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Therapeutic Strategies for Elderly Patients with DLBCL Michael - - PowerPoint PPT Presentation

Jun 03, 2023 663 likes •2.05k views

Therapeutic Strategies for Elderly Patients with DLBCL Michael Pfreundschuh German High-Grade Non-Hodgkin Lymphoma Study Group Internal Medicine I, Saarland University Medical School Homburg (Saar), Germany Aggressive Lymphomas in the Elderly

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SLIDE 1

Michael Pfreundschuh German High-Grade Non-Hodgkin Lymphoma Study Group Internal Medicine I, Saarland University Medical School Homburg (Saar), Germany

Therapeutic Strategies for Elderly Patients with DLBCL

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SLIDE 2

Aggressive Lymphomas in the Elderly

DSHNHL 09-19-00

  • Clinical relevance
  • Definition of „elderly“ patients
  • Specific features of elderly patients
  • Treatment options
  • Perspectives
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SLIDE 3

Aggressive Lymphomas in the Elderly

DSHNHL 09-19-00

Clinical Relevance:

  • ~ 40% of all lymphomas
  • > 50% diagnosed >65 years
  • > 15% dignosed >80 years
  • Octa- and nona-generians:

fast-growing population

  • Under- or no presentation in

studies

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SLIDE 4

Patients recruited for prospective trials*

5 10 15 20 25 30 35 40 45 50 <60 60 - 65 66 - 70 71 - 75 76 - 80 * Prospective population based KML Study (Saarland 2000-2003) Age Group (Years)

% recrutied per age group

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SLIDE 5

Aggressive Lymphomas in the Elderly

DSHNHL 09-19-00

  • Clinical relevance
  • Definition of „elderly“ patients
  • Specific features of elderly patients
  • Treatment options
  • Perspective
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SLIDE 6

Aggressive Lymphomas in the Elderly

DSHNHL 09-19-00

Age groups analyzed*:

  • 61 – 65 years
  • 66 – 70 years
  • 71 – 75 years
  • 76 – 81 years
  • >80 years [?]

Ricover-60 Trial of the DSHNHL

}

no difference

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SLIDE 7

RICOVER-60 Trial

Course of leukocytes

DSHNHL 19.05.2003

14 13 12 11 10 9 8 7 6 5 4 3 2 1 12 10 8 6 4 2

61 – 70 y 71 – 75 y 76 – 80 y

leucocytes x 10³/mm³ (median)

Day of CHOP-14 cycle

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SLIDE 8

Grade 3&4 Infections*

10 20 30 40 50 61-70 71-75 76-80 * RICOVER-60 Trial (Pats. # 001-500) % patients with infections

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SLIDE 9

Therapy-associated deaths*

1 2 3 4 5 6 7 8 9 10 11 12 61-70 71-75 76-80 * RICOVER-60 Trial (Pats. # 501-1000) % therapy-associated deaths

8/ 67 4/124 12 / 309

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SLIDE 10

RICOVER60 Trial

Treatment duration – 6 cycles CHOP-14 ± rituximab

DSHNHL 19.05.2003

140 120 100 80 60 40 20 1.0 .9 .8 .7 .6 .5 .4 .3 .2 .1 0.0

D a y s 61 – 70 y: 76 days 71 – 75 y: 73 days 76 – 80 y: 81 days

proportion of patients

median

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SLIDE 11

DSHNHL 19.05.2003

25 20 15 10 5 1.0 .9 .8 .7 .6 .5 .4 .3 .2 .1 0.0

M o n t h s

61 – 70 y 71 – 75 y 76 – 80 y

probability p1-2 = 0.315 p1-3 = 0.002 p2-3 = 0.076

RICOVER60 Trial

E v e n t – f r e e S u r v i v a l

61 – 70 y 71 – 76 y 76 – 80 y

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SLIDE 12

DSHNHL 19.05.2003

25 20 15 10 5 1.0 .9 .8 .7 .6 .5 .4 .3 .2 .1 0.0

M o n t h s probability

p1-2 = 0.004 p1-3 < 0.001 p2-3 = 0.032

RICOVER60 Trial

O v e r a l l S u r v i v a l

61 – 70 y 71 – 75 y 76 – 80 y 61 – 70 y 71 – 75 y 76 – 80 y

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SLIDE 13

IPI according to age groups*

10 20 30 40 50 60 70 80 90 100 61-70 71-75 76-80 * RICOVER-60 Trial (Pats. # 001-500) % IPI 3-5

41% 52% 70%

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SLIDE 14

Aggressive Lymphomas in the Elderly

DSHNHL 09-19-00

  • Clinical relevance
  • Definition of „elderly“ patients
  • Specific features of elderly patients
  • Treatment options
  • Perspectives
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SLIDE 15

Aggressive Lymphomas in the Elderly

DSHNHL 09-19-00

Specific features of „elderly“ DLBCL:

  • prognosis worsening with age
  • hardly explained by protocol adherence
  • partially explained by:
  • different biology
  • poorer risk profile
  • higher deather rate
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SLIDE 16

Aggressive Lymphomas in the Elderly

DSHNHL 09-19-00

Specific features of „elderly“ DLBCL:

  • prognosis worsening with age
  • hardly explained by protocol adherence
  • partially explained by:
  • different biology
  • poorer risk profile
  • higher deather rate
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SLIDE 17

Aggressive Lymphomas in the Elderly

DSHNHL 09-19-00

Specific features of „elderly“ DLBCL:

  • prognosis worsening with age
  • hardly explained by protocol adherence
  • partially explained by:
  • different biology
  • poorer risk profile
  • higher death rate
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SLIDE 18

Outcome Prediction: Molecular vs. Cytological

Ott et al., Blood 2010 (in press)

