Phase III Study of R-CVP Compared With

VOLUME

26

䡠

NUMBER

28

䡠

OCTOBER

1

2008

JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L

R E P O R T

Phase III Study of R-CVP Compared With Cyclophosphamide, Vincristine, and Prednisone Alone in Patients With Previously Untreated Advanced Follicular Lymphoma Robert Marcus, Kevin Imrie, Philippe Solal-Celigny, John V. Catalano, Anna Dmoszynska, Joa˜o C. Raposo, Fritz C. Offner, Jose´ Gomez-Codina, Andrew Belch, David Cunningham, Elisabeth Wassner-Fritsch, and George Stein From the Department of Hematology, Addenbrooke’s Hospital, Cambridge; Department of Medicine, Royal Marsden Hospital, Sutton, Surrey, United Kingdom; Department of Medicine Toronto–Sunnybrook Regional Cancer Centre, Toronto, Ontario; Cross Cancer Institute, Edmonton, Alberta, Canada; Department of Hematology and Medical Oncology, Clinique Victor Hugo, Le Mans, France; Department of Hematology, Monash Medical Centre, Clayton, Victoria, Australia; Department of Hematology, Medical University of Lublin, Lublin, Poland; Servicio de Hematologia, Hospital Santa Maria, Lisbon, Portugal; Dienst Hematologie, Universitair Ziekenhuis, Gent, Belgium; Servicio de Oncologa Medica, Hospital La Fe de Valencia, Valencia, Spain; F. Hoffmann-La Roche; and Statistics for Research, Basel, Switzerland. Submitted July 16, 2007; accepted May 7, 2008; published online ahead of print at www.jco.org on July 28, 2008.

A

B

S

T

R

A

C

T

Purpose To compare the long-term outcome of patients with previously untreated follicular lymphoma (FL) needing therapy, after treatment with cyclophosphamide, vincristine and prednisone (CVP) versus CVP plus rituximab (R-CVP) and to evaluate the predictive value of known prognostic factors after treatment with R-CVP. Patients and Methods Patients with previously untreated CD20-positive stage III/IV FL were randomly assigned to eight cycles of R-CVP (n ⫽ 159) or CVP alone (n ⫽ 162). The median follow-up period was 53 months. Results The primary end point—time to treatment failure (TTF), which included patients without a response after four cycles as an event—was significantly prolonged in patients receiving R-CVP versus CVP (P ⬍ .0001). Improvements in all other end points, including overall and complete response rates (P ⬍ .0001), time to progression (TTP; P ⬍ .0001), response duration (P ⬍ .0001), time to next antilymphoma treatment (P ⬍ .0001), and overall survival (OS; P ⫽ .029; 4-year OS: 83% v 77%;) were achieved with R-CVP versus CVP alone. Univariate analyses demonstrated an improvement in TTP with R-CVP versus CVP irrespective of the Follicular Lymphoma International Prognostic Index (FLIPI) subgroup, the International Prognostic Index (IPI) subgroup, baseline histology, and the presence or absence of B symptoms or bulky disease. By multivariate analysis, FLIPI retains a strong predictive power for TTP in the presence of the trial treatment effect.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Conclusion Analysis of all outcome measures, including OS, confirm the benefit of adding R to CVP in the front-line treatment of FL.

Corresponding author: Robert Marcus, MB, Department of Haematology, Kings College Hospital, Denmark Hill, London SE5 9RS UK; e-mail: Robert [email protected].

J Clin Oncol 26:4579-4586. © 2008 by American Society of Clinical Oncology

© 2008 by American Society of Clinical Oncology

Although prognostic factors for patients with follicular lymphoma (FL) have been studied extensively, it has been unclear until recently which are the most useful in a clinical setting and whether these now apply after the widespread incorporation of rituximab (R) into first-line therapy. The International Prognostic Index (IPI) for aggressive lymphomas1 is predictive of outcome in FL, but its utility is limited because few patients (10% to 15%) fall into the high-risk group. A scoring system specifically designed for FL—the Follicular Lymphoma Prognostic Factor Index (FLIPI)—was developed through an international cooperative study.2 This index divides patients into risk groups using five prognostic factors: age (⬎ 60 v ⱕ 60

0732-183X/08/2628-4579/$20.00 DOI: 10.1200/JCO.2007.13.5376

INTRODUCTION

years), Ann Arbor stage (III to IV v I to II), hemoglobin (ⱖ 12 v ⬍ 12 g/dL), number of affected nodal areas (⬎ four v ⱕ four), and serum lactate dehydrogenase (LDH) level (⬎ normal v ⱕ normal). Three risk groups were identified containing approximately equal numbers of patients: low risk (zero to one adverse factors), intermediate risk (two adverse factors, hazard ratio [HR] ⫽ 2.3), and poor risk (three to five adverse factors, HR ⫽ 4.3). This index allows for comparison of results across trials and may allow for studies of different therapies in the various groups. Until recently, standard treatment for advanced symptomatic FL was chemotherapy. Alkylating agents, anthracyclines, and purine analog-based regimens have all been used, with no regimen conclusively demonstrating a superior outcome with the © 2008 by American Society of Clinical Oncology

Downloaded from jco.ascopubs.org on September 13, 2015. For personal use only. No other uses without permission. Copyright © 2008 American Society of Clinical Oncology. All rights reserved.

