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Dr Faheema Hasan, MD DM
Consultant Hematologist & Associate Professor,
Department of Oncology,
Dr Faheema Hasan
Paradigm Shift in treatment of CLL
2023
ERA OF CHEMOTHERAPY ERA OF TARGETED THERAPY
Dr Faheema Hasan
Targeted Therapies and current FDA approval
in CLL
Dr Faheema Hasan
Indications for CLL Treatment (iwCLL
Guideline 2018)
Constitutional symptoms referable to
CLL (disease-related symptoms)
Progressive marrow failure
Autoimmune anemia ±
thrombocytopenia poorly responsive
to steroids or other therapy
Massive (≥6 cm) or progressive
splenomegaly
Massive (≥10 cm) or progressive
lymphadenopathy
Symptomatic or functional extranodal
involvement
Progressive lymphocytosis with ≥50%
increase over 2 mo or LDT <6 mo
Hallek. Blood. 2018;131:2745.
NO EARLY TREATMENT, EVEN FOR HIGH-RISK PATIENTS
Dr Faheema Hasan
Prognostic Testing prior to Initiation of
Therapy
Dr Faheema Hasan
Del 17p: The well known major therapy
deciding poor prognostic feature
Dr Faheema Hasan
BTKi Therapy was a major step forward in Del
17p/TP53 mutated CLL
Why continuous BTK i?
Dr Faheema Hasan
Real world data , despite these advances
Dr Faheema Hasan
Without del(17p)/TP53 mutation
Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for CLL/SLL v3.2023.
© National Comprehensive Cancer Network, Inc 2022. All rights reserved. To view the most recent and complete version of the guideline, go online to nccn.org.
Dr Faheema Hasan
With del(17p)/TP53 mutation
Dr Faheema Hasan
Major Mechanisms of Action of Current CLL
Therapies
p53
Apoptosis
BCL-2
Cytochrome C
BTK
PI3K
B-Cell Receptor
Idelalisib, duvelisib
BCR Pathway Inhibitors
Covalent
Ibrutinib
Acalabrutinib Nemtabrutinib
Zanubrutinib
Noncovalent
Pirtobrutinib
Venetoclax
BCL-2 inhibition
DNA Damage
Cyclophosphamide
Bendamustine
Fludarabine
BTK inhibitors
PI3K Inhibitors
CD20
Antibody-Dependent
Cellular Cytotoxicity
NK cell Rituximab,
Obinutuzumab
Anti-CD20 mAb
Young. Nat Rev Drug Discov. 2013;12:229. Dr Faheema Hasan
The Discovery of Bruton Tyrosine Kinase
• X-linked agammaglobulinemia :Dr Ogden Bruton.
• Lack of expression of BTK, a tyrosine kinase of the Tec-family, due
to mutations in a gene located on the X chromosome.
• BTK is essential for maturation of pre–B cells.
• Extensive molecular and cellular analyses have confirmed the
critical role of BTK in multiple hematopoietic signals, which go
beyond the B-cell antigen receptor pathway, and initial inhibitory
agents showed preliminary activity as antileukemic agents, setting
up BTK as a potential target in B-cell malignancies
Dr Faheema Hasan
Timeline showing the evolution of BTK-
targeting therapies for CLL.
Dr Faheema Hasan
BTK inhibitors
• Ibrutinib : 1st of its class.
• Initially synthesized in 2007 and
described as an irreversible BTK
inhibitor with potential therapeutic
value in rheumatoid arthritis
• Approved based on RESONATE-2 in
CLL
• <70 Yrs: Ibru –R vs FCR: superior PFS
and OS
• Ibru-0 vs Chlorambucil 0: PFS benefit
• continuous BTK inhibitor
monotherapy holds potential to
control TP53 aberrant CLL
• Role of added anti CD 20 Ab ?
Dr Faheema Hasan
Alliance A041202: First-line Ibrutinib ±
Rituximab vs Bendamustine + Rituximab
• International, randomized, open-label phase III study.
