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CLL treatment algorithm

and state of the art

Hematology

IOSI - Oncology Institute of Southern Switzerland

IOR - Institute of Oncology Research

Bellinzona - Switzerland

Davide Rossi, M.D., Ph.D.

• Newly presented pts

• First line pts

• Relapsed pts

CLL subgroups

Clinical applications of biomarkers in CLL

W&W

Asymptomatic Symptomatic

Clinical stage iwCLL criteria

Treatment

Hallek iwCLL 2017

Host Factors: Age, sex, etc

Disease Markers: Stage, lymphocyte count, LDT, etc

Ag expression: CD38, Zap70, CD49d, etc

Serology: 2M, TK, LDH, sCD23, etc

Genetics: del17p, TP53 mutation, del11q22, del13q14, trisomy 12, NOTCH1 mutation, SFRB1 mutation, etc

Biology Markers: IGVH-sequence, BCR-structure

Biomarker: variable that associates with disease outcome

CLL-IPI

Variable Adverse factor Coeff. HR

TP53 (17p) deleted and/or mutated 1.442 4.2

Grading

4

Prognostic Score 0 – 10

IGHV status Unmutated 0.941 2.6

B2M, mg/L > 3.5 0.665 2.0

Clinical stage Binet B/C or Rai I-IV 0.499 1.6

Age > 65 years 0.555 1.7

2

1

2

1

Risk group Score PatientsN (%)

5-year OS, %

HR (95% CI) p value

Very High 7 – 10 62 (5) 23.3 3.6 (2.6 - 4.8) < 0.001

High 4 – 6 326 (27) 63.6 1.9 (1.5 - 2.3) < 0.001

Intermediate 2 – 3 464 (39) 79.4 3.5 (2.5 - 4.8) < 0.001

Low 0 – 1 340 (29) 93.2

International CLL-IPI working group. Lancet Oncol 2016

Time (months)

Overa

ll surv

ival

Low

Intermediate

High

Very high

Overall survival (all patients)


• First line pts

• Relapsed pts

CLL subgroups

CLL10 trial: Progression-free survival

1.0

0.8

0.6

0.4

0.2

0.0

0 12 24 36 48 60

Cu

m s

urv

iva

l

P < 0.001 HR = 1.626 = > 1.388

Median PFS FCR 55.2 months BR 41.7 months

Time to event [PFS] (months)

Eichhorst B, et al. Lancet Oncol. 2016.

Key inclusion criteria: CIRS ≤ 6, CrCl >70 ml/min, no TP53 abn

Adverse event FCR (% of pt)

BR (% of pt)

p value

All 90.8 78.5 <0.001

Hematological AEs 90.0 66.9 <0.001

Neutropenia 81.7 56.8 <0.001

Anemia 12.9 9.7 0.28

Thrombocytopenia 21.5 14.4 0.036

Infection 39.0 25.4 0.001

TRM 3.9 2.1 0.23

FCR is more toxic than BR

Patients ≤65 years: p<0.001 Patients >65 years: p<0.170

FCR=53.6 months

BR=38.5 months

FCR=not reached

BR=48.5 months

FCR > BR in fit and untreated CLL patients (CLL10)

Eichhorst B, et al. Lancet Oncol. 2016

Goede V, et al. NEJM 2014/ Hillmen P. et al, Lancet 2015

CLL11 COMPLEMENT

G-Clb (n=336) R-Clb (n=321) O-Clb(n=217)

Age 74 (39 - 88) 73 (40 – 90) 69 (35 – 92)

ORR 78% 65% 82%

CR 21% 7% 14%

MRD neg. 20% 3% 8%

PFS med.

