Chronic Lymphocytic Leukemia (CLL): Diagnosis, Treatment, and … · 2020. 6. 15. · Onkologie. 2001;24:60. Dewald. Br J Haematol. 2003;121:287. Sindelárová. Cancer Genet Cytogenet

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Chronic Lymphocytic Leukemia (CLL):

Diagnosis, Treatment, and Side Effects Management

• Describe the various types and subtypes of chronic lymphocytic

leukemia (CLL)

• Identify tests used to diagnose disease and monitor treatment of CLL

• Explain the overarching goals of treatment for the types of CLL

• Explain approved and emerging treatment options for CLL, including stem

cell transplantation, and the role of clinical trials.

• Describe strategies to manage treatment side effects as well as potential

long-term and late effects of treatments for CLL

• Describe the roles of the pharmacist, the nurse and the social worker in

treating patients with CLL

LEARNING OBJECTIVES

1

2




FACULTY

William G. Wierda, MD, PhDProfessor of Medicine

Section Head – CLL

Department of Leukemia

The University of Texas MD Anderson Cancer Center

Houston, TX

Deborah McCue, PharmD, BCOPClinical Pharmacy Manager

Division of Pharmacy


Houston, TX

Jackie Broadway-Duren, DNP, APRN, FNP-BCFamily Nurse Practitioner

Department of Leukemia


Houston, TX

Chronic Lymphocytic Leukemia

3

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CLL/SLL: Background

▪ More than 20,000 estimated new cases in 2019 in the United States alone[1]

‒ Most common type of leukemia in adults (37%)

▪ Median age at diagnosis: 70 yrs[2]

▪ SLL and CLL considered the same B-cell malignancy[3]

‒ CLL: > 5000 clonal lymphocytes in peripheral blood

‒ SLL: presence of lymphadenopathy and/or splenomegaly and < 5000 clonal lymphocytes in peripheral blood

▪ Historical 5-yr survival: 66% (range: few mos to normal life span)[4]

‒ Current (2009-2015) 5-yr survival: 85%[2]

SLL, small lymphocytic lymphoma1. Siegel. CA Cancer J Clin. 2019;69:7. 2. SEER Cancer Stat Facts. Chronic lymphocytic leukemia.3. American Cancer Society. Chronic lymphocytic leukemia. 4. Nabhan. JAMA. 2014;312:2265.

CLL: Prognostic Value of FISHFISH Abnormalities Present in 268/325 Patients (82%)

Lesion % Median OS, Mos

del(13q) 55 133

del(11q) 18 79

Trisomy 12 16 114

del(17p) 7 32

del(6q) 6 N/A

Normal 18 111

Dohner. NEJM. 2000;343:1910. Dohner. Leukemia. 1997;11(suppl 2):S19. Oscier. Haematologica. 1999;84(suppl EHA-4):88. Jarosova. Onkologie. 2001;24:60. Dewald. Br J Haematol. 2003;121:287. Sindelárová. Cancer Genet Cytogenet. 2005;160:27.

Probability of OS From Diagnosis, by Genetic Aberration

100

80

60

40

20

0

Pat

ien

ts S

urv

ivin

g (%

)

Mos

17p deletion11q deletion12q trisomyNormal13q deletion as sole abnormality

FISH Lesion

Patients With Abnormality (%)

Dohner et al 1997

Oscier et al 1999

Jarosova et al 2001

Dewald et al 2003

Sindelarava et al 2005

del(13q) 45 36 18 47 54

Trisomy 12 15 15 13 25 16

del(17p) 10 8 11 8 16

del(11q) 20 17 11 15 12

FISH, fluorescence in situ hybridization; OS, overall survival

5

6




▪ OS effect of TP53 wild type:

‒ vs TP53 mut only: P = .013

‒ vs TP53 del only: P = .006

‒ vs TP53 mut + del: P < .001

▪ Analysis based on cases referred to the Munich Leukemia Laboratory between August 2005 and May 2013

CLL: Impact of TP53 Mutations and TP53 Deletion on OS (N = 1148)

Stengel. Leukemia. 2017;31:705.

9

8

7

6

5

4

3

2

1

0

Freq

uen

cy o

f TP

53

Alt

erat

ion

s in

Rel

atio

n t

o

Tota

l Siz

e o

f Ea

ch C

oh

ort

(%

)

CLL

TP53 mut onlyTP53 del onlyTP53 mut + del

Yrs

100

OS

(%)

80

60

40

20

0

TP53 wt

TP53alteration

P < .001

100 1 2 3 4 5 6 7 8 9Yrs

100

OS

(%)

80

60

40

20

0

TP53 wt

TP53 mut only

100 1 2 3 4 5 6 7 8 9

TP53 del only

TP53 mut + del

Survival in CLL According to IGHV Mutational Status

Surv

ivin

g (%

)

Su

rviv

ing

(%

)

P = .0008

All Patients (n = 84) Binet Stage* A Patients (n = 62)

P = .001

Mutated

UnmutatedUnmutated

Mutated

Mos0 50 100 150 200 250 300

0

20

40

60

80

100

Mos0 50 100 150 200 250 300

0

20

40

60

80

100

IGHV, immunoglobulin heavy chain variable regionHamblin. Blood. 1999;94:1848.

*See Staging Systems slide in Appendix

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8




Hallek et al Blood 2008;111:5446-5456

IWCLL-NCI: Indications to

Initiate Treatment for CLL• Constitutional symptoms referable to CLL

• Progressive marrow failure

• Autoimmune anemia +/- thrombocytopenia poorly responsive to steroids or other

• Massive (>6 cm) or progressive splenomegaly

• Massive (>10 cm) or progressive lymphadenopathy

• Progressive lymphocytosis, >50% increase over 2 months or LDT < 6 months

• NO EARLY TREATMENT, EVEN FOR HIGH-RISK

IWCLL-NCI, International Workshop on Chronic Lymphocytic Leukemia- National Cancer Institute; LDT, lymphocyte doubling time

Treatment Goals for CLL

• Potentially curative treatments: FCR for m-IGHV and allo-HCT

• Majority requiring treatment are older (>70 yo) with

comorbidities and more treatment-associated toxicities

• Goals for first-line:

Best opportunity for most effective treatment, most

eventually relapse and need retreatment:

– Deeper remission and treatment-free interval, later retreat

– Maintain disease control on continuous (IBR) treatment

Allo-HCT, allogeneic hematopoietic stem cell transplant; FCR, fludarabine, cyclophosphamide, and rituximab; IBR, ibrutinib

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Essential Tests for Selecting First-Line Treatment in CLL

1. FISH: del(17p) status – can change

– Know % of cells with deletion

2. TP53 mutation status – can change

3. IGHV mutation status – does not change

FISH, fluorescence in situ hybridization

Therapeutic Agents for CLL

Chemotherapy

CD20

Antibody BTK-inhibitor

PI3 kinase-

inhibitor

BCL2-

inhibitor Others

Chlorambucil

(Leukeran)

Rituximab

(Rituxan)

Ibrutinib

(Imbruvica)

Idelalisib

(Zydelig)

Venetoclax

(Venclexta)

Lenalidomide

(Revlimid)

Fludarabine

(Fludara)

Ofatumumab

(Arzerra)

Acalabrutinib

(Calquence)

Duvelisib

(Copiktra)CAR T cells

Cyclophosphamide

(Cytoxan)

Obinutuzumab

(Gazyva™)

Zanubrutinib

(Brukinsa™)Umbralisib

Bendamustine

(Treanda)Vecabrutinib

ARQ 531

LOXO-305

CG-806

(Aptose)

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First-Line Phase III Randomized Trials

• RESONATE-2

– IBR vs.

– CHLOR

• iLLUMINATE (PCYC-1130) (>65 yo or ≤65 yo with comorbidities)

– IBR + OBIN vs.

– CHLOR + OBIN

• Alliance (A041202) (>65 yo)

– IBR vs.

– IBR + RIT vs.

– BR

• ECOG E1912 [<70 yo; non-del(17p)]

– IBR + RIT vs.

– FCR

• CLL14 (CIRS >6; CrCl <70 mL/min)

– VEN + OBIN vs.

