CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL)State-of-the-art

Davide Rossi, MD, PhD

Haematology

IOSI - Oncology Institute of Southern Switzerland

IOR - Institute of Oncology Research

Bellinzona - Switzerland

DIAGNOSIS

WHO 2016 CLASSIFICATION OF CLL

Swerdlow SH, et al. Blood 2016 127:2375-2390

Disease Defining criteria

CLL • >5 G/L clonal B-cells CD5+/CD23+, <55% prolymphocyte in PB

SLL• <5 G/L clonal B-cells CD5+/CD23+

• Nodal, splenic or other extramedullary involvement

MBL

• <5 G/L clonal B-cells CD5+/CD23+

• Low-count MBL (<0.5 G/L)

• High-count MBL (>0.5-4.9 G/L)

• No nodal, splenic or other extramedullary involvement

DIFFERENTIAL DIAGNOSIS BASED ON MORPHOLOGY

Comparison of typical CLL cells vs. B-prolymphocytic leukaemia

CLL B-PLL

Typical lymphocytes from 45% to 100% in PB

Prolymphocytes >55% in PB

Hallek M, et al. Blood 2018;131(25):2745-2760

Images Courtesy of Prof Randy Gascoyne

DIFFERENTIAL DIAGNOSIS BASED ON

FLOW CYTOMETRY

CLL MCL SMZL HCL

CD19 + + + +

CD20 +low +bright +bright +bright

IgS +low +bright +bright +bright

CD5 + + -/+ -

CD23 + - -/+ -

FMC7 - + -/+ -

CD79b - + -/+ -

CD200 + - -/+ +

CD25 - - -/+ +

CD103 - - - +

Hallek M, et al. Blood 2018;131(25):2745-2760

BONE MARROW EVALUATION IS INDICATED ONLY IN

CASE OF OTHERWISE UNEXPLAINED CYTOPENIAS

E.g. differential diagnosis between bone marrow failure vs. autoimmune cytopenia

Extensive diffuse marrow infiltration by CLL

Cytopenia due to marrow failure

Limited nodular marrow infiltration by CLL

Immune cytopenia

Hallek M, et al. Blood 2018;131(25):2745-2760. Images from By LindseyRN/Shutterstock.com

COUNSELLING ABOUTEXPECTED SURVIVAL

CLL-IPI

CLL-IPI calculation requires for testing molecular biomarkers (i.e. FISH

and mutations of TP53 and IGHV)

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

Time (months)O

ve

rall

su

rviv

al

Low

Intermediate

High

Very high

Reprinted from Lancet Oncol, 17(6), International CLL-IPI working group. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data

779-790, Copyright (2016), with permission from Elsevier.

TREATMENT INDICATION

STAGING OF CLL

relies solely on a physical examination and standard laboratory tests

and does not require ultrasound or CT scan

Rai stage LN S Hb Platelets

0 - - >11 g/dl >100 x 199/l

I + - >11 g/dl >100 x 199/l

II - + >11 g/dl >100 x 199/l

III +/- +/- <11 g/dl >100 x 199/l

IV +/- +/- >o<11 g/dl <100 x 199/l

Binet stage Nodal areas Hb Platelets

A <3 >10 g/dl >100 x 199/l

B >3 >10 g/dl >100 x 199/l

C +/- <10 g/dl <100 x 199/l

Rai system

Binet system

CLUES OF DISEASE ACTIVITY

• Progressive marrow failure (cytopenias)

• Massive (i.e., at least 6 cm below the left costal margin) or progressive or symptomatic

splenomegaly

• Massive nodes (i.e., at least 10 cm in longest diameter) or progressive or symptomatic

lymphadenopathy

• Constitutional symptoms (rare in CLL)

• Progressive lymphocytosis / lymphocyte doubling time (carefully re-check)

