evolving treatment strategies for cll/sll and mcl

Evolving Treatment Strategies for CLL/SLL and MCL

2

• Identify novel therapies for treatment of CLL/SLL and MCL

• Formulate evidence-based approaches for individualization of therapy in CLL/SLL and MCL

• Apply strategies to appropriately manage treatment-associated toxicities in CLL/SLL and MCL

Learning Objectives

CLL = chronic lymphocytic leukemia; MCL = mantle cell lymphoma; SLL = small lymphocytic lymphoma.

3

Secondary Lymphoid Tissues

Bone Marrow

B-Cell Malignancies: Cell Types and Associated Diseases

Pre B-cell

Naive B-cell

Activated B-cell

Germinal-center B-cell

Memory B-cell

Lymphoplasmacytoid

Plasma cells

Mantle cell lymphoma,

marginal zone lymphoma, CLL

Diffuse large B-cell lymphoma

Follicular lymphoma, Diffuse large B-cell lymphoma,Hodgkin’s lymphoma

Burkitt lymphoma, CLL

Waldenström’s macroglobulinemia

Multiple myeloma,amyloidosis

Blood and Marrow

Associated Diseases

Acute lymphoblastic leukemia

Cell Types

Lymphoid progenitorBlood and Marrow

4

Ibrutinib Acalabrutinib Zanubrutinib

First-generation BTK inhibitor Second-generation BTK inhibitor Second-generation BTK inhibitor

Potent and irreversible Highly selective, potent, irreversible Highly selective, potent, irreversible

Approved for CLL/SLL, MCL, MZL, WM

Approved for MCL, CLL/SLL Approved for MCL, MZL, WM

Once-daily dosing

• 420 mg PO daily for CLL/SLL, WM

• 560 mg PO daily for MCL, MZL

Twice-daily dosing

• 100 mg PO every 12 hr for MCL, CLL/SLL

Once-daily dosing

• 320 mg PO daily for MCL, MZL, WM

Twice-daily dosing

• 160 mg PO every 12 hr for MCL, MZL, WM

Mechanisms of Action and Properties of Approved BTK Inhibitors

Acalabrutinib PI. Barf. J Pharmacol Exp Ther. 2017;363:240. Byrd. N Engl J Med. 2016;374:323. Ibrutinib PI. Zanubrutinib PI.MZL = marginal zone lymphoma; WM = Waldenström’s macroglobulinemia.

Mantle Cell Lymphoma

6

• Diagnosed with MCL at age 72, initially treated with bendamustine + rituximab plus rituximab maintenance

• Presenting now with recurrence of uncomfortable 3 cm lymph nodes in bilateral inguinal region and neck

Case Study: Mike, 74 Years Old With Relapsed/Refractory MCL

7

Guideline Recommendations for Stage III/IV MCL

ASCT = autologous stem cell transplant; BR = bendamustine + rituximab; HD = high-dose; HDT = high-dose therapy; PD = progressive disease; R = rituximab.NCCN Guidelines. B-cell lymphomas. V.5.2021.

Aggressive ChemotherapyR-DHA + cisplatin, carboplatin, or oxaliplatinR-CHOP/R-DHAP (alternating)NORDIC (maxi-CHOP/R + HD cytarabine)Hyper-CVAD + RBR → R, HD cytarabine

Less Aggressive ChemotherapyBRVR-CAPR-CHOPLenalidomide + R

MaintenanceAfter R-CHOP: R maintenance until PD

Preferred Second-lineTreatment

Options

BTK inhibitor• Ibrutinib • Acalabrutinib• Zanubrutinib

Lenalidomide ± R

Third-lineTreatment

Brexucabtagene autoleucel (after chemoimmunotherapy and BTK inhibitor)

Preferred First-line

Treatment Options

Consolidation and MaintenanceHDT + ASCT → R maintenance for 3 yr

8

0

20

40

60

80

100

0 3 6 9 12 15

Phase II PCYC-1104: Targeting BTK With Ibrutinib in R/R MCL

Patients with MCL and measurable disease (LN diameter ≥2 cm); 1-5 previous lines of tx;no less than PR to the most recent tx or PD

after the most recent tx; adequate organ function(N = 111)

Continue until PD or unacceptable AE

occurred

Ibrutinib 560 mg PO daily

AE = adverse event; CR = complete response; LN = lymph node; OS = overall survival; PFS = progression-free survival; PR = partial response; R/R = relapsed/refractory.Wang. NEJM. 2013;369:507. Wang. Blood. 2015;126:739.

0

20

40

60

80

100

Pat

ien

ts R

esp

on

din

g (%

)

PRCR

48

21

No prior bortezomib

exposure(n = 63)

68%

Prior bortezomib

exposure(n = 48)

40

25

65%

Total(N = 111)

44

23

67%

Median OS: 22.5 mo (95% CI: 13.7-NE)

47%P

FS (

%)

Median PFS: 13 mo (95% CI: 7.0-17.5)

31%

0

20

40

60

80

100

0 3 6 9 12 15 18 21 24 27 30

Mo

+ Censored

Patients at Risk, n111 91 67 55 52 47 36 27 22 11 0

PFS (All Patients)

18 21 24 27 30

Mo

OS

(%)

+ Censored

Patients at Risk, n111 103 88 71 64 59 55 49 33 25 3

33

0

OS (All Patients)

9

Most Common AEs (≥30% of Patients), % Any Grade Grade 3/4

Diarrhea 54 5 (6 patients)

Fatigue 50 —

Nausea 33 —

Dyspnea* 32 —

Most Common Grade ≥3 Hematologic AEs, % Grade 3/4

Neutropenia 17

Thrombocytopenia 13

Anemia 11

Phase II PCYC-1104 Trial of Ibrutinib: Summary of AEs

AEs of Interest

• Infection (all grade): 78%

— Grade ≥3: 28% (8% pneumonia)

• Bleeding/bruising (all grade): 50%

— Grade ≥3: 6% (no grade 5)

• Cardiac (all-grade AF): 11%

— Grade ≥3: 6%

— 10 of 12 with history of CVD

*Approximately two-thirds occurred in patients with a history of COPD, heart failure, and chronic lung infection and/or anxiety, or concurrently with AEs affecting respiratory function.CVD = cardiovascular disease.Wang. Blood. 2015;126:739.