• Primary endpoint: PFS
TN CLL ≥65 yr of age;
ECOG PS 0-2;
ANC ≥1000/µL;
PLT ≥30,000/µL;
CrClCG ≥40 mL/min;
AST/ALT ≤2.5 x ULN;
no heparin
or warfarin (N = 547)
Woyach. NEJM. 2018;379:2517. NCT01886872.
Ibrutinib 420 mg QD
Ibrutinib 420 mg QD +
Bendamustine† +
Rituximab*
Until PD
Until PD
*375 mg/m2/wk x 4 wk starting cycle 2 Day 1; cycles 3-6 Day 1; 28-day cycles. †90 mg/m2 on cycle Days 1, 2; 28-day cycles.
Rituximab* 6 cycles
6 cycles
STOP
STOP
Dr Faheema Hasan
Woyach. ASH 2021. Abstr 639.
Events,
n/N
Median PFS,
Mo (95% CI)
4-Yr PFS,
% (95% CI)
Ibrutinib 48/182 NR 76 (69-82)
Ibrutinib + R 47/182 NR 76 (69-82)
BR 94/183 44.9 (0-0) 47 (39-55)
0 6 12 18 24 30 36 42 48 54 60 66 72 78
Mo
0
0.2
0.4
0.6
0.8
1
PFS
Probability
Patients at Risk, n
BR
I
IR
183 148 139 132 114 97 87 76 63 39 20 7 1 0
182 168 158 152 142 135 131 122 114 86 52 23 4 0
182 168 156 148 142 134 130 127 117 82 44 21 2 0
• PFS significantly improved with
ibrutinib vs BR and ibrutinib + R
vs BR (P <.001)
• HR for ibrutinib vs BR:
0.36 (95% CI: 0.26-0.52)
• HR for ibrutinib + R vs BR:
0.36 (95% CI: 0.25-0.51)
• No significant difference for
ibrutinib + R vs ibrutinib
• HR: 0.99 (95% CI: 0.66-1.48)
Phase III A041202: Ibrutinib ± R vs BR in Untreated
Older Patients With CLL
Dr Faheema Hasan
Challenges with Ibrutinib
Dr Faheema Hasan
Implications of BTKi selectivity for off target
effects
Dr Faheema Hasan
ELEVATE-RR: PFS With Acalabrutinib vs Ibrutinib in
Previously Treated CLL
Byrd. ASCO 2021. Abstr 7500. Byrd. JCO. 2021;39:3441.
Dr Faheema Hasan
ELEVATE-RR: Ibrutinib vs Acalabrutinib AEs
Byrd. JCO. 2021;39:3441.
51
46
20 21
23 23
18
16
14 13 13 12
0
38
35 35
29
16
9
12
9 8 8
6
4 3
0
10
20
30
40
50
60
Most
Common
AEs
Occurring
(%)
Ibrutinib Acalabrutinib
Dr Faheema Hasan
ELEVATE-TN: PFS and OS With Acalabrutinib
(Indefinite Therapy) ± Obinutuzumab vs CIT (Time
Limited)
Dr Faheema Hasan
Phase I/II ACE-CL-001 Trial: Acalabrutinib in
Ibrutinib-Intolerant Cohort
• Among 33 patients who could not
tolerate ibrutinib, 23 remained on
acalabrutinib
• No acalabrutinib dose reductions
occurred
• Of 61 ibrutinib-related AEs, 72% did not
recur, and 13% recurred at lower grade
with acalabrutinib
• ORR: 76%
• Median PFS: not reached
• 1-yr PFS: 83.4%
Awan. Blood Adv. 2019;3:1553.