– CHLOR + OBIN

IBR, ibrutinib (Imbruvica); CHLOR, chlorambucil (Leukeran); OBIN, obinutuzumab (Gazyva™); RIT, rituximab (Rituxan) ; BR, bendamustine (Treanda) and rituximab (Rituxan); FCR, fludarabine (Fludara), cyclophosphamide (Cytoxan), and rituximab (Rituxan); VEN, venetoclax (Venclexta)

iLLUMINATE (PCYC-1130) Study Design

Primary end point• PFS by IRC assessment

Secondary end points include• PFS by IRC in high-risk population• Rate of undetectable MRD• ORR

• OS• Infusion-related reactions• Safety

Patients (N=229)• Previously untreated CLL/SLL • Requiring treatment per

iwCLL criteria • Age ≥65 years or <65 years

old with ≥1 coexisting condition:▪ CIRS >6▪ CrCl <70 mL/min▪ del(17p) or TP53

mutation

aPatients in the chlorambucil-obinutuzumab arm could receive next-line single-agent ibrutinib in crossover following IRC-confirmed PD.

R

A

N

D

O

M

I

Z

E

1:1

Ibrutinib – obinutuzumabIbrutinib 420 mg once daily until PD or unacceptable

toxicity + obinutuzumab1000 mg split on days 1-2, and on day 8 and 15 (cycle 1)

then day 1 (total 6 cycles)

Chlorambucil–obinutuzumabChlorambucil 0.5 mg/kg on days 1 and 15

(6 cycles) + obinutuzumab 1000 mg split on days 1-2 and on day 8 and 15 (cycle 1) then

day 1 (total 6 cycles)

After IRC-confirmed PD, patients were allowed to receive

single-agent ibrutiniba

Stratification: del(17p) vs. del(11q) vs. neither del(17p) or del(11q); ECOG 2 vs 0-1

Moreno et al. ASH 2018. Abstract 691.

Ibrutinib, (Imbruvica); obinutuzumab, (Gazyva™)CIRS, Cumulative Illness Rating Scale; IRC, independent review committee; iwCLL, International Working Group on CLL; MRD, minimal residual disease; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival

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14




Superior Progression-Free Survival With Ibrutinib (Imbruvica) -Obinutuzumab (Gazvya™)

Ibrutinib, (Imbruvica); Obinutuzumab, (Gazyva™); Chlorambucil, (Leukeran)INV, investigator; NR, not reached

Independent Review Assessment Investigator Assessment

▪ Median follow-up, 31.3 months (range, 0.2–36.9)▪ Estimated PFS at 30 months: 79% with ibrutinib-obinutuzumab vs. 31% with chlorambucil-obinutuzumab▪ Even after excluding patients with del(17p): 74% reduction in risk of progression or death with ibrutinib-obinutuzumab

Moreno et al. ASH 2018. Abstract 691.

Alliance (A041202) Schema

Stratify*

Documented progression

RANDOMIZE

Bendamustine (Treanda) 90 mg/m2 days 1 and 2 of each 28-day cycle +Rituximab (Rituxan) 375 mg/m2 day 0 cycle 1,then 500 mg/m2 day 1 cycles 2-6

Ibrutinib (Imbruvica)420 mg daily until disease progression

Stratification• High risk vs intermediate risk Rai stage*• Presence vs absence of del(11q22.3) or del(17p13.1) on FISH performed locally• <20% vs ≥20% Zap-70 methylation of CpG 3 performed centrally

P

R

E

-

R

E

G

I

S

T

E

R

Ibrutinib (Imbruvica) 420 mg daily until disease progression +Rituximab (Rituxan) 375 mg/m2 weekly for 4 weeks starting cycle 2 day 1, then day 1 of cycles 3-6

Untreated patients age ≥65 who meet IWCLL criteria for CLL treatment

Woyach et al. ASH 2018. Abstract 6.

*See Staging Systems slide in Appendix

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16




Primary Endpoint: Progression-Free SurvivalEligible Patient Population

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

32/170Arm C (IR)

34/178Arm B (I)

68/176Arm A (BR)

Events/TotalArm

Patients-at-Risk176 140 129 122 103 88 57 26 11 0178 165 154 147 136 120 78 45 22 0170 159 145 138 132 115 74 40 20 0

Pairwise Comparisons

I vs BR:Hazard Ratio 0.39 95% CI: 0.26-0.58

(1-sided P-value <0.001)

IR vs BR: Hazard Ratio 0.38 95% CI: 0.25-0.59

(1-sided P-value <0.001)

IR vs I: Hazard Ratio 1.00 95% CI: 0.62-1.62

(1-sided P-value 0.49)

Arm N 24-Month Estimate

BR 176 74% (95% CI: 66-80%)

I 178 87% (95% CI: 81-92%)

IR 170 88% (95% CI: 81-92%)

I , ibrutinib (Imbruvica); BR, bendamustine (Treanda) and rituximab (Rituxan); IR, ibrutinib (Imbruvica)

Woyach et al. ASH 2018. Abstract 6.

E1912: Study DesignArm A – Ibrutinib + RituximabCycles 1: Ibrutinib 420 mg PO daily, days 1-28

Cycle 2:Ibrutinib 420 mg PO daily, days 1-28 Rituximab 50 mg/m2 IV, day 1Rituximab 325 mg/m2 IV, day 2

Cycles 3-7: Ibrutinib 420 mg PO daily, days 1-28 Rituximab 500 mg/m2 IV, day 1

Arm B - FCRCycles 1-6:Fludarabine 25 mg/m2 IV, days 1-3Cyclophosphamide 250 mg/m2 IV, days 1-3

Cycle 1:Rituximab 50 mg/m2 IV, day 1, cycle 1Rituximab 325 mg/m2 IV, day 2, cycle 1

Cycle 2-6:Rituximab 500 mg/m2 IV, day 1, cycles 2-6

Cycle 8 until progression: Ibrutinib 420 mg PO daily, days 1-28

Planned Accrual: 519

E1912Eligibility:-Previously untreated CLL -Requires treatment (IWCLL 2008)-Age ≤70-ECOG 0-2-CrCL >40 -Able to tolerate FCR-No deletion 17p by FISH

Ran

do

miz

atio

n

Dis

ease

Pro

gres

sio

n

Shanafelt et al. ASH 2018. Abstract LBA-4.Fludarabine, (Fludara); Ibrutinib (Imbruvica); Rituximab (Rituxan)

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18




Progression-Free SurvivalIntent to Treat Eligible

HR = 0.35 (95% CI 0.22-0.5)One sided p<0.00001

HR = 0.32 (95% CI 0.20-0.51)One sided p<0.00001

Shanafelt et al. ASH 2018. Abstract LBA-4.

Overall Survival

Intent to Treat Eligible

0 1 2 3 4

0.0

0.2

0.4

0.6

0.8

1.0

Years

Pro

ba

bili

ty

IR (4 events/ 354 cases)

FCR (10 events/ 175 cases)

Number at risk

354 347 318 166 18

175 155 130 58 1

HR = 0.17 (95% CI 0.05−0.54)

One−sided p = 3.22 ´ 10-4

0 1 2 3 4

0.0

0.2

0.4

0.6

0.8

1.0

Years

Pro

ba

bili

ty

IR (3 events/ 332 cases)

FCR (10 events/ 166 cases)

Number at risk

332 327 298 154 18

166 149 125 54 1

HR = 0.13 (95% CI 0.03−0.46)

One−sided p = 9.86 ´ 10-5

HR = 0.17 (95% CI 0.05-0.54)One sided p<0.0003

HR = 0.13 (95% CI 0.03-0.46)One sided p<0.0001


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20




Causes of Death

Cause of DeathIR

n=354FCR

n=175CLL 1 6

Unexplained/unwitnessed 1 2

Other: acute/chronic respiratory failure; hx lung adenocarcinoma

1 0

Acute respiratory failure 1 0

Metastatic colon cancer 0 1

Drug overdose 0 1

TOTAL 4 10

Death during active treatment +30 days: IR (n=3); FCR (n=1)


T-MDS/AML AFTER FCR

N Treatment T-MDS/AML %

MDACC 2004-2012234

131

FCR-based

FCR only

5.1

0.7

MDACC 1999-2003 300 FCR 4.6

German CLL8 408 FCR 1.5

MDACC, MD Anderson Cancer Center; T-MDS, therapy-related myelodysplastic syndrome; T-AML: therapy related acute myeloid leukemiaJohn Benjamini. Leuk Lymphoma. 2015; Thompson. Blood. 2016; Fischer. Blood. 2016.