4579

Marcus et al

possible exception of anthracycline/interferon-␣ combinations.3 More recently, improvements in long-term outcome in patients with FL, including prolongation of overall survival (OS), have been demonstrated in large randomized studies by the addition of R to standard chemotherapy combinations in the first-line treatment of FL.4-7 Because R with chemotherapy is now widely used for first-line treatment of FL, it is important to establish whether these same prognostic factors still apply now as they did in the pre-R era. We report 53-month median follow-up data from a phase III study comparing eight cycles of R plus cyclophosphamide, vincristine, and prednisone chemotherapy (R-CVP) with eight cycles of CVP alone in patients with previously untreated FL. This analysis includes survival data as well as univariate and multivariate analyses of the prognostic factors for time to progression (TTP) in both arms of the study.

interaction of each prognostic factor with trial treatment were included in order to assess consistency of the treatment effect. Multivariate analyses with both forward and backward selection of prognostic factors (␣ ⫽ .05) were conducted to assess the predictive value of various parameters on TTP in the presence of the trial treatment effect. Owing to the composite nature of the IPI and FLIPI scores and because they share a number of features, multivariate analysis was carried out in three different ways. First, the FLIPI score was included as a composite along with the other prognostic factors that are not incorporated in the FLIPI. Second, the IPI score was included as a composite along with the other prognostic factors that are not incorporated in the IPI. Third, the individual components of each of the composite FLIPI and IPI indexes were included, together with other prognostic factors. All P values are two-tailed. Statistical analyses were performed using SAS software (SAS Institute, Cary, NC).

PATIENTS AND METHODS

Patient Characteristics As previously reported,4 the final analysis population consisted of 159 patients in the CVP group and 162 patients in the R-CVP group. More than 80% of the patients had at least one symptom requiring therapy according to local treatment guidelines (BNLI, Groupe d’Etudes de Lymphoma Folliculaire, Eastern Cooperative Oncology Group/Southwest Oncology Group). There were no clinically relevant differences between the two groups by any demographic, clinical, or pathologic criteria (Table 1). Although most patients had an IPI score of 0 to 2, 15% of patients receiving CVP and 13% receiving R-CVP had an IPI score of 3 to 4. According to the FLIPI, 45% of patients in the CVP group and 38% in the R-CVP group had scores of 3 to 5. All patients had an Ann Arbor disease stage of III or IV. Because patients had to have stage III/IV disease for enrollment, the FLIPI risk distribution in this cohort was skewed toward a higher proportion of high-risk patients when compared with an unselected population with FL.

Patients As discussed in detail elsewhere,4 patients were eligible for the study if they had previously untreated CD20⫹ stage III or IV FL and required therapy in the opinion of the treating clinician. This study complied with all the requirements of the Declaration of Helsinki and its current amendments and was conducted in accordance with Good Clinical Practice guidelines. Treatment Eligible patients were randomly assigned (1:1) to treatment with R-CVP or CVP alone for a maximum of eight cycles of therapy, as described previously.4 Random assignment was performed centrally for all participating centers, using stratification according to center and IPI scores (0 or 1 v 2 or 3).1 Assessments Disease response was determined in accordance with standard criteria.8 The primary end point was time to treatment failure (TTF), defined as the time between random assignment and any of the following events: progressive disease, relapse after response, institution of new antilymphoma treatment, stable disease after cycle 4 (SD4), or death resulting from any cause. Secondary parameters included TTP, response rates, OS, duration of response, time to next antilymphoma treatment or death, and disease-free survival. In the TTP analysis, patients who had SD4 were not censored at this time point but were followed, in the same way as responders, until progressive disease or death occurred, regardless of second-line therapy. Statistical Analyses A sample size of 318 patients was calculated as sufficient to detect a 50% increase in the median TTF in patients treated with R-CVP compared with those treated with CVP alone, with 85% power at a two-tailed significance level of 5%. All analyses of efficacy and safety were performed on an intention-totreat (ITT) basis. TTF and TTP were analyzed using the log-rank test, and the results were expressed as Kaplan-Meier plots. TTP was subsequently analyzed using the Cox regression model to assess the effects of treatment according to various baseline prognostic factors. The following factors were considered: age, number of extranodal sites, bone marrow involvement, LDH levels, ␤2-microglobulin levels, presence of B symptoms, bulky disease (defined as nodal or extranodal mass ⬎ 7 cm in its greater diameter), British National Lymphoma Investigation (BNLI) criteria for therapy, number of affected nodal areas, hemoglobin levels, composite IPI score, and composite FLIPI score. Univariate analyses were performed first, including one factor in the model in addition to trial treatment group and center pool. Terms for the 4580

