First-line Treatment Of Follicular Lymphoma Research Articles

Intensified Therapy Followed by Autologous Stem-Cell Transplantation (ASCT) versus Conventional Therapy as First-Line Treatment of Follicular Lymphoma

To define the treatment effect of intensified therapy followed by autologous stem-cell transplantation (ASCT) compared with conventional therapy as first-line treatment of patients with follicular lymphoma (FL) in terms of overall survival (OS) and event-free survival (EFS). Medline, Embase, the Cochrane controlled trials register and the Science Citation Index were searched. Four trials were identified, covering a total of 941 subjects. The random- effects summary Hazard Ritio (HR) comparing the treatment effect on OS between intensified and conventional therapy was 0.95 [0.70, 1.30] (P=0.75), indicating that no additional survival benefit was derived from the intensified therapy followed by ASCT. A significant benefit of intensified therapy followed by ASCT as first-line treatment was detected in terms of EFS: the random-effects summary HR (intensified versus conventional therapy) was 0.59 [0.44, 0.79] (P<0.001). In conclusion, despite its superior EFS, intensified therapy followed by ASCT does not improve OS compared with conventional therapy.

Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial

Patients with follicular lymphoma can have long survival times, but disease progression typically occurs 3-5 years after initial treatment. We assessed the potential benefit of 2 years of rituximab maintenance after first-line treatment in patients with follicular lymphoma receiving a rituximab plus chemotherapy regimen. The randomised, open-label PRIMA study was undertaken in 223 centres in 25 countries. 1217 patients with previously untreated follicular lymphoma needing systemic therapy received one of three non-randomised immunochemotherapy induction regimens used in routine practice. 1019 patients achieving a complete or partial response were then randomly assigned to receive 2 years of rituximab maintenance therapy (375 mg/m(2) every 8 weeks) or observation. Treatment was assigned equally by centralised block randomisation, stratified by induction regimen, response, region, and centre. Neither the participants nor those giving the interventions, assessing outcomes, and analysing data were masked to group assignments. The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00140582. 505 patients were assigned to rituximab maintenance and 513 to observation (one patient died during randomisation). With a median follow-up of 36 months (IQR 30-42), PFS was 74·9% (95% CI 70·9-78·9) in the rituximab maintenance group (130 patients progressed) and 57·6% (53·2-62·0) in the observation group (218 progressed; hazard ratio [HR] 0·55, 95% CI 0·44-0·68, p<0·0001). 2 years after randomisation, 361 patients (71·5%) in the rituximab maintenance group were in complete or unconfirmed complete response versus 268 (52·2%) in the observation group (p=0·0001). Overall survival did not differ significantly between groups (HR 0·87, 95% CI 0·51-1·47). Grade 3 and 4 adverse events were recorded in 121 patients (24%) in the rituximab maintenance group and 84 (17%) in the observation group (risk ratio 1·46, 95% CI 1·14-1·87; p=0·0026). Infections (grades 2-4) were the most common adverse event, occurring in 197 (39%) and 123 (24%) patients, respectively (risk ratio 1·62, 95% CI 1·35-1·96; p<0·0001). 2 years of rituximab maintenance therapy after immunochemotherapy as first-line treatment for follicular lymphoma significantly improves PFS. Groupe d'Etude des Lymphomes de l'Adulte (GELA) and F Hoffmann-La Roche.

Rituximab Plus Chlorambucil Compared with Chlorambucil and Prednisone In Patients with Untreated Follicular Lymphoma