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SLIDE 19

Aggressive Lymphomas in the Elderly

DSHNHL 09-19-00

DLBCL biology in the elderly:

  • immunoblastic subtype ⇑
  • ABC type ⇑
  • BCL2/MYC double expressors ⇑
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SLIDE 20

Specific Measures:

  • 1. Prephase Treatment
  • 2. Anti-infective Prophylaxis
  • 3. Hydrocortison Substitution

Aggressive Lymphomas in the Elderly

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SLIDE 21

Prephase treatment:

Vincristin 1 mg

i.v. day –7 Prednisone 100 mg p.o. days –7 to –1

Effects:

  • Improvement of performance state
  • Ameliorization of 1st-cycle effect

Aggressive Lymphomas in the Elderly

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SLIDE 22

Prephase treatment:

Vincristin 1 mg

i.v. day –7 Prednisone 100 mg p.o. days –7 to –1

Effects:

  • Improvement of performance state
  • Ameliorization of 1st-cycle effect

Aggressive Lymphomas in the Elderly

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SLIDE 23

Prephase treatment:

Vincristin 1 mg

i.v. day –7 Prednisone 100 mg p.o. days –7 to –1

Effects:

  • Improvement of performance state
  • Ameliorization of 1st-cycle effect

Aggressive Lymphomas in the Elderly

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SLIDE 24

Therapy-associated Deaths before and after Introduction of Prephase Therapy*

1 2 3 4 5

Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6

no prephase with prephase

% therapy-associated deaths

* DSHNHL NHL-B2 Trial

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SLIDE 25

Specific Measures:

  • 1. Prephase Treatment
  • 2. Anti-infective Prophylaxis

(Cotrimoxazole & Aciclovir)

Aggressive Lymphomas in the Elderly

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SLIDE 26

Supported by

Grade 3&4 Infections per Cycle

Effect of Prophylaxis on

Grade 3&4 Infections

DENSE-R-CHOP-14

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SLIDE 27

0% 10% 20% # <=20 # >20

Supported by

12.7%

P a t i e n t s

Grade 3&4 Infections per Cycle

Effect of Prophylaxis on

Grade 3&4 Infections

DENSE-R-CHOP-14

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SLIDE 28

0% 10% 20% # <=20 # >20

Supported by

12.7% 5.7%

P a t i e n t s

Grade 3&4 Infections per Cycle

Effect of Prophylaxis on

Grade 3&4 Infections

DENSE-R-CHOP-14

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SLIDE 29

0% 10% 20% # <=20 # >20

Supported by

p=0.007

12.7% 5.7%

P a t i e n t s

Grade 3&4 Infections per Cycle

Effect of Prophylaxis on

Grade 3&4 Infections

DENSE-R-CHOP-14

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SLIDE 30

0% 10% 20% # <=20 # >20

Supported by

p=0.007

12.7% 5.7%

P a t i e n t s

Grade 3&4 Infections per Cycle Grade 3&4 Infections per Patient

Effect of Prophylaxis on

Grade 3&4 Infections

DENSE-R-CHOP-14

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SLIDE 31

0% 10% 20% # <=20 # >20

0% 20% 40% # <=20 # >20

Supported by

p=0.007

12.7% 5.7% 35.0%

P a t i e n t s P a t i e n t s

Grade 3&4 Infections per Cycle Grade 3&4 Infections per Patient

Effect of Prophylaxis on

Grade 3&4 Infections

DENSE-R-CHOP-14

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SLIDE 32

Specific Measures:

  • 1. Prephase Treatment
  • 2. Anti-infective Prophylaxis
  • 3. Hydrocortisone Substitution

for intercycle fatigue

Aggressive Lymphomas in the Elderly

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SLIDE 33

Aggressive Lymphomas in the Elderly

DSHNHL 09-19-00

  • Clinical relevance
  • Definition of „elderly“ patients
  • Specific features of elderly patients
  • Treatment options
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SLIDE 34

Aggressive Lymphomas in the Elderly

DSHNHL 09-19-00

  • Clinical relevance
  • Definition of „elderly“ patients
  • Specific features of elderly patients
  • Treatment options
  • fit elderly
  • unfit elderly / very old
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SLIDE 35

6 x CHOP-14

+ 30-40 Gy (Bulk, E)

Random 2x2 Factorial Design 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+ DLBCL Stages I-IV 61 to 80 years

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SLIDE 36

RICOVER-60

Overall Survival

10 20 30 40 50 60 70 80 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=0.836 1, 3: p=0.018 1, 4: p=0.260 3, 4: p=0.200

Months Proportion

6x CHOP 14 8x CHOP 14 6x R-CHOP 14 + 2R 8x R-CHOP 14

Pfreundschuh et al., Lancet Oncol. (2008)

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SLIDE 37
  • III. Elderly Patients:

Do we still need Dose Densification / Interval Reduction?

[R-CHOP-14 vs. R-CHOP-21]

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SLIDE 38

LNH 03-6B

66-80 years, aaIPI = 1,2,3

  • R. Delarue, A. Bosly

4 IT MTX

R R-CHOP 21

3 6 9 Wks 12 15 18 21 0 2 4 6 10 14 Wks 8 12

R-CHOP 14

Primary endpoint: EFS Expected improvement: 10% at 3 years with R-CHOP 14 (55 to 65%) 600 patients required (over 4 years)