10

Phase II ACE-LY-004: Treating R/R MCL With Acalabrutinib

Adult patients with MCL; 1-5 prior lines of tx; ECOG PS 0-2; no notable CVD*; no concurrent use of warfarin/equivalent vitamin K

antagonists, no prior BTK inhibitors(N = 124)

Until PDAcalabrutinib 100 mg PO twice daily in 28-day cycles

*Includes class 3/4 cardiac disease per NYHA Functional Classification; CHF or MI within 6 mo of screening; QTc >480 ms; uncontrolled/symptomatic arrhythmias.ECOG PS = Eastern Cooperative Oncology Group performance status.Cheson. JCO. 2014;32:3059. Cheson. JCO. 2007;25:579. Wang. Lancet. 2018;391:659.

0

20

40

60

80

100

Pat

ien

ts R

esp

on

din

g (%

)

PRCR

Total(N = 124)

41

40

81%

124 0111 97 85 83 76 73 28 21 8 5 2 124 0120 115 110 107 104 103 95 46 18 11 8

12-mo PFS rate: 67% (95% CI: 58% to 75%)

12-mo OS rate: 87% (95% CI: 79% to 92%)

MoMo

PFS OS

OS

(%)

100

80

60

40

20

0

0 2 4 6 8 10 12 14 16 18 20 22 24

Patients at Risk, n

100

80

60

40

20

0

0 2 4 6 8 10 12 14 16 18 20 22 24

Patients at Risk, n

PFS

(%

)

11

Phase II ACE-LY-004 Trial of Acalabrutinib: Summary of AEs

AEs of Interest

• Infection (all grade): 53%

— Grade ≥3: 13% (5% pneumonia)

• Bleeding/bruising (all grade): 31%

— Grade ≥3: 1% (no grade 5)

• Cardiac (all grade): 8%

— Grade ≥3 cardiac: 2%

— No AF

Wang. Lancet. 2018;391:659.

Most Common AEs (≥20% of Patients), % Any Grade Grade 3/4

Headache 38 2

Diarrhea 31 3

Fatigue 27 1

Myalgia 21 1

Most Common Grade ≥3 Hematologic AEs, % Grade 3/4

Anemia 9

Neutropenia 11

Thrombocytopenia 5

12

Phase II BGB-3111-206: Treating R/R MCL With Zanubrutinib

Patients with MCL and ≥1 prior lines of tx; ECOG PS 0-2; no notable CVD; no

prior BTK inhibitors(N = 86)

Up to 3 yr or until PD, unacceptable toxicity,

or death

Zanubrutinib 160 mg PO twice daily

Song. Clin Canc Res. 2020.

100

80

60

40

20

0240 3 6 9 12 15 18 21

Updated PFS

Note: Only 4 patients were at risk at the last event time

Median PFS follow-up: 19.1 mo

PFS

(%

)

Mo

86 73 67 64 60 58 26 10 0

Censored95% CI

+

+

+

+

+++

++

+ +++++ +++

+++

Patients at Risk, n

72.1% (61.0-80.5)

74.6% (63.7-82.6)

0

20

40

60

80

100

Pat

ien

ts R

esp

on

din

g (%

)

PRCR

Total(N = 86)

69

15

81%

13

100

80

60

40

20

0340 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32

ZUMA-2: Brexucabtagene Autoleucel Efficacy in R/R MCL

Wang. NEJM. 2020;382:1331.

• All patients had up to 5 previous therapies including previous BTK inhibitor therapy

• Most common grade ≥3 AEs were cytopenias (94%) and infections (32%)

• CRS occurred in 91% of patients, but 76% were grade 1/2

100

80

60

40

20

0

Best Response

Pat

ien

ts (

%)

CR

PR

SD PDObjective Response

2 (3) 2 (3)

56 (93)

40 (67)

16 (27)

OS

Pat

ien

ts A

live

(%

)

Mo

Patients at Risk, n

Median: not reached (95% CI: 24.0-NE)

60 59 55 52 46 36 27 21 21 21 20 20 19 15 7 2 1 0

+++++++++++++++

+

+

++++++++++++++++

N = 74

14

• International, randomized, multistage, phase III trial: open-label safety run-in, double-blind randomized period, new open-label arm added after randomized arms fully enrolled

SYMPATICO (PCYC-1143): Ibrutinib + Venetoclax vs Ibrutinib in Previously Untreated and R/R MCL

DLT = dose-limiting toxicity.

Jurczak. ICML 2021. Abstr 1143. Tam. ASH 2020. Abstr 2938. NCT03112174.

Patients with MCL; 1-5 prior therapies; no PR with or PD after most recent tx; no prior BTK or

BCL inhibitors; ECOG PS 0-2(planned N = 260)

Ibrutinib 560 mg daily +Venetoclax 400 mg daily*

Ibrutinib 560 mg daily + Placebo

*Venetoclax ramp-up: 20 mg Wk 1, 50 mg Wk 2, 100 mg Wk 3, 200 mg Wk 4, 400 mg Wk 5.

At 2 yr, discontinue venetoclax/placebo and

continue ibrutinib until PD or unacceptable toxicity

• Primary endpoints: PFS, CR, TLS, DLT

‒ Open-label safety run-in (n = 21): primary endpoints, TLS and DLT

• New open-label arm (planned n = 75): Ibrutinib + venetoclax in previously untreated MCL; as of January 11, 2021, only those with TP53 mutations may enroll

‒ Primary endpoint: CR rate

15

• International, open-label, randomized phase III trial

Phase III BRUIN-MCL-321: Pirtobrutinib vs Investigator’s Choice of BTK Inhibitor in R/R MCL

DoR = duration of response; EFS = event-free survival; ORR = overall response rate; TTF = time to treatment failure.NCT04662255.