AbstractAbstract 3956 Background:Recently in large randomized studies, the addition of Rituximab to standard chemotherapy in the first-line treatment of follicular lymphoma (FL) demonstrated improvements in long-term outcome in FL. Methods:We compared the outcome of 111 naive FL patients (pts) treated at our institution from 1995 to 2009 with a single alkylating agent in combination or not with Rituximab: 58 pts received Chlorambucil plus Rituximab (R-Chl) and 53 pts Chlorambucil and prednisone (Chl+PDN). The 2 schedules included an induction phase, where Chlorambucil was given at 6mg/mq for 6 consecutive weeks in both groups and the Rituximab in 4 weekly administrations. The maintenance phase was longer in the Chl+PDN group: Chlorambucil was administered 6mg/mq daily 14 days each month for a total of 12-months of treatment versus 14 days with monthly-Rituximab for 4 consecutive months in the R-Chl group. Results:The demographic and prognostic factors are reported in Table 1.R-Chlorambucil (58 pts)Chlorambucil+prednisone (53 pts)Sex (n° M)2819Median age (range)56 yrs (29–79)53 yrs (28–93)Ann Arbor Stage III–IV44 (76%)30 (57%)Grading 1–2462336652 evaluble pts36 evaluable ptsFLIPI 0–1312521411>210355 evaluable pts39 evaluable ptsAt the end of treatment the ORR was 98% in the R-Chl pts and 77% in the Chl+PDN group, with a percentage of complete response of 79% and 55% respectively. No significant incidence of adverse events were reported and only one HBsAg positive patient in R-Chl group discontinued the therapy. One case of myelodysplastic syndrome was described in a Chl+PDN relapsed patient. With a median follow up of 34 months, the OS and the EFS in R-Chl pts is 95% and 76% respectively. Otherwise, with a median observation time of 82 months in the Chl+PDN group 73% are alive and only 28% of pts maintained the response. The median time to subsequent therapy (TTST) is 21 and 15 months respectively in the 2 groups. Conclusions:The addition of Rituximab to alkylating in first-line treatment in previously untreated FL pts improves significantly the EFS and prolongs the time to next antilymphoma therapy compared with alkylating alone. Because of its low toxicity profile, our combination with Rituximab and Chlorambucil could be considered a first-line therapy, especially in FL patients not eligible for aggressive chemotherapy regimens. Disclosures:No relevant conflicts of interest to declare.

Phase II study of short course CHOP-rituximab followed by 90-y ibritumomab tiuxetan as first-line treatment for follicular lymphoma: Extended follow-up and predictors of relapse.

8066 Background: We previously reported complete response rate (CR) of 89% in 60 patients with stage II-IV symptomatic or bulky follicular lymphoma(FL) who received a short-course CHOP-rituximab (R) × 3 cycles followed by ibritumomab tiuxetan (IT) and extended R as first-line treatment. (Clin Cancer Rsrch. 2008;14(21):7088-7094) This abstract will update the response rate at median follow-up of 45 months (range 30-60 months). Methods: Determination of response and duration of response included a fusion [18F] fluorodeoxyglucose (FDG)-positron emission tomography (PET)-computed tomography (CT) imaging performed at baseline, after the third cycle of CHOP-R, 12 weeks after RIT, then at 6-month intervals for the first three years, and then yearly or at physicians' discretion. Results: Of the 60 enrolled patients, 55 completed all protocol therapy. 54 patients are available for evaluation. The CR rate for all enrolled patients by PET-CT is 59%. To date, 22(41%) patients have relapsed at 7.8-55 months. Of the 32 patients with bone marrow involvement, 17 patients had relapses, while of the 22 patients with no bone marrow involvement, only 5 relapsed. 20 of 36 patients with bulky disease have relapsed compared to 2 of 18 patients with non-bulky disease. 9 of 18 patients (50%) with a positive PET scan after CHOP-R have relapsed compared to 13 relapses of 36(36%) patients with a negative PET scan after CHOP-R. 12 of 25 (48%) patients with FLIPI score ≥3 have relapsed compare to 10 of 29 patients (34%) with FLIPI score <3. Six patients have been diagnosed with a second malignancy. None of the patients developed myelodysplastic syndrome or acute myeloid leukemia. Conclusions: Short course CHOP-R followed by IT and extended R results in high CR rate. After median follow up of 45 months, 59% patients still remain in clinical remission. However, despite achieving a CR after initial therapy, positive bone marrow involvement (p=0.03) and bulky disease (p<0.001) at baseline are predictive of relapse. Further evaluation of the molecular marker, Fc gamma receptor genotyping, is planned as potential predictor of outcome. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Zevalin

Quantitative Real-Time PCR of Peripheral Blood t(14;18) Positive Cells Predicts Treatment Response and Long-Term Outcome in Patients with Follicular Lymphoma.