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SLIDE 39

Delarue et al., ASH 2009 / Lancet Oncology 2013

LNH-03 6B

The French Learning Curve (I) …

Toxic Deaths with R-CHOP-14

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SLIDE 40

% patients

Delarue et al., ASH 2009 / Lancet Oncology 2013

4.6%

LNH-03 6B

The French Learning Curve (I) …

Toxic Deaths with R-CHOP-14

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SLIDE 41

% patients

Delarue et al., ASH 2009 / Lancet Oncology 2013

4.6% 9.0%

LNH-03 6B

The French Learning Curve (I) …

Toxic Deaths with R-CHOP-14

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SLIDE 42

LNH-03 6B

The French Learning Curve (I) …

Toxic Deaths with R-CHOP-14 % patients

Delarue et al., ASH 2009 / Lancet Oncology 2013

4.6% 9.0% 2.5%

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SLIDE 43

3y-OS : 70% vs 73% HR: 0.98 (95%CI: 0.74-1.30); p=0.89 Delarue et al., ASH 2009 / Lancet Oncology 2013

GELA LNH03-6B: The French CHOP-14 Learning Curve (II)

70% 59% 2-year OS: 67% (R-CHOP14) vs 70% (R- CHOP21) 70% 67% 70% 73%

OS Pts. #1-200 OS Pts. #1-600

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SLIDE 44

Adherence to Protocol

RICOVER-60

Relative Dose Cyclophosphamide (median)

6 x CHOP-14 99% 6 x R-CHOP-14 99% 8 x CHOP-14 96% 8 x R-CHOP-14 96% GELA 8xR-CHOP-14 83%

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SLIDE 45

Adherence to Protocol

RICOVER-60

Relative Dose Cyclophosphamide (median)

6 x CHOP-14 99% 6 x R-CHOP-14 99% 8 x CHOP-14 96% 8 x R-CHOP-14 96% GELA 8xR-CHOP-14 83%

Are German patients tougher ?

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SLIDE 46

Adherence to Protocol

RICOVER-60 Relative Dose Intensity Cyclophosphamide (median) 6 x CHOP-14 99% 6 x R-CHOP-14 99% 8 x CHOP-14 96% 8 x R-CHOP-14 96%

  • supportive measures as discussed
  • no dose reductions unless delay >7 days
  • strict adherence to G-CSF schedule
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SLIDE 47

Unresolved Issues in DLBCL

R-CHOP-14 vs R-CHOP-21 in Elderly:

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SLIDE 48

Unresolved Issues in DLBCL

R-CHOP-14 vs R-CHOP-21 in Elderly:

  • Equal efficacy
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SLIDE 49

Unresolved Issues in DLBCL

R-CHOP-14 vs R-CHOP-21 in Elderly:

  • Equal efficacy
  • Equal acute toxicity
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SLIDE 50

ESMO GUIDELINES 2015

Recommendation Elderly DLBCL:

  • 6 cycles R-CHOP-14 + 2 R
  • 8 cycles R-CHOP-21

Tilly et al., Ann Oncol 2015

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SLIDE 51

Unresolved Issues in DLBCL

R-CHOP-14 vs R-CHOP-21 in Elderly:

  • Equal efficacy
  • Equal acute toxicity

What about long-term toxicity ?

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SLIDE 52

R-CHOP: Reduction of EF

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SLIDE 53

Unresolved Issues in DLBCL

R-CHOP-14 vs R-CHOP-21 in Elderly:

  • Equal efficacy
  • Equal acute toxicity
  • Less long-term toxicity (cardiac: yes; second

neoplasms: probably)

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SLIDE 54

Unresolved Issues in DLBCL

R-CHOP-14 vs R-CHOP-21 in Elderly:

  • Equal efficacy
  • Equal acute toxicity
  • Less long-term toxicity (cardiac: yes; second

neoplasms: probably)

  • Shorter time under chemo (10 vs. 21 weeks)
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SLIDE 55

Aggressive Lymphomas in the Elderly

DSHNHL 09-19-00

  • Clinical relevance
  • Definition of „elderly“ patients
  • Specific features of elderly patients
  • Treatment options
  • fit elderly
  • unfit elderly / very old (>80 years?)
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SLIDE 56

¡ ¡Rituximab ¡and ¡reduced ¡dose ¡R-miniCHOP ¡ ¡

for ¡pa7ents ¡aged ¡over ¡80 ¡with ¡DLBCL ¡ ¡

¡

Groupe ¡d’Etude ¡Des ¡Lymphomes ¡De ¡l’Adulte ¡(GELA) ¡ Study ¡LNH03-­‑7B ¡

¡ ¡ Frédéric ¡Peyrade, ¡Fabrice ¡Jardin, ¡ChrisIan ¡Gisselbrecht, ¡Antoine ¡Thyss, ¡Jean ¡François ¡Emile, ¡ ¡Sylvie ¡Castaigne, ¡Bertrand ¡Coiffier, ¡Corinne ¡Haioun, ¡Serge ¡Bologna, ¡Olivier ¡Fitoussi, ¡ ¡ Gérard ¡Lepeu, ¡Christophe ¡Fruchart, ¡Dominique ¡Bordessoule, ¡Michel ¡Blanc, ¡Richard ¡Delarue, ¡ Maud ¡Janvier, ¡Bruno ¡Salles, ¡Andre ¡Bosly, ¡and ¡Hervé ¡Tilly ¡ ¡ ¡

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SLIDE 57

Treatment

R-miniCHOP Dose D1 D2 D3 D4 D5 Prednisone 40 mg/m² X X X X X Rituximab 375 mg/m² X Doxorubicin 25 mg/m² X Cyclophosphamide 400 mg/m² X Vincristine 1 mg DT X

3 months C5 FU1 C1 Inclusion R-miniCHOP C2 C3 FU0 3 w C4 3 w 3 w 3 w 3 w 4 w C6 R-miniCHOP FUn RESPONSE RESPONSE

