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Keywords:

  • follicular lymphoma;
  • high tumor burden;
  • fludarabine-based combination;
  • immunochemotherapy

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

BACKGROUND:

This phase 2 trial was undertaken to evaluate the efficacy and safety of rituximab combined with intravenous fludarabine and mitoxantrone (R-FM) for patients with recurrent/refractory follicular lymphoma who had high tumor burden according to Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria.

METHODS:

Fifty patients were enrolled who had received a maximum of 2 previous regimens, including 1 cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)/CHOP-like regimen but no previous exposure to rituximab, fludarabine, or mitoxantrone. At baseline, 58% of patients had bulky disease (lesion >7cm), 56% had high-risk Follicular Lymphoma International Prognostic Index (FLIPI) scores (range, 3-5), and 22% were refractory. Treatment consisted of 4 courses of R-FM (rituximab 375 mg/m2 intravenously on Day 1, fludarabine 25 mg/m2 intravenously on Days 2 through 4, and mitoxantrone 10 mg/m2 intravenously on Day 2, recycling at Day 28) and consolidation with 2 courses of fludarabine and mitoxantrone (the same regimen without rituximab).

RESULTS:

The best response (84% overall response rate including 68% complete response/complete response unconfirmed) was achieved after 4 courses of R-FM. Response rates were high regardless of age, refractoriness to last previous therapy, and FLIPI score. After a median follow-up of 4 years, the 3-year progression-free survival rate was 47%, the event-free survival rate was 41%, and the 3-year overall survival rate was 66%. Grade ≥3 neutropenia and infections were the most common toxicities and occurred in 72% and 14% of patients, respectively.

CONCLUSIONS:

Cytoreduction with 4 courses of R-FM was safe and highly efficient in patients with recurrent/refractory follicular lymphoma who had high tumor burden; however, better consolidation than FM is needed to further improve outcome. Cancer 2010. © 2010 American Cancer Society.

Follicular lymphoma (FL) is the second most common lymphoma in adults, and patients with advanced-stage FL or adverse prognostic features usually are considered incurable with chemotherapy alone. Recently, investigators demonstrated that the addition of the humanized anti-CD20 antibody rituximab to a first-line chemotherapy regimen improved outcome.1-4 However, most patients who receive rituximab-containing regimens eventually will develop recurrent disease.

There is no standard salvage regimen in FL. Because alkylating or anthracycline-containing (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP]/CHOP-like) regimens are the preferred combination chemotherapies used in first-line treatment, nucleoside analog (predominantly fludarabine-based) combinations have been investigated extensively in patients with recurrent or refractory FL. In vitro, fludarabine has synergistic activities with mitoxantrone, cyclophosphamide, and rituximab.5 In the pioneering reports, fludarabine was combined preferentially with mitoxantrone and dexamethasone (the FND regimen) or with prednisone for the treatment of recurent/refractory, indolent non-Hodgkin lymphoma.6-10 Later, emphasis was put on core combinations of fludarabine with cyclophosphamide (the FC regimen),11, 12 possibly because of the larger body of in vitro data, the promising results observed in patients with chronic lymphocytic leukemia, or concerns that mitoxantrone may increase myelosuppression. Some groups choose to add mitoxantrone at lower doses to FC (the FCM regimen) as an alternative.13-16 When rituximab emerged as an efficient drug in single-agent studies, those who had pioneering experience with fludarabine and mitoxantrone chose to add rituximab to front-line chemotherapy17, 18 or after chemotherapy19 in de novo, indolent non-Hodgkin lymphoma, whereas most other teams focused on the combination of rituximab to FC (R-FC) or FCM (R-FCM).11, 20, 21 Most of those trials were quite heterogeneous in terms of histologic subtypes, disease status, and treatment criteria. Moreover, to our knowledge, there are no data on the combination of rituximab, fludarabine, and mitoxantrone in a well characterized, homogeneous population of patients with recurrent/refractory FL that required treatment according to validated, high tumor burden criteria.