Abstract 441 Introduction:By means of standard chemotherapy advanced stage follicular lymphoma (FL) is an incurable disease. Clinical courses are characterized by a continuous tendency to relapse caused by residual neoplastic cells. Quantitative polymerase chain reaction (qPCR) to detect lymphoma cell that carry the t(14;18) translocation is a suitable method to measure minimal residual disease (MRD) in patients with FL. Despite several reports dealing with MRD qPCR in FL, its role in the clinical management of patients is still not clearly defined. Therefore, we carried out a multicenter study, to assess the prognostic value of sequential quantitative MRD detection in first-line treatment of FL using an improved version of a LightCycler based qPCR specific for the major breakpoint region (MBR) positive IgH/bcl2 translocation, provided by Roche Diagnostics® (Penzberg Germany). Patients and Methods:We analysed 718 blood (PB) samples of 179 patients with newly diagnosed FL treated within the multicenter randomized trial NHL1, conducted by the German StiL group (Study group indolent Lymphomas), comparing 6 cycles of R–CHOP versus R–Bendamustin (R-B). Samples were taken at diagnosis, after 6 cycles of either R–CHOP or R–B immuno-chemotherapy and every three months during follow-up. All samples were analyzed in the department of Hematology at Heinrich-Heine University in Duesseldorf. Results:At diagnosis, 112 out of 179 patients (62.6%) were positive for IgH/bcl2 within the MBR in the peripheral blood. Significantly higher amounts of bcl2/IgH positive cells were found in patients with bone marrow infiltration (p=0.012) and depending on the number of lymphatic nodes (LN) with disease involvement (>3 LN p=0.003; >5 LN p=0.0009; >7 LN p=0.022). Overall, a remarkable inter-individual variation of bcl2/IgH positive cells in the PB at diagnosis, reflected by ratios from 0.000281 to 81, was found. The estimated event free survival (EFS) at 2 years of patients who presented at diagnosis low to normal amounts of bcl2/IgH positive cells in the PB (ratio < 2, n=83) was 82% (SE 0.045), which was significantly better than the 47% (SE 0.11) observed in patients showing the highest amount of bcl2/IgH positive cells (ratio >2, n=24) in the PB (p=0.003). By univariate and multivariate analysis, we found that the amount of bcl2/IgH positive cells in the PB at diagnosis (p=0.001) as well as the achievement of a negative MRD status after therapy (p=0.0001) were significant predictors for relapse free survival. Monitoring of MRD levels before and after therapy revealed that 6 cycles of immuno-chemotherapy significantly reduced the amount of bcl2/IgH positive cells in the PB compared with pre-treatment MRD levels (p=0.0001; median bcl2/IgH/tPA ratio: before treatment 0.0734, range: 0.000281–81, after treatment negative, range: negative–0.17). After treatment, 86% of the patients (n=82) achieved a molecular remission in the PB defined as qPCR negative, whereas 14% (13 patients) remained PCR positive. Not reaching a molecular remission in the PB at the end of therapy had a significant negative influence on PFS. After a median follow-up of two years, patients who remained MRD positive in the first measurement after therapy had a significant lower PFS than MRD negative patients (p=0.0001; 9 months vs. not reached). There was no significant difference in the degree of tumor cell depletion in the PB induced by the two different regimens. So far, 539 follow-up samples from 3 up to 39 months after therapy were analyzed. Patients with a consistent negative MRD status throughout follow-up showed a trend towards longer PFS. After 38 months follow-up, MRD positive patients had a PFS of 54% compared to 78% in the group of MRD negative patients (p=0.066). Conclusion:QPCR for the t(14;18) performed at diagnosis and during follow-up on PB samples predicts treatment response and long-term clinical outcome of patients with FL. Disclosures:Zohren:Roche: Honoraria, Research Funding. Rummel:Roche Pharma AG: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Amgen: Honoraria. Kobbe:Roche: Research Funding.