(mo) 29.2 15.4 22.4

Anti CD20-CLB > CLB in less fit and untreated CLL patients

CIRS score >6 and/or Cr Cl <70 mL/min

Adverse events in Clb-based chemoimmunotherapy

G-Clb (n=336) R-Clb (n=321) O-Clb(n=217)

Any AE grade ≥3 % 70 55 50

Infusion-related

reaction 20 4 10

Neutropenia 33 28 26

Anemia 4 4 5

Thrombocytopenia 10 3 5

Leukopenia 4 <1 -

Infection 12 14 9

Pneumonia 4 5 -

Goede V, et al. NEJM 2014/ Hillmen P. et al, Lancet 2015

Burger J, et al. New Engl J Med 2015

Outcome Ibrutinib (n = 136)

Chlorambucil (n = 133)

P Value

Median PFS, mos NE 18.9 < .0001

18-mo PFS rate, % 90 52

Ibrutinib is superior to chlorambucil as first line treatment in unfit CLL (RESONATE 2)

Key inclusion criteria treatment-naive CLL pts 65 yrs of age or older for pts 65-69 yrs, comorbidity that

precludes FCR no warfarin use no del(17p)

90% PFS at 5 years in TN CLL treated with ibrutinib

Median PFS 5-year PFS

TN (n=31) NR 92% R/R (n=101) 52 mo 43%

Progression-Free Survival Overall Survival

Median OS 5-year OS

TN (n=31) NR 92% R/R (n=101) NR 57%

RESONATE-2: Adverse Events

Tedeschi A, et al. ASH 2015. Abstract 495.

Parameter Ibrutinib (n = 136)

Chlorambucil (n = 133)

Selected AEs, %

Hypertension 14 0

Atrial fibrillation 6 1

Major hemorrhage 4 2

Infection 10 6

• Predictive biomarkes in the 1st line setting

Pts fitness

TP53

IGHV

• Predictive biomarkes in the relapsed setting

Remission duration

TP53

Histology

Outline

MDACC myelosuppression/dose reductions in patients >60 yrs1

early treatment discontinuations in patients 70 yrs2

CLL8 hematological toxicity in patients 65 yrs3

adverse events in pts with increased CIRS4

CLL10 infections in patients >65 yrs5

REACH adverse events in patients with decreased CrCl6 1Keating et al. J Clin Oncol. 2005; 2T Ferrajoli A, et al. Leuk Lymphoma. 2005: S86; 3Hallek et al. Lancet. 2010 ; 4Goede et al. Haematologica (EHA meeting abstracts). 2012; 5Eichhorst et al. Blood. 2014 (ASH meeting abstracts) ; 6Robak et al. J Clin Oncol. 2010

Biomarkers that identify unfit patients

SIOG recommendation for the identification of pts less fit for FCR:

– Older age (e.g. 65 years)

– Higher comorbidity burden (e.g. CIRS >6)

– Impaired renal function (e.g. CrCl <70 mL/min)

CrCl, creatinine clearance

CIRS, cumulative illness rating scale Stauder R et al. Ann Oncol 2017 28: 218-227


Pts fitness

TP53

IGHV


Remission duration

TP53

Histology

Outline

TP53 abnormalities in CLL

5’ 3’

1 DNA BINDING

EX4 EX9

393

Missense Nonsense Frameshift

TP53

Freq

uen

cy

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

MBL Early stage CLL

CLL requiring treatment

F-refactory CLL

Richter syndrome

TP53 M

del17p13

TP53 M/del17p13

N=1/63 (1.5%)

N=30/318 (9.4%)

N=44/99 (44.4%)

N=25/38 (65.7%)

N=13/268 (4.8%)

Dohner et al, New Engl J Med 2000 ; Rasi et al, Haematologica 2012; Zainuddin et al, Leuk Res 2011; Zenz et al J Clin Oncol 2010;Rossi et al Blood 2011; Rossi et al Blood 2014

Chr17

DNA damage

P

p53P

p21

cyclin B

p53P

cyclin B

cdc2p21

BAXCaspase 9

Apoptosis

Cell cycle arrest

M P

del(17p)

p53wt

(rare)

M P

del(17p)p53mut

(>80%)

P P

LOH

p53mut

M P

p53wt/mut

(rare)

M P

normal

p arm

p53

q arm

Badoux Blood 2011; Fisher J Clin Oncol 2011; O’Brien, ASH 2014; Sharman ASH 2014; Byrd ASH 2015; Stilgenbauer, ASH 2015