© 2008 by American Society of Clinical Oncology

RESULTS

Treatment As previously reported,4 68% of patients in the CVP arm and 85% of patients in the R-CVP arm completed the eight scheduled cycles of therapy; the difference is the result of fewer patients in the R-CVP arm withdrawing after cycle 4 after an insufficient response (Fig 1). Efficacy The primary end point for this study, TTF, was significantly prolonged in patients receiving R-CVP compared with those who received CVP alone (P ⬍ .0001; Table 2). Statistically significant and clinically relevant improvements in all other time-to-event variables— including TTP (P ⬍ .0001), response duration (P ⬍ .0001), and time to next antilymphoma treatment or death (P ⬍. 0001)—were demonstrated in patients treated with R-CVP compared with those who received CVP alone (Table 2). The median duration of response in R-CVP patients achieving a complete remission (CR) or unconfirmed CR (CRu) has not yet been reached and is 25 months for patients achieving a partial remission (PR). With a median 53 months of follow-up, a significant improvement in OS has now been demonstrated after treatment with R-CVP versus CVP alone (P ⫽ .029; Table 2; Fig 2). An exploratory analysis performed to assess the outcome of patients in the CVP group based on the type of their first second-line JOURNAL OF CLINICAL ONCOLOGY

Downloaded from jco.ascopubs.org on September 13, 2015. For personal use only. No other uses without permission. Copyright © 2008 American Society of Clinical Oncology. All rights reserved.

R-CVP v CVP in Previously Untreated Follicular Lymphoma

Table 1. Baseline Patient Characteristics CVP (n ⫽ 159) Characteristic Median age, years Male sex Histology class (IWF classification) A (CLL) Local review Central review B (FL grade 1) Local review Central review C (FL grade 2) Local review Central review D (FL grade 3) Local review Central review Other Local review Central review Not assessable/missing Local review Central review Stage (Ann Arbor) II III-1† III-2‡ IV Not assessable/missing International Prognostic Index score 0 1 2 3 4 Not assessable/missing FL International Prognostic Index score§ 0 to 1 (good prognosis) 2 (intermediate prognosis) 3 to 5 (poor prognosis) Not assessable/missing ⱖ 1 B symptom㛳 Bulky disease¶ Bone marrow involvement ⬎ 1 extranodal site Elevated LDH

R-CVP (n ⫽ 162) No.

%ⴱ

54

52 88

54

2 2

1 1

0 0

0 0

53 46

33 29

59 38

36 23

89 69

56 43

87 82

54 51

13 19

8 12

14 19

9 12

1 6

1 4

1 7

1 4

1 17

1 11

1 16

1 10

2 4 41 112 0

1 3 26 70 0

2 5 40 114 1

1 3 25 70 1

1 69 57 21 3 8

1 43 36 13 2 5

1 72 57 19 2 11

1 44 35 12 1 7

23 56 71 9 51 73 102 27 39#

15 35 45 6 32 46 64 17 26

28 62 61 11 65 63 103 28 39#

17 38 38 7 40 39 64 17 26

No.

%

53 85

ⴱ

Abbreviations: CVP, cyclophosphamide, vincristine, and prednisone; R, rituximab; IWF, International Working Formulation; CLL, chronic lymphocytic leukemia; FL, follicular lymphoma; LDH, lactate dehydrogenase. ⴱ Percentages based on assessable patients. †Stage III-1: involvement of lymph nodes on both sides of diaphragm. Abdominal disease limited to the upper abdomen (ie, spleen, splenic hilar nodes, celiac nodes, porta hepatica node). ‡Stage III-2: involvement of lymph nodes on both sides of diaphragm. Abdominal disease including para-aortic, mesenteric, and iliac involvement with or without disease in the upper abdomen. §Higher scores indicate a greater risk of death. 㛳B symptoms were defined as fever, weight loss, and night sweats. ¶Bulky disease is defined as nodal or extranodal mass ⬎ 7 cm at its greater diameter. #The percentage calculation was not based on the 159 and 162 patients in the CVP and R-CVP groups, respectively, because LDH normal values were unavailable for seven patients in the CVP group and 10 patients in the R-CVP group.

treatment did not confirm a significant difference in OS between the groups of patients receiving treatment at first relapse with a R-containing regimen and those receiving treatment without R. (logrank P ⫽ .1788). www.jco.org

Of the 45 patients treated with a R-containing regimen, 34 (76%) of 45 were still alive at the time of the analysis as compared with 56 (64%) of 88 patients treated with a regimen without R. Univariate and multivariate Cox regression analyses were © 2008 by American Society of Clinical Oncology

Downloaded from jco.ascopubs.org on September 13, 2015. For personal use only. No other uses without permission. Copyright © 2008 American Society of Clinical Oncology. All rights reserved.