Rituximab maintenance after R-CHOP in the first-line treatment of follicular lymphoma: A GOTEL phase II trial

e19502 Background: Rituximab maintenance have demonstrated improvements in progression-free and overall survival in relapsed patients with follicular lymphoma (FL). Ongoing trials are evaluating the benefit of rituximab maintenance following treatment of therapy-naive patients (pts) treated with rituximab-containing chemoinmunotherapy induction regimens. Methods: The current study evaluated the activity and toxicity of rituximab maintenance after chemoinmunotherapy in the first line treatment of advanced-stage FL. Pts with advanced stage FL were eligible. The induction treatment consisted in 8 courses of chemoinmunotherapy with R-CHOP (rituximab 375 mg/m2; cyclophosphamide 750 mg/m2; doxorubicin 50 mg/m2 and vincristine 2 mg). Pts entering a complete (CR) or partial remission (PR) received maintenance with 6 doses of rituximab (375 mg/m2/d) to be given every two months after the end of induction therapy. Results: From December 2004 to November 2006, 52 pts were included. Median age was 52 years (range, 36–85) and 26 pts were women. At baseline 32 (62%) pts had stage IV and 20 (38%) stage III. According to the Follicular Lymphoma International Prognostic Index (FLIPI), 8 pts (15%) had low risk disease, 24 pts (46%) intermediate risk, and 20 pts (39%) high risk disease. Six (12%) pts did not receive maintenance (3 pts progressed during induction, 2 pts refused maintenance and 1 pt had severe toxicity to induction). Of the 46 pts included in the maintenance phase, 32 (69%) were in CR/CRu and 14 pts (31%) in PR after induction therapy. Rituximab was well tolerated in the maintenance phase. Only 5 pts didn´t receive the 6 scheduled courses (toxicity: 1; progressive disease: 2; cardiovascular events: 2). Grade 3–4 toxicity occurred as follow: neutropenia in 4 pts (9%), and fever in 1 pt (2%). No severe infections were seen. After maintenance, 40 (87%) pts were in CR/CRu, 4 pts (9%) in PR and 2 (4%) progressed. With a median follow-up of 27 months, progression-free and overall survival at 30 months were 82% and 92%, respectively. Conclusions: Rituximab maintenance after first-line R-CHOP is safe and increase the complete remission rate obtained in the induction phase. No significant financial relationships to disclose.

Phase II Study of Short Course CHOP-Rituximab Followed by 90-Y Ibritumomab Tiuxetan as First-Line Treatment for Follicular Lymphoma: An Update and Extension of Preliminary Findings on Predictors of Relapse.

Sequential treatment with chemotherapy and radioimmunotherapy (RIT) results in overall response rates > 90% in untreated follicular lymphoma (FL). We previously reported a complete response rate (CR) of 89% in 60 patients with stage II–IV symptomatic or bulky FL who received a short-course CHOP-Rituximab (R) x 3 cycles followed by Ibritumomab Tiuxetan (IT) and extended R as first-line treatment in Clinical Cancer Research (in press). This report will update the CR and progression-free survival (PFS) at a median follow-up of 27.1 months (range 0.9–46.1 months). Determination of response and duration of response included a fusion [18 F] fluorodeoxyglucose (FDG)-positron emission tomography (PET)-computed tomography (CT) imaging performed at baseline, after the third cycle of CHOP-R, 12 weeks after RIT, then at 6-month intervals for the first three years, and then yearly or at physicians' discretion. Of the 60 enrolled patients, 55 completed all protocol therapy. The continuous CR rate for all enrolled patients by PET-CT is 73%. The median PFS for all enrolled patients is 38.3 months. To date, 11(18%) patients have relapsed at 7.8–38.3 months. Ten of 11 relapses were among the 35 patients who had positive bone marrow biopsies (28.6%) compared to 1 relapse among the 25 (4.0%) with negative biopsies. Eight of 18 patients with a positive PET scan after CHOP-R have relapsed compared to only 3 relapses of 37 patients with a negative PET scan after CHOP-R. Nine of 10 available relapse tissue biopsies showed FL, and one showed transformation to a diffuse large B-cell lymphoma. Seven patients have been diagnosed with a second malignancy: 1 uterine cancer, 1 colon cancer, 1 prostate cancer, 1 breast cancer, 1 lung cancer, 1 pancreatic cancer, and 1 T-cell lymphoma. There have not been any cases of myelodysplastic syndrome or acute myeloid leukemia. Conclusions: Short course CHOP-R followed by IT and extended R results in high CR rate. However, despite achieving a CR after IT, positive bone marrow involvement at baseline (p<0.001) and residual PET positivity after 3 cycles of CHOP-R (p=0.003) were predictive of early relapse. These predictors of early relapse may be utilized in the design of future clinical trials.Relapsed PatientGradeStageFlipi RiskBulk (cm)Bone MarrowPet Post CHOPPet Post RITTime (months) to ProgressionRelapse Biopsy12IV23.4+PosNeg13.5Follicular22IV35.8+PosNeg21.8Follicular33IV214+PosNeg31.2Follicular43IV313.5+PosPos7.8Follicular52III27.1–PosNeg38.3Follicular61IV34.8+NegNeg27.8Follicular71IV36+NegNeg17.2Follicular8N/AIV34.2+NegNeg20.0N/A92IV47.4+PosPos13.6Large Cell101IV27+PosNeg14.0Follicular112IV33.8+PosNeg9.3Follicular