In 1999, the Adult Lymphoma Study Group/East-West Study Group for Acute Leukemia and Other Blood Diseases (GELA-GOELAMS) Working Group initiated a phase 2 study of rituximab, fludarabine, and mitoxantrone (R-FM) for patients with recurrent/refractory FL after a maximum of 2 previous regimens, including 1 CHOP/CHOP-like regimen but no prior exposure to the 3 study drugs, who required treatment based on Follicular Lymphoma Study Group (GELF) high tumor burden criteria.22 Here, we report the results from that phase 2 trial with a median follow-up of 4 years.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Objectives

This was an open-label, multicenter study. The primary endpoint was progression-free survival (PFS). The calculation of sample size was based on the primary PFS endpoint. We anticipated a 3-year PFS of 50% and computed that a sample size of 48 evaluable patients who were recruited over 3 years and followed for at least 1 year would provide 80% power at the overall 5% (2-sided) significance level to detect a 3-year PFS rate >30% (null hypothesis, 30% 3-year PFS rate; alternative hypothesis, 50% 3-year PFS rate). The secondary endpoints were toxicity, response rate, overall survival (OS), and event-free survival (EFS).

The study management was operated by the GELA coordinating center, which issued treatment allocation by facsimile after confirming patient eligibility. Case report forms that were collected at participating centers were sent to the coordinating center and were keyed in twice for verification. Outliers and erroneous values were checked routinely. Queries and on-site monitoring were used for final validation. No interim analysis was done.

The protocol for this study was approved by the local or national ethics committees and the national regulatory agency according to French regulatory laws. All patients provided written informed consent. The study was registered as a national clinical trial (NCT) at clinicaltrials.gov as NTC00169208.

Patients

Eligible patients were ages 18 years to 75 years who had histologically confirmed, CD20-positive FL (grade 1 or 2 according to World Health Organization criteria),23 had developed recurrent/progressive disease after a maximum of 2 previous regimens (including 1 CHOP/CHOP-like regimen), and had no previous exposure to rituximab, fludarabine, or mitoxantrone. Patients who had received high-dose therapy followed by autologous stem cell transplantation (ASCT) as consolidation of first-line therapy were eligible, and high-dose therapy was counted as 1 regimen. In addition, patients were required to have at least 1 measurable lymph node or extranodal lesion and to fulfill at least any 1 of the following criteria of high tumor burden22: 1) the presence of a bulky tumor defined by either a tumor lesion with a greatest dimension ≥7 cm, or spleen enlargement with a greatest craniocaudal dimension >20 cm, or ≥3 lymph node sites with a greatest dimension at each site ≥3 cm in 3 distinct lymph node areas, or pleural effusion or ascites, or symptomatic compressive syndrome; or 2) systemic symptoms (fever >38°C for >5 days, drenching night sweats, or >10% weight loss); or 3) elevated serum levels of lactate dehydrogenase (above normal values); or 4) β2 microglobulin ≥30 mg/dL. Patients were excluded if they had contraindications to mitoxantrone, fludarabine, or rituximab; clinical suspicion of or biopsy-proven transformation to diffuse large B-cell lymphoma; known positive human immunodeficiency viral status or active viral hepatitis B or C; and a previous malignancy (except in situ cervical carcinoma).

