GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)

www.dshnhl.org

Hämatologie im Wandel 2015Aggressive B-und T Zell Lymphome

Lorenz Trümper, Klinik für Hämatologie und Medizinische Onkologie, UniversitätsKrebszentrum, Georg-August-Universität Göttingen

Für die DSHNHLMichael Pfreundschuh, Gerhard Held, Marita Ziepert, Bertram Glaß,

Maike Nickelsen, Gerald Wulf, Markus Loeffler, Norbert Schmitz

GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)

www.dshnhl.org

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

International Prognostic Factors Group NEJM 1993

Prognose aggressiver 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

2

GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)

www.dshnhl.org

IPI Modifikation: NCCN-IPI

Zheng Zhou et al. Blood 2014;123:837-842

©2014 by American Society of Hematology

Stärkere Gewichtungvon Alter undAbsolutem LDH Wert

GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)

www.dshnhl.org

Alizadeh et al. Nature403:503, 2000

Rosenwald et al. NEJM346:1937, 2002

Wright et al. PNAS100:9991, 2003

Prognose aggressiver B NHL: ABC versus GCB

Lenz et al. NEJM359, 2008

w/o rituximab

w rituximab

Aggressive B NHL Erlangen

Lorenz Trümper – Universitätsmedizin Göttingen

51 43 33 20 10 4 3 3 353 49 39 28 23 7 5 1 08 6 4 3 3 0 0 0 0

patients at risk:

p=0.013

GCB (n=66)

non-GCB (n=74)

MYC+ independent of GCB/ non GCB (n=14)

Months

Prop

ortio

n

0 10 20 30 40 50 60 70 80 900

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

51 43 33 20 10 4 3 3 353 49 39 28 23 7 5 1 08 6 4 3 3 0 0 0 0

patients at risk:

p=0.013

GCB (n=66)

non-GCB (n=74)

MYC+ independent of GCB/ non GCB (n=14)

Months

Prop

ortio

n

0 10 20 30 40 50 60 70 80 900

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Clinical Significance of Myc Break Positive NHL

-B1/B2 Trials of DSHNHL

Klapper et al., Leukemia 2009

Johnson et al. (2012) JCO 30: 3452-3459

MYC Expression + BCL2 + BCL6Signifikanter Prädiktor beim DLBCL

Horn et al. (2013) Blood

GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)

www.lymphome.de/en/Groups/DSHNHL

7

Aggressive B-NHLPrimärbehandlung: molekulare prognostische Faktoren

Kein signifikanter prognostischer Unterschied in der Cox-Regression für myc-Rearrangement, keine Unterschiede uni- oder multivariat für alle anderen getesteten Marker bzw. Kombinationen (double-hit, MIB1, p53, bcl6, bcl2, GCB vs nGCB)

B-Zell Rezeptor Mutationen

Wilson, Hematology 2013, ASH EDU

Prognose bei DLBCL• IPI nach wie vor „einfach und gut“• Genetische Daten:

– Genexpressions-Subtypen ABC und GCB haben prognostische Signifikanz

– Myc-Bruch hat prognostische Signifikanz– Double/Triple Hit – ?– Vielzahl von Mutationen und Kombinationen– Mutationen im B-Zell-Rezeptor –

Therapeutisch relevant wenn „addicted“• Prospektive Bio-Screens unerlässlich• Keine Änderung der Therapie!

Coiffier et al., N Engl J Med 2002 Pfreundschuh et al., Lancet Oncol 2006

LN98-5 (elderly) MInT (young good risk)

Immunchemotherapie – Standard beim DLBCL15

DLBCL: Strategien zur Optimierung

modulating humoral immunotherapytiming / dose of rituximab

dose escalationHD therapy / autologous tx

MegaCHOEP

TBICy

DexaBEAM

6-8 x R-CHOP-14/21

Rx

early modulation of therapye.g. PET-guided

intensification

addition of novel agents („targeting“) e.g. bortezomib, lenalidomide, ibrutinib

modulating chemotherapy back-bonee.g. CHOEP / ACVBP / DaEPOCH

dees

cala

tion

reduction of chemotherapy

Rx

reduction / omission of radiation

GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)

www.dshnhl.org

< 60 J. 60 - 80 J. > 80 J.

