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R-CVP vs R-CHOP vs R-FM as first line therapy for Advanced Stage Follicular Lymphoma. Final results of FOLL05 trial from the Fondazione Italiana Linfomi. M.Federico, S.Luminari, A.Dondi, S.Sacchi, V.Franco, S.Pileri, M.Lombardo, G.Rossi, L.Arcaini, T.Chisesi, M.Petrini, S.Galimberti, U.Vitolo, F.Di Raimondo, L.Rigacci, AM Carella, F.Angrilli, R.Freilone, A.Ferreri, M.Brugiatelli. On behalf of the FOLL05 Team


Follicular Lymphoma: what we knew in 2005 Phase III studies with Rituximab in FL Regimen

Median No. pts. f-up (mo)

R-Chemo versus Chemo* CR/CRu(%)

ORR (%)

Efficacy

CVP ± R1

321

30

41 vs 10

81 vs 57

median TTF: 27 vs 7 mo

CHOP ± R2†

428

24

20 vs 17

96 vs 90

2-yr PFS: 84% vs 63%

MCP+I ± R3

358

30

49 vs 25

92 vs 75

2-yr EFS: 83% vs 43%

359

31

73 vs 44

94 vs 86

2.5-yr EFS: 78% vs 63%

CHVP+I ± R4

* P < 0.05 for all comparisons between R-Chemo and Chemo † Patients subsequently received interferon or autologous transplant

PRESENTED BY: M. Federico

1. Marcus R, et al. Blood 2005; 105:1417–1423. 2. Hiddemann W, et al. Blood 2004; 104:Abstract 161. 3. Herold M, et al. Blood 2004; 104:Abstract 584. 4. Salles G, et al. Blood 2004; 104:Abstract 160.


Study Design Arm 1

R-CVP > PR

every 21 days R A N D O M

Arm 2

R-CHOP

every 21 days Arm 3

R E A S S E S S M E N T

every 21 days

> PR

+ 2 Rituximab every 21 days every 21 days

R-FM > PR

every 21 days

PRESENTED BY: M. Federico

+ 2 Rituximab every 21 days every 21 days


PRESENTED BY:


Definition of active disease: presence of at least one of the following • • • • • • • • • • •

B Symptoms Extranodal Disease Cytopenia due to BM infiltration Spleen enlargement Leukemic phase Serous Effusions ESR upper normal value LDH upper normal value Nodal or extranodal mass > 7cm 3 or more nodal masses, each of them greater than 3 cm Discomfort due to tumor masses PRESENTED BY: M. Federico


FOLL05

Primary endpoint

Time to Treatment Failure (TTF) Cohort: all pts from registration date

 Failure of induction therapy (<PR, maintenance)  Withdrawal due to unacceptable toxicity or shift to another therapy after at least 1 cycle  Relapse or progressive disease  Death in PR/CR from any cause other than FL Error type I

0.05 adjusted for multiple comparison (Bonferroni)

Sample size: if RR 40% (HR 0.60) 

Power 84% with N=509 (+5% drop out: 534) PRESENTED BY: M. Federico


Enrollment Period The last patient September 2010, 22th

The first patient February 2006, 28th PRESENTED BY: M. Federico


FLOW-CHART 534 Patients recruited Randomization stratified by FLIPI (0-2 vs 3-5)

178 R-CVP

178 R-CHOP

10 Excluded

13 Excluded

2 revised histology

10 revised histology

1 MZL 1 MCL

3 concurrent neoplasia 1 kidney 1 lung 1 AML

4 DLBCL 3 FL+DLBCL 3 MCL

1 HIV+ 2 consent withdrawal

178 R-FM 7 Excluded 5 revided histology 5 DLBCL

1 concomitant neoplasia 1 lung 1 consent withdrawal

5 consent withdrawal

168 eligible for ITT analysis

165 eligible for ITT analysis

171 eligible for ITT analysis

ITT Analysis: 504 patients PRESENTED BY: M. Federico


Patient characteristics - 1 Factor Median age

Status

R-CVP N=168

R-CHOP N=165

R-FM N=171

Total N=504

(range)

56 (31-75)

56 (33-75)

54 (30-75)

56 (30-75)