Assessments

A pathology review of all biopsy material was performed after registration by a panel of 3 expert pathologists. Parameters that were used to define the Follicular Lymphoma International Prognostic Index (FLIPI) (lactate dehydrogenase level greater than the upper normal limit, stage III-IV disease, hemoglobin <12 g/dL, >4 lymph node lesions, and aged >60 years) at study entry were collected retrospectively.24 Tumor assessments were based on computed tomography (CT) scans of the neck, thorax, abdomen, and pelvis; and patients underwent physical examinations at baseline, 4 weeks after the fourth course of R-FM, 3 months after the last chemotherapy dose, every 6 months for 2 years, and yearly thereafter until they developed disease progression. If patients had a positive bone marrow biopsy at baseline, then a bone marrow biopsy was repeated only to confirm a complete response (CR). Treatment responses were classified according to International Workshop Response Criteria as either a CR, an unconfirmed CR (CRu), a partial response (PR), stable disease (SD), or progressive disease (PD).25 No functional imaging methods were used. Blood samples for hematology and serum chemistries, serum immunoglobulins, T-cell (CD3-positive), B-cell (CD19-positive) and natural killer (NK)-cell (CD56-positive) levels were obtained before each cycle and 12 weeks after the last cycle. Safety was assessed by using Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class Preferred Terms. Laboratory and adverse event (AE) toxicity grading was assessed using National Cancer Institute Common Toxicity Criteria (version 2.0; available at: http://ctep.info.nih.gov accessed on May 21, 2010).

Treatment Schedule and Dose Adaptation

The treatment schedule consisted of a 4-course induction with R-FM (rituximab 375 mg/m2 intravenously on Day 1, fludarabine 25 mg/m2 intravenously on Days 2 through 4, mitoxantrone 10 mg/m2 intravenously on Day 2, recycling at Day 28) followed by consolidation with 2 courses of FM without rituximab. During consolidation, the FM regimen was planned at 56-day intervals to allow potentially prolonged hematologic recovery. This schedule with only 4 infusions of rituximab and 56-day recycling after Cycle 4 was based on the data available at the time this study was designed: First, it was reported that 4 courses of fludarabine and mitoxantrone (FM) provided shorter disease control compared with 6 courses at the cost of increased toxicity and delayed hematologic recovery after Courses 4 through 6.26, 27 Second, a preliminary report did not indicate an increased time to progression after 8 courses of rituximab compared with 4 courses.27 If patients developed grade 4 neutropenia or any febrile neutropenia after any cycle, then all following cycles were given with granulocyte-colony–stimulating factor (G-CSF) support (filgrastim 300 μg daily was started on Day 5 and was continued until granulocytes were >1000/μL for 3 consecutive days). If patients developed grade 4 neutropenia that led to infectious toxicity or delayed neutrophil count recovery (ie, neutrophil count <1000/μL or a return to the baseline count if patients had bone marrow involvement) occurred after 5 weeks but before 6 weeks despite G-CSF support, then the doses of fludarabine and mitoxantrone were reduced by 20%. If patients developed grade 4 thrombocytopenia or delayed platelet count recovery (ie, platelet count <100,000/μL or a return to the baseline count if patients had bone marrow involvement) occurred after 5 weeks but before 6 weeks, then the doses of fludarabine and mitoxantrone were reduced by 20%. If patients had a delay in recovery >6 weeks, then R-FM therapy was discontinued. Erythropoietin support was allowed during and after R-FM treatment according to the institution's guidelines. There was no routine Pneumocystis carinii pneumonia (PCP) or antiviral prophylaxis.

Statistical Analysis

All analyses were performed on an intent-to-treat basis. PFS was measured from the date of randomization to the date of either lymphoma progression or death from lymphoma. OS was measured from the date of randomization to the date of death from any cause. EFS was measured from the date of randomization to the date of disease progression, recurrence, or death from any cause. Duration of response was estimated from the date of CR, CRu, or PR assessment until the date of disease recurrence, progression, or death from any cause. Survival functions were estimated by using the Kaplan-Meier method and were compared using log-rank tests. Response rates were compared using a chi-square test. All P values are 2-tailed with a nominal α of .05. Statistical analyses were performed with SAS 9.1.3 software (SAS Institute, Cary, NC).