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22




Fischer, ASCO 2019 (Abstract 7502)

Safety Run-in Phase*

Venetoclax (Venclexta) –

Obinutuzumab

(Gazyva™)

Previously untreated

patients with CLL and

coexisting medical

conditions

CIRS >6 and/or

CrCl <70 mL/min

*Fischer K et al. Blood. 2017;129:2702-2705.

Chlorambucil

(Cytoxan) –

Obinutuzumab

(Gazyva™)

6 cycles

Venetoclax (Venclexta)

– Obinutuzumab

(Gazyva™)

6 cycles

Venetoclax

(Venclexta)

6 cycles

Obinutuzumab

(Gazyva™)

6 cycles

Follow-up Phase

Primary endpoint:

Progression-free survival

Key secondary endpoints:

Response, Minimal

Residual Disease, Overall

Survival

1:1

randomization

CLL14: TRIAL DESIGN


100

Patients

with r

esponse (

%)

Chlorambucil-

Obinutuzumab

Venetoclax-

Obinutuzumab

50%

35%

23%

48%

Overall response

P = 0.0007

Complete response

P<0.0001

Partial response

CLL14: RESPONSE TO TREATMENT

0

10

20

30

40

50

60

70

80

90

(Venclexta-

Gazyva™)

(Leukeran-

Gazyva™)

23

24





0

Investigato

r-assesse

d

Pro

gre

ssio

n-f

ree s

urv

ival (%

)10

0

80

60

40

20

00

Time on study in months

Hazard ratio 0.35 (95% CI 0.23‒0.53), P<0.0001

29-months median follow-up

6 12 18 24 30 36

Venetoclax–

Obinutuzumab

Chlorambucil–

Obinutuzumab

CLL14: PROGRESSION-FREE SURVIVAL

(Venclexta-

Gazyva™)

(Leukeran-

Gazyva™)

FCR300: PFS by IGHV Mutation Status (IGHV-MS)

Thompson PA, et al. Blood 2016; 127:303–309.

P<0.0001Perc

en

tag

e P

rog

ressio

n-f

ree

Time (Years)

0

25

50

75

100

0 1 2 3 4 8 9 105 6 7 11 12 13 14 15 16

N Prog-free

IGHV mutated 88 49

IGHV unmutated 126 12

25

26




CLL10 Study: FCR vs BR in Front-LineProgression-free survival by IGHV-MS

MS, mutation status.Eichhorst et al. Lancet Oncol. 2016;17:928-942.

IGHV-M

FCR

IGHV-M

BR

FCR First-Line: 6-Month Landmark PFS by MRD at EoT and IGHV-MS

0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 6 0 6 6 7 2 7 8 8 4 9 00

2 5

5 0

7 5

1 0 0

T im e (M o n th s )

Pe

rc

en

t p

ro

gre

ss

ion

-fre

e

IG H V -U M , M R D -p o s

IG H V -U M , M R D -n e g

IG H V -M , M R D -p o s

IG H V -M , M R D -n e g

N P ro g - fre e

4 5 4 1

2 9 2 0

6 4 2 3

4 3 3 1

p = 0 .0 2

Thompson PA et al. Leukemia. 2018;32:2388-2398.

IGHV-M

61% uMRD

EoT, end of treatment U-MRD, undetectable minimal residual disease

27

28





0

Inve

stig

ato

r-a

ssesse

d

Pro

gre

ssio

n-f

ree s

urv

ival (

%)

100

80

60

40

20

00

Time on study in months

6 12 18 24 30 36

CLL14: PFS BY IGHV MUTATIONAL STATUS

Venetoclax–Obinutuzumab

IGHV unmutated

Chlorambucil–Obinutuzumab

IGHV unmutated

Venetoclax–

Obinutuzumab

IGHV mutated

Chlorambucil–Obinutuzumab

IGHV mutated

Chlorambucil, (Leukeran); Obinutuzuman, (Gazyva™); Venetolclax, Venclexta

Fischer et al , N Engl J Med 2019; 380:2225-2236- Supplemental Appendix

CR, complete remission; ASO-PCR, allele-specific oligonucleotide polymerase chain reaction; Clb, chlorambucil; G, obinutuzumab; MRD, minimal residual disease negative; Ven, venetoclax.Data cutoff: August 17, 2018.

Deeper response rates (MRD negativity and CR) were significantly higher with VenG vs GClb in patients with mutated IGHV.

SubgroupsTotal

NVenG GClb Odds

Ratio 95% CIn MRD– (%) n MRD– (%)

All patients 432 216 75.5 216 35.2 5.67 3.74–8.60

Mutated IGHV 159 76 73.7 83 43.4 3.66 1.87–7.15

Subgroup Analysis for Undetectable PB MRD Rate (ASO-PCR)1

SubgroupsTotal

NVenG GClb Odds

Ratio 95% CIn CR (%) n CR (%)

All patients 432 216 49.5 216 23.1 3.26 2.15–4.93Mutated IGHV 159 76 51.3 83 34.9 1.96 1.04–3.71

Subgroup Analysis for Complete Response Rate2

CLL14: Subgroup Analysis for Mutated IGHVby MRD Negativity and by CR Rates

1. Fischer K et al. N Engl J Med. 2019;380:2225-2236. 2. Data on File.

29

30




First-Line Treatment for CLL

TP53 Status [del(17p)/TP53]

Age/Fitness IGHV-MS First-Line Treatment

Deleted and/or Mutated

All IrrelevantBTKi ±Obinutuzumab(Gazyva™)

Intact

Young/FitMutated

BCL2i + Obinutuzumab(Gazyva™)

Unmutated

Older/Unfit

Mutated

UnmutatedBTKi ±Obinutuzumab(Gazyva™)

BTKi, Bruton’s tyrosine kinase inhibitor; BCL2i, BCL-2 inhibitor

• Investigator-initiated phase II trial

• Ibrutinib (Imbruvica) monotherapy – 3 months

• Ibrutinib (Imbruvica) + venetoclax (Venclexta) – 24 months

• Option to continue ibrutinib (Imbruvica) if <CR or MRD+

• Tx-naive with at least 1 high-risk feature:

• Del(17p) or mutated TP53

• Del(11q)

• Unmutated IGHV

• Age ≥65 yrs

Ibrutinib (Imbruvica) + Venetoclax (Venclexta)

IBR + VEN in TN CLL. ASH 2018. Abstract 186.

31

32




Responses Improve With Ongoing Therapy

n=75 n=72 n=70 n=60 n=33 n=26

96

43

2717

124

1

57

7383 88

96

017

4052

6169

0

10

20

30

40

50

60

70

80

90

100

PR% CR/CRi % BM U-MRD4 %3 mo IBR 3 mo VEN+IBR 6 mo VEN+IBR 9 mo VEN+IBR 12 mo VEN + IBR 18 mo VEN + IBR

IBR + VEN in TN CLL. ASH 2018. Abstract 186.

Cri, complete response with incomplete blood count recovery; PR: partial response

Wierda et al. ASCO 2018;Abstract 7502.

Phase 2 CAPTIVATE Study Design (NCT02910583)

Patients (N=164)Key eligibility:• Treatment-naïve CLL/SLL• Active disease requiring

treatment per iwCLL criteria• Age <70 years• ECOG PS 0‒1

Randomizationb

Confirmed undetectable MRDc

Double-blind 1:1 randomization,

placebo:ibrutinib (Imbruvica)

Undetectable MRD not confirmed1:1 randomization,

ibrutinib: I+V(Imbruvica)

Study Populations:▪ MRD cohort (N=164): exposure and safety analysis

– Safety Run-in: first 14 patients completed C15 treatment (12 cycles of I+V); no dose-limiting toxicities (DLT) or clinical TLS during first 6 weeks of I+V combination

– First 30 patients completed C9 treatment (6 cycles of I+V) for MRD evaluation

▪ Fixed duration cohort (N=159): separate cohort; analysis not shown

a1 cycle = 28 days.bStratified by IGHV mutation status. cConfirmed undetectable MRD for randomization defined as undetectable MRD serially over at least 3 cycles in peripheral blood (PB), and undetectable MRD in both PB and BM.

