advances in the treatment of chronic lymphocytic leukemia · 2017-03-16 · advances in the...

Advances in the treatment of Chronic Lymphocytic Leukemia

Lab of B Cell Neoplasia - Division of Experimental Oncology

Strategic Research Program on CLL – Department of Onco-Hematology

Università Vita-Salute San Raffaele - Milano

Istituto Scientifico San Raffaele - Milano

Paolo GhiaPHBE/IBR/0217/0003

Disclaimer:

• The event is supported by Janssen, Pharmaceutical Companies of Johnson & Johnson in EMEA

• The views expressed in these slides are those of the individual speaker(s) and do not necessarily reflect the views of Janssen, Pharmaceutical Companies of Johnson & Johnson in EMEA

• The presentations may include discussions on off-label use of drugs

PHBE/IBR/0217/0003

a PFS representative only; cannot be used to compare regimens directly because results are drawn from across trials with different patient characteristicsB: bendamustine; C: cyclophosphamide; CIT: chemoimmunotherapy; CLL: chronic lymphocytic leukemia; F: fludarabine; PFS: progression-free survival; R: rituximab

1. Shanafelt T. Hematology Am Soc Hematol Educ Program 2013; 2013:158–167. 2. Eichhorst B, et al. ASH 2014 (Abstract 19; oral presentation).

Single-agent alkylating agents

(e.g. chlorambucil)

BR for patients not suitable for FCR2

Purine analogs(e.g. fludarabine)

Combinationchemotherapy (e.g. FC)

Chemoimmunotherapy(e.g. FCR)

1960s 1970s 1980s 1990s 2000s 2010s

1220

34

58

43

2014-16

Novel targeted agents:

idelalisib, ibrutiniband Venetoclax

Representative PFS/TFS (months)1,a

CLL treatment has evolved over multiple decades

PHBE/IBR/0217/0003

ESMO 2016 guidelines update for first line CLL

Confirmed diagnosis of CLL

Early-stage (Binet A/B) with active disease or

advanced stage (Binet C)

Early-stage (Binet A/B) without active disease

Watch and wait until symptomatic

del(17p) or TP53 mutation

FitIbrutinib

OrIdealisib + R*;

Consider alloSCT in remission

Less fitIbrutinib

OrIdealisib + R*;


No del(17p) or TP53 mutation

FitFCR (BR

considered in fit elderly

patients with history of infections)

Less fitClb + CD20 antibody

OrIbrutinib

Eichhorst B, et al. Appendix 6: CLL: eUpdate. Ann Oncol 2016* only if not suitable for alternative treatment

PHBE/IBR/0217/0003







FitIbrutinib

OrIdealisib + R*;


Less fitIbrutinib

OrIdealisib + R*;



FitFCR (BR

considered in fit elderly patients with history of

infections)


OrIbrutinib



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Updated BHS guidelines for first line CLL

Janssens et al, , Belg J Hematol 2015;6(5):195-202

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Long term remissions with FCR

1. Fischer K, et al. Blood 2016; 127:208–215;2. Thompson PA, et al. Blood 2016; 127:303–309.

N

IGHV-M, MRD neg 35

IGHV-M, MRD pos 34

IGHV-UM, MRD neg 35

IGHV-UM, MRD pos 66

75

50

25

0

100

Time (Years)

Per

cen

t P

rogr

essi

on

-Fre

e

1 2 3 4 5 160 6 7 8 9 10 11 12 13 14 15

CLL81

p<0.0001

MDACC2

IGHV, immunoglobulin heavy chain; M, mutated;MDACC, MD Anderson Cancer; UM, unmutated.

