CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) · DIFFERENTIAL DIAGNOSIS BASED ON MORPHOLOGY Comparison of...
Transcript of CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) · DIFFERENTIAL DIAGNOSIS BASED ON MORPHOLOGY Comparison of...
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!