Chemoimmunotherapy (CIT) vs novel agents in TP53 disrupted CLL

0%

20%

40%

60%

80%

100%

Re

spo

nse

rat

e

0%

20%

40%

60%

80%

100%

CR PR PR-L

35%

7%

83% 78% 79%

12

-mo

nth

s P

FS

18% 22%

80% 79% 72%

Response rate PFS

CIT Novel agents CIT Novel agents

Relapsed/Refractory CLL

‡


Pts fitness

TP53

IGHV


Remission duration

TP53

Histology

Outline

IGHV mutated patients gain the greatest benefit from FCR

1. Thompson PA, et al. Blood 2016; 127:303–309. 2. Fischer K, et al. Blood 2016; 127:208–215. 3. Rossi D et al. Blood 2015; 126 1921–1924, 4. Kipps T et al. ICML14 . .

2 4 6 8 10 12 14 0 16

p<0.0001 0

25

50

75

100

PFS

(%

)

Time (years)

PFS

(%

)

Time (years)

PFS

(%

)

Time (years)

0

25

50

75

100

0 10 2 4 6 8

IGHV mutated

IGHV unmutated

IGHV mutated, FCR

IGHV mutated, FC

p<0.001

MDACC Phase II study (N=300)1 CLL8 study vs. FC (N=817)2

Italian retrospective analysis (N=404)3

100

0

25

50

75

0 2 4 6 8

IGHV unmutated, FC

IGHV unmutated, FCR

IGHV mutated, Ibrutinib

IGHV unmutated, Ibrutinib

IGHV mutated, comparator

IGHV unmutated, comparator

ibrutinib vs ofatumomab

ibrutinib vs chrlorambucil

Ibrutinib-BR vs placebo-BR4

a In patients who are not eligible for any other therapies

Chl: chlorambucil; CIRS: Cumulative Illness Rating Scale; Cr: creatinine Personal communication.

FCR

Chl + anti-CD20

TP53

Chemo + anti-CD20

Age; CIRS;

Cr clearance

BR

Ibrutinib Idelalisib + Ra

IGHV Ibrutinib

Mutated and/or deleted

Wild type

Unmutated

Mutated

Can first line treatment be informed by biomarkers?


• First line pts

• Relapsed pts

CLL subgroups

BR in relapsed CLL lacking del(17p) (HELIOS)

• Chanan-Khan A, et al. Lancet Oncol 2016;17:200–211.

Key inclusion criteria: Relapsed CLL No del(17p)

Key exclusion criteria: Resistance to bendamustine

N=289 (placebo + BR arm)

Placebo + BR

Age, years 63 (median)

del(17p) 0%

Previous lines 2 (mean)

F-refractory 26%

Placebo + BR arm: ORR: 68% Median PFS: 13.3 months

Time (months)

80

60

40

20

0

100

PFS

(%

)

0 16 24 32 8 4 12 20 28

Placebo + BR (mPFS: 13.3 mos)

Ibrutinib + BR (mPFS: NR)


Pts fitness

TP53

IGHV


Remission duration

TP53

Histology

Outline

FC, fludarabine + cyclophosphamide; FCR, FC + rituximab; MDACC, MD Anderson Cancer Center.

1. Tam CS, et al. Blood 2014; 124:3059–3064; 2. Stilgenbauer S and Zenz T. Hematology Am Soc Hematol Educ Program 2010;2010:481–488

Late relapse after first-line chemoimmunotherapy supports maintained sensitivity

Survival after first salvage after FC/FCR first-line failure: CLL8 data2

Survival after first salvage after FCR first-line failure: MDACC data1

36-month cutoff

0.0

0.2

0.4

0.6

1.0

0.8

Cu

mu

lati

ve s

urv

ival

≥6 years (n=46), 5-year OS: 71%

Time (months) 0 24 48 72 96 120 144

3–5.9 years (n=61), mOS: 54 months

1–2.9 (n=34), mOS: 27 months

<1 year (n=15), mOS: 13 months

24-month cutoff

PFS >24 months

PFS 12–24 months

PFS <12 months

Ove

rall

surv

ival

Time (months)