N

FCR IGHV M patients 113

FC IGHV M patients 117

FCR IGHV UM patients 197

FC IGHV UM patients 195

0.8

0.6

0.4

0.2

0

1.0

Time (Months)

Pro

bab

ility

of

PFS

12 24 36 48 60 960 72 84

p<0.001 by log-rank test

PHBE/IBR/0217/0003







FitIbrutinib

OrIdealisib + R*;


Less fitIbrutinib

OrIdealisib + R*;



FitFCR (BR

considered in fit elderly patients with history of

infections)


OrIbrutinib



PHBE/IBR/0217/0003

1. Hallek et al. Blood. 2008;111:5446-5456; 2. Hallek et al, Blood. 2012; e-letter, June 04, 2012 Burger J et al, NEJM 2015

RESONATE-2 (PCYC-1115) Study Design

Patients (N=269)• Treatment-naïve

CLL/SLL with active disease

• Age ≥65 years• For patients 65-69

years, comorbidity that may preclude FCR

• del17p excluded• Warfarin use excluded

ibrutinib 420 mg once daily until PD or unacceptable toxicity

chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day

cycle up to 12 cycles

*Patients with IRC-confirmed PD enrolled into extension Study 1116 for follow-up and second-line treatment per investigator’s choice (including ibrutinib for patients progressing on chlorambucil with iwCLL indication for treatment).

Phase 3, open-label, multicenter, international study Primary endpoint: PFS as evaluated by IRC (2008 iwCLL criteria)1,2

Secondary endpoints: OS, ORR, hematologic improvement, safety

IRC-confirmed

progression

PCYC-1116 Extension

Study*

In clb arm, n=43

crossed over to ibrutinib

Stratification factors• ECOG status (0-1 vs. 2)• Rai stage (III-IV vs. ≤II)

RANDOMIZE

1:1

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RESONATE-2 updated efficacy and safety dataORR in the ibrutinib arm

Barr et al., ASH 2016 (abstract 234, oral presentation)

Ibrutinib CR rates continue to improve over time: increasing from 7% at 12 months to

15% at 24 months to 18% with median follow-up of 29 months

PHBE/IBR/0217/0003

Are We Harming Our Patients without MRD?

0 3 6 9 12 15 18 21 24 27 30 33 36 39

1.0

0.8

0.6

0.4

0.2

0.0

Time (months)

GCLLSG CLL11: Obinutuzumab + chlorambucil2

1. Barr et al., ASH 2016; 2. Goede V, et al. N Engl J Med 2014

G-Clb

R-Clb

15.2 26.7

Stratified HR: 0.39

95% CI: 0.31–0.49

p<0.0001

No MRD-negative cases were reported

RESONATE-2:Ibrutinib vs chlorambucil1

88% reduction in the risk of progression or death for patients randomized to ibrutinib

41% of patients receiving chlorambucil have crossed over to receive ibrutinib

PHBE/IBR/0217/0003







FitIbrutinib

OrIdealisib + R*;


Less fitIbrutinib

OrIdealisib + R*;



FitFCR (BR




OrIbrutinib



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TP53 disruption is associated with poor prognosis

Wt: wildtype; OS: overall survival

NonsenseMissense Frameshift

5’ 3’

1

DNA BINDING

EX4 EX9

393TP53

TP53 M

17p-

TP53 M /17p-

Wt

Aberration Incidence

(%)1

Median OS

(months)1

17p del 7 32

11q del 18 79

+12 16 114

Normal 18 111

13q del 55 133

13q deletion assole abnormality

17p deletion

NormalTrisomy 12q11q deletion

Months

% S

urv

ivin

g

0 12 24 36 48 60 72 84 98 108 132 156 180

100

80

40

20

0

60

Wt (n=277; median not reached)

TP53 M (n=14; 30.2 median months)17p- (n=16; median 19.2 months)

Time (months)

Fra

ction A

live

0OS2

0 12 24 36 48 60 72 84 96 108

1.0

0.4

0.10.20.3

0.50.6

0.90.80.7

del13q14

del17p13+12

del11q22-q23

OS1

1. Döhner H, et al. N Engl J Med 2000;343:1910–6; 2. Zenz T, et al. J Clin Oncol 2010;28:4473–9.

PHBE/IBR/0217/0003

FCR not effective in del17p/TP53 disrupted patients

Hallek M, et al. Lancet 2010; Stilgenbauer S, et al. Blood 2014; Pettitt A, et al. J Clin Oncol 2012

CLL8: FCR and FC

in patients with TP53 mut

FC and TP53WT FC and TP53mut

FCR and TP53WT FCR and TP53mut

Time (months)