ITT %

%

>60

32

34

34

33

M

52

50

55

52

Stage

III-IV

92

90

93

92

LDH

>UNL

18

21

21

20

BM

+

50

54

59

54

B2M

>UNL

42

44

47

44

LoDLIN

>6 cm

26

24

29

27

Histology *

grade 3

12

16

12

14

Age Gender

* After central review PRESENTED BY: M. Federico


Patient characteristics - 2 Factor

Status

R-CVP N=168

R-CHOP N=165

R-FM N=171

ITT % FLIPI

FLIPI 2

%

0-1

26

21

18

22

2

36

43

44

41

3-5

38

36

38

37

0

18

19

14

17

1-2

60

53

55

56

3-5

22

27

31

27

χ2 test FLIPI2 by ITT

PRESENTED BY: M. Federico

Total N=504

P= 0.310


Grade 3-4 Toxicity by Arm 63.5

χ2 test or Fisher’s exact test by ITT

60

Percentage

50.0 40

27.7

Anemia Neutropenia Thrombocytopenia Infections

P P P P

= 0.089 <0.001 <0.001 = 0.527

Neutropenia : R-CVP vs R-CHOP

P = 0.015

20

0

0.6

PRESENTED BY: M. Federico

7.6

3.0 4.1

3.0

4.7 2.4 3.0

Thrombocytopenia

Infections

0.0

Anemia

Neutropenia

R-CVP

R-CHOP

R-FM


Grade 3-4 Neutropenia by Arm and Cycle 40 36

36

30

WHO 3-4 (%)

31

30 27

22

21

20

20

18

17

17

15 13

10

12

7 4

0

5

3

1

2

3

4

# cycles R-CVP

PRESENTED BY: M. Federico

R-CHOP

R-FM

5

6


Response by Treatment Arm Response

R-CVP N=168

R-CHOP N=165

R-FM N=171

Total N=504 N (%)*

ITT, N (%) CR

113 (67)

119 (72)

123 (72)

355 (70)

PR

35 (21)

35 (21)

33 (19)

103 (20)

ORR

148 (88)

154 (93)

156 (91)

458 (91)

SD/PD/EW

19 (11)

10 (6)

14 (8)

43 (8)

1 (1)

1 (1)

1 (1)

3 (1)

Lost before treat χ2 test CR by ITT

P= 0.543

χ2 test ORR by ITT

P=0.247

PRESENTED BY: M. Federico

*Due to rounding total percentages may not be100


Time to Treatment Failure and Overall Survival â&#x20AC;&#x201C; FOLL05 (N=504) Cumulative probability (%)

100

75

50

Median follow-up

25

OS TTF

34 months (range 1-70 months)

95% (CI95% 92-97%) at 3y 56% (CI95% 51-60%) at 3y

0 0

6

12

18

24

30

36

42

48

54

60

152 87

87 52

53 29

17 10

Follow-up, months Number at risk OS 504 TTF 504 PRESENTED BY: M. Federico

496 433

478 395

439 335

368 252

290 185

217 133


Primary end-point: Time to Treatment Failure Status

R-CVP N=168

R-CHOP N=165

R-FM N=171

ITT, N (%)*

Total N=504 %*

Censored

82 (49)

105 (64)

105 (61)

292 (58)

<PR

19 (11)

10 (6)

14 (8)

43 (8)

Therapy shift

9 (5)

4 (2)

7 (4)

20 (4)

Maintenance

3 (2)

5 (3)

2 (1)

10 (2)

55 (33)

40 (24)

38 (22)

133 (26)

-

1 (1)

5 (3)

6 (1)

Relapse Death in CR/PR

Expected events at the end of the trial: 211, registered 212 Overall Logrank test PRESENTED BY: M. Federico

P = 0.002

*Due to rounding total percentages may not be100


Events = 212 R-CHOP vs R-CVP R-FM vs R-CVP R-CHOP vs R-FM

TTF by Arm

Logrank 9.35 7.41 0.16

Time to Treatment Failure (%)

100

HR 0.60 0.64 0.94

R-CHOP vs R-CVP R-FM vs R-CVP R-CHOP vs R-FM

75

P 0.002 0.006 0.692

P Adj 0.007 0.020 0.971 CI95% 0.43-0.83 0.46-0.88 0.66-1.33

50

25

R-CVP R-CHOP R-FM

45% at 3y 63% at 3y 59% at 3y

Median follow-up 34 months (range 1-70 months)

0 0

6

12

18

24

30

36

42

48

54

60

23 32 32

13 19 20

5 12 12

1 5 4

Time (months) R-CVP 168 R-CHOP 165 R-FM 171

136 147 150

PRESENTED BY: M. Federico

119 137 139

95 120 120

74 83 95

51 66 68

36 47 50


Risk of TTF with R-CHOP versus R-CVP, according to prespecified subgroups Variable

N

Fail

HR (95% CI)

Age<60

224 97

0.64 (0.43, 0.96)

Age >60

109 49

0.52 (0.29, 0.93)

Hb >12

280 120

0.61 (0.42, 0.87)

Hb <12

53

0.55 (0.25, 1.20)

LoDLIN <6

250 103

0.69 (0.47, 1.02)

LoDLIN >6

83

43

0.42 (0.22, 0.80)