Hallek M, et al. Blood 2018;131(25):2745-2760

IWCLL GUIDELINES CRITERIA FOR TREATMENT

Disease Stage/Status General Practice

Rai Stage 0 Not generally indicated

Binet Stage A Not generally indicated

Binet Stage BRai Stage I/II

Possible; indicated if the disease is active

Binet Stage CRai stage III/IV

Yes

Active/Progressive Disease Yes

Not Active/Progressive Disease Not generally indicated

Hallek M, et al. Blood 2018;131(25):2745-2760

FIRST LINE THERAPY

ESMO GUIDELINES

Eichhorst B, et al. Ann Oncol 2017

ESMO Guidelines Committee, Appendix 4: Chronic lymphocytic leukaemia: eUpdate published online 27 June 2017 (www.esmo.org/Guidelines/Haematological-Malignancies), Annals of Oncology 2017; 28 (suppl_4): iv149–

iv152, doi:10.1093/annonc/mdx242 by permission of Oxford University Press on behalf of the European Society for Medical Oncology.

PHYSICALLY FIT PATIENTS LACKING 17p DELETION

AND TP53 MUTATION

(ie, creatinine clearance >70 mL/min and CIRS <6)

Patients ≤65 years: p<0.001

Patients >65 years: p<0.17053.6 months

38.5 months

not reached

48.5 months

Adverse event

G3-5

FCR

(% of pt)

BR

(% of pt)

P-value

All 90.8 78.5 <0.001

Haematological AEs 90.0 66.9 <0.001

Neutropenia 81.7 56.8 <0.001

Anaemia 12.9 9.7 0.28

Thrombocytopenia 21.5 14.4 0.036

Infection 39.0 25.4 0.001

BR, bendamustine and rituximab; FCR, fludarabine, cyclophosphamide, and rituximab

Reprinted from Lancet Oncol, 17(7), Eichhorst B, First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia

(CLL10): an international, open-label, randomised, phase 3, non-inferiority trial, 928-942, Copyright 2016, with permission from Elsevier.

PFS

PHYSICALLY UNFIT PATIENTS LACKING 17p DELETION

AND TP53 MUTATION

(i.e., creatinine clearance <70 ml/min and CIRS >6)

AEObinutuzumab +

Chlorambucil

Rituximab +

Chlorambucil

Haematological G3-5

Neutrophils 33% 28%

Haemoglobin 4% 4%

Platelets 12% 3%

Infection G3-5 12% 14%

Infusion-related reaction G3-5 20% 4%

Goede V, et al. N Engl J Med. 2014

Goede V, et al. Presented at EHA23, 15th June 2018. Abstr. S151. Courtesy of Dr Valentin Goede.

SUPERIOR PFS BY IBRUTINIB +/-R IN PATIENTS WITH

17p DELETION VS. CHEMOIMMUNOTHERAPY

Arm C (IR)Arm B (I)

Arm A (BR)

% A

live a

nd

Pro

gre

ssio

n-F

ree

                                                                     

                 

0 6 12 18 24 30 36 42 48 52

Time (Months)

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 30 36 42 48 52

Time (Months)

0

10

20

30

40

50

60

70

80

90

100

Censor

3/11Arm C (IR)

2/9Arm B (I)

10/14Arm A (BR)

Events/TotalArm

Patients-at-Risk14 5 3 1 09 9 8 7 6 5 5 1 1 0

11 10 9 9 8 7 6 3 2 0

Arm N 24 Month Estimate

BR 14 0%

I 9 75% (95% CI: 31-93%)

IR 11 73% (95% CI: 37-90%)

From N Engl J Med, Woyach C, et al. Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL, 379:2517–28 . Copyright © 2018. Massachusetts Medical Society. Reprinted with permission from

Massachusetts Medical Society.

PERSPECTIVE IN LIGHT OF NEW EVIDENCE FROM STUDIES COMPARING IBRUTINIB VS.CHEMOIMMUNOTHERAPY

SUPERIOR PFS BY IBRUTINIB (+/- ANTI CD20) VS.