4581

Marcus et al

Event-Free Probability

Patients randomly assigned (N = 322) Consent withdrawn (n = 1) Patients receiving study treatment (n = 321) CVP (n = 159)

Completed eight cycles of trial treatment (n = 108)

R-CVP (n = 162)

Withdrew before completing eight cycles of trial treatment (n = 51)

Completed eight cycles of trial treatment (n = 137)

Withdrew before completing eight cycles of trial treatment (n = 25)

1.0 R-CVP: median not reached

0.9 0.8 0.7 0.6 0.5

CVP: median not reached

0.4 0.3 0.2 0.1 0

4-year overall survival estimates: R-CVP, 83%; CVP, 77%

P = .0290

6

12

18

24

30

36

42

48

54

60

66

72

120 111 132 124

67 81

30 40

8 7

0 0

Study Month Fig 1. CONSORT diagram showing the flow of patients through the trial. CVP, cyclophosphamide, vincristine, and prednisone; R-CVP, rituximab plus CVP.

conducted to assess the efficacy of treatment in terms of TTP according to various baseline prognostic factors. Univariate analyses. P values resulting from the analyses by patient subgroups are reported without stratification by center pools. Baseline FLIPI scores categorized patients as follows: low risk (zero to one risk factors), 17%; intermediate risk (two risk factors), 39%; and high risk (three to five risk factors), 44%. Baseline IPI categorized patients as follows: zero to one risk factors, 47%; two risk factors, 38%; and three to four risk factors, 15%. Although FLIPI was conceived as a prognostic index for OS, there are too few deaths reported in this study at this time point to draw any conclusion using this parameter for subgroup analysis. Here, TTP is used as a possible surrogate for OS. The addition of R to CVP was associated with significantly prolonged TTP compared with CVP alone in all FLIPI subgroups (Fig 3), all IPI subgroups, and irrespective of baseline histology, presence or absence of B symptoms, and presence or absence of bulky disease (Table 3; Fig 4). Most patients (80%) had baseline hemoglobin of at least 12 g/dL. A significant improvement in TTP was observed in these patients after

Patients at risk CVP 159 155 151 141 R-CVP 162 162 160 155

136 150

132 125 144 142

Fig 2. Overall survival in patients assigned to chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP) or with CVP plus rituximab (R-CVP).

treatment with R-CVP versus CVP alone (P ⬍ .0001; Table 3; Fig 4). However, no difference in TTP was observed between the treatment groups in the minority of patients (n ⫽ 64) with baseline hemoglobin less than 12 g/dL (P ⫽ .3941; Table 3; Fig 4). Multivariate analyses. Multivariate analysis was used to assess the prognostic value of various parameters (BNLI criteria, age, extranodal sites, LDH, FLIPI, IPI, bone marrow involvement, elevated ␤2microglobulin, B symptoms, bulky disease, nodal areas, hemoglobin level) on outcome in terms of TTP in the presence of the trial treatment effect. Only the FLIPI (categorized as 0 to 2 v 3 to 5 in the analysis) was found to be a significant prognostic parameter for TTP in addition to the trial treatment. Patients with a FLIPI score of 0 to 2 who received R-CVP had the longest TTP. No other prognostic factor improved the predictive power. In two further multivariate analyses (one utilizing IPI instead of FLIPI, the other considering neither of the composite factors FLIPI

Table 2. Intention-to-Treat Analysis of End Points After 53 Months’ Median Follow-Up CVP (n ⫽ 159) End Point

Median

95% CI

Time to progression, months Tumor responses Overall response rate† Complete response ⫹ complete response unconfirmed Partial response Stable disease Progressive disease Could not be assessed Time to treatment failure, months Duration of response, months Disease-free survival, months Time to new anti-lymphoma treatment or death, months Kaplan-Meier estimates for overall survival rate at 48 months

15

12 to 18 49 to 64 6 to 16

7 14 21 12

6 to 9 9 to 18 14 to 38 10 to 18 70 to 83

R-CVP (n ⫽ 162) No.

90 16 74 33 31 5

%

Median

95% CI

34

27 to 48

57 10 47 21 20 3

74 to 87 33 to 49

27 38 NR 49

104 18 77

25 to 37 28 to NE 35 to NE 32 to NE 77 to 89

No.