Ibrutinib (Imbruvica) lead-In:ibrutinib (Imbruvica)420 mg

once daily for 3 cyclesa

Followed by I+V:Add venetoclax (Venclexta)

ramp-up to400 mg once daily for

12 cycles

33

34




Bruton Tyrosine Kinase (BTK) Inhibitors

BTK Inhibitors – Dosing

Ibrutinib(Imbruvica)

Acalabrutinib*

(Calquence)

FDA Approval Date November 2013 October 2017 for mantle cell lymphoma (MCL)

Usual Starting Dose 420 mg PO once dailyTake with a glass of water with or without food

100 mg PO BIDTake with water with or without food

Dose in Hepatic Dysfunction Child-Pugh A: 140 mg PO dailyChild-Pugh B: 70 mg PO dailyChild-Pugh C: Avoid use

Child-Pugh A & B: No recommended dose reductionsChild-Pugh C: Not studied

Availability Capsules: 70 mg, 140 mgTablets: 140 mg, 280 mg, 420 mg, 560 mg (MCL)

Capsules: 100 mg

1. Imbruvica [ibrutinib (prescribing information)]. Sunnyvale, CA: Pharmacyclics LLC; 2019. 2. Calquence [acalabrutinib (prescribing information)]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017.

*Acalabrutinib approved for CLL/SLL in sNDA on 11-22-19

35

36




BTK Inhibitors – Drug InteractionsIbrutinib(Imbruvica)

Acalabrutinib(Calquence)

Substrate of CYP3A CYP3A, P-gp, BCRP

Effects on enzymes/transporters

Not a clinically significant inhibitor or inducer Not a clinically significant inhibitor or inducerMay inhibit BCRP transporter

Dosing Recommendations with Restricted Concomitant Medications

Moderate CYP3A inh. – 280 mg dailyStrong CYP3A Inhibitors:Voriconazole (Vfend )/Posaconazole(Noxafil) susp. ≤400 mg/day – 140 mg dailyPosaconazole (Noxafil) tabs or IV (any dose) or susp. >400 mg/day – 70 mg daily

Moderate CYP3A inh. – 100 mg dailyStrong CYP3A inh. – avoid use or interrupt acalabrutinib (Calquence) if short duration Strong CYP3A inducer – avoid use. If cannot avoid, increase to 200 mg BIDH2-blockers – take acalabrutinib (Calquence) dose 2 hours prior to H2-blocker Short-acting antacids – separate doses by at least 2 hours

Avoid concomitant use with: Any other strong CYP3A inhibitorsStrong CYP3A inducersGrapefruit and Seville oranges

Proton pump inhibitorsGrapefruit and Seville oranges

CYP, cytochrome p450; P-gp, P glycoprotein; BCRP:, breast cancer resistance protein.1. Imbruvica [ibrutinib (prescribing information)]. Sunnyvale, CA: Pharmacyclics LLC; 2019. 2. Calquence [acalabrutinib (prescribing information)]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017.

BTK Inhibitors – Warnings Ibrutinib(Imbruvica)


Cardiac Arrhythmias Atrial fibrillation: 4%Rare ventricular arrhythmiasCaution in patients with cardiac historyObtain an EKG in symptomatic patients

Atrial fibrillation: 3%Obtain an EKG in symptomatic patients

Cytopenias Grade 3 and 4 events can occurMonitor blood counts monthly

Grade 3 and 4 events can occurMonitor blood counts monthly

Hemorrhage Major bleeding: 4%; all grades: 39%Concomitant anticoagulants increase riskConsider holding ibrutinib at least 3-7 days prior to and postsurgical procedures depending on risks of surgery, bleeding, and ibrutinib interruption

Major bleeding: 2%; all grades: 50%Concomitant anticoagulants increases riskConsider holding acalabrutinib at least 3-7 days prior to and postsurgical procedures depending on surgery and bleeding risks

EKG, electrocardiogram.1. Imbruvica [ibrutinib (prescribing information)]. Sunnyvale, CA: Pharmacyclics LLC; 2019. 2. Calquence [acalabrutinib (prescribing information)]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017. 3. NCCN Clinical Practice Guidelines in Oncology for CLL/SLL V 1.2020.

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38




BTK Inhibitors – Warnings* Ibrutinib(Imbruvica)


Infections Grade 3 or greater: 24% Cases of progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation, invasive fungal infections & Pneumocystis jirovecii pneumonia (PJP)

Grade 3 or greater: 18%Cases of PML, hepatitis B reactivation, and invasive fungal infections have been reported

SecondaryMalignancies

10% occurrence rateMost common – non-melanoma skin cancers

11% occurrence rateMost common – non-melanoma skin cancers

Hypertension Any grade: 12%Grade 3 or greater: 5%Monitor blood pressure periodically

Not listed as a warning

Tumor lysis syndrome

Rarely occurs Not listed as a warning

1. Imbruvica [ibrutinib (prescribing information)]. Sunnyvale, CA: Pharmacyclics LLC; 2019. 2. Calquence [acalabrutinib] (prescribing information)]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017. 3. NCCN Clinical Practice Guidelines in Oncology for CLL/SLL V 1.2020.

*Embryo-Fetal Toxicity: Based on findings in animals, BTK Inhibitors can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant and to use contraception. See Full PI for each drug for more specifics

BTK Inhibitors – Other Common Side EffectsNon-lab events occurring in ≥20% of patients in Ibrutinib (Imbruvica) clinical trials

• Rash

• Musculoskeletal pain

• Fatigue

• Pyrexia

• Cough

• Diarrhea

• Nausea

Non-lab events occurring in ≥20% of patients in Acalabrutinib (Calquence) clinical trials

• Headache• Occurs early and typically resolves with

continued therapy

• Fatigue

• Myalgia

• Diarrhea

• Bruising

1. Imbruvica [Ibrutinib (prescribing information)]. Sunnyvale, CA: Pharmacyclics LLC; 2019. 2. Calquence [acalabrutinib (prescribing information)]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017.

• Advise patients about the possibility of lymphocytosis after initiating treatment• Occurs within the first month of therapy and can persist for several weeks. Not progression!

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40




Venetoclax(Venclexta)

Venetoclax (Venclexta) Dosing

• Inhibits the B-cell lymphoma 2 (BCL2) protein, which is overexpressed in CLL leading to prolonged cell survival

• Inhibition of BCL2 by venetoclax (Venclexta) restores apoptosis

• CLL dosing (requires a ramp-up at initiation):• Each dose should be taken with a meal and water• Week 1: 20 mg PO daily x 7 days• Week 2: 50 mg PO daily x 7 days• Week 3: 100 mg PO daily x 7 days• Week 4: 200 mg PO daily x 7 days• Week 5 and thereafter: 400 mg PO daily, continuously

• Dosing in hepatic impairment:• Child-Pugh C: Decrease dose by 50%

• See prescribing information for modifications for toxicity

• Availability:• Tablets: 10 mg, 50 mg, 100 mg

Venclexta [venetoclax (prescribing information)]. North Chicago, IL: AbbVie Inc; 2019.

41

42




Venetoclax (Venclexta) Drug Interactions

• Substrate of CYP3A, P-gp; inhibitor of P-gp and BCRP; weak inhibitor of CYP2C9 (may affect warfarin)

• Dosing recommendations for specific concomitant medications:• Concomitant strong or moderate CYP3A inhibitors and P-gp inhibitors are

contraindicated during ramp-up or require a venetoclax (Venclexta) dose reduction

• Concomitant posaconazole – 70 mg PO daily (82.5% reduction)• Other strong CYP3A inhibitor – 100 mg PO daily (75% reduction)• Moderate CYP3A inhibitor or P-gp inhibitor – 200 mg PO daily (50% reduction)• P-gp substrate – administer at least 6 hours before venetoclax (Venclexta) dose

• Advise patient to avoid grapefruit, Seville orange, and starfruit consumption while taking venetoclax (Venclexta)

Venclexta [venetoclax (prescribing information)]. North Chicago, IL: AbbVie Inc.; 2019.