CHEMOIMMUNOTHERAPY AS FIRST LINE THERAPY

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0

20

30

40

50

60

70

80

90

Pro

gre

ssio

n-f

ree

su

rviv

al(%

)

9 12 15 18 21 24 27 30 33 36

Months

Ibrutinib-obinutuzumab (N=113) Chlorambucil-obinutuzumab (N=116)

Median (mo)10 Hazard ratio

(95% CI)

0 3 6

Ibrutinib- Chlorambucil-

obinutuzumab obinutuzumab

NR 19.00.231 (0.145–0.367);

P<0.0001

ECOG E19121 ALLIANCE A0412022 iLLUMINATE3

ECOG E1912: Age <70, CrCl >40, able to tolerate FCR, No deletion 17p by FISH

ALLIANCE A041202: Age ≥65,CrCl ≥40

iLLUMINATE: Age ≥65 yrs or <65 yrs old with ≥1 coexisting condition: CIRS >6, CrCl <70 mL/min, del(17p) or TP53 mutation

1. Shanafelt TD, et al. ASH 2018, #LBA-4;

2. From N Engl J Med, Woyach C, et al. Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL, 379:2517–28 . Copyright © 2018. Massachusetts Medical Society. Reprinted with permission from

Massachusetts Medical Society; 3. Reprinted from Lancet Oncol, 20, 1, Moreno C, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a

multicentre, randomised, open-label, phase 3 trial, 43–56, Copyright 2019, with permission from Elsevier.

SUPERIOR OS ONLY BY IBRUTINIB + R VS. FCR

0

10

20

30

60

50

40

70

80

90

100

0

Ov

era

ll s

urv

iva

l(%

)

Ibrutinib-obinutuzumab (N=113)

Chlorambucil-obinutuzumab (N=116)

9 12 15 18 21 24 27 30 33 36 39

Months

Median (mo) Hazard ratio (95% CI)

3 6

Ibrutinib-obinutuzumab

Chlorambucil-obinutuzumab

NR NR0.921 (0.479–1.722);

P=0.81

ECOG E19121 ALLIANCE A0412022 iLLUMINATE3

1. Shanafelt TD, et al. ASH 2018, #LBA-4; 2. From N Engl J Med, Woyach C, et al. Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL, 379:2517–28 . Copyright © 2018. Massachusetts

Medical Society. Reprinted with permission from Massachusetts Medical Society; 3. Reprinted from Lancet Oncol, 20, 1, Moreno C, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line

treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial, 43–56, Copyright 2019, with permission from Elsevier.

SUMMARY OF THE SAFETY PROFILE OF

IBRUTINIB (+/- ANTI CD20) VS.

CHEMOIMMUNOTHERAPY

Overall number of AE Type of AE

Young fit1 Ib+R < FCR

• Haematological FCR > Ib+R

• Febrile neutropenia FCR > Ib+R

• Infection FCR > Ib+R

• Atrial fibrillation Ib+R > FCR

• Hypertension Ib+R > FCR

Elderly fit2 Ib+/-R = BR

• Haematological BR > Ib+/-R

• Febrile neutropenia BR > Ib+/-R

• Atrial fibrillation Ib+R > BR

• Hypertension Ib+R > BR

Elderly unfit3 Ib+G = Clb+G• Haematological Clb-G > Ib+G

• Atrial fibrillation Ib+G > Clb+G

1. Shanafelt TD, et al. ASH 2018, #LBA-4; 2. Woyach C, et al. N Engl J Med. 2018;379(26):2517-2528; 3. Moreno C, et al. Lancet Oncol 2019;20(1):43-56

BENEFIT FROM IBRUTINIB VS. CHEMOIMMUNOTHERAPY

IN IGHV UNMUTATED BUT NOT IGHV MUTATED CLL

iLLUMINATEIncluded high risk

ALLIANCEIncluded del(17)p

E1912No del(17)p

uIGHV: HR 0.15 (0.08 – 0.27)

mIGHV: HR 0.30 (0.12 – 0.75)

uIGHV: HR 0.26 (0.14-0.5; p < 0.0001)

mIGHV: HR 0.44 (0.14-1.36; p = 0.07)IGHV HR: not reported

0 1 2 3 4

0.0

0.2

0.4

0.6

0.8

1.0

Years

Pro

babi

lity

IR IGHV Mutated (8 events/ 70 cases)

IR IGHV Unmutated (20 events/ 210 cases)

FCR IGHV Mutated (6 events/ 44 cases)

FCR IGHV Unmutated (21 events/ 71 cases)

Number at risk

70 67 59 25 2

210 203 177 90 12

44 38 31 18 0

71 64 43 14 0

1. Reprinted from Lancet Oncol, 20, 1, Moreno C, et al, Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised,

open-label, phase 3 trial, 43–56, Copyright 2019, with permission from Elsevier.