%

P ⬍ .0001ⴱ

131 66 65 12 17 2

81 41 40 7 11 1

137 66 83

⬍ .0001‡ ⬍ .0001‡ ND ND ND ND ⬍ .0001ⴱ ⬍ .0001ⴱ .0001ⴱ ⬍ .0001ⴱ .0290ⴱ

Abbreviations: CVP, cyclophosphamide, vincristine, and prednisone; R, rituximab; ND, not done; NE, not estimable; NR, not reached. ⴱ Log-rank test stratified by center pools. †Complete response plus complete response unconfirmed plus partial response. ‡␹2 test.

4582

© 2008 by American Society of Clinical Oncology

JOURNAL OF CLINICAL ONCOLOGY

Downloaded from jco.ascopubs.org on September 13, 2015. For personal use only. No other uses without permission. Copyright © 2008 American Society of Clinical Oncology. All rights reserved.

R-CVP v CVP in Previously Untreated Follicular Lymphoma

A Event-Free Probability

DISCUSSION 1.0 0.9 0.8 0.7

R–CVP: median not reached

0.6 0.5 0.4 0.3 0.2 0.1 0

CVP: median 22 months

P = .0085

6

12

18

24

30

36

42

48

54

60

66

72

Study Month Event-Free Probability

B 1.0 0.9 0.8 0.7 0.6 0.5

R–CVP: median 37 months

0.4 0.3 0.2 0.1 0

CVP: median 17 months P = .0003

6

12

18

24

30

36

42

48

54

60

66

72

Study Month Event-Free Probability

C 1.0 0.9 0.8 0.7 0.6 0.5 0.4

R–CVP: median 26 months

0.3 0.2

CVP: median 11 months

0.1 0

P = .0004

6

12

18

24

30

36

42

48

54

60

66

72

Study Month Fig 3. Time to treatment progression in patients assigned to chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP) or with CVP plus rituximab (R-CVP), according to baseline Follicular Lymphoma International Prognostic Index (FLIPI) score. (A) FLIPI 0 to 1, good prognosis; (B) FLIPI 2, intermediate prognosis; (C) FLIPI 3 to 5, poor prognosis.

and IPI), only hemoglobin level and number of nodal areas were found to be statistically significant predictors of TTP in addition to trial treatment. Adverse Events As previously reported,4 the incidence of adverse events was similar in the R-CVP and CVP groups. Although there was a higher incidence of grade 3/4 neutropenia during treatment with R-CVP (24%) compared with CVP (14%), this did not translate into a higher rate of infections. There were no treatment-related deaths. www.jco.org

These follow-up data (median, 53 months) confirm that the addition of R to CVP chemotherapy in patients with previously untreated FL significantly improves the CR rate, TTF, TTP, duration of response, disease-free survival, and time to next antilymphoma treatment compared with CVP chemotherapy alone. These data with long-term follow-up are consistent with the early results reported from this trial.4 An improvement in OS has also now been observed, although the delay between first relapse and death is long. Thirty-four percent (45 of 133) of the patients receiving secondline therapy in the CVP group and 21% (18 of 84) of patients receiving second-line therapy in the R-CVP group were treated with R monotherapy or R-containing immunochemotherapy regimens, suggesting that, because there is an OS benefit in the R-CVP group, not all patients relapsing after chemotherapy alone can have successful salvage treatment with second-line R-containing therapy. The study design allowed for collection of the second-line treatment only; therefore, the proportion of patients treated with R at subsequent relapses over the length of their disease is likely to be higher than the 34% reported here, especially as the indication for R treatment of patients with FL was extended to cover its use with chemotherapy after 2004. This is one of four randomized trials to show a significant improvement in progression-free survival (PFS) or TTP and OS associated with the addition of R to standard chemotherapy in first-line treatment of FL. Hiddemann et al5 demonstrated a significant improvement in PFS and OS with the addition of R to cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) chemotherapy in patients with untreated, advanced-stage FL: After 3 years, only six of 223 patients in the R-CHOP arm had died compared with 17 of 205 patients treated with CHOP alone (P ⫽ .016). Herold et al6 demonstrated significant prolongation of OS with R, mitoxantrone, chlorambucil, and prednisolone arm compared with mitoxantrone, chlorambucil, and prednisolone alone in patients with previously untreated advanced FL (4-year OS in FL patients, 87% v 74%; P ⫽ .0096).6 Foussard et al7 initially reported a significant improvement in OS in this setting by the addition of R to cyclophosphamide, doxorubicin, etoposide, prednisone, and interferon compared with cyclophosphamide, doxorubicin, etoposide, prednisone, and interferon alone (OS at 42 months, 91% v 84%; P ⫽ .029), but recent 5-year follow-up suggests that this benefit is confined to those patients in the high FLIPI groups. In each of these four studies, the benefits achieved by the addition of R to chemotherapy were attained without substantially increasing toxicity. The OS rates for the other reported studies for chemotherapy alone and R-chemotherapy combinations (90% v 95% at 2 years;5 74% v 87% at 4 years;6 and 84% v 91% at 42 months,7 respectively) may be superior to those reported here (77% v 83% at 48 months; Table 2), but it is important to note that patients in the other studies who received the more aggressive treatment regimens also received interferon-␣. The effect is similar in all studies that compare chemotherapy versus R plus chemotherapy. In our study, the additional benefit of R-CVP over chemotherapy alone is estimated to be a 40% reduction in the risk of death (HR ⫽ 0.60; 95% CI, 0.38 to 0.96). There is as yet no © 2008 by American Society of Clinical Oncology