0.0

0.2

0.4

0.6

0.8

1.0

24 36 48 60 72 840 12 96

Ove

rall

su

rviv

al

Time since randomisation (months)

+12q

13q-single

11q–

Not11p–/11q–/+12q/13q–

17p–

0 6 18 30 32 42 48 662412 54 60

0

10

50

70

100

30

40

60

80

90

20

CLL8: FCR

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ibrutinibdel17p, no

ibrutinibdel17p, yes

ofatumumabdel17p, no

ofatumumabdel17p, yes

Median PFS (mo) NR NR 8.2 5.9

Hazard ratio 1.314 1.413

(95% CI) (0.698-2.473) (1.017-1.963)

P value 0.396 0.039

Thornton et al, EHA 2015 Vienna

No Difference in PFS With or Without Del17p

0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4 2 6

0

2 0

4 0

6 0

8 0

1 0 0

T im e (m o n th s )

No del 64 61 59 59 52 37 21 14 11 8 4 1 1 1

Del 46 41 36 36 33 30 22 12 8 4 3 0

Del17p/TP53mut: Present vs Not Present

Del17p/TP53mut (n=46)No del17p/TP53mut (n=64)

Median PFS (95% CI) p-value

No del 20.3 mo (19.4, ‒ )0.94

Del 16.6 mo (13.9, ‒ )

Pro

gre

ss

ion

fre

e s

urv

iva

l (%

)

Sharman, ASH, 2014, Abstract 330

PHBE/IBR/0217/0003

TP53 Network

• ERIC aims to advance assessment of

TP53 aberrations through education

about:

– Importance of testing all cases needing

therapy, before first and later lines of

treatment

– Quality of appropriate techniques in

diagnostic laboratories to ensure reliable

and comparable results between

institutions

Certification of laboratoriesThessaloniki

Brno

Uppsala

Ulm

London

NovaraMadrid

Paris

Amsterdam

Copenhagen

Bellinzona

www.ericll.org.1L: first-line; 2L: second-line Pospisilova S, et al. Leukemia 2012; 26:1458–1461.

Disease stage Clinical trial General

practiceComment

Diagnosis Recommended Not

indicated

Results of TP53 mutation testing will not influence

initial watch and wait strategy

1L treatment Recommended Desirable Patients with TP53 mutation should be entered

onto a clinical trial exploring new therapeutic

agents>2L treatment Recommended Desirable

Patients should be treated with BCR

pathway inhibitor Recommended

Update coming soon

PHBE/IBR/0217/0003







FitIbrutinib

OrIdealisib + R*;


Less fitIbrutinib

OrIdealisib + R*;



FitFCR (BR




OrIbrutinib



PHBE/IBR/0217/0003

Idelalisib in first line: changes in 2016

March SeptemberApril May June July August

2016

EC: European Commission; EMA: European Medicines Agency; CHMP: Committee for Medicinal Products for Human Use; PJP: Pneumocystis jirovecii pneumonia; PRAC: Pharmacovigilance Risk Assessment Committee

EMA press release (8 July 2016; available at www.ema.europa.eu). EMA press release (22 July 2016; available at www.ema.europa.eu).

Zydelig SmPC (Date TBC 2016; available at www.ema.europa.eu).

8 July

• PRAC concluded its review of idelalisib and recommended idelalisib-treated patients: • receive PJP prophylaxis during treatment and for up to 6 months after treatment end

• are regularly monitored for CMV infection if CMV serology is positive at start of treatment or if

there is a history of CMV infection

• Patients with evidence of CMV viraemia and clinical signs of infection should have their

treatment interrupted until the infection is resolved

• are monitored for infection and have regular blood tests for white cell counts

• PRAC also concluded that idelalisib can again be initiated in first-line CLL treatment, in

patients with del(17p)/TP53 mutation who are ineligible for other therapies

15 September. Final EC decision

22 July

• The CHMP confirmed the PRAC recommendations

PHBE/IBR/0217/0003

A cross-study analysis: ORR, del(17p)

Median time on

study, mo (range)42 (0.9-61) 31 (0.3-37) 28 (0.5-31) 28 (0.3-61)