Patients with MCL; previously treated with ≥1 systemic tx; no

prior BTKi; ECOG PS 0-2(planned N = 500)

Pirtobrutinib*

Investigator’s choice of BTK inhibitor (ibrutinib, acalabrutinib, zanubrutinib)

• Primary endpoint: PFS

• Secondary endpoints: EFS, ORR, DoR, OS, TTF, time to worsening of MCL-related symptoms, tolerability

*A next-generation, highly selective, noncovalent BTK inhibitor

Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia

17

• More than 21,000 estimated new cases in 2021 in the United States

‒ 7% of all non-Hodgkin lymphomas are CLL/SLL

• Median age at diagnosis: 70 yr

• SLL and CLL considered the same B-cell malignancy

‒ 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 mo to normal life span)

‒ Recent (2011-2017) 5-yr survival: 87%

CLL/SLL: Background

Nabhan. JAMA. 2014;312:2265. SEER Cancer Stat Facts. Chronic lymphocytic leukemia. Siegel. CA Cancer J Clin. 2021;71:7. Zelenetz. J Natl Compr Canc Netw. 2015;13:326.

18

• A 67-year-old woman presents complaining of night sweats and fatigue

• Previous medical history significant for diagnosis of asymptomatic CLL 1.5 years earlier (observation selected, with no prognostic workup at diagnosis)

• Physical exam: 2-3 cm nodes, spleen palpable 4 cm below costal margin

• WBC count: 79.6; Hgb: 9.6; Platelets: 103

• FISH reveals 17p deletion

• Mutated IGHV gene detected

Case Study: Doris, 67 Years Old With Previously Untreated CLL With Mutated IGHV and 17p Deletion

FISH = fluorescence in situ hybridization; Hgb = hemoglobin; WBC = white blood cell.

19

• Doris was started on ibrutinib

• 3-mo follow-up: Complained only of easy bruising and cramps in the feet

‒ Adenopathy and splenomegaly resolved; ALC: 67.3; Hgb: 11.2; Platelets: 95

• 6-mo follow-up: Complained of intermittent palpitations

‒ ALC: 37.5; Hgb: 11.3; Platelets: 98

‒ ECG: Sinus rhythm, Ziopatch placed, showed intermittent AF, rate 70-128

Case Study (cont’d): Doris Now Presents With Ibrutinib-Related AF

ALC = absolute lymphocyte count.

20

FISH Abnormalities Present in 268/325 Patients (82%)

Lesion Percent Median OS, Mo

del(13q) 55 133

del(11q) 18 79

Trisomy 12 16 114

del(17p) 7 32

del(6q) 6 N/A

Normal 18 111

FISH Lesion

Patients With Abnormality, %

Dohner et al.

Oscier et al.

Jarosova et al.

Dewald et al.

Sindelaravaet al.

del(13q) 45 36 18 47 54

Trisomy 12 15 15 13 25 16

del(17p) 10 8 11 8 16

CLL: Prognostic Value of FISH (Outcomes Prior to Novel Targeted Therapies)

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

)

Mo

17p deletion11q deletion12q trisomyNormal13q deletion as sole abnormality

21

OS effect of TP53 wt: vs TP53 mut only: P = .013; vs TP53 del only: P = .006; vs TP53 mut + del: P <.001

CLL: Impact of TP53 Mutations and TP53 Deletion on OS (Outcomes Prior to Novel Targeted Therapies)

del = deletion; mut = mutation; wt = wild type.Stengel. Leukemia. 2017;31:705.

5

4

3

2

1

0Fre

qu

ency

of

P5

3A

lte

rati

on

s in

Re

lati

on

to

To

tal S

ize

of

Each

Co

ho

rt

(%)

CLL

TP53 mut only

TP53 del only

TP53 mut + del

Yr

100

OS

(%)

80

60

40

20

0

TP53 wt

TP53 alteration

P <.001

100 1 2 3 4 5 6 7 8 9

Yr

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

N = 1148

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

22

FCR300: PFS by IGHV Mutation Status in CLL

NProgression

Free

88 49126 12

100

75

50

25

0

PFS

(%

)

1614120 2 4 6 8 10Yr

IGHV mutatedIGHV unmutated

P <.0001

Thompson. Blood. 2016;127:303.

23

Current Treatment Landscape in CLL

No del(17p)/TP53 mutations• FCR (IGHV mutated and <65 yr/fit)• Ibrutinib• Acalabrutinib ± obinutuzumab• Venetoclax + obinutuzumab

With del(17p)/TP53 mutations• Ibrutinib• Acalabrutinib ± obinutuzumab• Venetoclax + obinutuzumab

With or without del(17p)/TP53 mutations• Ibrutinib• Acalabrutinib • Venetoclax + rituximab• Idelalisib + rituximab• Duvelisib

Second-line treatment

options

First-line treatment

options

24

0

Phase III E1912 Trial of Ibrutinib + Rituximab (IR) vs FCR in Younger Patients With Treatment-Naive CLL: 3-Yr PFS

Shanafelt. ASH 2019. Abstr 33. Shanafelt. NEJM. 2019;381:432.

100

80

60

40

20

0 1 2 3 4 5Yr

PFS

(%

)

HR: 0.39 (95% Cl: 0.26-0.57)P <.0001

3-yr rates: 89% vs 71%

Patients at Risk, n175354

145338

123321

82280

31121

08

IR (58 events/354 cases)

FCR (52 events/175 cases)

25

E1912: 3-Year PFS by IGHV Status

IGHV Unmutated IGHV Mutated

Shanafelt. ASH 2019. Abstr 33. Shanafelt. NEJM. 2019;381:432.