Downloaded from jco.ascopubs.org on September 13, 2015. For personal use only. No other uses without permission. Copyright © 2008 American Society of Clinical Oncology. All rights reserved.

4583

Marcus et al

Table 3. TTP According to Baseline Prognostic Factors CVP Prognostic Factor FLIPI score 0 to 1 2 3 to 5 IPI score 0 to 1 2 3 to 4 Histology at central review (IWF) Class B Class C Class D B symptoms† ⱖ1 All absent Bulky disease Yes No Hemoglobin, g/dL ⱖ 12 ⬍ 12

R-CVP

No.

Median TTP (months)

95% CI

No.

Median TTP (months)

95% CI

Pⴱ

23 56 71

22 17 11

16 to 40 13 to 25 10 to 15

28 62 61

NR 37 26

38 to NE 28 to NE 16 to 34

.0085 .0003 .0004

70 57 24

20 14 12

13 to 26 10 to 17 8 to 25

73 57 21

44 27 40

30 to NE 20 to 39 11 to NE

⬍ .0001 .0003 .0333

46 69 19

17 15 14

11 to 24 10 to 21 7 to 24

38 82 19

34 35 NR

27 to NE 26 to NE 30 to NE

.0037 ⬍ .0001 .0046

51 108

17 14

12 to 23 11 to 20

65 97

32 37

22 to NE 26 to 48

.0014 ⬍ .0001

73 86

13 16

11 to 21 13 to 21

63 99

38 32

25 to 48 26 to NE

⬍ .0001 ⬍ .0001

121 35

17 12

13 to 22 10 to 16

132 29

39 11

31 to NE 9 to 28

⬍ .0001 .3941

Abbreviations: TTP, time to progression; CVP, cyclophosphamide, vincristine and prednisone; R, rituximab; FLIPI, Follicular Lymphoma International Prognostic Index; IPI, International Prognostic Index; IWF, International Working Formulation; NR, not reached; NE, not estimable. ⴱ P values without stratification by center pools. †B symptioms were defined as fever, weight loss, and night sweats.

The Cochrane Group meta-analysis of seven randomized studies comparing R-chemotherapy with chemotherapy alone in a combined total of 1,943 patients with previously untreated and relapsed/refractory FL, mantle-cell lymphoma (MCL), or other indolent lymphoma, also recently confirmed a significant survival benefit associated with the addition of R to chemotherapy both for

study directly comparing anthracycline- and non–anthracyclinebased regimens and therefore no proof that such intensive regimens confer long-term benefit compared with R-CVP. It is also worth noting that patients achieving a CR with R-CVP have a prolonged disease-free survival, suggesting that such patients may not require more intensive treatment.

Baseline Parameter

Category

All patients BNLI criteria

Total Yes No

Age (years) Extra-nodal sites BM involved (local) Elevated LDH Elevated B2M IPI (CRF validated) B symptoms Bulky disease Nodal sites Hemoglobin (g/dL) FLIP index (prognosis)

4584

0

0.4

0.8

1.2

1.6

n

Upper Lower 95% CI Estimate 95% CI 0.332 0.231 0.321

0.435 0.390 0.444

≤ 60 > 60 >1 0–1 Yes No Yes No Yes No 0–1 >1

321 91 230 236 85 55 266 205 112 78 226 140 148 143 159

0.336 0.229 0.412 0.299 0.354 0.208 0.250 0.280 0.313 0.242 0.274 0.322

0.461 0.403 0.791 0.406 0.494 0.340 0.446 0.393 0.461 0.375 0.422 0.468

0.570 0.659 0.615 0.632 0.708 1.519 0.549 0.689 0.556 0.794 0.551 0.681 0.580 0.649 0.681

Yes No Yes No 12 ≤ 12 0–2 (good) 3–5 (poor)

116 205 136 185 54 267 251 66 169 132

0.323 0.278 0.277 0.309 0.187 0.317 0.271 0.419 0.271 0.340

0.510 0.396 0.419 0.448 0.415 0.425 0.373 0.740 0.401 0.510

0.806 0.564 0.634 0.649 0.920 0.570 0.513 1.307 0.595 0.764

© 2008 by American Society of Clinical Oncology

Fig 4. Cox regression model of time to treatment progression among patients assigned to chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP) or with CVP plus rituximab, according to baseline prognostic factors. BNLI, British National Lymphoma Investigation; BM, bone marrow; LDH, lactate dehydrogenase; B2M, ␤2-microglobulin; FLIP index, Follicular Lymphoma International Prognostic Index; IPI, International Prognostic Index; CRF, case record form.

