of event-free survival comparing favorably to the control arm or to other rituximab+chemotherapy combinations.

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.

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