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Patient Characteristics

Fifty patients were enrolled on this study at 13 French institutions between April 2001 and January 2004. Demographics and patient characteristics are summarized in Table 1. The median patient age was 61 years (range, 30-75 years). At the time of inclusion, the median time from primary diagnosis was 34 months (range, 3-116 months). Forty-seven patients (94%) had received an anthracycline-containing regimen as part of first-line therapy, including either cyclophosphamide, doxorubicin, vindesine, and prednisone (CHVP) (n = 6); or CHVP combined with interferon alpha (n = 28); or CHOP (n = 13).4, 22, 31-33 The median doxorubicin dose received was 260 mg/m2 (range,: 75-485 mg/m2). Six patients had undergone first-line, consolidative ASCT with a conditioning regimen that cyclophosphamide, etoposide, and total body irradiation (10 grays [Gy]). Six patients (12%) had received second-line treatment with a regimen that contained cytarabine and cisplatin (n = 3), or CHVP (n = 1), or chlorambucil (n = 1), or involved-field radiotherapy (2 times 2 Gy; n = 1). Seventy-eight percent of patients had responded to their last prior therapy (50% CR/CRu rate), and 22% had refractory disease at study entry. The median PFS after the last prior therapy was 27 months (range, 3-114 months), and 7 of 50 patients (14%) had a duration of previous remission <1 year. The majority of patients had several adverse prognostic parameters at baseline (Table 1). Given the low number of patients with FLIPI scores of 0 and 1, these patients were pooled with patients who had a FLIPI score of 2 for the sake of comparisons with patients who had high-risk FLIPI scores of 3 to 5. After central pathologic review, 3 patients were classified with grade 3a FL but were retained in the final analysis, because their outcomes were reported subsequently as similar to the outcomes of patients with grade 1 or 2 FL.

Table 1. Characteristics of 50 Patients With Recurrent/Refractory Follicular Lymphoma at Study Entry
CharacteristicNo. With Missing ValuesNo. of PatientsFrequency, %
  1. ECOG PS indicates Eastern Cooperative Oncology Group performance status; FLIPI, Follicular Lymphoma International Prognostic Index; LDH, lactate dehydrogenase; CR, complete response; CRu, unconfirmed CR; PR, partial response; SD, stable disease; PD, progressive disease.

Age >60 y03060
Men02958
ECOG PS >1012
B symptoms present01020
Ann Arbor stage III or IV disease04284
Extranodal sites >101836
FLIPI   
 0-10816
 201428
 3-502856
Bone marrow infiltration03060
Bulky lesion >7 cm52658
≥3 Lymph node sites, each of which measured ≥3 cm in 3 distinct lymph node areas11615
Serous effusion0714
Compressive disease01020
LDH >upper normal value01836
Hemoglobin <12 g/dL025
B2-microglobulin ≥3 mg/L41941
Best response to last regimen   
 CR/CRu02550
 PR01428
 Failure (SD/PD)011 (3/8)22 (6/16)
Duration of previous remission <1 y0714

Treatment Administration

Overall, 192 of 200 cycles of R-FM and 75 of 84 cycles of FM were given. All 50 patients received at least 1 cycle of R-FM. Fifteen patients (30%) did not complete the 6 planned cycles because of disease progression (7 patients) or toxicity (8 patients), but only 3 patients (6%) did not complete 4 cycles (2 patients with disease progression after 1 cycle and 1 patient who had persistent myelosuppression after 3 cycles). Across the first 4 cycles, the median dose intensities of rituximab, fludarabine, and mitoxantrone were 98.4% (range, 78%-102%), 96.6% (range, 70%-102%), and 96.4% (range, 71%-104%) of the designated doses, respectively. Eight patients (16%) had at least 1 dose reduction. Dose reductions (any drug) and premature withdrawals because of toxicity did not differ significantly in patients aged >60 years compared with patients aged ≤60 years (P = .85), including those who underwent previous ASCT. Six patients (12%) required erythrocyte transfusions (29 packs), and 5 patients (10%) required platelet transfusions (19 packs). G-CSF and erythropoietin support were given during 68 of 284 cycles (24%) and 18 of 284 cycles (6%), respectively.