JOURNAL OF CLINICAL ONCOLOGY

Downloaded from jco.ascopubs.org on September 13, 2015. For personal use only. No other uses without permission. Copyright © 2008 American Society of Clinical Oncology. All rights reserved.

R-CVP v CVP in Previously Untreated Follicular Lymphoma

the overall cohort and for the subgroups of patients with FL and MCL.9 We have shown that the addition of R to CVP significantly improved TTP across all IPI and FLIPI subgroups. Similarly, the three other studies discussed herein5-7 also demonstrate improvements in all FLIPI or IPI groups, with the index retaining its prognostic significance irrespective of the induction regimen used. Utilizing a different approach to the use of R in previously untreated patients with indolent lymphoma, the Eastern Cooperative Oncology Group study group has reported results of a randomized study to evaluate the role of R maintenance therapy in patients with newly diagnosed indolent non-Hodgkin’s lymphoma after induction chemotherapy alone.10 After CVP treatment to maximum response (six to eight cycles), stable and responding patients were randomly assigned to R maintenance with four once-weekly doses of 375 mg/m2 repeated at 6-month intervals for up to 2 years or to observation. In the subgroup of 237 patients with FL, R maintenance produced a significantly longer PFS compared with no further treatment (61 v 15 months, respectively; P ⫽ 3 ⫻ 10⫺7). This benefit was observed across all FLIPI subgroups, particularly in patients with initial high tumor burden and those with only minimal residual disease after induction. An increase in OS (P ⫽ .03) was also observed in the R maintenance group. However, 20% of patients entering this study were not eligible for random assignment for a variety of reasons. The results of the Primary Rituximab Maintenance trial, now fully recruited but not yet reported, will confirm whether R maintenance is also useful after front-line R-containing chemotherapy induction. In our study, the clinical benefit associated with the addition of R to CVP was confirmed across all subgroups of patients with FL, with the exception of patients with baseline hemoglobin less than 12 g/dL. Low hemoglobin has also been shown to be an unfavorable prognostic factor for response to a standard or prolonged course of R monotherapy in patients with FL or MCL.11,12 This validation of the FLIPI raises the question of whether it might facilitate risk-adapted therapy now that we have confirmed its prognostic value: In our study, poorprognosis (FLIPI 3 to 5) patients receiving R-CVP had a median TTP of only 26 months, suggesting that this subgroup of patients might benefit from more aggressive regimens. This is supported by the results from the German Low-Grade Lymphoma Study Group study of R-CHOP versus CHOP (⫾ interferon or autologous stem-cell transplantation in patients achieving at least a PR after induction) published by Buske et al.13 After an albeit shorter follow-up of only 20 months, the 2-year TTF for R-CHOP followed by interferon-␣ in the subgroup of FLIPI high-risk patients was 67%, significantly shorter than that reported in the low- or intermediate-risk patients (92% and 90%, respectively; P ⬍ .001). The median disease-free survival of the 41% of patients who achieved a CR/CRu with R-CVP has still not been reached after a median follow-up of 53 months. This suggests that this regimen of modest intensity has long-lasting effects in responsive patients and raises the further possibility that future trials might stratify patients by initial response to treatment. For patients achieving less than

CR, the potential role of peripheral-blood stem-cell transplantation or radioimmunotherapy should now be examined. Whether maintenance therapy in all patients with R might further prolong remission in all or a subset of patients receiving R-based induction is also currently being evaluated. This report confirms that the benefits of the addition of R to first-line chemotherapy continue to be observed with long-term follow-up and reinforces the notion that R-containing chemotherapy should be the current standard of care for patients with FL requiring treatment. In addition, we can confirm the continued utility of FLIPI as a tool for predicting duration of response to treatment in the R era. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Elisabeth Wassner-Fritsch, Hoffman La Roche (C) Consultant or Advisory Role: Robert Marcus, Roche (C), Genentech (C); Philippe Solal-Celigny, Roche (C); John V. Catalano, Roche (C); David Cunningham, Roche (C); George Stein, Roche (C) Stock Ownership: None Honoraria: Robert Marcus, Roche, Genentech; Kevin Imrie, Roche; Philippe Solal-Celigny, Roche; John V. Catalano, Roche; David Cunningham, Roche Research Funding: Philippe Solal-Celigny, Roche; John V. Catalano, Roche; Anna Dmoszynska, Roche; David Cunningham, Roche Expert Testimony: David Cunningham, Roche (C) Other Remuneration: None

