aggressive b-celllymphomas in theelderly · 2019. 6. 7. · aggressive lymphomas in theelderlysiog...

Aggressive Lymphomas in the Elderly SIOG Berlin Oct 09

Lorenz Trümper – Universitätsmedizin Göttingen

„ Treatment of aggressive B-Cell Lymphomas in the Elderly “

Lorenz TrümperAbteilung Hämatologie & Onkologie

Göttingen Comprehensive Cancer Center Universitätsmedizin Göttingen

1

Centroblastic Immunoblastic

Diffuse large B-cell lymphoma, not otherwise specified (NOS)

3

NHLim Alter NHL – 10 most frequent

DiagnoseH

äufig

keit

in %

NHLim Alter Lymphoma Characteristics

Diagnose

0

20

40

60

80

100

Chronische lymphatische

Leukämie

Follikuläres LymphomDiffus großzelliges Lymphom

Burkitt-Lymphom

Therapieerfolg Überleben

5 Ja

hre

nach

Dia

gnos

e %

NHLim Alter Treatment strategies

Therapie

Indolent Lymphoma

CLLAggressive Lymphoma

Limited Radiation Watch & waitChemotherapy

± Moab± RadiationAdvanced

Chemotherapy± Moab

± Radiation

Chemotherapy(+) Moab

Trials/singlecases

TransplantationRadioimmunthx

MoabTransplantation

TransplantationRadioimmunthx

Lymphoma

Involvement

Risk Score CR (%) 5-year OS (%)

International Prognostic Factors Group NEJM 1993

Prognosis of aggressive NHL: IPI

Risk Group # Factors 5-y OSAge > 60 y Low 0,1 73ECOG PS > 1 Low-Intermed 2 51Stage III or IV High Intermed 3 43Extr sites > 1 High 4,5 26LDH > normal

7



0%

20%

40%

60%

80%

100%

0 5 10 15 20 25Years from Registration

ProMACE-CytaBOMm-BACODCHOPMACOP-B

At Risk233223225218

Events173164175170

10-YearEstimate

37%35%34%32%

Fisher et al. NEJM 1993

Primary Treatment of aggressive B-NHL: CHOP

8

NHLim Alter Life expectancy – RKI data

Basis

Sonnen & Kuse, DMW 1998

Aggressive NHL in elderlyTreatment outcome and prognosis

Autor, JahrGruppe

Therapie n AlterMedian

CR%

OAS%

nach

Tirelli, 1998 EORTC CHOPVMP

6060

70-93 75

4527

65*30 2 J

Bastion, 1997GELA

CTVPCVP

233220

> 6975

47*32

27*19 5 J

Sonneveld, 1995 DHOSG

CHOPCNOP

7276

60-84 70

49*31

42*26 3 J

Meyer, 1995 Ontario CHOPCHOPw

1919

> 6571

6874

74*51

2 J

Osby, 2003 (NLG) CHOPCNOP

203205

7171

60*34

57*32 3J

Treatment of aggressive lymphomas in the elderlyTx with less intensity – no anthracycline?

NHLim Alter CHOP: Bad in old age?

Therapie

"Alters-CHOP"CHOP0

20

40

60

80

100

VMP CHOPw CNOP

2-3

J-Ü

berle

ben

%



12–2004

07–2000: Interim analysis (ASH 2000)05–2001: Update of interim analysis (EHA 2001)09–2001: Analysis at end of study (NEJM 2002)12–2002: 3-year follow-up analysis12–2004: 5-year analysis (Feugier JCO)

09–200105–2001

07–2000

12–2002

Years

1.0

0 1 2 3 4 5 6 70.0

0.2

0.4

0.6

0.8

Even

t-fre

e su

rviv

alImprovement 1 over CHOP: Rituximab – CHOP (elderly)

GELA / Coiffier et al.