Venetoclax (Venclexta) Warnings

• Tumor lysis syndrome (TLS)• Fatal and serious TLS events have occurred in patients with high tumor burden (rate 2% after ramp-

up schedule/aggressive prophylaxis instituted)• See prescribing information for risk assessment and TLS prophylaxis guidance based on risk

• Neutropenia• Grade 3 or 4 neutropenia occurred in approximately 63% of patients in clinical trials• Monitor counts periodically during therapy

• Infections• Fatal and serious infections have occurred

• Embryo-Fetal Toxicity• May cause embryo-fetal harm when administered to a pregnant woman. Advise females of

reproductive potential to avoid pregnancy during treatment

• Immunization• Do not administer live attenuated vaccines prior to, during, or after treatment until B-cell recovery

occurs. Advise patients that vaccinations may be less effective.


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44




Venetoclax (Venclexta): Other Common Side Effects

• Events (non-lab) occurring in 20% or greater of patients in clinical trials

• Edema• Upper respiratory tract infections• Musculoskeletal pain• Fatigue• Cough• Diarrhea• Nausea

• Venetoclax (Venclexta): does not cause lymphocytosis compared to some of the other oral agents being discussed


Chemoimmunotherapy

45

46




Anti-CD20 Monoclonal Antibodies• Three anti-CD20 monoclonal antibodies currently on the market:

• Rituximab [Rituxan (IV)] and rituximab (Rituxan)/hyaluronidase (SQ) (chimeric)• Ofatumumab [Arzerra (human)]• Obinutuzumab [Gazyva™ (humanized)]

• Toxicities profiles are fairly similar:• Infusion-related reactions (follow premedication recommendations)• Injection site reactions (SQ)• Tumor lysis syndrome• Mucocutaneous reactions (rituximab)• Cytopenias• Risk of infections (eg, hepatitis B reactivation, PML)

• Add minimal overlapping toxicity when combined with other agents, such as chemotherapy or oral targeted agents

• Based on human data, RITUXAN can cause fetal harm due to B-cell lymphocytopenia in infants exposed to rituximab in-utero. Advise pregnant women of the risk to a fetus. Females of childbearing potential should use effective contraception while receiving RITUXAN and for 12 months following the last dose of RITUXAN

• ARZERRA (ofatumumab) may cause fetal B-cell depletion based on findings from animal studies and the drug’s mechanism of action There are no data on ARZERRA use in pregnant women to inform a drug-associated risk. See full PI.

• GAZYVA™ is likely to cause fetal B-cell depletion based on findings from animal studies and the drug’s mechanism of action There are no data with GAZYVA™ use in pregnant women to inform a drug-associated risk. See full PI.

1. Rituxan [rituximab (prescribing information)]. South San Francisco, CA: Genentech; 2019.2. Rituxan Hycela [(Rituxan)/hyaluronidase (SQ) (chimeric) (prescribing information)]. South San Francisco, CA: Genentech; 2018.3. Arzerra [ofatumumab (prescribing information)]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2016.4. Gazyva™ [obinutuzumab (prescribing information)]. South San Francisco, CA: Genentech; 2017.

Chemoimmunotherapy

• Chemoimmunotherapy = Anti-CD20 monoclonal antibody + alkylating agent +/-purine nucleoside analog

• Alkylating agents – bendamustine (Treanda), cyclophosphamide (Cytoxan), chlorambucil (Leukeran)

• Purine analogs – fludarabine, pentostatin• Anti-CD20 monoclonal antibodies – rituximab (Rituxan), ofatumumab (Azerra), obinutuzumab

(Gazvya)

• Alkylating agents crosslink DNA strands leading to impaired DNA replication and transcription, and ultimately cell death

• Purine analogs inhibit DNA synthesis by inhibiting critical enzymes involved in the process, such as DNA polymerase and adenosine deaminase

• Anti-CD20 monoclonal antibodies attach to the CD20 antigen expressed on CLL cells and activate antibody-dependent cellular and complement-dependent cytotoxicity

• Up to 6 cycles of chemotherapy may be given with cycles repeated every 28 days• Chlorambucil regimens may be given for up to 12 cycles• After completion of cycles, patients are observed until progression

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48




Chemoimmunotherapy Side Effects

• Major toxicities associated with chemoimmunotherapy are myelosuppression and infections

• Infection prophylaxis is indicated, and growth factor support may be necessary• FCR > BR > Clb-R

• Chemotherapy-induced nausea and vomiting can be managed per the guidelines

• Ensure patients have a PRN antiemetic for home

• Tumor lysis syndrome is also a risk in patients with high tumor burden• Assess patient’s TLS risk and provide appropriate prophylaxis

• Secondary malignancies are also a long-term risk of chemoimmunotherapy

• Potential risks to fetal health must be weighed against risks of delaying treatment in pregnant women. Pregnancy should be avoided during treatment and after as indicated by prescribing information.

PRN, “as needed”1. Eichhorst B et al. Lancet Oncol. 2016;17:928-42.2. Michallet AS et al. Haematologica. 2018;103(4):698-706.

R/R CLL

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50




Phase III RESONATE: Ibrutinib (Imbruvica) vs

Ofatumumab (Arzerra) in R/R CLL/SLL

▪ At time of interim analysis, median time on study was 9.4 mos

Protocol amended for crossover with support of data-monitoring committee and discussion with health authorities.

Enrollment dates:June 2012 - April 2013

Patients with CLL/SLL diagnosis; ≥1 prior therapy; ECOG PS 0/1; measurable

nodal disease (N = 391)

Ibrutinib (Imbruvica)420 mg/day PO until PD or

unacceptable toxicity (n = 195)

Ofatumumab (Arzerra)IV starting dose of 300 mg

followed by 2000 mg x 11 doses for 24 wks

(n = 196)

Crossover to Ibrutinib (Imbruvica)

420 mg/day following PD(n = 122)

Stratified by refractory to purine analogue chemoimmunotherapy (no response or relapsed within 12 mos); presence or absence of 17p13.1 (17p del)

Byrd. NEJM. 2014;371:213.

RESONATE: PFS (Primary Endpoint) and OS

HR for progression or death: 0.22 (95% CI: 0.15-0.32; P<.001 by log-rank test)

Ibrutinib

0

20

40

60

80

100

0 3 6 9 12 15Mos

PFS

(%

)

Patients at Risk, n

IbrutinibOfatumumab

195196

183161

11683

3815

71 0

OfatumumabHR for death: 0.43 (95% CI: 0.24-0.79; P = .005 by log-rank test)

Ibrutinib

0

20

40

60

80

100

0 3 6 9 12 15Mos

OS

(%)

Patients at Risk, nIbrutinib

Ofatumumab195196

191183

184164

11588

3221

53

Ofatumumab

18

Byrd. NEJM. 2014;371:213.

Ibrutinib, (imbruvica ); ofatumumab, (Arzerra)

51

52




Phase III ASCEND Trial of Acalabrutinib (Calquence) vs

Idelalisib (Zydelig) + Rituximab (Rituxan) or BR in R/R CLL

R/R: relapsed/refractory, DoR: duration of responseGhia. EHA 2019. Abstr LB2606. NCT02970318.

▪ International, randomized, open-label phase III trial

▪ Primary endpoints: PFS per IRC

▪ Secondary endpoints: ORR, DoR, PFS per investigator, OS

▪ Interim analysis planned after ≈79 PFS events

Patients with R/R CLL, ≥1 previous systemic therapy for

CLL excluding BCL-2 or B-cell receptor inhibitors, ECOG PS ≤2

(N = 310)

Acalabrutinib (Calquence) 100 mg PO BID

Idelalisib (Zydelig) 150 mg PO BID +Rituximab (Rituxan)

orBendamustine (Treanda) 70 mg/m2 IV on

Days 1, 2 + Rituximab (Rituxan)

del(17p)(yes vs no), ECOG PS (0/1 vs 2), prior lines of therapy (1-3 vs ≥ 4)

PD (crossover from IdR/BR arm to acalabrutinib

allowed)

ASCEND: PFS by IRC Review (Primary Endpoint)

Ghia. EHA 2019. Abstr LB2606.

