A phase III trial comparing R-CHOP 14 and R-CHOP 21 for the

treatment of newly diagnosed diffuse large B cell lymphoma

Results from a UK NCRI Lymphoma

Group Study

D. Cunningham, P. Smith, P. Mouncey, W. Qian, C. Pocock, K. M. Ardeshna,

J. Radford, J. Davies, A. McMillan, D. Linch on behalf of the NCRI trial collaborators

Abstract: 8506

Author Disclosures

• No disclosures

Background and rationale

• Non-Hodgkin lymphoma is increasing in incidence;– 287,000 cases worldwide each year1

• Diffuse large B cell lymphoma (DLBCL) accounts for 31% all NHL2

• The addition of rituximab to 6-8 cycles of CHOP21 improves overall survival of DLBCL by 9-13% 3-5

• 6 cycles of CHOP14 improved 5yr survival by 13% compared with 6 cycles of CHOP21 in patients aged >60yrs6

1Ferlay et al, GLOBOCAN 2001; 2Armitage et al, JCO 1998, 3Coiffier et al, NEJM2002. 4Feugier et al JCO 2005;

5Pfreundschuh et al, Lancet Oncol 2006, 6Pfreundschuh et al, Blood 2004

RICOVER-60 study

Pfreundschuh M; Lancet Oncol 2008

Findings•Only R-CHOP14 superior to CHOP14 in terms of event- free survival, PFS and OS (3 yr OS 78.1% vs 67.7%)

•R-CHOP14 x 8 no better than R-CHOP14 x 6

Does 6 or 8 cycles of R-CHOP14 improve outcomes compared to CHOP14 in patients aged 61-80?

6x CHOP14

8x CHOP14

6x R-CHOP14

8x R-CHOP14

RandomisedStage I-IVn=1222

Study aim: R-CHOP14 vs 21

Does R-CHOP14 improve outcomes compared to R-CHOP21 in treatment of DLBCL?

Trial design: R-CHOP14 vs 21

Newly diagnose

dCD20+ve

DLBCL

RANDOMISATION

R-CHOP21CHOP21 8 cycles

Rituximab 8 cycles

R-CHOP14CHOP14 6 cyclesRituximab 8 cyclesLenograstim Day 4-12

n=540

n=540Stratified by

•IPI (0-1, 2, 3, 4-5)•Age <60 vs. 60•Treatment centre

Major eligibility criteria• Inclusion

– Age ≥ 18 years– Histologically proven CD20+ DLBCL (WHO classification)

• Pathology centrally reviewed– Stages: bulky IA (>10cm), IB, II, III, IV– Previously untreated– WHO Performance status 0-2– Normal cardiac function

• Exclusion– Transformed follicular lymphoma– Previous indolent lymphoma

• New diagnosis of DLBCL with some small cell infiltration in bone marrow or lymph node allowed

– CNS involvement– Known to be HIV, Hepatitis B or C serology positive

Outcome measures and sample size

Primary: -Overall survival (OS)Secondary:-Failure free survival (FFS)

-Toxicity up to 30 days post Rx-Response (CR, CRu)*

Sample size:330 events required to detect a difference of 8% in 2-year OS from 70% to 78%; a total of 1080 patients planned

*International Workshop Standardised Response Criteria for NHL

Trial recruitment

1080 patients; 119 sitesRecruitment March 2005 - Nov 2008

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Patient characteristicsR-CHOP21 % (n=540)

R-CHOP14 % (n=540)

Age ≤ 60 yrsmedian

4761yrs (19-88)

4861yrs (19-85)

Gender male 54 54

WHO PS 0-12

8613

8613

B symptoms yes 44 47

stage I-IIIII-IV

3863

3762

Bulky disease yes 49 52

IPI score 0-12-34-5

315317

315517

Central review confirmed DLBCL in 96%

Recruitment by age

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50

100

150

200

250

300

350

400

450

<30 30-39 40-49 50-59 60-69 70-79 80+

Age range

Pat

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ecru

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52%

Treatment administrationR-CHOP21

n=462n (%)

R-CHOP14 n=481n (%)

Total no. of cycles received

0-45-67-8

33 (7) 58 (13) 379 (82)*

23 (5)23 (5)

435 (91)*

Total number stopped early

Reasons for stopping early

ToxicityLack of

response/PD/deathPatient/Clinician choiceChange in diagnosisOther

n=89

3028146

11

n=50

2312546

Final data on 183 patients pending *p=0.0002

Patients without Rx delaysR-CHOP21 R-CHOP14*

Cycle # treated without delay

# receiving cycle

# patients receiving G-CSF

# treated without delay

# receiving cycle

1 16 %

2 80 % 28 % 86 %

3 85 % 36 % 91 %

4 85 % 40 % 91 %

5 83 % 45 % 87 %

6 83 % 48 % 81 %

7 85 % 51 % 90 % (R alone)

8 86 % 44 % 95 % (R alone)