Phase II study of short course CHOP-rituximab (R) followed by ibritumomab tiuxetan (IT) as first-line treatment for follicular lymphoma (FL)

8005 Background: Therapy with CHOP-R and radioimmunotherapy (RIT) is a promising treatment for untreated FL. Press reports complete responses (CR) of 69% in FL patients (pts.) with 6 cycles of CHOP followed by I-131 tositumomab. We report efficacy and safety using 3 cycles of CHOP-R followed by IT and extended R. Methods: Eligibility criteria include symptomatic or grade 3 untreated FL. 60 pts. have been accrued and 47 evaluated. The treatment consists of two phases: CHOP-R for 3 cycles followed by IT. One week after IT, pts receive R weekly × 4. Bone marrow (BM) biopsies and fusion PET-CT scans are obtained at baseline, after CHOP-R, and 12 weeks post RIT. The primary endpoint is CR rate. CR requires a neg. PET scan and conventional Working Group criteria. Results: Toxicity data are available for 47 pts of median age 56 (range, 39–78), 44 of whom completed both phases of therapy and are evaluated for response. Characteristics and CR rates after IT are shown: 3 pts. did not receive RIT (1 second malignancy, 1 non-compliance, 1 septic death). Of the 44, CR after CHOP-R is 41%. After IT, CR improved to 89%. Of the 5 pts who did not achieve CR, 3 had neg. PET scans (2 with PR, 1 with SD by CT), and 2 had residual disease by PET with PR by CT. At a mean follow-up of 16 months (range, 6–33 months), there are 4 relapses: 3 who achieved CR by PET-CT, 1 with PR by PET-CT. Toxicity was predominantly myelosuppression. There was 1 episode of febrile neutropenia after RIT. Conclusions: 3 cycles of CHOP-R followed by IT and R achieve a high CR in previously-untreated pts. with FL. Addition of RIT increased CR from 41% to 89%. Data will be presented on the affect of bulky disease, positive BM, grade 2 or 3 histology, and high FLIPI score on CR. Further follow-up is necessary to evaluate response duration and determine whether there is a correlation with early or late CR. [Table: see text] [Table: see text]

A Phase IIIb Study of Rituximab Maintenance Therapy in Patients with Follicular Non-Hodgkin's Lymphoma Who Have Responded to Induction Therapy - MAXIMA-Protocol.

Five randomized trials (four Phase III and one phase II) have confirmed that rituximab maintenance therapy provides clinical meaningful improvements in terms of Progression Free Survival, Event Free Survival and response duration for patients. Two studies have also found an overall survival advantage for rituximab maintenance therapy (Hoechster et al. 2005, van Oers et al. 2005) and a third study could demonstrate a strong trend towards overall survival advantage (Dreyling et al. 2006). A Cochrane meta-analysis of several randomised Phase III trials (Schulz et al. 2005) demonstrated that rituximab plus-chemotherapy for first-line treatment of Follicular Lymphoma is superior to chemotherapy alone and significantly prolongs overall survival. To further broaden the available basis for maintenance treatment in the first-line and relapsed setting, the MAXIMA (MAintenance rituXImab in Follicular LymphoMA) trial has been started in August 2006 and will last 5 years. Patients with first line or relapsed/refractory advanced Follicular Lymphoma are included in this trial. In total 500 patients are planned for this international trial running in 23 countries.Patients who achieve a Complete Remission, Complete Remission unconfirmed or Partial Remission after rituximab containing induction therapy (rituximab with or without chemotherapy) are eligible to enter the study to receive rituximab maintenance therapy administered at the standard dose of 375 mg/m2 every 2 months for 2 years. This regimen is also investigated in the ongoing PRIMA study, and also in an ongoing SAKK study which investigates the benefit of rituximab maintenance therapy for up to five years.The previous five randomized trials did not detect significant safety issues for rituximab maintenance therapy. The main objective of the MAXIMA trial is to confirm this safety data in a wider patient population.Secondary objectives of the study include standard time dependent parameters (PFS, EF, OS). In addition, the effect of rituximab maintenance therapy on improving response quality (PR =>CR) after induction therapy will be evaluated.