100

80

60

40

20

00 1 2 3 4 5

Yr

PFS

(%

)

HR: 0.42 (95% Cl: 0.16-1.16)P = .036

3-yr rates: 88%, 82%

FCR (8 events/ 44 cases)

Patients at Risk, n

4470

3867

3464

2554

1120

01

100

80

60

40

20

00 1 2 3 4 5

Yr

PFS

(%

)

HR: 0.28 (95% Cl: 0.17-0.48)P <.0001

3-yr rates: 89%, 65%

FCR (29 events/71 cases)

Patients at Risk, n

71210

63202

50193

31165

872

07

IR (36 events/210 cases)IR (10 events/70 cases)

26

100

80

60

40

20

0

• PFS significantly improved with ibrutinib vs BR and ibrutinib + rituximab vs BR (both 1-sided P <.001)

‒ HR for ibrutinib vs BR: 0.39 (95% CI: 0.26-0.58)

‒ HR for ibrutinib + rituximab vs BR: 0.38 (95% CI: 0.25-0.59)

• No significant difference for ibrutinib + rituximab vs ibrutinib only (1-sided P = .49)

‒ HR: 1.00 (95% CI: 0.62-1.62)

ALLIANCE (A041202): First-line Bendamustine + Rituximab vs Ibrutinib ± Rituximab in CLL/SLL: PFS

*524 of 547 randomized patients.NR = not reached.Woyach. NEJM. 2018;379:2517.

Events, n/N

Median PFS, Mo (95% CI)

2-Yr PFS,% (95% CI)

Ibrutinib 34/178 NR 87 (81-92)

IR 32/170 NR 88 (81-92)

BR 68/176 43 (38-NR) 74 (66-80)

PFS

(%

)Patients at Risk, n

IbrutinibIR

BR

Mo

178170176

165159140

154145129

147138122

787457

136132103

12011588

454026

222011

000

Ibrutinib

IR

BR

0 6 12 18 24 30 36 42 48 52

27

0.8

0.6

0

1.0

0.4

0.2

0.8

0.6

0.4

0.2

0

1.0

0.8

0.6

0

1.0

0.4

0.2

• PFS benefit with ibrutinib-containing regimens vs BR observed in all cytogenetic factor-related subgroups, with del(17p) being most pronounced

ALLIANCE (A041202): PFS by del(17p) and del(11q) Status

del(17p) del(11q) Neither del(17p) or del(11q)

Events, n/N


Ibrutinib 2/9 NE

IR 3/11 NE

BR 10/14 7 (4-23)

Events, n/N


Ibrutinib 4/35 NE

IR 7/37 NE

BR 15/33 41 (36-NE)

Events, n/N


Ibrutinib 27/137 NE

IR 25/132 NE

BR 45/134 51 (43-NE)

Woyach. NEJM. 2018;379:2517.

Pro

bab

ility

of

PFS

Mo

0 6 12 18 24 30 36 42 48 52Mo

0 6 12 18 24 30 36 42 48 52Mo

0 6 12 18 24 30 36 42 48 52

Ibrutinib

Ibrutinib

Ibrutinib

IR

IRIR

BRBR

BR

28

iLLUMINATE: First-line Ibrutinib + Obinutuzumab vs Chlorambucil + Obinutuzumab in CLL/SLL: PFS

Moreno. Lancet Oncol. 2019;20:43.

HR: 0.23 (95% CI: 0.15-0.37; P <.0001)

Patients at Risk, n (number censored)

Ibrutinib + obinutuzumab

Chlorambucil + obinutuzumab

113 109 106 105 99 94 90 85 82 82 28 6 0(0) (1) (3) (3) (5) (6) (8) (9) (9) (9) (62) (84) (89)

116 111 109 102 81 67 56 47 35 33 6 5 0(0) (4) (4) (6) (7) (7) (8) (8) (10) (10) (36) (37) (42)

PFS

(%

)

Patients,n

Median PFS, Mo

30-Mo PFS,% (95% CI)


113 NR 79 (70-85)


116 19.0 31 (23-40)

100

80

60

40

20

00 3 6 9 12 15 18 21 24

Mo27 30 33 36



29

Phase III ELEVATE-TN: Acalabrutinib ± Obinutuzumab vs Chlorambucil + Obinutuzumab in Treatment-Naive CLL: 4-Yr PFS

*HR per unstratified Cox proportional hazards model with unstratified log-rank P values.Sharman. ASCO 2021. Abstr 7509.

Outcome A + O A O + ClbHR (95% CI)*

A + O vs O + Clb A vs O + Clb A + O vs A

Overall population n = 179 n = 179 n = 177

• Median PFS, mo (primary endpoint)

NR NR 27.80.10 (0.07-0.17;

P <.0001)0.19 (0.13-0.28;

P <.0001)0.56 (0.32-0.95;

P = .0296)

• 48-mo PFS rate, % 87 78 25

With del(17p) and/or TP53 mut n = 25 n = 23 n = 25

• Median PFS, mo NR NR 17.50.17 (0.07-0.42;

P <.0001)0.18 (0.07-0.46;

P <.0001)—

• 48-mo PFS rate, % 76 75 18

With unmutated IGHV n = 103 n = 119 n = 116

• Median PFS, mo NR NR 22.20.06 (0.04-0.11;

P <.0001)0.10 (0.06-0.16;

P <.0001)—

• 48-mo PFS rate, % 86 77 4

With mutated IGHV n = 74 n = 58 n = 59

• Median PFS, mo NR NR NR0.26 (0.11-0.63;

P = .0012)0.52 (0.24-1.13;

P = .0551)—

• 48-mo PFS rate, % 89 81 62

30

• Single-arm, open-label, phase II expansion study (N = 99)

‒ Median age: 64 yr

‒ del(17p): 10%

‒ Unmutated IGHV: 62%

• Median follow-up: 53 mo

• DoR: median NR; 48-mo rate: 97%

• Reduced lymph node disease noted in all patients

• No PR with lymphocytosis

ACE-CL-001: Long-term Efficacy of Acalabrutinib in Treatment-Naive CLL/SLL

Byrd. ASCO 2020. Abstr 8024. Byrd. Blood. 2021;137:3327.

Characteristics Acalabrutinib (N = 99)

Median EFS, mo (95% CI) NR (NR)

48-mo EFS, % (95% CI) 90 (82-94)

ORR, %• CR• PR• SD

977

901

ORR by subgroup, n/N (%)• Unmutated IGHV• del(17p)• TP53 mutation• Complex karyotype

57/57 (100)9/9 (100)9/9 (100)

12/12 (100)

31

ACE-CL-001: Long-term Safety

*Excluding non-melanoma skin cancer.Byrd. ASCO 2020. Abstr 8024. Byrd. Blood. 2021;137:3327.