Did not recur
72%
Lower grade
13%
Same
grade
11%
Higher grade
3%
Recurred
28%
Recurrence of Ibrutinib-Related AEs (n = 61)
During Acalabrutinib Treatment
Dr Faheema Hasan
ALPINE: Zanubrutinib vs Ibrutinib in
Relapsed/Refractory CLL/SLL
• International, open-label, randomized phase III trial
• Preplanned interim analysis performed at data cutoff ~12 mo after randomizing 415 patients
Hillmen. EHA 2021. Abstr LB1900. NCT03734016.
 Primary endpoint: noninferiority and
superiority of investigator-assessed ORR
 Secondary endpoints: DoR, PFS, OS, TTF,
rate of PR-L or higher, PROs, atrial
fibrillation, safety
Patients with R/R CLL/SLL; ≥1 prior
systemic tx for CLL/SLL; measurable
lymphadenopathy; no Richter
transformation, prior BTKi,
warfarin, other vitamin K
antagonists; ECOG PS 0-2
(N = 652; interim analysis: n = 415)
Until PD or
unacceptable toxicity
Zanubrutinib 160 mg PO BID
(interim analysis: n = 207)
Ibrutinib 420 mg PO QD
(interim analysis: n = 208)
Dr Faheema Hasan
ALPINE: PFS With Zanubrutinib vs Ibrutinib
in Relapsed/Refractory CLL/SLL
Brown. ASH 2022. Abstr LBA-6
Dr Faheema Hasan
ALPINE: AEs of Special Interest
Hillmen. EHA 2021. Abstr LB1900.
AE of Special Interest in Safety
Analysis Population, n (%)
Zanubrutinib (n = 204) Ibrutinib (n = 207)
Any Grade Grade ≥3 Any Grade Grade ≥3
Cardiac disorders 28 (13.7) 5 (2.5) 52 (25.1) 14 (6.8)
Atrial fibrillation and flutter 5 (2.5) 2 (1.0) 21 (10.1) 4 (1.9)
Hemorrhage
 Major hemorrhage*
73 (35.8)
6 (2.9)
6 (2.9)
6 (2.9)
75 (36.2)
8 (3.9)
6 (2.9)
6 (2.9)
Hypertension 34 (16.7) 22 (10.8) 34 (16.4) 22 (10.6)
Infections 122 (59.8) 26 (12.7) 131 (63.3) 37 (17.9)
Neutropenia 58 (28.4) 38 (18.6) 45 (21.7) 31 (15.0)
Thrombocytopenia 19 (9.3) 7 (3.4) 26 (12.6) 7 (3.4)
Secondary primary malignancies
 Skin cancers
17 (8.3)
7 (3.4)
10 (4.9)
3 (1.5)
13 (6.3)
10 (4.8)
4 (1.9)
2 (1.0)
*Includes serious or grade ≥3 hemorrhage or any-grade CNS hemorrhage.
Dr Faheema Hasan
SEQUOIA: Frontline Zanubrutinib (Indefinite)
vs Bendamustine/Rituximab (Time Limited)
• Multicenter, multicohort, open-label, part-randomized phase III trial
• Primary endpoint (cohort 1): IRC-assessed PFS
Tam. Lancet Oncol. 2022;23:1031.
Patients with untreated
CLL/SLL meeting iwCLL
criteria for treatment; aged
≥65 yr or ≥18 yr with
comorbidities; unsuitable
for FCR treatment;
anticoagulation and CYP3A
inhibitors permitted
Zanubrutinib 160 mg BID
Bendamustine +
Rituximab
Cohort 1
without del(17p)
by central FISH
(planned n ~450)
Cohort 2
with del(17p)
(planned n ~100)
Cohort 3
with del(17p)
(planned n ~80)
*Bendamustine 90 mg/m2 on Days 1 and 2 + rituximab 375 mg/m2 in cycle 1, then 500 mg/m2 in cycles 2-6.
Until PD/
intolerable
toxicity
6 cycles
STOP
Dr Faheema Hasan
SEQUOIA: PFS With Zanubrutinib vs BR in
Treatment-Naive CLL/SLL Without del(17p)
Kahl. Pan Pacific Lymphoma Conference 2022. Tam. Lancet Oncol. 2022;23:1031.