FLYER

OPTIMAL R-BendaUNFOLDER

MegaCHOEPAmendment 2

aaIP

I 1aa

IPI 0

aaIP

I 2 /

3

Risikogruppen der

supported by

CHOP

CHOP

CHOP

CHOP

CHOP

CHOP

R R R R R R

CHOP

R

CHOP

CHOP

R R R

Rando

Low-risk Very Favourable Group:FLYER (6-6/6-4) STUDY

CHOP

R R

506 Patienten rekrutiert

FLYER (6-6/6-4): 2nd PLANNED INTERIM ANALYSIS (07/13)

Months

Prop

ortio

n

0 10 20 30 40 50 60 70 80 90 1000.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months

Prop

ortio

n

0 10 20 30 40 50 60 70 80 90 1000.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

P F S O S

CHOP21

CHOP21

CHOP21

CHOP21

CHOP21

CHOP21

R R R R R R

CHOP14

R R R R

R

CHOP14

CHOP14

CHOP14

CHOP14

CHOP14

R R

d 105d 1 d 75

+/- Radiation to Bulky Disease

IPI = 1and/orBulk

+/- Radiation to Bulky Disease

Low-risk Less Favourable Group:UNFOLDER (21/14) STUDY

UNFOLDER Study: Interim AnalysisEFS – Patients randomized to 4 arms (n=285)

65%

R-CHOP 21/14 + Rx

(n=146)R-CHOP 21/14 - Rx

(n=139)

p=0.004

Months

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 800

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Prop

ortio

n

81%

UNFOLDER (21/14) STUDY DESIGN

CHOP21

CHOP21

CHOP21

CHOP21

CHOP21

CHOP21

R R R R R R

CHOP14

R R R R

R

CHOP14

CHOP14

CHOP14

CHOP14

CHOP14

R R

d 105d 1 d 75

+ Radiation to BulkyDisease

IPI = 1and/orBulk

+ Radiation to BulkyDisease Recruited 621 pts

Intensified chemotherapy with ACVBP plus rituximab vs. standard CHOP plus rituximab for the treatment of

diffuse large B-cell lymphoma (LNH03-2B) an open-label randomised phase 3 trial

Recher et al. LANCET 2011; 378:1858-67

60 3 12 15 189 21

R-ACVBP

R-CHOP

RWks

MTX R-IFM-VP16 Ara-C

0 2 4 6 10 14 24 Wks

4 IT-MTX

Progression-Free Survival

3-y PFS: 73% after 8x R-CHOP-21

87% after R-ACVBP

p=0.0015, HR 0.48

Junge Patienten mithohem Risiko (aa IPI = 2, 3)

Conventional chemotherapy (CHOEP-14) with rituximab orhigh-dose chemotherapy (MegaCHOEP) with rituximabfor young, high-risk patients with aggressive B-cell lymphoma

Schmitz et al. The Lancet Oncology Volume 13, Issue 12 2012 1250 - 1259

Event-free survival (A), progression-free survival (B), and overall survival (C)for all patients. Overall survival for the 192 patients with age-adjusted IPI 2 (D).

Schmitz et al. The Lancet Oncology Volume 13, Issue 12 2012 1250 - 1259

FOLLOW UP

PFS OS

HDT conventional HDT conventional

Stiff et al.* 2 yrs. 72% 62% 76% 72%

Vitolo et al. 2 yrs. 71% 59% 82% 80%

Schmitz et al. 4 yrs. 67% 72% 75% 85%

Le Gouill et al. 3 yrs. 37% 56% 82% 85%

* PFS and OS for pts. treated with R-CHOP ± HDT

R-HDT or Conventional Therapy (R-Chemo) in Younger Patients with Poor-risk Aggressive B-cell Lymphoma

Ältere Patienten(60 – 80 Jahre)

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=0.6161, 3: p<0.0011, 4: p=0.0013, 4: p=0.317

Months

Prop

ortio

n

RICOVER-60- Progression-free Survival -

3-year rates:

73.4%

68.8%

56.9%

56.9%8x CHOP 146x CHOP 14

6x R-CHOP 14

Pfreundschuh et al., Lancet Oncol. (2008)

8x R-CHOP 14

Figure 2 Survival endpoints (A) Event-free survival. (B) Progression-free survival. (C) Disease-free survival. (D) Overall survival. Shaded areas show 95% CIs.

Richard Delarue , Hervé Tilly , Nicolas Mounier , Tony Petrella , Gilles Salles , Catherine Thieblemont , Serge B...

Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial

The Lancet Oncology, Volume 14, Issue 6, 2013, 525 - 533

http://dx.doi.org/10.1016/S1470-2045(13)70122-0

Failure-free survival

R-CHOP14 533 438 355 224 102 25 1

Patients at Risk

R-CHOP21 534 429 358 216 116 25 1

Years from randomisation

R-CHOP21 R-CHOP14

Pro

babi

lity

0.00.10.20.30.40.5

0.60.70.80.9

1.0

0 1 2 3 4 5 6

0.99 (0.79–1.24)HR (95% CI)p=0.94Log-rank test

75%75%2-yr FFS153 (28)155 (29)Events, n (%)

R-CHOP14R-CHOP21

Cunningham et al. The Lancet. Published online April 22, 2013

M o n t h s0 10 20 30 40 50 60 70 80

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Male without Rituximab(n=325); 3 year rate: 55%

Male with Rituximab(n=325); 3 year rate: 68%

Female without Rituximab(n=287); 3 year rate: 60%

Female with Rituximab(n=285); 3 year rate: 75%

Prop

ortio

n

DSHNHL 26.03.09

RICOVER-60 Trial (n=1222)PFS according to Sex and Rituximab

Murawski et al., ASH 2009

Effect of age, gender, tumor load, and IPI on rituximab clearance.

Michael Pfreundschuh et al. Blood 2014;123:640-646

©2014 by American Society of Hematology

SEXIE-R-CHOP-14

P F S O S

Pfreundschuh et al, ASCO 2014

GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)

www.dshnhl.org

„SMARTER“ - CHOP

Pfreundschuh et al., JCO 2014

Phase II Studie, n = 189 Patienten

6+2 Gaben Rituximab mit „Erhaltung“ bisTag + 240

Im Historischen Vergleich zu Ricover 60

1. Verbesserung Ergebnisse Männer2. Verbesserung Ergebnisse High – Risk

Phase III OPTIMAL rekrutiert

Ausserhalb Studien „on label“ bestes Regime

Gesamtüberleben

Alle

IPI 1,2

IPI 3-5

2xR-CHLIP-14+ 2R + 36 Gy*

Study Design OPTIMAL >60

CD20+ DLBCLIPI=1

No bulk61 to 80 years

4xR-CHOP-14PET +

2xR-CHOP-14+ 2R + 36 Gy

4xRPET -

4 x R4xR-CHLIP-14

PET -

PET +

Vitamin-D ≤8 ng/ml Vitamin-D >8 ng/ml

p=0.094

p<0.001

0.00.10.20.30.40.50.60.70.80.91.0

0 10 20 30 40 50 60 70 80

Months

0 10 20 30 40 50 60 70 800.00.10.20.30.40.50.60.70.80.91.0

Prop

ortio

n

0.00.10.20.30.40.50.60.70.80.91.0

0 10 20 30 40 50 60 70 800.0

0.10.2

0.3

0.40.5

0.60.70.8

0.9

1.0

0 10 20 30 40 50 60 70 800 10 20 30 40 50 60 70 800.0

0.10.2

0.3

0.40.5

0.60.70.8

0.9

1.0

0.0

0.10.2

0.3

0.40.5

0.60.70.8

0.9

1.0

p=0.094 p<0.001

Months

Prop

ortio

n

3-Year EFS Improvement by Rituximab in RICOVER-60

16%31%

Bittenbring et al., JCO 2014

R-CHOP-14

R-CHOP-14

CHOP-14 CHOP-14

GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)

www.dshnhl.org

DLBCL & Rituximab

• „one size fits all“ passt nicht !– Clearance Alters- und Geschlechtsabhängig– Dosis / Expositionsdauer lymphom-typspezifisch– Zelluläre Funktion (ADCC) korreliert mit Vit. D

• Empfehlung– Vit. D substituieren (Zielspiegel 65 ng/ml)– SMARTER schedule „on label“ & wirksam– Optimal?

GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)

www.dshnhl.org

Aggressives B-NHL – DLBCL >65 Jahre

pre Treatment CGA, z.b. Staging, IPI, N CCN-IPI Gespräch mit Patient-CIRS Ausführliche Untersuchung Aufklärung-ADL Anamnese .Gespräch mit Angehörigen-IADL Echokardiographie-KPS Lungenfunktion

Evaluation-Entscheidung

FEV1>50%, Diff. Kap>50% CIRS>6EF > 50%, CIRS < 6

Kurative Therapie Unklar Palliativ-lebensv.TherapieVorphasentherapie VorphasentherapieStratifizierung nach IPI! dann Reevluation

6-8 x R-CHOP-21 R-Bendamustin(BRENDAStudie)6 x R-CHOP-14+ 8 x R R-miniCHOPz.B. OPTIMAL Studie Palliativ-supportive Therapie