AEs Occurring in ≥40% of Patients (Any Grade), %

Acalabrutinib (N = 99)

Diarrhea 51

Headache 45

Upper respiratory infection 44

Arthralgia 42

Contusion 42

• Most adverse events were grade ≤2

• Serious AEs occurred in 38%, including pneumonia (n = 4), sepsis (n = 3), grade 5 multiorgan failure (n = 2)

AEs of Special Interest, %

Acalabrutinib (N = 99)

Any Grade ≥3

Cardiac events• Atrial fibrillation• Ventricular

tachyarrhythmias

2050

420

Hemorrhage• Major hemorrhage

664

33

Hypertension 22 11

Infections 84 15

2nd primary malignancy* 11 5

Tumor lysis syndrome 0 0

32

Acalabrutinib vs IdR/BR Acalabrutinib vs IdR or BR

PFS

(%

)

Mo

0

20

40

60

80

0 2 4

100

6 8 10 12 14 16 18 20 22 24 26 28

MoP

FS (

%)

0

20

40

60

80

0 2 4

100

6 8 10 12 14 16 18 20 22 24 26 28

Phase III ASCEND Trial of Acalabrutinib vs Idelalisib + Rituximab (IdR) or BR in Previously Treated CLL: PFS

Ghia. ASCO 2020. Abstr 8015. Ghia. J Clin Oncol. 2020;38:2849.

• International, randomized, open-label phase III trial for R/R CLL

Acalabrutinib

(n = 155)

IdR/BR

(n = 155)

Median PFS, mo NR 16.8

HR (95% CI) 0.27 (0.18-0.40); P <.0001

Acalabrutinib

(n = 155)

IdR

(n = 119)

BR

(n = 36)

Median PFS, mo NR 16.2 18.6

HR (95% CI) A vs IdR 0.27; P <.0001 —

HR (95% CI) A vs BR — 0.29; P <.0001

Acalabrutinib Acalabrutinib

IdR/BR

IdR

BR

33

Acalabrutinib with del(17p) and TP53 mutationIdR/BR with del(17p) and TP53 mutationAcalabrutinib without del(17p) and TP53 mutationIdR/BR without del(17p) and TP53 mutation

ASCEND: PFS in del(17p) and IGHV Subgroups

Ghia. ASCO 2020. Abstr 8015. Ghia. J Clin Oncol. 2020;38:2849.

By del(17p)/TP53 Mutation Status By IGHV Status

PFS

(%

)

100

80

60

40

20

0

Mo

280 4 8 12 16 20 24P

FS (

%)

100

80

60

40

20

0

Mo

280 4 8 12 16 20 24

With del(17p) and TP53mutationAcalabrutinib: IdR/BRHR: 0.11 (95% CI: 0.04-0.34)

Without del(17p) and TP53 mutationAcalabrutinib: IdR/BRHR: 0.29 (95% CI: 0.19-0.45)

With unmutated IGHVAcalabrutinib: IdR/BRHR: 0.28 (95% CI: 0.18-0.43)

With mutated IGHVAcalabrutinib: IdR/BRHR: 0.30 (95% CI: 0.12-0.76)

Acalabrutinib with unmutated IGHVIdR/BR with unmutated IGHVAcalabrutinib with mutated IGHVIdR/BR with mutated IGHV

++

+

+

++

+++

++ +

++++ +++++++

+++ ++ ++++++ +++++

+ + ++ ++

++

+

+

+

+ ++

+ +

++++++ ++++++

+++++

++

+ + +

++

++++

+

+++

+ +++

+++

+

+

+++++++ +++ +

+

+

+ +++ +

+ ++ ++++++++ +++ ++++ ++ ++++ +++++++

34

• Randomized, open-label phase III noninferiority trial

ELEVATE-RR: Study Design

iwCLL = International Workshop on Chronic Lymphocytic Leukemia; PI3K = phosphoinositide 3-kinase.Byrd. JCO. 2021 [EPub]. Byrd. ASCO 2021. Abstr 7500.

Adults with previously treated CLL requiring treatment per iwCLL 2008; presence of del(17p) or

del(11q); no significant CVD; no prior tx with BTK, PI3K, Syk, or BCL2 inhibitors; ECOG PS 0-2

(N = 533)

Acalabrutinib 100 mg PO twice daily(n = 268)

Ibrutinib 420 mg PO daily(n = 265)

Stratified by del(17p) (yes vs no), ECOG PS (0/1 vs 2), number of prior therapies (1-3 vs ≥4)

Continued until PD or unacceptable toxicity

• Primary endpoint: noninferiority of IRC-assessed PFS (upper bound of 2-sided 95% CI for HR <1.429)

• Secondary endpoints: any-grade AF/flutter, grade ≥3 infection, Richter transformation, OS

1:1

35

• Median PFS: 38.4 mo for both acalabrutinib and ibrutinib (HR: 1.00; 95% CI: 0.79-1.27)

• Median follow-up: 40.9 mo (range: 0-59.1)

• No significant difference between treatments based on evaluated subgroups

ELEVATE-RR: PFS

Byrd. JCO. 2021 [EPub]. Byrd. ASCO 2021. Abstr 7500.

100

80

60

40

20

0510 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 54 57

PFS

(%

)

Mo

HR: 1.00 (95% CI: 0.79-1.27)

Acalabrutinib (n = 268)Ibrutinib (n = 265)

Median PFS, Mo(95% CI)

38.4 (33.0-38.6)38.4 (33.0-41.6) + Censored

36

ELEVATE-RR: AEs of Clinical Interest

NMSC = non-melanoma skin cancer; SPM = secondary primary malignancy.Byrd. JCO. 2021 [EPub]. Byrd. ASCO 2021. Abstr 7500.