Survival Parameters and Outcome

Survival parameters at 3 years according to age and FLIPI score are shown in Table 2. At a median follow-up of 4 years, 28 progressions/recurrences or deaths from lymphoma (56%) have been observed. The median PFS was 33 months (95% confidence interval [CI], 21-50 months) (Fig. 1A). Thirty-three progressions/recurrences or deaths from any cause (66%) have occurred. The median EFS was 26 months (95% CI, 15-40 months) (Fig. 1B). Nineteen patients died (38%) because of lymphoma (12 patients), study treatment toxicity (2 patients), second cancer (1 patient), or other causes (3 infections occurred after a subsequent salvage regimen or ASCT, and 1 patient had a hemorrhagic cerebral stroke during follow-up). The median OS was not reached (Fig. 1C). In patients who had FLIPI scores from 0 to 2, the median PFS was 50 months, the median EFS was 40 months, and the OS was not reached; for patients who had FLIPI scores from 3 to 5, the median PFS was 25 months, the median EFS was 16 months, and the median OS was 46 months (Fig. 2).

Table 2. Survival Parameters at 3 Years for Patients According to Age and Follicular Lymphoma International Prognostic Index at a Median Follow-Up of 4 Years After the Initiation of Combined Rituximab, Fludarabine, and Mitoxantrone
Patient Group3-Year PFS (95% CI), %P3-Year EFS (95% CI), %P3-Year OS (95% CI), %P
  • CI indicates confidence interval; PFS, progression-free survival; EFS, event-free survival; OS, overall survival; FLIPI, Follicular Lymphoma International Prognostic Index.

  • a

    Age >60 years versus age ≤60 years.

  • b

    FLIPI 3-5 versus FLIPI 0-2 risk factors at disease recurrence/progression.

All patients47 (32-61) 41 (27-54) 66 (50-77) 
Age, y      
 ≤6049 (25-69).51a40 (20-60).73a73 (49-87).47a
 >6046 (25-64) 42 (23-59) 59 (38-75) 
FLIPI      
 0-269 (44-85).0195b59 (36-76).0473b77 (53-90).0729b
 3-530 (13-49) 26 (12-44) 56 (36-72) 
thumbnail image

Figure 1. Outcomes are illustrated for the 50 patients who received combined rituximab, fludarabine, and mitoxantrone (R-FM) at a median follow-up of 4 years, including (A) progression-free survival, (B) event-free survival, and (C) overall survival.

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thumbnail image

Figure 2. Progression-free survival is illustrated for the 50 study patients according to Follicular Lymphoma International Prognostic Index (FLIPI) score at baseline.

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Response to Treatment

After 4 courses, 42 patients responded including 34 patients who achieved CR/CRu, 3 patients had SD, 2 patients had PD, and the 3 remaining patients without a clear response at the end of inductions were considered as treatment failures. Thus, the overall response rate was 84%, and the CR/CRu rate was 68%. After 6 courses, 33 patients were in CR/CRu/PR, and 29 patients were in CR/CRu, resulting an overall response rate of 66% and a CR rate of 58%. Thus, the best response was achieved at the end of induction with 4 courses of R-FM. After 4 courses, response rates were high regardless of FLIPI score, age, or disease refractoriness at baseline. The CR/CRu rate was significantly lower for patients who had disease that was refractory to their last previous regimen (36% vs 77%; P = .010) (Table 3).

Table 3. Overall and Complete Response Rates After 4 Courses of Combined Rituximab, Fludarabine, and Mitoxantrone for Patients According to Age, Sensitivity to Last Prior Therapy, and Follicular Lymphoma International Prognostic Index
Patient GroupOR After 4 Courses (95% CI), %PCR/CRu Rate at 4 Courses (95% CI), %P
  • OR indicates overall response; CI, confidence interval; CR, complete response; CRu, unconfirmed CR; FLIPI, Follicular Lymphoma International Prognostic Index.

  • a

    Sensitivity versus refractoriness to last therapy.