Primary endpoint: overall survival

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SLIDE 58

Median: 29 months At two years: 59%

Primary endpoint: Overall survival

Intent-to-treat population

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SLIDE 59

Conclusions

  • R-miniCHOP : adapted regimen for DLBCL patients older 80

years

  • Acceptable toxicity, but first treatment cycles represent a

crucial period

  • 59% patients are alive at two years
  • Less toxicity with perphase treatment*

* ASH 2014

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SLIDE 60

Aggressive Lymphomas in the Very Old

DSHNHL 09-19-00

Specific evaluation:

  • Comprehensive geriatric assessment

(CGA)

  • Activities of daily life (ADL)
  • Instrumental acitivties of daily linving

(IADL)

  • Cumulative illness rating score (CIRS)
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SLIDE 61

Aggressive Lymphomas in the Elderly

DSHNHL 09-19-00

Basic geriatric evaluation:

  • Gait speed
  • Timed up and go
  • Hand grip
  • Tinetti gait and blance test
  • Hurria Self Assessment Test
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SLIDE 62

Geriatric ¡Assessment-­‑modified ¡Strategy ¡

Spina et al. 2012

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SLIDE 63

Geriatric ¡Assessment-­‑modified ¡Strategy ¡

Spina et al. 2012

Geriatric ¡Assessment-­‑modified ¡Strategy ¡

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SLIDE 64

Patients >60 Years of Age with Diffuse Large B-Cell Lymphoma (DLBCL) Treated with Standard or Liposomal Chemotherapies Romega et al. ASH 2015

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SLIDE 65

0.00 0.25 0.50 0.75 1.00

Cumulative probability

49 40 35 30 28 25 25 20 11 6 5 5 4 OS 49 36 30 26 23 19 19 15 8 6 4 3 2 PFS 3 6 9 12 15 18 21 24 27 30 33 36

Follow-up, months

PFS OS

Median follow-up: 23 months (range 1-39)

R-BENDA Frail: Outcome

Median OS : 23 months Median PFS : 13 months

2-years OS: 49% 2-years PFS: 38%

R-BENDA Frail, Sergio Storti, Campobasso -Italy

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SLIDE 66

Aggressive ¡Lymphomas ¡in ¡the ¡Elderly ¡

DSHNHL 09-19-00

  • Clinical relevance
  • Definition of „elderly“ patients
  • Specific features of elderly patients
  • Treatment options
  • Perspectives
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SLIDE 67
  • 1. Intensified chemotherapy ?
  • 2. Intensified rituximab ?

Improvement Strategies In Elderly DLBCL

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SLIDE 68
  • 1. Intensified chemotherapy ?
  • 2. Intensified rituximab ?

Improvement Strategies In Elderly DLBCL

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SLIDE 69

RICOVER-60 Trial: Rituximab Clearance

Males Females

p=0.003 Müller et al., Blood 2012

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SLIDE 70

RICOVER-60

Trough Serum Levels

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SLIDE 71

M o n t h s

10 20 30 40 50 60 70 80 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% Female without Rituximab (n=287); 3 year rate: 60%

Proportion

RICOVER-60 Trial (n=1222)

PFS according to Sex and Rituximab

Müller et al, Blood 2012

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SLIDE 72

M o n t h s

10 20 30 40 50 60 70 80 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%

Proportion

RICOVER-60 Trial (n=1222)

PFS according to Sex and Rituximab

Müller et al, Blood 2012

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SLIDE 73

RR p LDH 1.526 0.002 ECOG 1.672 0.001 Stage 1.957 <0.001 Ex>1 1.650 0.001 Male vs. Female 1.127 0.348

RICOVER-60 Trial (n=1222)

Multivariate Analysis PFS

Without Rituximab

Müller et al, Blood 2012

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SLIDE 74

RR p LDH 2.210 <0.001 ECOG 1.743 0.004 Stage 1.450 0.045 Ex>1 1.075 0.724 Male vs. Female 1.592 RR p LDH 1.526 0.002 ECOG 1.672 0.001 Stage 1.957 <0.001 Ex>1 1.650 0.001 Male vs. Female 1.127 0.348

RICOVER-60 Trial (n=1222)

Multivariate Analysis PFS

Without Rituximab With Rituximab

1.592 0.004

Müller et al, Blood 2012

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SLIDE 75

Outcome of Young Females and Males with DLBCL in the MInT Study

24 48 72 96 120 10 20 30 40 50 60 70 80 90 100

Event free survival (%)

male without R (n=221) male with R (n=257) female without R (n=189) female with R (n=156) 115 189 118 116 82 130 81 84 63 94 54 56 14 17 11 13 Number atrisk male without R male with R female without R female with R

months

10 20 30 40 50 60 70 80 90 100 24 48 72 96 120 137 202 127 124 98 138 85 89 75 100 57 61 15 17 11 13 Number atrisk male without R male with R female without R female with R

months Progression-free survival (%)

male without R (n=221) male with R (n=257) female without R (n=189) female with R (n=156) 10 20 30 40 50 60 70 80 90 100 24 48 72 96 120 170 221 153 144 118 157 108 102 94 119 81 71 20 27 20 14 Number atrisk male without R male with R female without R female with R

months Overall survival (%)

male without R (n=221) male with R (n=257) female without R (n=189) female with R (n=156)

E F S P F S O S

Females without rituximab Males without rituximab Males with rituximab Femals with rituximab

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SLIDE 76

Rituximab Clearance in DLBCL according to Age ¡

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SLIDE 77

Rituximab Clearance in DLBCL according to Age ¡

All Patients

p=0.320

20 30 40 50 60 70 80

age

5.0 6.0 8.0 9.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0

Rituximab clearance (ml/hr)

7.0 11.0 10.0

Pfreundschuh et al., Blood 2014

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SLIDE 78

Rituximab Clearance in DLBCL according to Age ¡

All Patients

p=0.320

Males

p=0.168

20 30 40 50 60 70 80

age

5.0 6.0 8.0 9.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0

Rituximab clearance (ml/hr)