0.0

0.2

0.4

0.6

1.0

0.8

0 6 24 30 36 42 48 12 18

Byrd JC et al. New Engl J Med 2014 371:213-2

Salvage treatment in CLL not suitable for chemoimmunotherapy

R/R CLL Not suitable for F-based Tx • PFS <36 mo • del17p

Ofatumumab (n=195) Ibrutinib (n=196)

100

90

80

70

60

50

40

30

20

10

0 0 6 12 18

Months

Pro

gre

ssio

n-f

ree

su

rviv

al 75% PFS

ORR: 63%

R/R CLL Not suitable for cytotoxic Tx: • PFS <24 mo

Ibrutinib (RESONATE)

R/R CLL Not suitable for cytotoxic Tx: • del17p

Idelalisib-R (116)

ORR: 81%

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 )

Pro

gre

ss

ion

-fr

ee

S

urv

iva

l (

%)

Idelalisib + R (n=110)

Placebo + R (n=110)

60% PFS

ORR: 79%

51% PFS

Venetoclax M13-982

Furman R et al. New Engl J Med 2014 370:997-1007 Stilgenbauer S et al. Lancet Oncol 2016;17:768-78


Pts fitness

TP53

IGHV


Remission duration

TP53

Histology

Outline

Ibrutinib Venetoclax

Eve

nt-

free

su

rviv

al

(pro

po

rtio

nal

)

0.0

0.2

0.4

0.6

0.8

1.0

PFS: 6.8 months2

Time (months)

del(17p) median

0 6 12 18 24 30 36 42

del(11q) del(17p)

Trisomy 12q del(13q) single Other*

Bendamustine -R

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Pro

gre

ssio

n-f

ree

surv

ival

(%

)

Time (months)

Del(17p)/TP53mut

No del(17p)/TP53mut

Idelalisib-R

P=0.94

Event-free survival in relapsed TP53 disrupted patients

1. Imbruvica® SmPC. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003791/WC500177775.pdf (accessed June 2017); 2. Zydelig® SmPC. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003843/WC500175377.pdf (accessed June 2017); 3. Venclyxto® SmPC. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004106/WC500218800.pdf (accessed June 2017).

Idelalisib2 Ibrutinib1 Venetoclax3

Gastrointestinal disorders (consider diarrhoea/colitis risk)

Respiratory insufficiency (consider pneumonitis risk)

Mild/moderate liver impairment

Risk of bleeding-related events (incl. anticoagulant therapy)

History of atrial fibrillation/flutter, cardiac risk

factors, hypertension

Tumour lysis syndrome

Infections

• Cytopenias • Interstitial lung disease • Tumour lysis syndrome • Non-melanoma skin cancer • Drug–drug interactions • Women of childbearing

potential

• Neutropenia • Transaminase elevations • Stevens-Johnson syndrome and

toxic epidermal necrolysis • CYP3A inducers • CYP3A substrates • Hepatic impairment • Chronic hepatitis • Women of childbearing

potential

• CYP3A inducers • Women of childbearing

potential

Neutropenia

Toxicities and management for novel therapies

Lymph node

BCR

CLL CLL

Blood

chemokines

Kinase

Kinase

integrins

Kinase

Inhibitor

De Rooij, Blood 2012; Ponader, Blood 2012; Herman, abstract #185

CLL

CLL

CLL

CLL

Redistribution lymphocytosis

Lymphocytosis + Nodal Reduction with BCR Antagonists

New response criteria are required

Restoration of apoptosis through BCL2 inhibition

Response Classification MRD-negative MRD-positive Not Evaluable

CR/CRi (n=25) 20 5 0

nPR/PR (n=17) 8 8 1a

Other (n=7) 0 1b 6c

Total, n/N (%) 28/49 (57) 14/49 (29) 7/49 (16)

Venetoclax induces deep remissions

Seymour JF, et al. Lancet Oncol. 2017 Feb; 18(2): 230–240.