CR*8%

CR*8%

CR*10%

CR*9%

ORR81%

ORR89%

ORR83%

ORR84%

*CR = CR + CRi Median duration of response not reached at 30 months

– Of patients with CR/CRi (n=23), 81% maintained response at 30 months

CLL, chronic lymphocytic leukemia; CR, complete response; CRi, CR with incomplete marrow recovery; IBR, ibrutinib; ORR, overall response rate; PR, partial response; PR-L, partial response with lymphocytosis; R/R, relapsed/refractory; SLL, small lymphocytic lymphoma; TN, treatment-naïve Jones, EHA 2016, S429

PHBE/IBR/0217/0003

Results: PFS and OS, del(17p)

12-mo OS, % (95% CI)

24-mo OS, % (95% CI)

30-mo OS, % (95% CI)

85% (80, 89) 75% (68, 80) 67% (59, 74)

Median OS not reached

With a median (range) study duration of 28 (0.3-61+) months, median PFS and OS were not reached

12-mo PFS, % (95% CI)

24-mo PFS, % (95% CI)

30-mo PFS, % (95% CI)

80% (74, 84) 63% (57, 69) 55% (48, 62)

Median PFS not reached

CLL, chronic lymphocytic leukemia; IBR, ibrutinib; OS, overall survival; PFS, progression-free survival; R/R, relapsed/refractory; SLL, small lymphocytic lymphoma

PFS OS

Jones, EHA 2016, S429

PHBE/IBR/0217/0003

21

EMA approval for Venclyxto on 08DEC16

• Venclyxto monotherapy is conditionally approved for the treatment of

chronic lymphocytic leukaemia (CLL) in the presence of 17p deletion or

TP53 mutation in adult patients who are unsuitable for or have failed a

B-cell receptor pathway inhibitor


CLL in without 17p deletion or TP53 mutation in adult patients who

have failed both chemoimmunotherapy and a B-cell receptor pathway

inhibitor

Venetoclax WE&C Advisory Board I 2016

PHBE/IBR/0217/0003

IRC,

n (%)

Investigator, n (%)

Overall Response 85 (79.4) 79 (73.8)

CR or CRi 8 (7.5) 17 (15.9)

nPR 3 (2.8) 4 (3.7)

PR 74 (69.2) 58 (54.2)

No response 22 (20.6) 28 (26.2)

Stable disease NA 24 (22.4)

Disease progression NA 2 (1.9)

Incomplete data NA 2 (1.9)

• 25 of 48 patients with no CLL in the bone marrow

• 18 of 45 patients assessed were MRD-negative in PB

Stilgenbauer et al, Lancet Oncology 2016

Ultra-high Risk R/R CLL patients with del17pBest Response with Venetoclax

PHBE/IBR/0217/0003

Of 45 patients tested, 18

achieved MRD-negativity in

peripheral blood

MRD-Negativity

Cumulative Incidence of Response

Stilgenbauer et al, Lancet Oncology 2016

PFS and OS (N=107)

• 12-month estimates (95% CI):

– PFS: 72.0% (61.8, 79.8)

– OS: 86.7% (78.6, 91.9)PHBE/IBR/0217/0003

ESMO 2015 clinical practice guidelines for R/R CLL

Relapsed CLL requiring treatment or refractory CLL

Early relapse(within 24–36 months after

chemoimmunotherapy)

FitClinical studyBCR inhibitor

(± R)Consider allo-

SCT in remission

Less fitClinical studyBCR inhibitor

(± R)(BR or FCR-Lite may be

considered if no del(17p)

or TP53 mutation)

Late relapse(≥24–36 months after

chemoimmunotherapy)


FitClinical study

Repeat frontlineor change to

BR/FCR or BCR inhibitor (± R)

Less fitClinical study

Repeat frontlineor change to BR or BCR inhibitor

(± R)


Treat as perearly relapse

Eichhorst B, et al. Ann Oncol 2015; 26(Suppl 5):v78–v84

PHBE/IBR/0217/0003

Updated BHS guidelines for Relapsed/Refractory CLL

Janssens et al, , Belg J Hematol 2015;6(5):195-202

PHBE/IBR/0217/0003

Median PFS 5-year PFS

TN (n=31) NR 92%

R/R (n=101) 52 mo 43%

Median OS 5-year OS

TN (n=31) NR 92%

R/R (n=101) NR 57%

5-year experience with ibrutinib in TN and R/R CLL

O’Brien et al., ASH 2016 (abstract 233, oral presentation)

PHBE/IBR/0217/0003

5-year experience with ibrutinib in TN and R/R

O’Brien et al., ASH 2016 (abstract 233, oral presentation)

• Dose reductions and dose discontinuations due to AEs occurred more frequently in R/R patients

than in TN patients, and during the first year after treatment compared with subsequent time periods.