B2M <UNL

190 75

0.60 (0.38, 0.95)

B2M >UNL

143 71

0.58 (0.36, 0.94)

BM -

159 54

0.63 (0.36, 1.08)

BM +

174 92

0.57 (0.38, 0.86)

FLIPI 0-2

211 82

0.59 (0.38, 0.91)

FLIPI 3-5

122 64

0.63 (0.38, 1.04)

26

.2 R-CHOP

.3

.5

.7

1 1.2 1.5

Hazard Ratio PRESENTED BY: M. Federico

2

3 R-CVP


Risk of TTF with R-FM versus R-CVP, according to prespecified subgroups Variable

N

Fail

HR (95% CI)

Age<60

228 95

0.58 (0.39, 0.88)

Age >60

111 57

0.75 (0.45, 1.27)

Hb >12

287 123

0.63 (0.44, 0.90)

Hb <12

52

0.65 (0.31, 1.34)

LoDLIN <6

244 101

0.68 (0.46, 1.01)

LoDLIN >6

95

51

0.54 (0.31, 0.94)

B2M <UNL

188 73

0.58 (0.36, 0.94)

B2M >UNL

151 79

0.65 (0.42, 1.01)

BM -

154 50

0.57 (0.32, 1.01)

BM +

185 102

0.62 (0.42, 0.92)

FLIPI 0-2

210 80

0.57 (0.37, 0.90)

FLIPI 3-5

129 72

0.71 (0.44, 1.12)

29

.2 R-FM

.3

.5

.7

1 1.2 1.5

Hazard Ratio PRESENTED BY: M. Federico

2

3 R-CVP


Events = 183 R-CHOP vs R-CVP R-FM vs R-CVP R-CHOP vs R-FM

PFS by Arm Progression Free Survival (%)

100

R-CHOP vs R-CVP R-FM vs R-CVP R-CHOP vs R-FM

75

Logrank 7.54 5.24 0.23 HR 0.61 0.67 0.91

P 0.006 0.022 0.628

CI95% 0.43-0.87 0.47-0.94 0.63-1.33

50

25

R-CVP 52% at 3y R-CHOP 68% at 3y R-FM 63% at 3y

0 0

6

12

18

Median follow-up 34 months (range 1-70 months) 24

30

36

42

48

54

60

27 36 36

14 22 23

6 14 14

1 6 5

Time (months) R-CVP 168 R-CHOP 165 R-FM 171

154 157 163

PRESENTED BY: M. Federico

136 147 151

108 128 130

85 89 101

60 70 73

41 51 55


Causes of Death by Arm Cause

R-CVP N=168

R-CHOP N=165

R-FM N=171

Total N=504

Disease Progression

4

6

9

19

2nd Cancer

-

1*

4 **

5

Heart Failure

-

1

2

3

Infections

-

-

2

2

Unrelated

-

1

-

1

Total

4

9

17

30

* Glioblastoma ** 2 AML, colon cancer, endometrial cancer PRESENTED BY: M. Federico


Second Malignancies (not Censored as Events)

P = 0.030 PRESENTED BY: M. Federico


How FOLL05 Compares with Literature Data Study

N

ORR %

CR %

OS %

PFS %

Marcus (Blood 2005)

R-CVP

162

81

41

FOLL05

R-CVP

168

88

67

98 (3y)

52 (3y)

Hiddemann (Blood 2005) R-CHOP 222

96

20

95 (3y)

75 (3y)

FOLL05

93

72

96 (3y)

68 (3y)

R-CHOP 165

89 (2.5 y) 50 (32 mo)

Zinzani (JCO 2004)

R-FM

72

96

68

-

71 (3y)

FOLL05

R-FM

171

91

72

92 (3y)

63 (3y)

PRESENTED BY: M. Federico


PFS: comparison with PRIMA study Obs PRIMA study FOLL05 study

57.6% (CI95% 53.2-62.0%) at 3 yr 58.9% (CI95% 53.1-64.2%) at 3 yr

FOLL05

Only patients in CR/PR after induction therapy

PRESENTED BY: M. Federico


Conclusions  R-CHOP and R-FM are both superior to R-CVP in terms of TTF (Primary endpoint of the study)  R-CHOP and R-FM have similar anti-lymphoma activity  R-CHOP and R-CVP are less toxic than R-FM  Maintenance therapy could improve the PFS (indirect conclusion)  R-CHOP is associated with the best risk/benefit ratio

PRESENTED BY: M. Federico


Thanks to All Patients and ……. The Trial office

And

FOLL05 theteam perseverance

The Investigators

of the Coach


R-CVP vs R-CHOP vs R-FMas first line therapy for Advanced StageFollicular Lymphoma