TLS risk assessment and prevention

Tumor burden (blood count and CT scan)

Renal function

Other co-morbidities

Assess risk factors for TLS

All LN <5 cm and ALC <25 G/L

Any LN 5 to 10 cm or ALC >25 G/L

Any LN >10 cm or ALC >25 G/L and LN >5 cm

Creatinine clearance <80 ml/min increases risk

Risk might increase with co-morbidities, splenomegaly, abnormal baseline chemistry labs, dehydratation

Establish TLS risk Low Medium High

TLS prophylaxis

Low Medium High TLS risk

HYDRATATION

Ensure adequate hydratation throughout dose-titration, particularly 2 days prior to and the days of dosing at initiation and each subsequent dose increase; IV fluids based on TLS risk who cannot mantain adequate oral hydratation

Oral (1.5-2 L) Oral (1.5-2 L) and consider additional IV if tolerated

Oral (1.5-2 L) and IV (150-200 ml/h as tolerated)

ANTI-HYPERURICEMIC AGENTS

Start anti-hyperuricemic agents 2 to 3 days prior to first dose, which may be continued through the titration phase based on the ongoing risk of TLS. Subjects allergic to allopurinol must use another uric acid reducer

Anti-hyperuricemic agents (e.g., allopurinol)

Anti-hyperuricemic agents (e.g., allopurinol)

Anti-hyperuricemic agents (consider rasburicase if

baseline uric acid is high)

BLOOD CHEMISTRY MONITORING

Correct pre-existing blood chemistry abnormalities prior to initiation of treatment. Monitor blood chemistry in real time (turn around <2h): potassium, uric acid, phosphorus, calcium, creatinine

Outpatient monitoring

• Pre-dose, 6-8, 24 h* (at 1° dose of 20 and 50 mg)

• Pre-dose at subsequent ramp-up dosease

Outpatient monitoring

• Pre-dose, 6-8, 24 h* (at 1° dose of 20 and 50 mg)

• Pre-dose at subsequent ramp-up dosease

Consider hospitalization if CrCl <80 ml/min at 1° dose of 20 and 50 mg

In hospital monitoring (1° dose of 20 and 50 mg)

• Pre-dose, 4, 8, 12, 24 h*

Outpatient monitoring (subsequent ramp-up doses)

• Pre-dose, 6-8, 24 h*

*24 h labs: do not administer the next dose until 24 h chemistry results have been evaluated.

Venetoclax in CLL After Failure of Ibrutinib or Idelalisib

100

75

50

25

0

2 4 6 8

PF

S (

%)

10 12 14

PFS

Mos Since First Dose

R/R ibrutinib

R/R idelalisib

All pts

Pts at

Risk, n

43

21

64

0

37

17

54

36

15

51

28

6

34

27

5

32

15

2

17

3

3

0%

20%

40%

60%

80%

100%

Ibrutinib Idelalisib

PR CR

Jones J, et al. ASH 2016. Abstract 637.

• 1. Schetelig J, et al. J Clin Oncol 2008; 26:5094–5100;

2. Dreger P, et al., Blood 2010; 116: 2438–2447; 3. Dreger P, et al. Blood 2013; 121:3284–3288.

Allo-SCT in high-risk CLL (CLL3X)

Eve

nt-

fre

e s

urv

ival

2

Time from SCT (months)

80

60

40

20

0

100

0 96 48 72 24

Eve

nt-

fre

e s

urv

ival

3

Time from SCT (months)

80

60

40

20

0

100

0 120 96 72 48 24

Pro

bab

ility

of

surv

ival

1

Time after HCT (years)

0.8

0.6

4.0

2.0

0.0

1.0

0 7 9 4 3 6 2 1 5 8

OS

PFS

Cu

mu

lati

ve in

cid

en

ce1

Time after HCT (years)

0.8

6.0

4.0

2.0

0.0

1.0

0 7 4 3 6 2 1 5

Relapse incidence

Non-relapse mortality

unknown (18) del(17p) (13) del(11q) (26) Other (21) del(13q) (12)