• Most common grade ≥3 infections: pneumonia (acalabrutinib vs ibrutinib, 10.5% vs 8.7%), sepsis (1.5% vs 2.7%), and urinary tract infections (1.1% vs 2.3%)

AE, n (%)Acalabrutinib (n = 266) Ibrutinib (n = 263)

Any Grade Grade ≥3 Any Grade Grade ≥3

Cardiac events• Atrial fibrillation/flutter• Ventricular arrhythmias

64 (24.1)25 (9.4)

0

23 (8.6)13 (4.9)

0

79 (30.0)42 (16.0)

1 (0.4)

25 (9.5)10 (3.8)

0

Bleeding events• Major bleeding events

101 (38.0)12 (4.5)

10 (3.8)10 (3.8)

135 (51.3)14 (5.3)

12 (4.6)12 (4.6)

Hypertension 25 (9.4) 11 (4.1) 61 (23.2) 24 (9.1)

Infections 208 (78.2) 82 (30.8) 214 (81.4) 79 (30.0)

Interstitial lung disease/pneumonitis 7 (2.6) 1 (0.4) 17 (6.5) 2 (0.8)

SPMs, excluding NMSC 24 (9.0) 16 (6.0) 20 (7.6) 14 (5.3)

37

Ibrutinib

• Less impact on gastric pH

• More arthralgias/myalgias

• Daily

• Higher rates of atrial fibrillation

Selecting Between BTK Agents in CLL/SLL

Acalabrutinib

• Decreased absorption with PPI

• Transient headache

• Twice daily

• Good for patients who are intolerant of ibrutinib

38

CLL14: First-line Obinutuzumab + Venetoclax or Chlorambucil in CLL With Comorbidities: PFS

Al-Sawaf. Lancet Oncol. 2020;21:1188.

82%

50%

PFS

(%

)

HR: 0.31 (95% CI: 0.22-0.44; P <.0001)

Mo

42

100

80

60

40

20

00 6 12 18 24 30 36 48

Venetoclax + obinutuzumab (n = 216)

Chlorambucil + obinutuzumab (n = 216)

39

720 6 12 18 24 30 36 42 48 54 60 66

100

80

60

40

20

0

100

80

60

40

20

0720 6 12 18 24 30 36 42 48 54 60 66

MURANO Study of Venetoclax + Rituximab vs BR in Previously Treated CLL/SLL: 5-Yr PFS and OS Analysis

EOT = end of treatment; MRD = minimal residual disease.Kater. ASH 2020. Abstr 125.

• This report included:— Outcomes with a median follow-up of 59 mo (range: 0-71.5)

— Outcomes of patients off-therapy based on MRD status at EOT

— MRD kinetics and MRD status of patients who received VenR retreatment


185165

176128

17084

16165

14244

13231

11621

9911

572

15 3

PFS

EOT

53.6 mo17.0 mo

Mo

PFS

(%

)

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

Median PFS, Mo(95% CI)

53.6 (48.4-57.0)17.0 (15.5-21.7)

HR*(95% CI)

0.19 (0.15-0.26)Stratified P <.0001†

5-YrPFS, %37.8NE


185175

182162

178152

173147

166140

164134

161124

159115

139102

7049

99

OS

EOT

82.1%

62.2%

Mo

OS

(%)

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

Median OS, Mo(95% CI)

NENE

HR*(95% CI)

0.40 (0.26-0.62)Stratified P <.0001†

5-YrOS, %82.162.2

*Unstratified HR = 0.21 †P values are descriptive ‡Unstratified HR = 0.42

40

• Open-label phase II study of venetoclax for patients with CLL relapsed after or refractory to ibrutinib (N = 91)*

Venetoclax for Patients With CLL Who Progressed After/During Ibrutinib Therapy

*Included patients who discontinued ibrutinib for AEs and progressed when off therapy. Sharman. JCO. 2019;37:1391.

PFS

50

% W

ith

ou

t P

rogr

ess

ion 100

75

00 2 4 8 10 12 146 16

25

Mo After First Dose

18 20 22 24 26 28 30

12-mo estimate: 75% (95% CI: 64% to 83%)

41

BTK Inhibitor

• Logistically very easy

• Indefinite therapy

• TLS not of concern

• More cardiac risk

• Some favor in del(17p)/TP53 mutation

Selecting a BTK vs BCL2 Inhibition Strategy in CLL/SLL

Acalabrutinib PI. Awan. Am Soc Clin Oncol Educ Book. 2020;40:1. Ibrutinib PI. Venetoclax PI. Zanubrutinib PI.

BCL2 Inhibitor

• Cumbersome initiation

• Fixed duration

• Risk for TLS requires monitoring

• GFR sensitivity

• Question if best for high-risk patients

42

Phase III Trial of Idelalisib + Rituximab vs Placebo + Rituximab Followed by Idelalisib in Relapsed CLL: PFS, OS

Sharman. JCO. 2019;37:1391.

100908070605040302010

0

Pro

bab

ility

of

PFS

(%

)

Mo

240 2 4 6 8 10 12 14 16 18 20 22

IdRPlacebo/R

PFS, median mo (95% CI)

IdR(n = 110)

19.4 (12.3-NR)

Placebo/R(n = 110)

6.5(4.0-7.3)

100908070605040302010

0

Pro

bab

ility

of

OS

(%)

Mo

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

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

OS, median mo (95% CI)

IdR(n = 110)

40.6(28.5-57.3)

Placebo/R(n = 110)

34.6(16.0-NR)

60 64 68

43

Phase III DUO Trial of Duvelisib vs Ofatumumab in R/R CLL/SLL: PFS

Flinn. Blood. 2018;132:2446.

PFS

Patients at Risk, n

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

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

PFS

(%

)

Mo

0

20

40

60

80

100

0 3 6 9 12 15 18 21 24 27 30

Duvelisib 25 mg twice dailyOfatumumab

33 36

160159

149126

10895

9577

7843

5815

337

296

133

102

31

21

00

DuvelisibOfatumumab

Future Directions in CLL/SLL

45

Phase II CAPTIVATE—First-line Ibrutinib + Venetoclax in CLL Fixed-Duration Cohort: Efficacy From Primary Analysis

*Defined as progression free ≥12 cycles after achieving first CR. †uMRD rates in MRD cohort (n = 164): PB: 75%, BM: 68%.

