ideal management of cll with fcr. is mrd negativity the ... · phase iii cll8: fc vs fcr •...
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Ideal Management of CLL withFCR.
Is MRD negativity the target?Guilherme Fleury Perini
Médico Hematologista
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Conflicts of Interest
Speaker: Janssen, Roche, Takeda, Abbvie, BMS
Suporte Educacional: Janssen, Takeda, Roche, Abbvie,
Advisory Board: Janssen, Abbvie
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Conflicts of Interest
All my practice is on PRIVATE hospitals andclinical research facilities, where access totests/new drugs is easier.
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To be discussed...
Ideal Management of FCR
Who benefit from FCR?
How to avoid toxicity?
Can we modify/abbreviate treatment?
Minimal residual disease
Is it necessary or desirable?
When, how, when?
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Phase III CLL8: FC vs FCR
• Primary endpoint: PFSHallek M, Lancet. 2010;376:1164-1174.
Fischer K, et al. Blood. 2016;127:208-215.
FC
Fludarabine 25 mg/m2 IV Days 1-3 +
Cyclophosphamide 250 mg/m2 Days 1-3
FCR
Fludarabine 25 mg/m2 IV Days 1-3 +
Cyclophosphamide 250 mg/m2 Days 1-3 +
Rituximab 375 mg/m2 IV Day 0, cycle 1 +
Rituximab 500 mg/m2 IV Day 1, cycles 2-6
Pts with untreated,
active CLL and good
physical fitness
(ECOG PS ≤ 1,
CIRS ≤ 6, creatinine
clearance ≥ 1.17 mL/s)
(N = 817)
Slide credit: clinicaloptions.com
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CLL8: FCR as Gold Standard
• Hallek et al, 2010: – Ph III with 817 patients randomized to FC x FCR
– Exclusion criteria: ClCr<70, ECOG>1
– 6 cycles of treatment
Hallek M et al, Lancet 2010
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FCR: There is a price to pay
Hallek M et al, Lancet 2010
26% did not receive the planned 6 cycles47% had reduction of >10% of any of the drugs (FCR)
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CLL8: Longer Follow up
Fischer K, et al. Blood. 2016;127:208-215.
PFS OS
FCR ( = 408) 56.8
FC (n = 409) 32.9
Median
PFS, Mos
HR: 0.59 (95% CI: 0.50-0.69; P < .001)
FCR (n = 408) NR
FC (n = 409) 86.0
Median
PFS, Mos
HR: 0.68 (95% CI, 0.54-0.89; P = .001)
1.0
0.8
0.6
0.4
0.2
0.0
Pro
ba
bil
ity o
f P
FS
960 12 24 48 60 72 8436
Mos on Study
1.0
0.8
0.6
0.4
0.2
0.0
Pro
ba
bil
ity o
f O
S
960 12 24 48 60 72 8436
Mos on Study
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CLL8: Longer Follow up
Most Common Grade 3/4 AEs, n (%)[1] FC (n = 396) FCR (n = 404) P Value
Any grade 3/4 event 249 (63) 309 (76) < .0001
Hematologic toxicity 157 (40) 225 (56) < .0001
Infections 85 (21) 103 (25) .18
Neutropenia 83 (21) 136 (34) < .0001
Leukocytopenia 48 (12) 97 (24) < .0001
Thrombocytopenia 44 (11) 30 (7) .07
Long-term Safety, n (%)[2] FC (n = 396) FCR (n = 404)
Prolonged neutropenia
(2 mos after end of tx)
67 (17) 34 (9)
Prolonged neutropenia
(12 mos after end of tx)
16 (4) 14 (4)
Secondary primary malignancies 53 (13) 69 (17)
Slide credit: clinicaloptions.com
1. Hallek M, et al. Lancet. 2010;376:1164-1174.
2. Fischer K, et al. Blood. 2016;127:208-215.
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For whom the toxicity of FCR isworthy?
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Cytogenetics in CLL8
CD20 expresssionis higher in trisomy 12
No Benefit in del17p
Fischer K, et al. Blood. 2016;127:208-215.
X
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FCR 300: Seminal Study
Thompson PA, et al. Blood. 2016;127:303-309.
1614120 2 4 6 8 10
100
75
50
25
0
PF
S (
%)
Yrs
IGHV mutated
IGHV unmutated
n Pts Tested, %
88 41
126 59
P < .0001
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FCR x IgHV in CLL8
Median observationtime
5.9 years
Median PFS
FCR IGHV mutated
Not reachedFC IGHV mutated
42 monthsFCR IGHV unmutated
42 monthsFC IGHV unmutated
29 months
FC vs. FCRHR 2.12,
95% CI 1.464 - 3.063
Fischer K, et al. Blood. 2016;127:208-215.