Acalabrutinib(n = 155)

IdR/BR(n = 155)

Median PFS, mos NR 16.5

HR (95% CI) 0.31 (0.20-0.49; P < .0001)

1-yr PFS rate, % 88 68

100

80

0

60

40

20

01 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

Mos

PFS

(%

)

Patients at Risk, nAcalabrutinib

IdR/BR155155

153150

153150

149146

147144

146142

145136

143130

143129

139112

139105

137101

11882

6144

11677

7356

6039

2110

2518

0218

10

1 1

acalabrutinib , (Calquence); NR, not reached

53

54




BTK Inhibitors in Clinical DevelopmentAgent Mechanism Disease

Current

PhaseStatus

Ibrutinib

(Imbruvica)

irBTKi-C481 MCL, CLL Approved

(CLL/MCL)

Being tested in combinations

Acalabrutinib

(Calquence)

irBTKi-C481 MCL, CLL Approved

(MCL); III (CLL)

To be filed for FDA approval in

newly diagnosed and R/R CLL*

Zanubrutinib

(Brukinsa™)

irBTKi-C481 MCL, CLL III (CLL); I/II

(MCL)

Under FDA review for R/R MCL**

Ono-/GS-4059 irBTKi-C481 CLL, NHL I completed No clear plan

Spebrutinib irBTKi-C481 CLL I/Ib No clear plan

M7583 irBTKi-C481 Heme malignancies I/II Early development

Evobrutinib irBTKi-C481 Autoimmune II Autoimmune development

Fenebrutinib rBTKi CLL, NHL I completed Autoimmune development

Vecabrutinib rBTKi CLL Ib/II Early development for CLL

ARQ-531 rBTKi Heme malignancies I Early development

LOXO-305 rBTKi CLL I Early development; plan for CLL

*FDA approved for CLL,November 2019; **FDA approved for MCL November, 2019.

Phase III Trial of Venetoclax (Venclexta) + Rituximab

(Rituxan) vs BR in R/R CLL/SLL (MURANO): Study Design

▪ Multicenter, randomized, open-label phase III trial

Seymour. NEJM. 2018;378:1107. NCT02005471.

Adult patients with R/R CLL, 1-3 prior tx lines (with

≥1 CT-containing regimen), prior bendamustine

(Treanda) permitted if DoR ≥24 mos

(N = 389)

Venetoclax (Venclexta)monotherapy

until PD, unacceptable toxicity, or maximum of

2 yrs from day 1 of cycle 1

Venetoclax (Venclexta) dose ramp-up 20-400 mg PO QD for 5 wks then 400 mg PO QD for cycles 1-6 +

Rituximab (Rituxan) 375 mg/m2 on day 1 of cycle 1, then 500 mg/m2 on day 1 of cycles 2-6

(n = 194)

Bendamustine (Treanda) 70 mg/m2 on Days 1, 2 of cycles 1-6 + Rituximab (Rituxan) 375 mg/m2

on Day 1 of cycle 1, then 500 mg/m2 Day 1 of cycles 2-6(n = 195)

Stratified by del(17p), prior tx response,* geographic region

*High-risk CLL defined as del(17p); no response to first-line CT-containing tx; or relapsed in ≤12 mos after CT or in ≤24 mos after chemoimmunotherapy.

▪ Primary endpoint: investigator-assessed PFS ▪ Secondary endpoints: IRC-assessed PFS and MRD negativity, IRC-assessed CR → ORR → OS (hierarchical testing), safety

28-day cycles

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MURANO: Updated PFS and OS

▪ Median follow-up: 36.0 mos

Kater. J Clin Oncol. 2019;37:269.

PFS

(%

)

OS

(%)

Mos Mos

Median: 17 mos

Median: NR

Median: NR

Median: NR

0 3 6 9 12 15180

20

40

60

80

100

21 24 27 30 33 36 39 42 45 48 51

HR: 0.16 (95% CI: 0.12-0.23; P < .001)

VenR (n = 194)BR (n = 195)

194195

VenRBR

185164

179142

176128

174103

17084

16779

16165

15055

13541

9926

6110

212

6 2 1190178

Mos0 3 6 9 12 1518

0

20

40

60

80

100

21 24 27 30 33 36 39 42 45 48 51

HR: 0.50 (95% CI: 0.30-0.85; P = .0093)

194195

VenRBR

185175

183167

182162

179155

178152

176150

173147

168141

163136

128111

8776

3934

139

41

2190181

Patients at Risk, n Patients at Risk, n

MURANO: MRD and Progression Status at EOT

MRD Status at EOT (n = 130)

Missing

High MRD+ ( 10–2)

Low MRD+ (10–4 to < 10–2)

uMRD (< 10–4)

83

10

1423

Status Off Therapy, n (%)

uMRD(n = 83)

Low MRD+

(n = 23)

High MRD+

(n = 14)

Missing (n = 10)

Progression free

81 (97.6) 20 (87.0) 3 (21.4) 10 (100)

Progressive disease

2 (2.4) 3 (13.0) 11 (78.6) 0

EOT, end of treatment; MRD, minimal residual disease; uMRD, undetectable minimal residual diseaseKater. J Clin Oncol. 2019;37:269.

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MURANO: Predictors of Disease Progression at EOT

Characteristic, n/N (%) Patients With PD P Value

Blood MRD status at EOT▪ Undetectable▪ Low ▪ High

2/83(2.4 )3/23 (13.0)

11/14 (78.6)< .0001

del(17p) and/or TP53 mutation▪ At least one present▪ Neither present

10/43 (23.3)5/78 (6.4)

.01

del(11q)▪ No▪ Yes

13/80 (16.3)1/38 (2.6)

.03

del(11q) without del(17p)▪ No▪ Yes

7/58 (12.1)1/32 (3.1)

.25

Characteristic, n/N (%) Patients With PD P Value

IGHV mutation▪ No▪ Yes

13/84 (15.5)2/38 (5.3)

.14

No. previous therapies▪ 1▪ ≥2

9/78 (11.5)7/52 (13.5)

.79

Bulky disease (largest lymph node diameter)▪ <5 cm▪ ≥5 cm

9/67 (13.4)7/53 (13.2)

1.0

Nodal status at EOCT▪ <1.5 cm▪ ≥1.5 to <2 cm▪ ≥2 cm

5/64 (7.8)2/23 (8.7)

9/39 (23.1).08

Univariate analysis of clinical and cytogenetic risk factors in VenR pts who completed therapy without progression

EOT, end of treatment; EOCT: end of combination therapyKater. J Clin Oncol. 2019;37:269.

BCL-2 Coding Mutation Detected in 7 Patients With

CLL-Type Progression on Venetoclax (Venclexta)

▪ BCL-2 c.302G>T, p.(Gly101Val) detected in samples from 7 of 15 patients sequenced at CLL-type progression on venetoclax(Venclexta)

Blombery. Cancer Discov. 2019;9:342.

Exon 1

Exon 2 Exon 3

c.302G>Tp.(Gly101Val)

BCL-2 - NM_00063

Pre-VEN

C C G G C G A

Progression

C C G G C G A

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Phase III Trial of Idelalisib (Zydelig) + Rituximab (Rituxan) in Relapsed

CLL: Final Results of PFS (Primary Endpoint) and OS

▪ Phase III trial in patients with relapsed CLL after at least 1 prior line of tx

‒ Primary study 116 with idelalisib (Zydelig) /rituximab (Rituxan) followed by extension study 117 with single-agent idelalisib (Zydelig)

Sharman. JCO. 2019;37:1391.