PHBE/IBR/0217/0003

Searching for MRDHELIOS (BRI versus BR)

Fraser G, et al. J Clin Oncol 2016; 34(suppl):Abstract 7525.

BR, bendamustine + rituximab;CRi, CR with incomplete marrow recovery; OR, overall response.

As of March 2016, 60/289 (20.7%) on

IBR+BR demonstrated MRD-negativity

2-yr update (October 2015)

Fraser G, et al. EHA 2016

ORR (investigator assessment)

53,3%

0

20

40

60

80

100

Ibrutinib + BR Placebo + BR

7.2%

Pat

ien

ts (

%)

OR = 87.2% versus 66.1% (p<0.0001)

PR

CR/CRi

58.9%

33.9%

PHBE/IBR/0217/0003

29

EMA approval for Venclyxto on 08DEC16


chronic lymphocytic leukaemia (CLL) in the presence of 17p deletion or

TP53 mutation in adult patients who are unsuitable for or have failed a

B-cell receptor pathway inhibitor


CLL in without 17p deletion or TP53 mutation in adult patients who

have failed both chemoimmunotherapy and a B-cell receptor pathway

inhibitor

Venetoclax WE&C Advisory Board I 2016

PHBE/IBR/0217/0003

Roberts AW, et al. N Engl J Med 2016; 374(4): 311-22; EHA 2016 P209

80%MRD-neg (% of CR) 35%

Complete responses with BCL2 inhibitors: ABT-199

PHBE/IBR/0217/0003

Brander, EHA 2016 P223

M13-365: Venetoclax Combined with

Rituximab in Patients with R/R CLL/SLL

* Two discontinued with no

evidence of progression. Seymour JF et al, Lancet Oncol 2017

None of the MRD-negative patients have progressed;

2 patients with MRD-positive CR/CRi had

asymptomatic progression

55% of patients MRD-negative (27/49)

11 patients stopped venetoclax after achieving

an objective response (9 MRD-negative);

9 remain in follow-up*

Venetoclax + Rituximab in Patients with R/R CLLM13-365 (N=49)

*

*

#

0 5 10 15 20 25 30 35 40

Time on venetoclax

Time off venetoclax

# MRD-negative PR

* Discontinued from study

Asymptomatic progression

PHBE/IBR/0217/0003

Arm An=43

Arm Bn=21

Best response, n (%)

Assessed by Assessed by

IRC Investigator IRC Investigator

ORR 30 (70) 29 (67) 13 (62) 12 (57)

CR/CRi 0/1 (2) 2 (5)/1 (2) 0/0 2 (10)/1 (5)

nPR 0 2 (5) 0 0

PR 29 (67) 24 (56) 13 (62) 9 (43)

Non-responder*

SD

PD

D/C‡

13 (30)

–

–

–

14 (23)

9 (21)

1† (2)

4 (9)

8 (38)

–

–

–

9 (43)

8 (38)

1† (5)

0*Non-responder category for IRC includes both SD or PD, which were not identified as separate categories per IRC.†CLL progression and discontinued due to progression.‡D/C, patient discontinued the study prior to assessment.

ORR to ABT-199 in CLL after Ibrutinib or Idelalisib10 June 2016

Jones J et al, ASH 2016 Oral presentation

PHBE/IBR/0217/0003

ORR to ABT-199 in CLL after Ibrutinib or Idelalisib10 June 2016

PD, progressive disease. PD-RT, progressive disease due to Richter's transformation. Early discontinuations were due to AEs (n=3) and withdrawn consent (n=1).