*R-CHOP14: all receive G-CSF cycles 1-6

Toxicity during treatmentToxicity grade ≥ 3 R-CHOP21

%R-CHOP14

%Neutropenia* 58 31

Thrombocytopenia* 4 9

Anaemia 1 2

Febrile neutropenia* 13 (2 deaths) 5

Infection 22 (1 death) 18 (2 deaths)

Cardiac 0.4 2

Neurological 7 11

Other grade 5 toxicities

n=4 n=4

*p< 0.01 (considered significant due to multiple testing)

Overall response rates

Based on end of treatment scan

n=831

R-CHOP21 n= 405

%

R-CHOP14 n=426

%

CR 49 40

CRu 14 18

PR 24 32

SD 6 5

PD/relapse 6 4

CR/CRu p=0.183

63 58

CR/CRu/PR p=0.139

88 91

249 patients not evaluable or data missing

CR/CRu by characteristics

n R-CHOP21

%R-CHOP14

%

Age

≤ 60 (406)> 60 (425)

5669

5661

WHO 0 (443)1 (288)2 (100)

675765

625552

Stage I/II (317)III (243)IV (260)

676360

655754

IPI 0-1 (265) 2-3 (450)4-5 (116)

676259

665357

All p values for interaction >0.05

Follow up

Median follow up: • 17 months

Events:• Deaths n=150 (14%)

• Total progression/relapse/death n=209 (19%)

Cause of death

Any Cause of Death

n=150 (%)

Disease 103 (69)

Treatment related toxicity

13 (9) R-CHOP21: 6, R-CHOP14: 7

Cardiac* 4 (2)*All in R-CHOP21 arm

Secondary malignancy 7 (5)

Other 18 (12)

Unknown 5 (3)

*All cardiac deaths occurred 3-15 months after completing Rx

Failure-free survival: Entire cohort

209 1080Events Totals

PATIENTS at Risk1080 804 575 391 256 126 58 8 0

0.0

0.2

0.4

0.6

0.8

1.0

Months from randomisation0 6 12 18 24 30 36 42 48

2-year FFS: 74%; 95% CI: 71%-77%

Overall survival: Entire cohort

150 1080Events Totals

PATIENTS at Risk1080 834 621 434 278 134 61 8 0

0.0

0.2

0.4

0.6

0.8

1.0

Months from randomisation

0 6 12 18 24 30 36 42 48

2-year OS: 81%; 95% CI: 78%-84%

FFS and OS by response*

OSFFS

1.0

53 9144 23670 504

Events Totals

PATIENTS at RiskCR/CRuPRSD/PD/Relapse

504 468 353 247 168 87 38236 215 155 102 67 28 1491 63 34 21 12 7 5

CR/CRuPR SD/PD/Relapse

0.0

0.2

0.4

0.6

0.8

Months from randomisation0 6 12 18 24 30 36

53 9144 23670 504

Events Totals

504 468 353 247 168 87 38236 215 155 102 67 28 1491 63 34 21 12 7 5

CR/CRu

PR

SD/PD/Relapse

0.0

0.2

0.4

0.6

0.8

1.0

Months from randomisation0 6 12 18 24 30 36

*Based on end of treatment scan (n=831)

FFS and OS by IPI score

IPI score

43 16783 58424 329

Events Totals

329 264 205 149 92 41 18584 447 330 229 149 70 32167 123 86 56 37 23 11

0-12-3 4-5

0.0

0.2

0.4

0.6

0.8

1.0

Months from randomisation0 6 12 18 24 30 36

OS

47 167125 58437 329

Events Totals

329 257 194 139 88 39 16584 429 301 203 135 66 31167 118 80 49 33 21 11

0-1 2-3 4-5

0.0

0.2

0.4

0.6

0.8

1.0

Months from randomisation0 6 12 18 24 30 36

FFS

0-12-34-5

Patients at risk

FFS and OS by prognostic factors

Failure Free Survival 0verall Survival

2 year FFS % p value 2 year OS % p value

Age≤60>60

7673

p=0.488379

p=0.047

WHO012

807356

p<0.0001877963

p=<0.0001

StageI/IIIIIIV

817068

p=0.0017858175

p=0.012

IPI score0-12-34-5

857260

p<0.0001908064

p<0.0001

• Response rate (CR/CRu +/- PR)-6 x R-CHOP14 (+ 2 x R) no better than 8 x R-CHOP21-No difference amongst prognostic subgroups (including IPI)

• Toxicity-Non-haematological toxicities similar in both arms

-More neutropenia, febrile neutropenia with R-CHOP21

-More thrombocytopenia with R-CHOP14

Conclusions

• Overall survival for the entire cohort is favourable with 80% patients still alive at 2 years from time of randomisation

• Final analysis will be performed when 330 deaths have occurred (predicted in Oct 2010)

Conclusions

Acknowledgements

• 119 participating centres in the UK• CRUK & UCL Cancer Trials Centre• Chugai Biopharmaceuticals• 1080 patients and their relatives