Ideal Management of CLL with FCR. Is MRD negativity the ... · Phase III CLL8: FC vs FCR •...

Ideal Management of CLL withFCR.

Is MRD negativity the target?Guilherme Fleury Perini

guilherme.perini@einstein.br

Médico Hematologista

Conflicts of Interest

Speaker: Janssen, Roche, Takeda, Abbvie, BMS

Suporte Educacional: Janssen, Takeda, Roche, Abbvie,

Advisory Board: Janssen, Abbvie

Conflicts of Interest

All my practice is on PRIVATE hospitals andclinical research facilities, where access totests/new drugs is easier.

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?

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

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

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)

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

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.

For whom the toxicity of FCR isworthy?

Cytogenetics in CLL8

CD20 expresssionis higher in trisomy 12

No Benefit in del17p

Fischer K, et al. Blood. 2016;127:208-215.

X

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

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.

14

First Line Treatment of unmutatedIgHV

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

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

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

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

19

20

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

Don’t be radical!

You can alway dose-adjust FCR!

Can you?

FCR Lite

FCR Lite

Can we modify FCR?

Can we abbreviate FCR?

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

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

Baseline Characteristics

Thompson PA, ASH 2016.

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.

Results

Thompson PA, ASH 2016.

Results

Thompson PA, ASH 2016.

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

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!

MRD in multiple Clinical Trials

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%

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

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.

Obrigado!

guilherme.perini@einstein.br

(11)99292-6463

@guiperini