10090

8070605040302010

0

Pro

bab

ility

of

PFS

(%

)

Mos Since Treatment Assignment

240 2 4 6 8 10

12 14 16 18 20 22

IdRPlacebo/R

PFS, median mos (95% CI)

IdR(n = 110)

19.4 (12.3-NR)

Placebo/R(n = 110)

6.5(4.0-7.3)

10090

8070605040302010

0

Pro

bab

ility

of

OS

(%)

Mos Since Treatment Assignment

560 4 8 12 16 20 24 28 32 40 44 52

IdR (to idelalisib in the extension study)Placebo/R (to idelalisib in the extension study)

OS, median mos (95% CI)

IdR(n = 110)

40.6(28.5-57.3)

Placebo/R(n = 110)

34.6(16.0-NR)

60 64 68

Phase III DUO Trial of Duvelisib (Copiktra) vs Ofatumumab

(Arzerra) in R/R CLL

▪ Duvelisib is a dual inhibitor of PI3K delta and PI3K gamma[1]

▪ Administered orally twice daily[1]

▪ Prolonged PFS compared with ofatumumab in the DUO study[2]

▪ FDA approved for patients with R/R CLL/SLL and ≥2 previous therapies in September 2018

1. Flinn. Blood. 2018;131:877. 2. Flinn. Blood. 2018;132:2446.

DUV OFAMedian PFS, mos (95% CI) 13.3 9.9

(12.1-16.8) (9.2-11.3)HR: 0.52; P < .0001

PFS

by

IRC

(%

)

PFS[2]

Mos

0

20

40

60

80

100

0 3 6 9 12 15 18 21 24 27 30

Duvelisib 25 mg BIDOfatumumab

33 36

160159

149126

10895

9577

7843

5815

337

296

133

102

31

21

00

Patients at Risk, nDuvelisib

Ofatumumab

61

62




Phosphatidylinositol 3-Kinase (PI3K) Inhibitors

PI3K Inhibitors – Dosing

Idelalisib (Zydelig) Duvelisib (Copiktra)

Enzyme isoform(s) inhibited PI3K delta PI3K delta and gamma

FDA Approval Date July 2014 September 2018

Usual Starting Dose 150 mg PO BID continuouslyTake with or without food

25 mg PO BID continuouslyTake with or without food

Dose in Hepatic Dysfunction No dose adjustments are recommended but limited data in patients with baseline AST or ALT > 2.5 x ULN or bilirubin > 1.5 x ULN. Monitor for toxicity.

No specific recommendations as no effect of Child-Pugh A, B, or C hepaticimpairment on duvelisib exposure was seen

Availability Tablets: 100 mg, 150 mg Capsules: 15 mg, 25 mg

AST, aspartate aminotransferase, ALT, alanine aminotransferase, ULN, upper limit of normal1. Zydelig® [idelalisib (prescribing information)]. Foster City, CA: Gilead Sciences, Inc.; 2018. 2. Copiktra® [duvelisib (prescribing information)]. Needham, MA: Verastem, Inc.; 2018.

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PI3K Inhibitors – Drug Interactions

Idelalisib (Zydelig®) Duvelisib (Copiktra®)

Substrate of CYP3A, P-gp, BCRP CYP3A, P-gp, BCRP

Effects on enzymes/transporters Strong inhibitor of CYP3A Moderate inhibitor of CYP3A

Dosing Recommendations with Restricted Concomitant Medications

Strong CYP3A inhibitor – avoid use. If not possible, monitor patient more closely for side effectsSensitive CYP3A substrates – avoid use

Strong CYP3A inhibitor – 15 mg BIDSensitive CYP3A substrates – use with caution

Avoid concomitant use with: Strong CYP3A inducers Strong CYP3A inducers

1. Zydelig [idelalisib (prescribing information)]. Foster City, CA: Gilead Sciences, Inc.; 2018. 2. Copiktra [duvelisib (prescribing information)]. Needham, MA: Verastem, Inc.; 2018.

PI3K Inhibitors – WarningsIdelalisib (Zydelig) Duvelisib (Copiktra)

Hepatotoxicity Fatal/serious hepatotoxicity: 18%Avoid concomitant agents that are liver toxicMonitor AST and ALT:• Every 2 weeks for the first 3 months, then• Every 4 weeks for the next 3 months, then• Every 1 to 3 months thereafter

Grade 3 or 4 ALT and AST elevations: 8% and 2%, respectivelyAvoid concomitant agents that are liver toxicMonitor AST and ALT periodically

Diarrhea/Colitis Grade 3 or higher diarrhea or colitis: 14% Responds poorly to antimotility agents; slow to respond to treatment interruption with or without corticosteroids

Fatal/serious diarrhea or colitis: 18%

Pneumonitis Pneumonitis: 4%Onset ranged from within the first month to 15 months into therapyDo not rechallenge

Fatal/serious pneumonitis: 5%

1. Zydelig® [idelalisib (prescribing information)]. Foster City, CA: Gilead Sciences, Inc.; 2018. 2. Copiktra® [duvelisib (prescribing information)]. Needham, MA: Verastem, Inc.; 2018. 3. NCCN Clinical Practice Guidelines in Oncology for CLL/SLL V 1.2020. 4. Cuneo A et al. Hematol Oncol. 2019;37:3-14.

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66




PI3K Inhibitors – WarningsIdelalisib (Zydelig®) Duvelisib (Copiktra®)

Infections Fatal and/or serious infections: 21%Cases of cytomegalovirus (CMV) reactivation and Pneumocystis jirovecii pneumonia have been reported

Serious/fatal infections: 31%Cases of CMV reactivation and Pneumocystis jirovecii pneumonia have been reported

Neutropenia Grade 3 or 4 neutropenia: 25%Monitor blood counts every 2 weeks for the first 6 months, then as clinically indicated. Monitor weekly when ANC is less than 1K

Grade 3 or 4 neutropenia: 42% Monitor blood counts every 2 weeks for the first 2 months, then as clinically indicated. Monitor weekly when ANC is less than 1K

Cutaneousreactions

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have occurred.Do not rechallenge if SJS or TEN occurs

Serious/fatal cutaneous reactions: 5% Drug reaction with eosinophilia and systemic symptoms (DRESS) and TEN have occurred

Intestinalperforation

Rare occurrence, not always in the setting of diarrhea/colitisDo not rechallenge

Not listed as a warning

Anaphylaxis Rare occurrence Not listed as a warning

Embryo-fetal toxicity

May cause fetal harm. avoid pregnancy while taking; use effective contraception during and at least 1 month after treatment

Can cause fetal harm when administered ; conduct pregnancy testing before initiating treatment. Advise females, and males with female partners of reproductive potential, to use effective contraception during treatment and for at least 1 month after the last dose

ANC, absolute neutrophil count; CMV, cytomegalovirus 1. Zydelig [idelalisib (prescribing information)]. Foster City, CA: Gilead Sciences, Inc.; 2018. 2. Copiktra [duvelisib (prescribing information)]. Needham, MA: Verastem, Inc.; 2018.3. NCCN Clinical Practice Guidelines in Oncology for CLL/SLL V 1.2020.

PI3K Inhibitors – Other Common Side Effects

Non-lab events occurring in ≥20% of patients in idelalisib (Zydelig ®) clinical trials

• Rash

• Pneumonia

• Fatigue

• Pyrexia

• Cough

• Diarrhea

• Nausea

Non-lab events occurring in ≥20% of patients in duvelisib (Copiktra ®) clinical trials

• Fatigue

• Pyrexia

• Upper respiratory tract infection

• Diarrhea

• Nausea

• Rash

• Pneumonia

• Cough

1. Zydelig® [idelalisib (prescribing information)]. Foster City, CA: Gilead Sciences, Inc.; 2018. 2. Copiktra® [duvelisib (prescribing information)]. Needham, MA: Verastem, Inc.; 2018.

• Advise patients about the possibility of lymphocytosis after initiating treatment• Occurs within the first month of therapy and can persist for several weeks. Not progression!

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Additional Patient Support

Infection Monitoring and ProphylaxisNewly Diagnosed CLL Relapsed/Refractory CLL

Ibrutinib (Imbruvica) HSV, HBV* HSV, HBV*

Acalabrutinib (Calquence) --- HSV, HBV*

Venetoclax (Venclexta) HSV HSV

Idelalisib (Zydelig) --- HSV, PJP, HBV*, CMV**

Duvelisib (Copiktra) --- HSV, PJP, HBV*, CMV**

CD20 monoclonal antibodies HBV* HBV*

Chemoimmunotherapy HSV, PJP, HBV*, CMV**#Consider bacterial/fungal during periods of neutropenia

HSV, PJP, HBV*, CMV**#Consider bacterial/fungal during periods of neutropenia

Alemtuzumab --- HSV/VZV, PJP, HBV*, CMV** Considerfungal

CMV, cytomegalovirus; HSV, herpes simplex virus; HBV, hepatitis B virus; PJP, Pneumocystis jirovecii pneumonia ;VZV, varicella zoster virus1. NCCN Clinical Practice Guidelines in Oncology for CLL/SLL V 1.2020. 2. NCCN Clinical Practice Guidelines in Oncology for Prevention and Treatment of Cancer-Related Infections V 1.2019.