7.0 11.0 10.0 20 30 40 50 60 70 80

age

5.0 6.0 8.0 9.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0

Rituximab clearance (ml/hr)

7.0 11.0 10.0

Pfreundschuh et al., Blood 2014

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SLIDE 79

Rituximab Clearance in DLBCL according to Age ¡

All Patients

p=0.320

Males Females

p=0.168

20 30 40 50 60 70 80

age

5.0 6.0 8.0 9.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0

Rituximab clearance (ml/hr)

7.0 11.0 10.0 20 30 40 50 60 70 80

age

5.0 6.0 8.0 9.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0

Rituximab clearance (ml/hr)

7.0 11.0 10.0

20 30 40 50 60 70 80

age

5.0 6.0 8.0 9.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0

Rituximab clearance (ml/hr)

7.0 11.0 10.0

Pfreundschuh et al., Blood 2014

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SLIDE 80

Rituximab Clearance in DLBCL according to Age ¡

All Patients

p=0.320

Males Females

p=0.168 p=0.004

20 30 40 50 60 70 80

age

5.0 6.0 8.0 9.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0

Rituximab clearance (ml/hr)

7.0 11.0 10.0 20 30 40 50 60 70 80

age

5.0 6.0 8.0 9.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0

Rituximab clearance (ml/hr)

7.0 11.0 10.0

20 30 40 50 60 70 80

age

5.0 6.0 8.0 9.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0

Rituximab clearance (ml/hr)

7.0 11.0 10.0

Pfreundschuh et al., Blood 2014

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SLIDE 81

n = 25 24 13 20 5.0 6.0 8.0 9.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0

Rituximab clearance (ml/hr)

7.0 11.0 10.0

♀ ♀ ♂ ♂

eldery patients young patients

Rituximab Clearance in DLBCL Subgroups

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SLIDE 82

n = 25 24 13 20 5.0 6.0 8.0 9.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0

Rituximab clearance (ml/hr)

7.0 11.0 10.0

p=0.005

♀ ♀ ♂ ♂

eldery patients young patients

Rituximab Clearance in DLBCL Subgroups

slide-83
SLIDE 83

n = 25 24 13 20 5.0 6.0 8.0 9.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0

Rituximab clearance (ml/hr)

7.0 11.0 10.0

p=0.005 p=0.004

♀ ♀ ♂ ♂

eldery patients young patients

Rituximab Clearance in DLBCL Subgroups

slide-84
SLIDE 84

n = 25 24 13 20 5.0 6.0 8.0 9.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0

Rituximab clearance (ml/hr)

7.0 11.0 10.0

p=0.005 p=0.004 p=0.015

♀ ♀ ♂ ♂

eldery patients young patients

Rituximab Clearance in DLBCL Subgroups

slide-85
SLIDE 85

Rituximab Pharmacokinetics in DBLC

Clinical Consequences ?

slide-86
SLIDE 86

Rituximab Pharmacokinetics in DBLC

Clinical Consequences (I):

SEXIER-CHOP-14

slide-87
SLIDE 87

Study Design

SEXIE-R-CHOP-14

CD20+ DLBCL Stages I-IV 61 to 80 years

W e e k s

Rituximab 375 mg/m2 Rituximab 500 mg/m2

♀ ♂

12 10 8 6 4 2 14 12 10 8 6 4 2 14

slide-88
SLIDE 88

SEXIE-R-CHOP-14

Trough Serum Levels

  • ­‑1 ¡

0 ¡ 3 ¡ 7 ¡ 14 ¡ 21 ¡ 28 ¡ 42 ¡ 56 ¡ 70 ¡ 84 ¡ 98 ¡ 128 ¡ 154 ¡ 210 ¡ 266 ¡ 294 ¡ 350 ¡ 0 ¡ 50 ¡ 100 ¡ 150 ¡ 200 ¡ 250 ¡

Males ¡ Females ¡

Pfreundschuh et al., ASCO 2014

slide-89
SLIDE 89

SEXIE-R-CHOP-14: PFS

SEXIE-R

Pfreundschuh et al., ASCO 2014

slide-90
SLIDE 90

SEXIE-R-CHOP-14: PFS

RICOVER-60 SEXIE-R

Pfreundschuh et al., ASCO 2014

slide-91
SLIDE 91

Sex ¡as ¡a ¡Risk ¡Factor ¡in ¡Elderly ¡DLBCL ¡Pa7ents ¡ ¡ ¡

Mul7variable ¡Analysis: ¡RICOVER-60 (375mg/m2) vs. ¡SEXIE-R-CHOP-14 (500 mg/m2 )

E F S ¡ P F S ¡ O S ¡

Hazard ratio ¡ [95%-CI] ¡ RICOVER ¡ (n=610) ¡ Hazard ratio ¡ [95%-CI] ¡ SEXIE-R ¡ (n=168) ¡ Hazard ratio ¡ [95%-CI] ¡ RICOVER ¡ (n=610) ¡ Hazard ratio ¡ [95%-CI] ¡ SEXIE-R ¡ (n=168) ¡ Hazard ratio ¡ [95%-CI] ¡ RICOVER ¡ (n=610) ¡ Hazard ratio ¡ [95%-CI] ¡ SEXIE-R ¡ (n=168) ¡

Elevated LDH ¡

1.8 ¡ (p<0.001) ¡ 1.7 ¡ (p=0.170) ¡ 2.2 ¡ (p<0.001) 1.6 ¡ (p=0.238) ¡ 2.1 (p<0.001) 2.2 ¡ (p=0.107) ¡