TP53 mutations (18) TP53 wt (54)

TP53 mutations vs wt: HR=0.82 (95% CI: 0.43–1.58); p=0.56

Retrospective analysis CLL3X trial

CLL3X trial: TP53 mutations

Baseline characteristics that predict outcome after alloSCT: • Remission at the time of alloSCT • Donor–patient HLA match • Donor–patient sex match

• CIR, cumulative incidence of relapse; EBMT, European Group for Blood and Marrow Transplantation; NRM, non-relapse mortality. • Van Gelder M, et al. Blood 2016; 128: Abstract 522 (oral presentation).

Outcome stratification after alloSCT in CLL (EBMT)

1.0

0.8

0.6

0.4

0.2

0.0 0 1 2

Pro

ba

bil

ity

Pro

ba

bil

ity

1.0

0.8

0.6

0.4

0.2

0.0 0 4 8 6 2

Two-year NRM, CIR, and PFS

Time since alloSCT (years)

PFS

PFS

CIR

NRM

Eight-year PFS

‘Good transplant risk’ 46-year-old reference patient with high-risk cytogenetics

Time since alloSCT (years)


Pts fitness

TP53

IGHV


Remission duration

TP53

Histology

Outline

Histology of progressed CLL

Ginè E, et al. Haematologica 2010; 95:1526–1533.

DLBCL-t

‘Accelerated’ CLL

‘Non-accelerated’ CLL

Survival from biopsy (months)

Pro

bab

ility

0.0

0.2

0.4

0.6

0.8

1.0

0 24 48 72 96 120 144 168

DLBCL-t, diffuse large B-cell lymphoma transformation.

Prolymphocytoid

evolution

Richter’s

syndrome

DLBCL variant

WHO 2016 Classification Richter syndrome

Clinical suspicion of transformation1,2

• Asymmetric growth of localised lymph

nodes

• Bulky disease

• B symptoms

• Sudden excessive rise in LDH level

RT

Sensitivity 91%

Specificity 80%

Positive predictive value 53%

Negative predictive value 97%

Max SUV cut-off = 5

PET/CT in RT diagnosis3

CT: computed tomography; LDH: lactate dehydrogenase; PET: positron emission tomography; SUV: standardised uptake values

1. Giné E, et al. Haematologica 2010; 95:1526–1533. 2. Rossi D, et al. Semin Oncol 2016; 43:311–319.

3. Bruzzi JF, et al. J Nucl Med 2006; 47:1267–1273.

DLBCL

Prolymphocytoid

CLL

Second cancer

Histological patterns observed in

biopsies from patients with CLL1,3

Cwynarski K, et al. J Clin Oncol 2012; 30: 2211–2217.

Ove

rall

surv

ival

(p

rop

ort

ion

)

0.8

0.6

0.4

0.2

0.0

1.0

Time (months)

0 60 48 36 24 12

0.8

0.6

0.4

0.2

0.0

1.0

Time (months)

0 60 48 36 24 12 O

vera

ll su

rviv

al

(pro

po

rtio

n)

Allo-SCT (n=25) Auto-SCT (n=34)

Prognostic Factors Chemosensitive disease; RIC

No prognostic factors identified

Post remission SCT is a potentially curative approach for Richter syndrome (EBMT)

Can treatment of R/R CLL be informed by

biomarkers?

BCR: B-cell receptor; R-chemo: rituximab chemotherapy; R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; RIC-allo-SCT: reduced-intensity conditioning allogeneic stem cell transplant; RT: Richter transformation Personal communication.

Histology: CLL

Previous Tx:

R-chemo and

BCR inhibitor

Previous Tx:

R-chemo

BR

Ibrutinib

Idelalisib + R

Venetoclax

Histology: RT

Venetoclax R-CHOP

RIC-allo-SCT RIC-allo-SCT

TP53 wt

Long

remission

duration

TP53 mutated and/or deleted

or

Short remission duration

RIC-allo-SCT

cll treatment algorithm and state of the art - sgh-ssh · cll treatment algorithm and state of the...

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