BM = bone marrow; CRi = complete response with incomplete hematologic recovery; PB = peripheral blood; uMRD = undetectable measurable residual disease.Ghia. ASCO 2021. Abstr 7501.

OutcomePatients Without del(17p)

(n = 136)All Patients

(N = 159)

CR/CRi, n (%) 76 (56) 88 (55)

Durable CR/CRi,* n/N (%) 66/76 (87) 78/88 (89)

ORR, n (%) 130 (96) 153 (96)

uMRD,† n (%) • PB• BM

104 (76)84 (62)

122 (77)95 (60)

24-mo rate, % (95% CI)• PFS• OS

96 (91-98)98 (93-99)

95 (90-97)98 (94-99)

46

Phase III GLOW: Fixed-Duration Ibrutinib + Venetoclax vs Chlorambucil + Obinutuzumab in Frontline CLL: PFS

I + V =

Kater. EHA 2021. Abstr LB1902.

180 3 6 9 12 15 21 24 27 30

100

80

60

40

20

0

PFS

(%

)

Mo

I + VClb + O

Median PFS: NR vs 21.0 moHR: 0.216 (95% CI: 0.131-0.357; P <.0001)

Patients at Risk, nI + V

Clb + O

106105

98104

8954

8747

7136

5925

206

98101

9495

9293

9163

End of Clb + O(6 cycles x 28d)

End of I + V(15 cycles x 28d)

Median Follow-up: 27.7 mo

47

GLOW: CR/CRi and uMRD Rates

CLB = chlorambucil; EOT = end of treatment; I = ibrutinib; IRC = independent review committee; ITT = intent to treat; NGS = next-generation sequencing; nPR = nodular partial response; O = obinutuzumab; uMRD = undetectable measurable residual disease; V = venetoclax.Kater. EHA 2021. Abstr LB1902.

100

80

60

40

20

0I + V Clb + O

Response by IRC

*P <.0001

Pat

ien

ts (

%)

ORR 84.8%

CR/CRiPR/nPRSDPD

ORR 86.8%

1.9%12.4%

73.3%

11.4%*

38.7%*

48.1%

7.5% 1.9%

uMRD Rates at EOT +3 by NGS (ITT)

Pat

ien

ts (

%)

Peripheral Blood

I + VClb + O

Bone Marrow

P <.0001 P = .0259

51.9%

17.1%

54.7%

39.0%

Peripheral BloodBone Marrow100

80

60

40

20

0

48

Phase III ALPINE—Ibrutinib vs Zanubrutinib in Patients With R/R CLL: Results

Hillmen. EHA 2021. Abstr 1900.

Outcome, % (95% CI)Zanubrutinib

(n = 207)Ibrutinib(n = 208) P Value

Efficacy

ORR (Invest.-assessed)

78.3(72.0-83.7)

62.5(55.5-69.1)

.0006

ORR (IRC-assessed) 76.3 64.4 .0121

ORR in del(17p) 83.3 53.8 NR

12-mo PFS 94.9 84.0HR: 0.40 (0.23-0.69)

.0007

Overall Safety

AEs (any) 95.6 99.0 —

AEs (grade ≥3) 55.9 51.2 —

Serious AEs 27.5 32.4 —

Fatal AEs 3.9 5.8 —

Select AEs, Any Grade %

Zanubrutinib(n = 207)

Ibrutinib(n = 208)

AF or flutter 2.5 10.1

Cardiac disorders 13.7 25.1

Hemorrhage 35.8 36.2

Major hemorrhage 2.9 3.9

Hypertension 16.7 16.4

Infections 59.8 63.3

Neutropenia 28.4 21.7

SPMs 8.3 6.3

Skin cancers 3.4 4.8

Thrombocytopenia 9.3 12.6

Managing Adverse Events

50

Kinase Selectivity of BTK Inhibitors

IC50/EC50 (nM)

Kinase Ibrutinib Acalabrutinib Zanubrutinib

BTK 1.5 5.1 0.5

TEC 10 126 44

ITK 4.9 >1000 50

BMX 0.8 46 1.4

EGFR 5.3 >1000 21

ERBB4 3.4 16 6.9

JAK3 32 >1000 1377

BLK 0.1 >1000 2.5

Kaptein. ASH 2018. Abstr 1871.

Kinase Selectivity Profiling at 1 mol/L (in vitro)

Larger red circles represent stronger inhibition

Ibrutinib Acalabrutinib

Zanubrutinib

51

AEs of Available BTK Inhibitors

Acalabrutinib PI. Ibrutinib PI. Zanubrutinib PI.


Cytopenias (grade 3/4)

• Neutropenia 13% to 29%• Thrombocytopenia 5% to 17%• Anemia 0% to 13%

• Neutropenia 10% to 23%• Thrombocytopenia 5% to 8%• Anemia 5% to 11%

• Neutropenia 15% to 27%• Thrombocytopenia 5% to 10%• Anemia 8%

Hold BTK inhibitor for grade 3 neutropenia with infection or fever or grade 4 cytopenia

Infection (≥ grade 3)

• 14% to 29% • 11% to 18% • 23%

Consider prophylaxis in patients who are at increased risk for opportunistic infections

Other notable AEs

• Cardiac arrhythmia• Bleeding/bruising• Rash• Diarrhea, early and self-limiting• Muscle cramping, late• Pneumonitis, rare but serious, discontinue

ibrutinib

• Cardiac arrhythmia• Bleeding/bruising• Rash• Headaches• Diarrhea

• Cardiac arrhythmia• Bleeding/bruising• Rash• Diarrhea• Hypertension

52

AEs of Available BTK Inhibitors: Bruising and Hemorrhage

Ibrutinib PI. Acalabrutinib PI. Zanubrutinib PI.