Rituximab plus CVP chemotherapy vs. CVP alone as first-line treatment for follicular lymphoma: Treatment effect according to baseline prognostic factors

6525 Background: In patients with advanced previously untreated follicular lymphoma (FL), the addition of 8 cycles of rituximab to standard CVP (cyclophosphamide, vincristine, prednisone) chemotherapy (R-CVP) resulted in highly clinically and statistically significant improvements in major clinical endpoints compared with CVP alone, without increased toxicity (Marcus R et al. Blood 2004; Epub ahead of print). Median time to progression (TTP) was 32 vs 15 months for R-CVP and CVP, respectively (p< 0.0001). Treatment efficacy according to baseline risk factors had to be analyzed. Methods: A multivariate Cox regression analysis of TTP following the intention-to-treat principle was performed to assess the benefit of R-CVP on patient subgroups according to baseline prognostic factors. Results: 321 patients were randomized; the majority had intermediate or high risk disease according to the Follicular Lymphoma International Prognostic Index (FLIPI) (126 patients with FLIPI 2; 146 patients with FLIPI > 3). Patients in both prognostic groups who received R-CVP achieved significantly longer TTP (Table 1) than those who received CVP chemotherapy alone (p< 0.0001). The same observation was made if patients were scored according to the IPI. R-CVP significantly prolonged TTP compared to CVP regardless of histologic subtype of FL (IWF classes B, C, D), presence of B symptoms or bulky disease (p< 0.05 for all). The impact of Hemoglobin levels was also analyzed. The only subgroup where the difference between R-CVP and CVP was not significant is the group of patients with Hb < 12 g/dl. Conclusions: The addition of 8 cycles of rituximab to CVP chemotherapy as first-line treatment in FL significantly improves clinical outcomes, irrespective of baseline patient or disease characteristics, without adding toxicity. The R-CVP regimen may overcome adverse prognostic factors in previously untreated patients with FL. Table 1.Median TTP according to baseline prognostic factors Prognostic factor CVP n CVP median(months) R-CVP n R-CVP median (months) p value FLIPI score 2 65 17 61 39 <0.0001 3–5 75 12 71 26 <0.0001 B 46 17 38 32 0.0021 IWF class C 69 15 82 36 <0.0001 D 19 14 19 38 0.0023 B-Symptoms Yes 51 16 65 39 0.01 No 108 14 97 32 <0.0001 Bulky disease Yes 73 12 63 36 <0.0001 No 86 16 99 32 <0.0001 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Roche

High-dose therapy followed by autologous purged stem-cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by GOELAMS

AbstractDoxorubicin-based immunochemotherapy, with interferon, has been shown to improve survival in patients with advanced follicular lymphoma. High-dose chemotherapy with stem-cell support is effective in follicular lymphoma in relapse but remains controversial as a first-line therapy. In a randomized study using a purged autologous stem-cell support, we compared these 2 approaches in patients with advanced follicular lymphoma. Newly diagnosed advanced follicular lymphoma patients (172 patients) were randomly assigned either to an immunochemotherapy regimen (cyclophosphamide, doxorubicin, teniposide, prednisone, and interferon) or to a high-dose therapy followed by purged autologous stem-cell transplantation. Compared with the patients who received chemotherapy and interferon, patients treated with high-dose therapy had a higher response rate (69% vs 81%, P = .045) and a longer median event-free survival (not reached vs 45 months). This did not translate into a better survival rate due to an excess of secondary malignancies after transplantation. The Follicular Lymphoma Prognostic Index identified a subgroup of patients with a significantly higher event-free survival rate after high-dose therapy. Autologous stem-cell transplantation cannot be considered as the standard first-line treatment of follicular lymphoma for patients younger than 60 years old with a high tumor burden.