*Patients should be screened for hepatitis and those patients HBsAg positive should receive prophylaxis**Monitor for CMV reactivation weekly using quantitative PCR while on therapy and for a period of time after. #Fludarabine-based chemoimmunotherapy.

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Medication Access• Oral agents present unique challenges with regard to patient access to the

medication• Most patients will not be able to start a new therapy on the day the prescription is written• Challenges in scheduling concomitant IV medication if combination therapy planned

• Prescriptions may require prior authorization, which can delay the start of therapy

• Covered prescriptions may still have high copays that necessitate applications to programs/foundations for financial assistance

• Patients without prescription coverage must rely on manufacturer’s assistance programs to acquire free drug

• Many members of the healthcare team may need to assist the patient in obtaining access to the medication

Medication Adherence

• The transition to oral therapies as the backbone of CLL therapy has highlighted the importance of monitoring patient adherence to therapy

• Therapy is continuous with no defined end point

• Data in other disease states as well as CLL demonstrate the importance of adherence on outcomes

• A retrospective analysis of patients receiving Ibrutinib on the RESONATE study evaluated the effect of dose intensity on CLL outcomes

• Patients that maintained high dose intensity with ibrutinib therapy had improved PFS

• Treatment interruptions of greater than 7 days were associated with increased PFS events

• Members of the healthcare team should assess patient’s adherence to therapy at each visit at a minimum

• More frequent assessments may be necessary at therapy initiation and when managing toxicities

Barr PM et al. Blood. 2017;129(19):2612-5.

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Oral CLL Therapies – Patient Counseling Points

• When initiating therapy, encourage patients to reach out for any barriers acquiring the medication

• Stress adherence to prescribed dose, taking at the same time(s) each day

• Educate patients on the common or serious side effects

• Remind patients to report any changes to medical problems and concomitant medications to healthcare teams

Nursing Considerations in CLLJACKIE BROADWAY-DUREN, DNP, APRN, FNP-BC

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Who Are Oncology Nurses?

Registered nurses (RNs) have varied levels of educational preparation

▪Associate degree

▪Bachelor’s degree

▪Doctorate degrees

▪DNP/PhD

▪ Many oncology nurses are oncology certified (OCN)

▪ Have specialized training applicable to area of specialty

Rationale for Nurses in CLL▪ Nurses are vital to oncology patient care

▪ Deliver high-quality clinical services

▪ Contribute to improved patient outcomes

▪ Serve in multifaceted roles in CLL patient care

Oncology Nursing Society. Retrieved from http://www.ons.org

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http://www.ons.org/




Nursing Roles in CLL Patient Care

Patient Care Advocate

EducatorResearch Study

Coordinators

Oncology Nurse Roles

Interprofessional Team MemberAs a member of the interprofessional team, nurses:

▪ Triage patients based on symptoms

▪Assist in patient education for oral therapies

▪Assist in coordinating treatment schedules and patient appointments

▪Administer IV infusions (i.e., antibody therapy)

▪Collaborate with physicians, APPs, pharmacists, social work, and patient

advocates in coordinating patient care

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Role of the RN in Patient Care▪ Review medications during each clinic visit

▪ Provide initial review of systems with each clinic visit

▪ Administer outpatient injections (vaccine) and monitor patients for side effects

▪ Perform bedside nursing for hospitalized patients (Richter’s)

▪ Work with multidisciplinary teams to ensure patient needs are met

Nurse Educator Role in CLL▪RNs provide pertinent patient education

▪RNs provide written drug side effect information

▪Instruct patients on oral drug adherence and assist in patient follow-up

▪APRNs educate patients with specific disease-related information and mechanism of action of various therapies (e.g., MAB, BTK inhibitors)

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Patient Advocacy in CLL▪ Transitional care – collaborate with patient’s community providers

▪ Facilitate prior authorizations

▪Collaborate with specialty pharmacies to ensure patient medications are delivered on time

▪Care coordination is an integral component of the oncology nurse’s job

▪Assist with communication among patients, family members, and other disciplines

▪ Prepare patients and caregivers on expectations for clinic and treatments

Research Nurse Role in CLL▪Collaborate with the interprofessional team members to determine best

treatment recommendations

▪Research nurses (RNs) educate patients regarding research protocols, specific drug information, and study requirements

▪Register patients for research protocols

▪Obtain consent for research studies

▪Monitor adverse events of therapy and report to PI, attending physician/APP

▪Collaborate with pharmaceutical and FDA sponsors of research studies and report adverse events using grading scales

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Advanced Practice Nurses (APRNs) in CLL▪APRNs perform physical examinations, order and interpret laboratory and

radiologic diagnostic tests, and order blood products and growth factors as indicated

▪APRNs consent patients for treatments for off-protocol therapy

▪Collaborate with physicians and pharmacists regarding appropriate treatments

▪APRNs assist in managing adverse drug effects (AEs) by:

▪Monitoring lab data with intervention as indicated (TLS)

▪ Prescribe appropriate medications or needed intervention to manage AEs

Integration of Interprofessional Roles▪New patient presents to clinic with new diagnosis of B CLL

▪ The RN is the first point of contact upon patient entering clinic

▪ The RN does initial review of systems (ROS), reviews and updates medications

▪ The RN hands the patient off to the APRN or PA (APP)

▪ The APRN assesses the patient, including past medical history, past cancer therapies, performs H&P and medication review, and orders appropriate tests

▪ The attending physician is then given a report on the patient, and further evaluation and decisions are made with team input

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RESOURCES FOR YOU & YOUR PATIENTS

FROM THE LEUKEMIA & LYMPHOMA SOCIETY (LLS)

WWW.LLS.ORG

LLS RESOURCES FOR HEALTHCARE PROFESSIONALS

Online and in-person CE/CME webinars, symposia & rounds

Free CME & CE www.LLS.org/CE

Podcast series for healthcare professionals Conversations with experts about diagnosing & treating blood

cancers www.LLS.org/HCPpodcast

HCP palm card – User friendly links to resources for you & your patients

www.LLS.org/CE

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http://www.lls.org/CE

http://www.lls.org/HCPpodcast

http://www.lls.org/CE




LLS RESOURCES FOR PATIENTS AND CAREGIVERS

❑ Information Specialists – disease information, emotional support, financial, travel & co-pay assistance, support

through local LLS patient access staff. Also send free materials to patients & HCPs

❑Nutrition Consultations – One-on-one consultations from certified dietitian

Specialists can serve as a resource for your HCP team

M - F, 9 am to 9 pm ET:

❑ Phone: (800) 955-4572

❑ Live chat: www.LLS.org/InformationSpecialists

❑ Email: [email protected]

❑Additional support for patients & caregivers – www.LLS.org/Support

❑Booklets on disease, treatment, & support - www.LLS.org/Booklets

❑Webinars, videos, in-person programs - www.LLS.org/Programs & www.LLS.org/Educationvideos

CLINICAL TRIAL NURSE NAVIGATORS

Help patients find and enroll in

clinical trials based on highly

detailed individualized assessments

www.LLS.org/Navigation

602patients provided with in-depth clinical trial

navigation and support in past year

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http://www.lls.org/InformationSpecialists

mailto:[email protected]

http://www.lls.org/Support

http://www.lls.org/Booklets

http://www.lls.org/Programs

http://www.lls.org/educationvideos

http://www.lls.org/Navigation




We have one goal: A world without blood cancers

THANK YOU

Appendix

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Rai and Binet Staging Systems and CLL International Prognostic Index

Chronic Lymphocytic Leukemia Booklet, The Leukemia & Lymphoma Society- LLS.org

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Documents

Chronic Lymphocytic Leukemia (CLL): Diagnosis, Treatment, and … · 2020. 6. 15. · Onkologie. 2001;24:60. Dewald. Br J Haematol. 2003;121:287. Sindelárová. Cancer Genet Cytogenet