ECOG>1 ¡

1.8 ¡ (p=0.001) 1.1 ¡ (p=0.873) ¡ ¡ 1.7 ¡ (p=0.004) ¡ ¡ 1.2 ¡ (p=0.719) ¡ ¡ 1.9 (p=0.001) 1.3 ¡ (p=0.644) ¡ ¡

Stages III&IV ¡

1.5 ¡ (p=0.011) ¡ 1.2 ¡ (p=0.755) ¡ 1.5 ¡ (p=0.045) ¡ 1.2 ¡ (p=0.686) ¡ 1.5 (p=0.047) 1.1 ¡ (p=0.791) ¡

>1 extra- lymphatic site ¡

1.0 ¡ (p=0.937) ¡ 1.9 ¡ (p=0.121) ¡ 1.1 ¡ (p=0.724) ¡ 2.0 ¡ (p=0.103) ¡ 1.1 (p=0.817) 1.5 ¡ (p=0.420) ¡

Male vs. female ¡

1.4 ¡

p=0.016 ¡

0.9

p=0.708

1.6

p=0.004

0.8

p=0.613

1.4

p=0.063

0.7

p=0.252

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SLIDE 92

Rituximab Pharmacokinetics in DBLC

Clinical Consequences (II):

SMARTE-R-CHOP-14

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SLIDE 93

time (weeks) Concentration (mg/ml) 10 20 30 40 0.0 0.1 0.2 0.3 0.4 0.5 0.6

Scenario 7

SMARTE-R-CHOP-14 Simulation for a Maximum Area under the Curve (AUC) with 8 x Rituximab

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SLIDE 94

Rituximab Schedules for DLBCL SMARTE- R-CHOP-14 (8 x R)

C H O P C H O P C H O P C H O P C H O P C H O P 15 29

  • 1

43 57 71 85 99

  • 4

155 239

slide-95
SLIDE 95

Rituximab Schedules for DLBCL

C H O P C H O P C H O P C H O P C H O P C H O P 15

RICOVER-60 R-CHOP-14 (8 x R)

Supported by

SMARTE- R-CHOP-14 (8 x R)

29 1 43 57 71 85 99 C H O P C H O P C H O P C H O P C H O P C H O P

  • 4

15 29

  • 1

43 57 71 85 99 155 239

d a y s

slide-96
SLIDE 96

Overall Survival

RICOVER-60 (n=306) SMARTER (n=189) Proportion 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 M o n t h s 5 10 15 20 25 30 35 40 45 50 55 60

78%

median time of observation: 37 / 34 months

SMARTE-R-CHOP-14

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SLIDE 97

Overall Survival

RICOVER-60 (n=306) SMARTER (n=189) Proportion 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 M o n t h s 5 10 15 20 25 30 35 40 45 50 55 60

84% 78%

median time of observation: 37 / 34 months

p=0.118

SMARTE-R-CHOP-14

slide-98
SLIDE 98

Overall Survival

IPI=1,2

SMARTE-R-CHOP-14

slide-99
SLIDE 99

Overall Survival

IPI=1,2

RICOVER-60 (n=183) SMARTER (n=90)

p=0.489

Proportion 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Months 0 5 10 15 20 25 30 35 40 45 50 55 60

SMARTE-R-CHOP-14

slide-100
SLIDE 100

Overall Survival

IPI=1,2 IPI>2

RICOVER-60 (n=183) SMARTER (n=90)

p=0.489

Proportion 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Months 0 5 10 15 20 25 30 35 40 45 50 55 60

SMARTE-R-CHOP-14

slide-101
SLIDE 101

Overall Survival

IPI=1,2 IPI>2

RICOVER-60 (n=183) SMARTER (n=90)

p=0.489

Proportion 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Months 0 5 10 15 20 25 30 35 40 45 50 55 60 RICOVER-60 Proportion 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Months 0 5 10 15 20 25 30 35 40 45 50 55 60 SMARTER (n=99)

67%

(n=123)

SMARTE-R-CHOP-14

slide-102
SLIDE 102

Overall Survival

IPI=1,2 IPI>2

RICOVER-60 (n=183) SMARTER (n=90)

p=0.489

Proportion 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Months 0 5 10 15 20 25 30 35 40 45 50 55 60 RICOVER-60 Proportion 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Months 0 5 10 15 20 25 30 35 40 45 50 55 60 SMARTER

80% 67%

SMARTE-R-CHOP-14

(n=99) (n=123)

slide-103
SLIDE 103

Overall Survival

IPI=1,2 IPI>2

RICOVER-60 (n=183) SMARTER (n=90)

p=0.489

Proportion 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Months 0 5 10 15 20 25 30 35 40 45 50 55 60 RICOVER-60

p=0.034

Proportion 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Months 0 5 10 15 20 25 30 35 40 45 50 55 60 SMARTER (n=99)

80% 67%

(n=123)

SMARTE-R-CHOP-14

slide-104
SLIDE 104

SMARTE-R vs. RICOVER Sex-differential Improvement

Pfreundschuh et al., J Clin Oncol 2014

slide-105
SLIDE 105

Months 0 5 10 15 20 25 30 35 40 45 50 55 60 65 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

80% 76%

SMARTE-R vs. RICOVER Sex-differential Improvement

OS of Females (IPI=3-5)

female RICOVER female SMARTER (n=48) (n=57)

Pfreundschuh et al., J Clin Oncol 2014

slide-106
SLIDE 106

Months 0 5 10 15 20 25 30 35 40 45 50 55 60 65 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

(n=48) female RICOVER (n=57) female SMARTER

80% 76%

Months 0 5 10 15 20 25 30 35 40 45 50 55 60 65 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

male RICOVER (n=66) male SMARTER (n=51)