AUTHOR CONTRIBUTIONS Conception and design: Robert E. Marcus, Philippe Solal-Celigny Financial support: Elisabeth Wassner-Fritsch Administrative support: Elisabeth Wassner-Fritsch Provision of study materials or patients: Robert E. Marcus, Kevin Imrie, Philippe Solal-Celigny, John Catalano, Anna Dmoszynska, Joao Raposo, Fritz Offner, Jose Gomez-Codina, Andrew Belch, David Cunningham Collection and assembly of data: Robert E. Marcus, Kevin Imrie, Elisabeth Wassner-Fritsch, George Stein Data analysis and interpretation: Robert E. Marcus, Kevin Imrie, Philippe Solal-Celigny, Elisabeth Wassner-Fritsch, George Stein Manuscript writing: Robert E. Marcus, Kevin Imrie, Philippe Solal-Celigny, Andrew Belch, David Cunningham, Elisabeth Wassner-Fritsch Final approval of manuscript: Robert E. Marcus, Kevin Imrie, Philippe Solal-Celigny, John Catalano, Anna Dmoszynska, Joao Raposo, Fritz Offner, Jose Gomez-Codina, Andrew Belch, David Cunningham, Elisabeth Wassner-Fritsch, George Stein

REFERENCES

2. Solal-Ce´ligny P, Roy P, Colombat P, et al: Follicular lymphoma international prognostic index. Blood 104:1258-1265, 2004

1. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project: A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 329:987-994, 1993

3. Rohatiner AZ, Gregory WM, Peterson B, et al: Meta-analysis to evaluate the role of interferon in follicular lymphoma. J Clin Oncol 23:2215-2223, 2005

www.jco.org

4. Marcus R, Imrie K, Belch A, et al: CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 105:1417-1423, 2005 5. Hiddemann W, Kneba M, Dreyling M, et al: Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine

© 2008 by American Society of Clinical Oncology

Downloaded from jco.ascopubs.org on September 13, 2015. For personal use only. No other uses without permission. Copyright © 2008 American Society of Clinical Oncology. All rights reserved.

4585

Marcus et al

and prednisone (CHOP) significantly improves the outcome for patients with advanced stage follicular lymphoma compared with therapy with CHOP alone: Results of a prospective randomised study of the German Low-Grade Lymphoma Study Group. Blood 106:3725-3732, 2005 6. Herold M, Antje H, Srock S, et al: Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: An East German Study Group Hematology and Oncology Study. J Clin Oncol 25:1986-1992, 2007 7. Salles GA Mounier N, de Guibert S et al: Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: Final analysis of the GELA–GOELAMS FL2000 study with a five year follow up. Blood 110:110a, 2007 (abstr 792)

8. Cheson BD, Horning SJ, Coiffier B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphoma. J Clin Oncol 17:1244-1253, 1999 9. Schulz H, Bohlius JF, Trelle S, et al: Immunochemotherapy with rituximab and overall survival in patients with indolent or mantle cell lymphoma: A systematic review and meta-analysis. J Natl Cancer Inst 99:706-714, 2007 10. Hochster HS, Weller E, Gascoyne RD, et al: Maintenance rituximab after CVP results in superior clinical outcome in advanced follicular lymphoma (FL): Results of the E1496 Phase III trial from the Eastern Cooperative Oncology Group and the Cancer and Leukemia Group B. Blood 106:106a, 2005 (abstr) 11. Ghielmini M, Rufibach K, Salles G, et al: Single agent rituximab in patients with follicular or mantle cell lymphoma: Clinical and biological factors that

are predictive of response and event-free survival as well as the effect of rituximab on the immune system—A study of the Swiss Group for Clinical Cancer Res (SAKK). Ann Oncol 16:1675-1682, 2005 12. Ghielmini M, Schmitz S, Cogliatti S, et al: Effect of single-agent rituximab given at the standard schedule or as prolonged treatment in patients with mantle cell lymphoma: A study of the Swiss Group for Clinical Cancer Res (SAKK). J Clin Oncol 23:705-711, 2005 13. Buske C, Hoster E, Dreyling M, et al: The Follicular Lymphoma International Prognostic Index (FLIPI) separates high-risk from intermediate- or low-risk patients with advanced-stage follicular lymphoma treated front-line with rituximab and the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with respect to treatment outcome. Blood 108:1504-1508, 2006

■ ■ ■

Acknowledgment The Acknowledgment is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF version (via Adobe® Reader®).

4586

© 2008 by American Society of Clinical Oncology

JOURNAL OF CLINICAL ONCOLOGY

Downloaded from jco.ascopubs.org on September 13, 2015. For personal use only. No other uses without permission. Copyright © 2008 American Society of Clinical Oncology. All rights reserved.