Median time on study (range): Arm A, 13 months (0.1–18); Arm B, 9 months

(1.3–16)

T im e o n v e n e to c la x , m o n th s

0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0

P D

P D

P DP D

P D -R T

P D

P D

P D -R T

P DP D

P D

P D

P D

P D

P D

Arm

AA

rm

B

* #

#

#

#

#

#

#

#

#

#

#

#

#

#

A rm A (R /R ib ru t in ib )

A rm B (R /R id e la lis ib )

D is c o n tin u e d

C R i a s b e s t re s p o n s e*M R D n e g a tiv e in b lo o d#

Jones J et al, ASH 2016 Oral presentation

PHBE/IBR/0217/0003

Anthony Mato. Optimal Sequencing of Ibrutinib,

Idelalisib, and Venetoclax in CLL:Results from a Large Multi-Center Study of 683 US-Patients

• 683 patients treated with KI therapy (IBR=621; IDELA=62) were included

• Significantly better PFS for IBR vs IDELA in all settings; front-line, R/R, clinical trials, commercial use, del17p, or CKT

Response to first kinase inhibitor

ORR 69%

ORR 81%

Mato A et al, ASH 2016 Oral presentation

PHBE/IBR/0217/0003

ESMO 2015 clinical practice guidelines for R/R CLL

Relapsed CLL requiring treatment or refractory CLL

Early relapse(within 24–36 months after

chemoimmunotherapy)

FitClinical studyBCR inhibitor

(± R)Consider allo-

SCT in remission

Less fitClinical studyBCR inhibitor

(± R)(BR or FCR-Lite

may be considered if no del(17p) or TP53

mutation)

Late relapse(≥24–36 months after

chemoimmunotherapy)


FitClinical study

Repeat frontlineor change to

BR/FCR or BCR inhibitor (± R)

Less fitClinical study

Repeat frontlineor change to BR or BCR inhibitor

(± R)


Treat as perearly relapse

Eichhorst B, et al. Ann Oncol 2015; 26(Suppl 5):v78–v84

Patients not responding nor progressing upon therapy with kinaseinhibitors might be switched to a different kinase inhibitor or to

BCL2 antagonists when available (according to clinical trials) Eichhorst B, et al. Appendix 6: CLL: eUpdate. Ann Oncol 2016

PHBE/IBR/0217/0003

IS THIS THE END OF CHEMOTHERAPY?

Previously untreated Fit CLL patients (N=920)(CIRS ≤6 and normal creatinine clearance)

FCR*or

BR^

ABT-199+

Rituximab

Randomise

Follow-up for progression and survival

ABT-199+

Obinutuzumab

ABT-199Obinutuzumab

Ibrutinib

2 primary endopints- Rate of MRD negativity- PFS

*<65 years of age

^>65 years of age

Obinutuzumab: 6 cycles

Venetoclax: 12 cycles

Ibrutinib: 36 cycles or MRDneg

CLL13-TRIAL OF THE GCLLSG in cooperation with HOVON, Nordic CLL

Study Group and SAKK (GAIA)

PHBE/IBR/0217/0003

Laboratory of B Cell Neoplasia

Lydia Scarfò, Andreas Agathangelidis, Maria Gounari,

Alessandra Rovida, Tania Veliz-Rodriguez, Engin Bojnik,

Pamela Ranghetti, Federica Barbaglio, Cristina Scielzo

Laboratory of Lymphocyte Activation

Eleonora Maria Fonte, Maria Giovanna Vilia,

Marta Muzio

Strategic Research Program on CLL

Lydia Scarfò, Piera Angelillo, Maria Colia,

Virginia Sgarlato, Stefania Cresta, Eloise Scarano

Università Vita-Salute San Raffaele

Istituto Scientifico San RaffaeleDepartment of Onco-Hematology

Division of Experimental Oncology

CERTH, Thessaloniki

Anna Vardi, Stavroula Ntoufa,

Aliki Xochelli, Anastasia

Hadzidimitrious,

Kostas Stamatopoulos

Uppsala University, Uppsala

Lesley Ann Sutton, Panayotis

Baliakas, Viktor Ljungstrom,

Richard Roseqnuist

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advances in the treatment of chronic lymphocytic leukemia · 2017-03-16 · advances in the...

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