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First Line Treatment of unmutatedIgHV
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CLL10 Study: Impact of Age
Non-Inferiority of BR in comparison to FCR for PFS:
HR (λ BR/FCR) less than 1.388
Randomization
Patients with untreated, active CLL without del(17p) and good physical fitness
(CIRS ≤ 6, creatinine clearance ≥ 70 ml/min)
FCRFludarabine 25 mg/m² i.v., days 1-3
Cyclophosphamide 250 mg/m², days 1-3,
Rituximab 375 mg/ m2 i.v. day 0, cycle 1
Rituximab 500 mg/m² i.v. day 1, cycle 2-6
BRBendamustine 90mg/m² day 1-2
Rituximab 375 mg/m² day 0, cycle 1
Rituximab 500 mg/m² day 1, cycle 2-6
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CLL10 Study: FCR VS BR in FrontLine
ITT Best Response according to IWCLL
Response FCR (%)n=282
BR (%)n=279
p value
CR (CR + CRi) 39.7 30.8 0.034
CR 35.1 30.4
CRi 4.6 0.4
PR 55.7 64.9
ORR 95.4 95.7 1.0
SD/PD 2.2 2.2
Missing response 2.5 2.1
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CLL10 Study: FCR VS BR in Front-Line
ITT Progression-free survival = Primary endpoint
P < 0.001HR = 1.626 =
> 1.388
Median PFS
FCR 55.2 months
BR 41.7 months
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CLL10 Study: FCR VS BR in Front-line
Progression-free survival by age group
Patients ≤ 65 years: P < 0.001
FCR 53.6 months BR 38.5 months
Patients > 65 years: P = 0.170
FCR not reached BR 48.5 months
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Who benefits from FCR?
Sharman et al: <20% of patients satisfy age, renal clearance and fitness profile of inclusion criteria from CLL8 and CLL10, DESPITE molecular features that exclude FCR as Treatment
Young fit patients with active CLL- Age <65- no del17p- IgHV mutated patients
7% estimate byOpat et al
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Don’t be radical!
You can alway dose-adjust FCR!
Can you?
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FCR Lite
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FCR Lite
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Can we modify FCR?
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Can we abbreviate FCR?
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Can we abbreviate FCR?
20 patients achieved MRD-negative status after course 3 and stopped treatment, mostly owing to patients’ performance status, comorbidities, or myelosuppression.
MRD@3 x 3FCR = MRD@3 x 6 FCR = MRD@EOT
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Early Achievement of MRD-Negativity in IGHV-Mutated (IGHV-M) Patients Portends Highly Favorable Outcomes after First-Line Treatment of CLL with Fludarabine, Cyclophosphamide and Rituximab (FCR). Serial Monitoring for Minimal Residual Disease (MRD) in Blood after Achieving MRD-Negativity Predicts Subsequent Clinical Relapse
Thompson PA, ASH 2016
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Baseline Characteristics
Thompson PA, ASH 2016.
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Results
• MRDneg (BM) Achievement: 46/239 patients (19%) after 3 courses120/231 (51%) at EOT achieved MRD negativity
in BM.
IGHV-M was significantly associated with MRD-negativity [OR 3.7 (1.7-8.2), p=0.001].
11/22 patients who were MRD-negative after 3 courses received no further therapy and only 3/22 received 6 courses
Thompson PA, ASH 2016.
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Results
Thompson PA, ASH 2016.
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Results
Thompson PA, ASH 2016.
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MRD: How? Where? For Whom?
• How?– Flow Cytometry (10-4)
• Where?– PB– If negative in PB, then you may look at it in bone
marrow
• For Whom?– For patients receiving regimens capable of
inducing MRDneg (FCR, R-venetoclax)
Hallek iWCLL 2017
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Is MRD the objective of Treatment?
• Yes and No!
• For patients with IgHVmut receiving FCR, MRD negativity may be the objective oftreatment
• However, ~50% of patients will notachieve MRD negativity!
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MRD in multiple Clinical Trials
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Abbreviated FCR: Argentina Experience
• 35 pacientes com MRDneg após 4 FCR– 28 MRDneg na medula
• median PFS: 65.8 months• OS: not reached• PFS and OS at 72 months was 46% and
68%
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The optimal management of FCR
• FCR is not for everyone!– It is actually, for a FEW patients!
– Young, fit, mIGHV patients
– <10% of patients will have long term benefits
– >10% will have secondary neoplasms
• I don’t believe unmIGHV patients should betreated with FCR
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The optimal management of FCR
• I can not recommend testing MRD outsideclinical trials– But I do it in patients receiving FCR
• I can not recommend stopping FCR after 3-4 cycles if MRDneg
– But I do it in patients in patients with toxicities
• Salvage is now better. Let patients get to it.