LN98-5

13


Lorenz Trümper – Universitätsmedizin Göttingen 14

Improvement 2: Dose density,G-CSF supported (CHOP-14)

9080706050403020100

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

CHOEP-14 (n=169)

CHOEP-21 (n=170)

CHOP-21 (n=178)

CHOP-14 (n=172)

months

Pfreundschuh, Trümper et al (Blood 2004)

CHOP-14 56%

CHOP-21 42%

6 x CHOP-14+ 30-40 Gy (Bulk, E)

Random2x2

FactorialDesign

8 x CHOP-14+ 30-40 Gy (Bulk, E)

8 x CHOP-14+ 36 Gy (Bulk, E)

+ 8 x Rituximab

6 x CHOP-14+ 36 Gy (Bulk, E)

+ 8 x Rituximab

Study Design RICOVER-60

CD20+ DLBCLStages I-IV

61 to 80 years

RICOVER-60 - Event-free survival -

0 10 20 30 40 50 60 70 800

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1: 6 x CHOP 14(n=307)2: 8 x CHOP 14(n=305)3: 6 x R-CHOP 14(n=306)4: 8 x R-CHOP 14(n=304)

1, 2: p=0.0371, 3: p<0.0011, 4: p<0.0013, 4: p=0.561

Months

Prop

ortio

n

3-years rate:

66.5%

63.1%

53.0%

47.2%

6x R-CHOP 14

8x R-CHOP 14

8x CHOP 14

6x CHOP 14

Pfreundschuh et al. Lancet Oncology 2008

16

NHLim Alter Pre-Phase Treatment

Diagnose

„Sick due toNHL“

Pre PhaseTreatment

Re-assessment⇨ ⇨



RICOVER-60: Conclusion

• CHOP-14 plus Rituximab is safe and feasible

• EFS – significant increase !

• No significant difference between 6 or 8 cycles of R-CHOP-14

• 6 x CHOP-14 + 8 x Rituximab is the new standard– less toxicityand cost, same efficacy as 8 cycles

III. Elderly Patients

Is further

Improvement

possible ?

Study Design DENSE-R-CHOP-14


61 to 80 years

CHOP

CHOP

CHOP

CHOP

CHOP

CHOP

12 141086420

W e e k s

Study Design DENSE-R-UP-CHOP-14


61 to 80 years

121086420

121086420

W e e k s

Rituximab 375 mg/m2

Rituximab 500 mg/m2

♀

♂

121086420 14

121086420 14

1

2

2

1

R-CHOP-14+ 36 Gy IN-RT*

Random2x2

FactorialDesign

DENSE-R-CHOP-14+36 Gy IN-RT*

DENSE-R-CHMP-14+ 36 Gy IN-RT*

R-CHMP-14+ 36 Gy IN-RT*

Study Design DENSE-R-CHO/MP-60UNFAVORABLE

CD20+ DLBCLIPI 2-4

IPI 1 Bulky61 to 80 years

* Except Interim-PET-neg.



„ Denser“ RituximabConclusion

• Pharmakokinetics ….. Also important forMoAb Tx

• Phase III for early densification planned• Significant sex-related differences• Increased rate of opportunistic

infections – prophylaxis in the elderlylike in AML etc !!!

23



m o n t h s

Prop

ortio

n

0 10 20 30 40 50 60 70 800

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

6xR-CHOP-14 / no Rxbulk(n=47)

6xR-CHOP-14 + Rxbulk(n=117) 68%

43%

p=0.002

RICOVER-Trials Follow up: EFS of patients in PR

Depending on Consolidative Radiation



RICOVER-Follow up Trial: PFS of patients in CR

0 10 20 30 40 50 60 70 800

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Months

Prop

ortio

n

p=0.512

6xR-CHOP-14 + Rxbulk(n=33)

6xR-CHOP-14 / no Rxbulk(n=20)

Median time of observation: 18/34 months



Role of Radiation Tx in elderlyAggressive NHL pts

• Consolidation (36-40 Gy GHD)– In initial bulky disease pts only when

remaining lymphoma on CT– Dto. In extranodal– Contralateral testis in testis lymphoma

• Palliative• Decreased Chemo-Tx + Radiation – not

superior to full dose chemotherapy

26

Radioimmuntherapie bei Lymphomen – Onkologische Aspekte


Bias in clinical trials: KML results

27



DSHNHL Elderly Trial - BR

• Open, non-randomized phase II• Elderly non-fit pts (not fit for R-CHOP-14)• Geriatric assessment• Dose-dense Rituximab + Bendamustin• PI U. Wedding / DSHNHL trial office

28



Acknowledgements

• DSHNHL – M. Pfreundschuh, N. Schmitz, L. Trümper B. Glaß, G. Wulf, M. Ziepert, S. Zeylanova, M. Loeffler

• UMG – C. Binder, K. Hohloch, G. Wulf, E. Stitz, J. Hasenkamp, A. Borgerding

D S H N H L

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aggressive b-celllymphomas in theelderly · 2019. 6. 7. · aggressive lymphomas in theelderlysiog...

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