Entscheidungsbaum – Ältere Patienten

Studie für Patienten ≥ 81 Jahre, oder Alter 61 bis 80 und CIRS >6, die nicht für eine Therapie mit CHOP qualifizieren

InterimStaging(RE1)

Ende

4x

3x Benda

Final-Staging(RE2)

Re-Staging

(RE3)

RTX*

Follow-Up

PR, SD

CR

Benda3xPrednisolon

R i.v. s.c.

s.c.R R

PD

CR, PR, SD

Vorphase * Therapiephase

InterimStaging

(RE1)

Ende

4x

3x Benda

Final-Staging(RE2)

Re-Staging(RE3)

RTX*

Follow-Up

PR, SD

CR

Benda3xPrednisolon

R i.v.i.v.

i.v.

PD

CR, PR, SD

Vorphase * Therapiephase

RR

Run-In Phase (Patient 1-20)* bei Residualbefund nach initialem Bulk

Hauptphase (Patient 21-100)* bei Residualbefund nach initialem Bulk

DSHNHL 2010-1 (BRENDA)

GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)

www.dshnhl.org

Herrera et al. Cancer 2014.

Bedeutung der Referenzpathologie

Bei peripheren T NHL

GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)

www.dshnhl.org

Schmitz et al., Blood 2010;116(18):3418-3425

Periphere T NHL: Ergebnisse CHOP-ähnlicher Primärtherapie

Event-free survival18-60 years, LDH < UNV)

NHL-B1all PTCL

GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)

www.dshnhl.org

5-y OS (%)

CHOEP and HD-therapy w autol. PBSCT: Swedish registry data

Ellin et al., Blood 2014; 124; 1570-1577

GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)

www.dshnhl.org

6x CHOEP-14/21+ / - IFRT

6x CHOP-14+ / - IFRT

HD-therapyautol. SCT

novel compounds / combinations phase II

HDAC-IRomidep

sin

new agentse.g.Aurora KI

allogeneic SCT

prospective trials

PTCL PTCL

< 60 years > 60 years

primary

treatment

salvagetreatm

ent

prospective trials

ABsz.B. CD52

anti folatepralatrexate

CTXmultiple

regimens

specific entities

ALCLNK/T

aspar.„SMILE“

RT+ CT

6x CHOEP+ / - IFRT

ALK neg: HD-therapyautol. SCT

Adcetris

SCT

prospective trials

IITs

pT-NHL: Treatment Strategies

CHOP versus CHP with Brentuximab vedotin as first line therapy: ECHELON2

• O’Connor OA, et al. ASCO 2013; Chicago, US (Abstract #TPS8611)

DSHNHL: http://www.dshnhl.org/

DSHNHL 2006-1B / ACT-2

alemtuzumab 30 mg s.c.30 mg day 1 courses 1-4 of CHOP-14

antibiotic/antimycotic/virostatic prophylaxisCMV and EBV monitoring

1days 15 29 43

R

71

CHOP

CHOP

CHOP

CHOP

CHOP

CHOP

57

T-cell lymphomaexcept ALCL

61-80 yearsall stagesexcept stage I, IPI 0w/o bulk

CHOP

CHOP

CHOP

CHOP

CHOP

CHOP

A AA A

accrual completed 09.2013

ORR results combined with ACT-1 (NLG)2015

DSHNHL 2006-1A

accrual stopped 08.2013

DSHNHL: http://www.dshnhl.org/

GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)

www.dshnhl.org

Aktuelle Studien und Empfehlungen:

www.dshnhl.org

CHEMO14 according to center decision:- ACVBP14- CHOP14

GAINEDDLBCL, 18-60y, aaIPI = 1-3

Phase III – 2 arms

GA101: 1000mg by injectionD1-D8 cycles 1 -2

MTX BEAM + ASCT

Salvage therapy

∆SUV 0-2> 66%

2-/4-

PET results

PET 0

∆ SUV0-≤ 70%

4+

4

According to randomization arm and CHEMO14 regimen

R

Arm A

Arm B

MTX / GA101-VP-IFOSFAMIDE / Arac

A

B GA101-CHOP-14 x 4

PET 2 PET 4

Induction

∆ SUV0-4>70%

4-

∆SUV 0-2≤ 66%

2+/4-

C1 C2 C3 C4

C1 C2 C3 C4

R-CHEMO14

consolidation

MTX / R-VP-IFOSFAMIDE / AracR-CHOP-14 x 4

GA101-CHEMO14