2. From N Engl J Med, Woyach C, et al.., Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL, 379:2517–28 . Copyright © 2018. Massachusetts Medical Society. Reprinted with permission

from Massachusetts Medical Society; 3. Shanafelt TD, et al. ASH 2018. Abstract LBA-4.

Republished with permission of American Society of Hematology, from Blood, Rossi D, et al. 126(16), 2015; permission conveyed through Copyright Clearance Center, Inc.

PATIENTS WITH IGHV-MUTATED STATUS AND WILD

TYPE 17P/TP53 GAIN LONG TERM REMISSION FROM

FCR AND SURVIVE AS THE GENERAL POPULATION

Months

Cu

mu

lati

ve p

rob

ab

ilit

y o

f O

S (

%)

02

04

06

08

01

00

0 12 24 36 48 60 72 84 96 108 120

Months

Cu

mu

lati

ve p

rob

ab

ilit

y o

f P

FS

(%

)

02

04

06

08

01

00

0 12 24 36 48 60 72 84 96 108 120

Events Total Median PFS 95% CI

22 90 nr na

102 197 51.7 46.1-57.2

27 30 22.5 8.5-36.4

Events Total 5-years OS 95% CI

5 90 91.4 87.1-95.7

32 197 83.2 80,0-86.4

14 30 57.5 47.6-67.4

p

- 0.0001 <0.0001

0.0001 - <0.0001

<0.0001 <0.0001 -

p

- 0.0341 <0.0001

0.0341 - 0.0004

<0.0001 0.0004 -

Events 5-year

N Observed Expected OS (%)relative

OS (%)p

90 5 3.0 91.4 95.8 .2770

197 32 8.7 83.2 87.2 <.0001

30 14 1.5 57.5 60.2 <.0001

Pairwise comparisons Pairwise comparisons

High-risk group (17p deletion)Low-risk group (IGHV mutated) Intermediate-risk group (IGHV unmutated and/or 11q deletion)

UPDATED ALGORITHM FOR FIRST LINE TREATMENT

Ibrutinib (+/- anti CD20)

Chemoimmunotherapy

TP53 disruption

and/or

IGHV unmutated

Ibrutinib (+/- anti CD20)

At least oneNone

Algorithm by Dr Davide Rossi

THERAPY OF RELAPSE

ESMO GUIDELINES

Eichhorst B, et al. Ann Oncol 2017

ESMO Guidelines Committee, Appendix 4: Chronic lymphocytic leukaemia: eUpdate published online 27 June 2017 (www.esmo.org/Guidelines/Haematological-Malignancies), Annals of Oncology 2017; 28 (suppl_4): iv149–

iv152, doi:10.1093/annonc/mdx242, by permission of Oxford University Press on behalf of the European Society for Medical Oncology.

TP53 DISRUPTION OR EARLY RELAPSE MARK NO

BENEFIT FROM REPEATING CHEMOIMMUNOTHERAPY

Survival after first salvage by length of first remission2

0.0

0.2

0.4

0.6

1.0

0.8

Ove

rall

surv

ival

Time (months)0 24 48 72 96 120 144

≥6 years (n=46), 5-year OS: 71%

3–5.9 years (n=61), mOS: 54 months

1–2.9 (n=34), mOS: 27 months

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

del(11q)

del(17p)

Trisomy 12q

del(13q) single

Other*

Survival after first salvage by genetics at relapse1

1. Fischer K, et al. J Clin Oncol29(26), 2011:3559–66. Reprinted with permission. © 2011 American Society of Clinical Oncology. All rights reserved; 2. Republished with permission of American Society of Hematology from

Blood, Tam CS, et al., 124(20):3059–3064, 2014, permission conveyed through Copyright Clearance Center, Inc.