  • b

    Age >60 years versus age ≤60 years.

  • c

    FLIPI 3-5 versus FLIPI 0-2 risk factors at disease recurrence/progression.

All patients84 (71-93) 68 (53-80) 
Sensitivity to last therapy87 (73-96).24a77 (61-89).010a
Refractory to last therapy73 (39-94) 36 (11-89) 
Age ≤60 y82 (60-95).70b82 (60-95).063b
Age >60 y86 (67-96) 57 (37-75) 
FLIPI 0-287 (65-97).68c77 (55-92).21c
FLIPI 3-582 (63-94) 61 (40-78) 

Among the 42 patients who responded at the end of induction, 21 progressions/recurrences or deaths from any cause have been observed. Transformation in diffuse large B-cell lymphoma was diagnosed in 4 of 11 patients who had histologic documentation at disease recurrence or progression after R-FM; none of those 4 patients had responded to R-FM, and none responded to subsequent treatment. At the time of the current analysis, 16 patients (32%) were in continuous CR/CRu. The median response duration was 35 months (95% CI, from 23 months to not reached). The 3-year response duration rate was 44% (95% CI, 27%-60%).

Toxicity and Safety Laboratories

Toxicity per patient (all grades) is shown in Table 4. Grade ≥3 neutropenia and infections were the most common toxicities and occurred in 72% and 36% of patients, respectively. Grade ≥3 infections or febrile neutropenia occurred in 4% of courses and concerned 14% of patients. To date, 2 episodes of prolonged, late-onset neutropenia have been observed, both after Cycle 5, and 1 of those episodes led to death most probably because of infection. Other grade ≥3 toxicities that concerned >5% patients were thrombocytopenia (12%) and anemia (6%). Among the 18 patients who had infections during treatment, 6 patients had febrile neutropenia, and there was only a single documented episode of Herpes simplex (HSV) reactivation, but no PCP or fungal infection was reported. No significant changes in T-cell/NK-cell populations or immunoglobulin levels were observed throughout treatment (data not shown).

Table 4. Overview of Patients With Increases in National Cancer Institute Common Toxicity Criteria Version 2.0 Toxicity Grades From Baseline (n=50)
Type of ToxicityNo. of Patients (%)
All ToxicitiesGrade 0Grade 1Grade 2Grade 3Grade 4Unknown GradeGrade ≥3
  1. ANC indicates absolute neutrophil count; WBC, white blood cell count.

Hematologic toxicity        
 ANC39 (78)11 (22)1 (2)1 (2)7 (14)29 (58)1 (2)36 (72)
 WBC18 (36)32 (64)1 (2)3 (6)2 (4)11 (22)1 (2)13 (26)
 Infection/febrile neutropenia18 (36)32 (64)3 (6)8 (16)4 (8)3 (6)0 (0)7 (14)
 Platelets23 (46)27 (54)14 (28)2 (4)5 (10)1 (2)1 (2)6 (12)
 Hemoglobin25 (50)25 (50)12 (24)10 (20)2 (4)1 (2)0 (0)3 (6)
Nonhematologic toxicity        
 Cardiovascular13 (26)37 (74)2 (4)9 (18)0 (0)2 (4)0 (0)4 (1)
 Liver24 (48)26 (52)17 (34)5 (10)0 (0)1 (2)1 (2)1 (2)
 Kidney10 (20)40 (80)7 (14)0 (0)0 (0)1 (2)2 (4)1 (2)
 Fever9 (18)41 (82)7 (14)1 (2)1 (2)0 (0)0 (0)1 (2)
 Neurologic9 (18)41 (82)5 (10)3 (6)1 (2)0 (0)0 (0)1 (2)
 Alopecia9 (18)41 (82)2 (4)4 (8)1 (2)0 (0)2 (4)1 (2)
 Lungs5 (10)45 (90)1 (2)3 (6)1 (2)0 (0)0 (0)1 (2)
 Nausea/vomiting19 (38)31 (62)15 (30)4 (8)0 (0)0 (0)0 (0)0 (0)
 Diarrhea10 (20)40 (80)6 (12)4 (8)0 (0)0 (0)0 (0)0 (0)
 Mucositis9 (18)41 (82)8 (16)1 (2)0 (0)0 (0)0 (0)0 (0)
 Others33 (66)17 (34)11 (22)15 (30)6 (12)1 (2)0 (0)7 (14)