The Role of Mitoxantrone in the Treatment of Indolent Lymphomas

With the introduction of newer therapeutic approaches, survival in indolent non-Hodgkin's lymphoma (NHL) appears to be improving. Mitoxantrone (Novantrone; Serono, Inc.; Rockland, MA, http://www.seronousa.com), an anthracenedione with low cardiotoxic potential, has demonstrated activity in indolent NHL in combination with fludarabine (Fludara; Berlex Laboratories; Wayne, NJ, http://www.berlex.com) and other agents. In a Southwest Oncology Group trial (SWOG 9501), treatment with fludarabine and mitoxantrone (FM) induced a complete remission (CR) rate of 44% and a partial remission (PR) rate of 50% in untreated patients. The estimated 4-year progression-free survival (PFS) rate was 38%. In a multicenter Italian trial comparing the efficacy of FM with that of cyclophosphamide, doxorubicin (Adriamycin; Bedford Laboratories; Bedford, OH, http://www.bedfordlabs.com), vincristine (Oncovin; Eli Lilly and Company; Indianapolis, IN, http://www.lilly.com), and prednisone (Deltasone; Pfizer Pharmaceuticals; New York, NY, http://www.pfizer.com), CHOP, followed by rituximab (Rituxan; Genentech, Inc.; South San Francisco, CA, http://www.gene.com) for patients with incomplete clinical or molecular responses, the CR and molecular response rates were significantly higher in the FM arm, but the PFS and overall survival (OS) rates did not differ between the two arms. However, FM was also significantly less toxic than CHOP. The administration of rituximab following chemotherapy resulted in higher clinical and molecular response rates in both arms. In a separate trial, FM plus dexamethasone (Decadron; Merck and Co., Inc.; Whitehouse Station, NJ, http://www.merck.com), FND, plus concurrent rituximab produced a CR rate of 92%. In a randomized German study, patients with indolent lymphomas received FM plus cyclophosphamide (FCM) or FCM with rituximab. PFS and OS times were significantly better for patients who received combined chemoimmunotherapy. Mitoxantrone-based regimens are highly active and well tolerated in patients with both relapsed and previously untreated indolent lymphomas. The addition of rituximab appears to increase the activity of the FM, FND, and FCM regimens. Although the results of the Italian multicenter study support the superiority of FM over CHOP in terms of clinical and molecular responses and tolerability, additional studies using rituximab in combination with both of these regimens should be attempted to determine the possible further benefit of both in the management of indolent lymphoma. Because cure remains elusive in patients with indolent lymphoma, maximum prolongation of PFS with minimal toxicity and maximum preservation of quality of life should remain central goals of treatment.

The role of fludarabine in the treatment of follicular and mantle cell lymphoma.

Advanced-stage follicular lymphoma (FL) and mantle cell lymphoma (MCL) cannot be cured using conventional chemotherapy. Fludarabine, the most widely used purine analog, exhibits a particularly high level of activity against small lymphocytic lymphoma and chronic lymphocytic leukemia (CLL). Numerous studies have investigated the efficacy of fludarabine as a single agent or in combination with other cytostatic compounds in the treatment of FL and MCL. Hematologic toxicity is the most commonly observed adverse event in patients treated with fludarabine, but serious infectious complications are relatively rare. Fludarabine monotherapy has proven to be particularly effective in the treatment of FL; however, complete responses (CRs) are observed in only approximately 20-40% of all cases. In contrast, combinations containing fludarabine and anthracyclines or alkylating agents have yielded superior response rates and longer periods of progression-free survival (PFS), and the addition of the anti-CD20 antibody rituximab appears to yield even better results. In a randomized trial, an immunochemotherapy regimen consisting of a fludarabine-containing combination and rituximab resulted in superior remission and survival rates compared with the fludarabine-containing combination alone. In summary, fludarabine has proven to be a safe and effective agent in the treatment of indolent lymphoma. In particular, combinations containing fludarabine, anthracyclines and/or alkylating agents, and rituximab have yielded remarkable CR and PFS rates. Consequently, current research efforts have focused on the use of fludarabine-containing combinations in the first-line treatment of FL and MCL.