IBRUTINIB, IDELALISIB+R AND VENETOCLAX

CONTINUOUS THERAPY

Are effective in relapsed CLL not suitable for chemoimmunotherapy

because of early relapse or 17p deletion

R/R CLL

Not suitable for cytotoxic Tx

• del17p

ORR: 79%

51% PFS

Venetoclax (M13-982) 3

R/R CLL

Not suitable for cytotoxic Tx

• PFS <24 mo

Idelalisib-R (116)2

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)

55% PFS

Ofatumumab (n=195)

Ibrutinib (n=196)

R/R CLL

Not suitable for F-based Tx

• PFS <36 mo

• del17p

100

90

80

70

60

50

40

30

20

10

00 6 12 18

Months

Pro

gre

ssio

n-f

ree

surv

ival

(%

)

75% PFS

ORR: 63%

Ibrutinib (RESONATE)1

1. Brown JR, et al. Leukemia 2018;32(1):83-91; under licence from Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. http://creativecommons.org/licenses/by-nc-nd/4.0/; 2. Sharman JP, et al. ASH 2014; 3.

Reprinted from Lancet Oncol 17(6), Stilgenbauer S, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study, 768-78, Copyright 2016, with permission from Elsevier.

PFS AND OS BY FIXED DURATION VENETOCLAX+R

THERAPY IS SUPERIOR THAN BR IN RELAPSED CLL

Kater AP, et al. J Clin Oncol 37(4), 2019:269–77. Reprinted with permission. © 2019 American Society of Clinical Oncology. All rights reserved.

VENETOCLAX CONTINUOUS MONOTHERAPY IS AN

EFFECTIVE SALVAGE AFTER IBRUTINIB FAILURE

ORR: 65%

CR: 9%

MRD-neg PB: 26%

Median PFS: 25 mo

Reprinted from The Lancet Oncol, 19(1), Jones JA, et al. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial 65-75, Copyright (2018), with

permission from Elsevier.

UPDATED ALGORITHM FOR SALVAGE TREATMENT

Previous Tx:

R-chemo and BCR

inhibitor

Previous Tx:

R-chemo

BR

Ibrutinib

Venetoclax+R

Idelalisib+R

Venetoclax + R

Venetoclax

Ibrutinib

Idelalisib + R

Venetoclax

RIC-allo-SCT

TP53 wt

Long remission

duration

TP53 mutated and/or deleted

or

Short remission duration

RIC-allo-SCT

Algorithm by Dr Davide Rossi

Both clinical symptoms and PET/CT have a very high negative predictive value for Richter transformation and a 50%

positive predictive value

Absence of symptoms rules out Richter transformation

Presence of symptoms mandates PET/CT

Negative PET/CT rules out Richter transformation

Positive PET/CT mandates a biopsy of the most 18FDG avid site

Clinical suspicion of transformation

◆ Asymmetric growth of localised lymph nodes

◆ Bulky disease

◆ B symptoms

◆ Sudden and excessive rise in levels of LDH

DIFFERENTIAL DIAGNOSIS BETWEEN CLL

PROGRESSION AND RICHTER TRANSFORMATION

Rossi D, et al. Semin Oncol 2016 43:311-9; Gine’ E, et al. Haematologica. 2010 95:1526-33; Buzzi JF, et al. J Nucl Med 2006 47:1267-73; Mauro FR, et al. Leukemia 2015 29:1360-5.

PET/CT in Richter syndrome diagnosis

Richter

Positive predictive value 53%

Negative predictive value 97%

Max SUV cut off=5

MANAGEMENT OF RICHTER SYNDROME

Clinical suspicion of RT

PET PET tailored open biopsyManage as a CLL

CLL or ‘accelerated’ CLL DLBCL Second cancer

Clonal

relationshipClonally related RT Clonally unrelated RT

Manage as a de novo

DLBCL (i.e. R-CHOP)

Clinical trial

or R-CHOP

RIC-allo-SCTClinical trial

or follow-up

– +

+–

+ –

Donor

Auto-SCT

+–

Fit

Rossi D, et al. Blood 2018; 131:2761-2772

THANK YOU!