Adverse Events and Second Cancers

Twenty-seven patients had ≥1 AE during the study, and 23 patients required treatment. Nineteen serious AEs (SAEs) were reported in 13 patients. Seventeen SAEs were considered treatment-related, including febrile neutropenia (n = 6), cytopenias that required transfusion (n = 4), infusion-related reaction after rituximab (n = 3), infections (n = 2), severe asthma (n = 1), and arthritis (n = 1). The remaining 2 SAEs were chylous ascites (n = 1) and jaundice secondary to main biliary duct compression (n = 1), both because of underlying disease. Four patients were diagnosed with second cancers: Two patients had cutaneous cancers (epithelioma nonmelanoma) diagnosed 6 months and 7 months after inclusion, 1 patient had preexisting myelodysplastic syndrome (MDS) (based on a post hoc review of bone marrow smears) that was misdiagnosed at baseline, and 1 patient in ongoing CR after R-FM was diagnosed with chronic myeloid leukemia 45 months after study entry.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

To our knowledge, this is the first report of a phase 2 trial evaluating the safety and efficacy of R-FM, a regimen that combines rituximab, fludarabine, and mitoxantrone for the treatment of patients with recurrent/refractory FL who require treatment on the basis of GELF-defined high tumor burden criteria. At a median follow-up of 4 years, the median 3-year PFS rate was 47%, the median 3-year EFS rate was 41%, and the median 3-year OS rate was 66% in a difficult-to-treat group of patients. Fifty-eight percent of patients had bulky disease (lesion >7 cm), 56% had high-risk FLIPI scores, 22% were refractory to their last previous therapy, and all had received CHOP or CHOP-like regimens and had a median PFS of 27 months, shorter than what would expected with such first-line treatments.31 The best overall response (84% ORR with 68% CR/CRu) was achieved at the end of induction with 4 courses of R-FM, and the response rates consistently were high regardless of age, FLIPI score, or refractoriness to the last previous therapy with the exception of the significantly lower 36% CR/CRu rate observed for patients who were refractory to their last therapy (Table 3).

Toxicity was mainly hematologic, as expected, and was manageable even in patients aged >60 years. Grade ≥3 infections were infrequent and occurred in 4% of courses and concerned 14% of patients. Only 1 patient died of infection after prolonged neutropenia after the fifth cycle. There was only 1 documented viral (HSV) reactivation, and no opportunistic infections were observed. There was no case of secondary MDS, but the median follow-up of 4 years is still relatively short in this context.