80% 60%

SMARTE-R vs. RICOVER Sex-differential Improvement

OS of Females (IPI=3-5) OS of Males (IPI=3-5)

Pfreundschuh et al., J Clin Oncol 2014

slide-107
SLIDE 107

Adherence to Protocol

RICOVER-60

1.2 1.1 1.0 .9 .8 .7 .6 .5 .4 .3 .2 .1 0.0 1.0 .9 .8 .7 .6 .5 .4 .3 .2 .1 0.0

6 x CHOP-14 99% 6 x R-CHOP-14 99% 8 x CHOP-14 96% 8 x R-CHOP-14 96%

Relative Dose Cyclophosphamide (median)

slide-108
SLIDE 108

Dosage [mg] cycle 1 cycle 2 cycle 3 cycle 4 cycle 5 cycle 6 cycle 7 cycle 8 total 2.5% 2.4% 5.3% 9.8% 16.4% 22.0% 30.4% 35.5% 11.8% 0.1 - 1.9 10.9% 12.5% 14.7% 17.0% 17.6% 17.4% 17.3% 15.2% 15.0% 2 86.5% 84.9% 79.5% 72.6% 65.3% 59.0% 51.0% 47.9% 72.5% > 2

  • 0.1%

0.2%

  • 0.2%
  • 0.3%

0.1% Vinblastine 0.1% 0.2% 0.3% 0.6% 0.8% 1.4% 1.3% 1.1% 0.6%

Vincristine Administration

RICOVER-60

slide-109
SLIDE 109

Vincristine polyneuropathy: an unmet medical need

Towards the Cure of DLBCL

slide-110
SLIDE 110

R-CHOP-14§

+ 36 Gy BULK-IN-RT*

Random 2x2 Factorial Design Opti-R-CHOP-14§

+36 Gy BULK-INRT*

Opti-R-CHLIP-14&

+ 36 Gy BULK-IN-RT*

R-CHLIP-14&

+ 36 Gy BULK-IN-RT*

Study Design OPTIMAL >60

CD20+ DLBCL IPI 2-4 IPI 1 Bulk 61 to 80 years

Except PET-neg.

§ conventional vincristine 2 mg (absol.) & liposomal vincristine 2 mg/m2

slide-111
SLIDE 111

CHOP:

Cyclophosphamide 750 mg/m2 i.v. day 1 Doxorubicin 50 mg/m2 i.v. day 1 Vincristine 1.4 mg/m2 i.v. (max. 2mg) day 1 Prodniso(lo)ne 100 mg p.o. days 1-5

CHLIP:

Cyclophosphamide 750 mg/m2 i.v. day 1 Doxorubicin 50 mg/m2 i.v. day 1 liposomal Vincristine 2.0 mg/m2 i.v. day 1 Predniso(lo)ne 100 mg p.o. days 1-5

Towards the Cure of DLBCL

slide-112
SLIDE 112

C H O P C H O P C H O P C H O P C H O P C H O P 15

2-week R-CHOP-14 R-CHLIP-14 (8 x R)

Supported by

29 1 43 57 71 85 99

OPTIMAL R-CHOP-14 R-CHLIP-14 (12 x R)

C H O P C H O P C H O P C H O P C H O P C H O P 15 29

  • 1

43 57 71 85 99

  • 4

155 239

d a y s

Study Design OPTIMAL >60

slide-113
SLIDE 113

OPTIMAL>60: Further Improvement ?

Overall Survival

OPTIMAL>60 (n=245) RICOVER-60: 6xR-CHOP-14 (n=306)

slide-114
SLIDE 114

Beyond Rituximab Pharmacokinetics …

slide-115
SLIDE 115

¡ Vitamin ¡D ¡Deficiency: ¡ Not ¡a ¡Problem ¡in ¡„Sunny ¡Rimini“ ¡? ¡ ¡

slide-116
SLIDE 116

RICOVER-­‑60: ¡ Vitamin ¡D ¡serum ¡levels ¡(n=359) ¡

Median: ¡9,2 ¡ng/ml ¡ Bittenbring et al., J Clin Oncol 2014

slide-117
SLIDE 117

RICOVER-­‑60: ¡ Event-­‑free ¡Survival ¡

CHOP ¡

Bittenbring et al., J Clin Oncol 2014

slide-118
SLIDE 118

RICOVER-­‑60: ¡ Event-­‑free ¡Survival ¡

Bittenbring et al., J Clin Oncol 2014

CHOP ¡ R-­‑CHOP ¡

slide-119
SLIDE 119

Rituximab-­‑mediated ¡Cellular ¡Cytotoxicity ¡in ¡ ¡ Vitamin-­‑D ¡Deficient ¡Individuals ¡ before ¡and ¡a_er ¡Subs7tu7on ¡

p = 0.0013 p = 0.0001 p = 0.0027 p = 0.0031 p = 0.0001

R i t u x i m a b c o n c e n t r a t i on

10 20 30 40 50 60 70 0.0 µg/ml 0.0001 µg/ml 0.001 µg/ml 0.01 µg/ml 0.1 µg/ml

Relative lysis (%)

Bittenbring et al., J Clin Oncol 2014 4.5 ng/ml 39 ng/ml

slide-120
SLIDE 120

Rituximab-­‑mediated ¡Cellular ¡Cytotoxicity ¡ ¡ before ¡and ¡a_er ¡Vitamin-­‑D-­‑Subs7tu7on ¡

Bittenbring et al., ASH 2015 0 ¡ 10 ¡ 20 ¡ 30 ¡ 40 ¡ 50 ¡ 60 ¡ 11,2 ¡ 30,4 ¡ 68,5 ¡ 100,5 ¡