• Bleeding consistent with “hemostatic failure” with bruising and subcutaneous bleeding with minor trauma in up to 50%

• Grade ≥3 hemorrhage: up to 6%

• Overall, bleeding events including bruising and petechiae of any grade occurred in approximately 50% of patients

• Grade ≥3 hemorrhage: up to 3%

• Bleeding events including bruising and petechiae of any grade occurred in 50% of patients

• Grade ≥3 hemorrhage: 2%

Clinical Management

• Impact of platelet aggregation is reversible within 1 wk of discontinuation• Recommend holding BTK inhibitor prior to and after invasive procedures for 3 (minor) to 7 days (major)• Blood thinner or antiplatelet agents (aspirin, clopidogrel, prasugrel, ticagrelor) may increase bleeding risk• Anticoagulants may increase bleeding risk by impacting multiple hemostatic pathways

53

AEs of Available BTK Inhibitors: AF and Cardiac Arrhythmias

Ibrutinib PI. Acalabrutinib PI. Zanubrutinib PI.


• Incidence of AF:– 11% in MCL– 5% in CLL (8% all

cardiac dysfunction)– 2% in WM (7% all

cardiac dysfunction)

• Incidence of AF:– 0 in MCL (8% other

cardiac dysfunction)– 3% in CLL– 5% in WM

• AF and atrial flutter have occurred in 2% of patients

• Grade ≥3: 0.6% of patients

Clinical Management

• Risks include cardiac risk factors, acute infections, prior history of AF• AF is not an absolute indication to discontinue BTK inhibitors; continued BTK treatment is

reasonable with controlled AF• Anticoagulation should be used with caution• If AF persists, consider the risks and benefits of treatment and dose modification

54

RESONATE: Prevalence of Most Grade ≥3 AEs of Clinical Interest With Ibrutinib Decreased Over Time

Munir. Am J Hematol. 2019;94:1353.

Conclusions

• With up to 6 yr of follow-up, extended ibrutinib treatment effective in R/R CLL/SLL, including similar efficacy with high-risk genomic features

• Safety acceptable with low rates of discontinuation due to AEs; no new safety signals over long-term treatment

• These results further establish long-term benefit and tolerability for continuous ibrutinib in R/R CLL/SLL

Infections

Major hemorrhage

Peripheral neuropathy

Congestive heart failure

Arthralgia

Fatigue

AF

Hypertension

Diarrhea

Pneumonia

Thrombocytopenia

Anemia

Neutropenia

0 20 30 50 70 9010 40 60 80 100

Patients (%)

>0-1 yr (n = 195)

>1-2 yr (n = 160)

>2-3 yr (n = 137)

>3-4 yr (n = 103)

>4-5 yr (n = 79)

>5 yr (n = 57)

Prevalence of grade ≥3 AEs of clinical interest over time for the

ibrutinib arm (ITT population)

55

• In general, AEs are more common in first yr of acalabrutinib treatment

ACE-CL-001: Acalabrutinib in CLL, Select AEs Over Time

URTI = upper respiratory tract infection.Byrd. ASH 2018. Abstr 692.

10

0

30

20

50

40

≤1 yr (n = 99)1-2 yr (n = 96)2-3 yr (n = 93)3-4 yr (n = 87)

Pat

ien

ts(%

)

Diarrhea URTI ArthralgiaHeadache PetechiaeContusion Ecchymosis HTN

19

33

17

3

44

64

20

24

8 6

23

710

3

22

6 6

2

16

13

16

12

1 25

0 0000

56

CLL14: First-line Obinutuzumab + Venetoclax or Chlorambucil in CLL With Comorbidities: Safety

Dose ramp-up for venetoclax

AEVen + Obin

(n = 212)Obin + Clb(n = 214)

Grade 3/4 AE, n (%) 167 (79) 164 (76)

• Neutropenia 112 (53) 103 (48)

• Febrile neutropenia

11 (5) 8 (4)

• Infections 37 (18) 32 (15)

All-grade TLS, n3; all lab, no

clinical, during obin

5; all lab, no clinical

IRR, % 9 10

Deaths, n (%)

• During treatment 5 (2) 4 (2)

• After treatment 11 (5) 4 (2)

*Low: nodal mass <5 cm and ALC <25,000 K/µL; medium: nodal mass >5 cm and <10 cm and ALC ≥25,000 K/µL; high: nodal mass ≥10 cm or ≥5 cm but <10 cm and ALC ≥25,000 K/µL. BL = baseline.Davids. Blood. 2017;130:1081. Fischer. NEJM. 2019;380:2225.

TLS Risk Categories

Low Risk* Medium Risk* High Risk*

Oral hydration (1.5-2 L), allopurinol

Oral hydration (1.5-2 L), consider IV hydration,

allopurinol

Oral hydration (1.5-2 L), IV hydration (150-200 ml/hr) as

tolerated, allopurinol;consider rasburicase if elevated

BL uric acid

Outpatient administration Outpatient administration;consider inpatient if

CrCl <80 mL/min

Inpatient administration for initial 20-mg and 50-mg dose;outpatient administration for subsequent dose escalations

Labs pre-dose, then 6-8 and 24-hr post-dose after initial

dose of 20, 50 mg

Labs pre-dose, then 6-8 and 24-hr post-dose after initial

dose of 20, 50 mg

Inpatient: Labs pre-dose, then 4, 8, 12, 24-hr post-dose

Outpatient: Labs pre-dose, then 6-8 and 24-hr post-dose

57

PCE Action Plan

✓ Reinforce with patients the importance of informing their healthcare providers promptly of any symptoms that may be related to BTK inhibitor treatment, particularly infections, cardiac symptoms, bleeding or bruising, and rash

✓ Assess cardiac risk of patients at baseline before treatment with a BTK inhibitor; monitor patients clinically for cardiac arrythmias and cardiac failure throughout treatment period and manage appropriately

✓ Inform patients considering or being treated with BTK inhibitor therapy that the prevalence of most grade ≥3 AEs of clinical interest decrease over time

✓ Explain to patients the need for a gradual increase in dosing with venetoclax therapy over 5 weeks during treatment initiation to reduce the risk of tumor lysis syndrome

PCE Promotes Practice Change

evolving treatment strategies for cll/sll and mcl

Documents