Our results with R-FM in patients with recurrent/refractory FL who had well defined and broadly recognized high-risk features are consistent with those achieved with R-FC, or R-FCM, or other fludarabine-containing regimens, as summarized in Table 5, especially in terms of overall response and CR rates. The median PFS of 33 months obtained in patients, all of whom were rituximab-naive at baseline, suggests that combining 4 infusions of rituximab with FM was at least additive and possibly synergistic given the respective median PFS of 14 months and 12 months reported previously with FM and single-agent rituximab in patients with recurrent/refractory FL.26, 27, 34 Despite similar overall response rates and CR rates after cytoreduction with 4 courses of R-FM in patients with low/intermediate-risk and high-risk FLIPI scores at baseline, 3-year PFS and EFS were significantly shorter in patients with high-risk FLIPI scores (Table 4). Especially for these high-risk patients, our results do not really support further consolidation with 2 additional courses of FM. New concepts, such as rituximab maintenance35 and consolidation with radioimmunotherapy (RIT),36 currently have emerged in FL. Rituximab maintenance reportedly improved response duration in recurrent patients after R-FCM37; it also has been tested as first-line treatment after R-FND.38 Consolidation with RIT reportedly provided high rates of conversion from PR to CR and significant PFS improvement in the first-line setting.36 According to our series with R-FM, it may be an interesting option for patients who failed their last prior therapy, patients aged >60 years, and patients with FLIPI scores of 3 to 5, whose CR/CRu rate could be further improved. It is noteworthy that a consolidation strategy with ibritumomab tiuxetan (a radiolabeled antibody) currently is being tested after R-FND in high-risk FLIPI patients as first-line therapy.39 Consolidation with high-dose therapy followed by ASCT would be a third option for younger patients. Although there are some reports that fludarabine combination regimens severely affect peripheral blood stem cell mobilization,40, 41 stem cell collection and ASCT appear to be feasible after R-FND or R-FC.12, 42 We did not investigate stem cell collection after R-FM in the current study, in that most of our patients were not considered eligible for ASCT because of their age or because they had undergone previous ASCT.

Table 5. Efficacy and Toxicity of Fludarabine-Containing Regimens in Patients With Follicular Lymphoma
Regimen: StudyNo. of Patients (All/FL)Disease Status for FL: No. Untreated/ Recurrent or RefractoryMedian No. of Courses (Range)Refractory Disease, %OR/CR, %PFS RateOS RateGrade ≥3 Infection, %aGrade ≥3 Neutropenia, %a
  • FL indicates follicular lymphoma; OR, overall response; CR, complete response; PFS, progression-free survival; OS, overall survival; F, fludarabine; C, cyclophosphamide; R, rituximab; M, mitoxantrone; NA, not available; D, dexamethasone.

  • a

    Percentages are given on a per-patient basis.

  • b

    Second randomization with 2 additional courses of R.

  • c

    The percentage of all courses is shown because the percentage on a per-patient basis was not available.

FC-R: Tam 20061276/227/154 (1-6)1587/6742% at 3 y72% at 3 y2736 (Grade 4)
R-FCMb70/350/354 (3-4)1494/40Not reached at 3 y90% at 2 y2.5c40c
FM then R: Zinzani 20041941/4141/06+4R0100/9071% at 3 y94% at 3 yNA30
F-R: Czuczman 20052840/4027/136 (1-6)090/7060% at 3 y80% at 4 yNA80
FC+R: Sacchi 20072954/540/544 (2-4)090/7461% at 4 y75% at 4 y7.440
FMD without R: Tsimberidou 20053073/5454/06 (NA-8)097/79NANA1977
FCM: Montoto 200813120/120120/06 (2-6)094/8358% at 5 y89% at 5 y2.4c6.4c
R-FM50/500/506 (1-6)2286/6847% at 3 y66% at 3 y1476

All of our patients were rituximab-naive at study entry, and the relevance of our results may be regarded as questionable now that combining rituximab and chemotherapy is the gold standard in first-line therapy for FL. It is noteworthy that, in the German Low-Grade Lymphoma Study Group experience, overall and complete response rates to R-FCM were not modified by previous exposure to rituximab,43 which strongly suggests R-FM remains an entirely valuable option for patients who develop disease recurrence after prior therapy with rituximab.

In conclusion, a 4-course R-FM treatment was feasible, safe, and yielded high overall and complete response rates in patients with recurrent/refractory FL who had high tumor burden and high-risk features, and R-FM should be considered a highly valuable cytoreduction regimen. Two additional consolidative FM cycles without rituximab did not seem to improve outcome, which calls for further testing of options like rituximab maintenance, RIT consolidation, consolidative high-dose therapy, and other innovative options.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

We thank Delphine Germain for monitoring patient data, Marion Fournier for expert statistical assistance, and Karina Dordonne for technical assistance.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Supported by a grant from Bayer Schering Pharma, which also supplied fludarabine free of charge.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES
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