% ¡Lysis ¡of ¡CD20+ ¡Daudi ¡Cells ¡ ¡ 0.01 ¡µg/ml ¡Rituximab ¡ ¡

Vitamin D Serum Level (ng/ml)

slide-121
SLIDE 121

Vitamin-D ≤8 ng/ml Vitamin-D >8 ng/ml

p=0.094 p<0.001

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 10 20 30 40 50 60 70 80

Months

10 20 30 40 50 60 70 80 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Proportion

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 10 20 30 40 50 60 70 80 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 10 20 30 40 50 60 70 80 10 20 30 40 50 60 70 80 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

p=0.094 p<0.001 Months Proportion

3-Year EFS Improvement by Rituximab in RICOVER-60

16% 31% Bittenbring et al., J Clin Oncol 2014

slide-122
SLIDE 122

The future:

  • [ Vitamin D substitution: „DR.CHOP“]
  • Lenalidomide
  • BTK inhibitors (Ibrutinib)
  • PI3K inhibitors
  • Bcl-2 inhibitors
  • Combos (PPM + BTK-I + mTor-I)

Towards the Cure of DLBCL

slide-123
SLIDE 123

REAL07 phase II R2-CHOP21 in elderly high risk untreated DLBCL

2-­‑year ¡OS All ¡paIents 92% 2-­‑year ¡PFS ¡ All ¡paIents ¡ 80% ¡ Overall survival (%)

49 47 43 17 39 28 11 7 5

Progression-free survival (%)

At risk, n 49 45 41 15 34 25 9 6 4

100 25 75 50 Time (months) 6 12 30 18 24 36 42 48 Time (months) 6 12 30 18 24 36 42 48

At risk, n

100 25 75 50

PFS ¡ OS ¡

Vitolo ¡U, ¡et ¡al. ¡Lancet ¡Oncol. ¡2014;15:730-­‑7. ¡

slide-124
SLIDE 124

The future:

  • [ Vitamin D substitution: „DR.CHOP“]
  • Lenalidomide
  • BTK inhibitors (Ibrutinib)
  • PI3K inhibitors
  • Bcl-2 inhibitors
  • Combos (PPM + BTK-I + mTor-I)
  • BARs

Towards the Cure of DLBCL

slide-125
SLIDE 125

The future:

  • [ Vitamin D substitution: „DR.CHOP“]
  • BTK inhibitors (Ibrutinib)
  • PI3K inhibitors
  • Bcl-2 inhibitors
  • Combos (PPM + BTK-I + mTor-I)
  • BCR-Antigens for Reverse Targeting

Towards the Cure of DLBCL

slide-126
SLIDE 126

Forward vs. Reverse Targeting

Forward ¡Trage7ng ¡

An7body ¡binds ¡to ¡An7gen, ¡e. ¡g. ¡CD20 ¡

slide-127
SLIDE 127

Forward vs. Reverse Targeting

Forward ¡Trage7ng ¡

An7body ¡binds ¡to ¡An7gen, ¡e. ¡g. ¡CD20 ¡

Reverse ¡Targe7ng ¡

B-­‑Cell ¡Receptor ¡An7gen ¡ ¡ binds ¡to ¡B-­‑Cell ¡Receptor ¡

BCR B Cell

slide-128
SLIDE 128

Forward vs. Reverse Targeting

Forward ¡Trage7ng ¡

An7body ¡binds ¡to ¡An7gen, ¡e. ¡g. ¡CD20 ¡

Reverse ¡Targe7ng ¡

B-­‑Cell ¡Receptor ¡An7gen ¡ ¡ ¡ ¡ ¡ ¡ binds ¡to ¡B-­‑Cell ¡Receptor ¡

BAR BCR B Cell

slide-129
SLIDE 129

Forward vs. Reverse Targeting

Forward ¡Trage7ng ¡

An7body ¡binds ¡to ¡An7gen, ¡e. ¡g. ¡CD20 ¡

Reverse ¡Targe7ng ¡

B-­‑Cell ¡Receptor ¡An7gen ¡ (with ¡Toxin) ¡ binds ¡to ¡B-­‑Cell ¡Receptor ¡

BAR Toxin BCR B Cell

slide-130
SLIDE 130

Forward vs. Reverse Targeting

Forward ¡Trage7ng ¡

An7body ¡binds ¡to ¡An7gen, ¡e. ¡g. ¡CD20 ¡

Reverse ¡Targe7ng ¡

B-­‑Cell ¡Receptor ¡An7gen ¡ (with ¡Toxin) ¡ binds ¡to ¡B-­‑Celr ¡Receptor ¡

BAR BCR B Cell B Cell

slide-131
SLIDE 131

Clinical Relevance of BCR Antigens Homburg BARs identified (25.03.15):

  • 30-50% of MGUS/MM (2 antigens, 1 epitope)
  • 30% of CLL (diverse, ≥2 epitopes each)
  • 25% of FL (1 antigen, 1 epitope)
  • 66% of all PCNSL (1 antigen, 1 epitope)
  • 60% all ABC-DLBCL (1 antigen, 1 epitope)
  • 45% of all MCL (1 antigen, 1 epitope)
  • 90% of IgD-NLPHL (Moraxella catarrhalis)
slide-132
SLIDE 132

Specific Killing of ARS2-pos ABC-DLBCL by BAR-Toxins (Pseudomonas Exotoxin)

slide-133
SLIDE 133
slide-134
SLIDE 134

Growth ¡of ¡heterotransplanted ¡ ARS2-­‑pos. ¡OCI-­‑LY3 ¡in ¡SCID ¡mice ¡

15 µg PE toxin- conjugated BAR i.v.

slide-135
SLIDE 135

BARs: A new dimension in the treatment for a broad spectrum of various B-cell malignancies

  • r :

„Personalized and Precision Medicine at the Limits“

slide-136
SLIDE 136

Thank you !