TN CLL/SLL
without del(17p),
≥65 yr of age or
unsuitable for FCR
treatment
HR: 0.42 (95% CI: 0.28-0.63; 2-sided P <.0001)
100
80
60
40
20
0
PFS
Probability
(%)
Mo
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
241
238
237
218
230
210
224
200
222
187
214
176
208
164
195
150
123
89
79
54
31
20
17
8
2
1
1
0
0
Zanubrutinib
BR
Censored
24-mo PFS
85.5% (95% CI: 80.1-89.6)
69.5% (95% CI: 62.4-75.5)
Zanubrutinib
BR
Dr Faheema Hasan
Phase II Trial of Zanubrutinib in R/R B-Cell
Malignancies Intolerant to Ibrutinib/Acalabrutinib
Shadman. Lancet Haematol. 2022;S2352.
Intolerance Events: Ibrutinib*
Patients, n
Intolerance Events: Acalabrutinib†
Fatigue
Arthralgia
Hemorrhage
Hypertension
Stomatitis
Constipation
Nausea
Insomnia
Rash
Headache
Myalgia
Diarrhea
Atrial Fibrillation
Muscle Spasms
Dizziness
Lymphedema
AST increased
ALT increased
Pain in extremity
Neutropenia
Myalgia
Arthralgia
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Recurred at same grade
Recurred at a lower grade
Did not recur
*18 additional ibrutinib-related intolerance events occurred in 1 patient and did not recur on zanubrutinib (not shown).
†11 additional acalabrutinib-related intolerance events occurred in 1 patient and did not recur on zanubrutinib (not shown).
Dr Faheema Hasan
Should we prefer Zanubrutinib upfront ?
• It is important to recognize the ‘dead-kinase’ mutations at codon L528
of BTK which have been observed with disease progression on Zanu and
pirtobrutinib
• These have been described at lower frequency with Ib or Acala.
• They may have important implications for double class-refractory disease for
whom effective treatment options are limited.
• Dead-kinase L528 mutations following Zanu may induce cross-resistance to Pirto.
• However, the precise incidence of L528 BTK mutations arising following Zanu
therapy is presently undefined and should not currently influence selection of
initial BTKi until more data are available.
Dr Faheema Hasan
The Overall Safety Experience with BTKi
Dr Faheema Hasan
When using BTKi , which is the preferred
BTKi?
Dr Faheema Hasan
When using a BTKi, should you add an
anti‐CD20 monoclonal antibody?
• ILLUMINATE and E1912 studies
demonstrate that IbO and IbR: uMRD did
not associate clearly with improved PFS
outcomes.
• Ibru may impair rituximab-induced ADCC
due to inhibition of ITK, which may
explain lack of PFS benefit with the
combination.
• ELEVATE-TN, the addition of Obi to Acala
(AO) appeared to improve rates of CR/CRi
in TP53 aberrant CLL and umIGHV
• Greater incidence of hematological
adverse events was observed following
AO versus A, including all-grade
neutropenia and thrombocytopenia.
• RITUXIMAB
• OBINUTUZUMAB
Dr Faheema Hasan
Dr Faheema Hasan
Is there still a role forchemoimmunotherapy as
first line therapy?
• Time limited
• FCR : Young , fit, Ig HV mutated, No Del 17p or TP53 unmutated.
• BR, Chl/O: Older, unfit, Ig HV mutated, NON TP53 aberrant CLL
• FCR :hematological toxicity and infection, risk of secondary myeloid
malignancies, lymphoid clonal evolution,
• Appealing when financial toxicity is considered
Dr Faheema Hasan
What About BTKi and BCL2 combinations ?
Dr Faheema Hasan
Current Treatment Landscape in R/R CLL
Therapy for R/R Disease After Prior BTKi- and Venetoclax-Based Regimens
• Non-covalent (reversible) BTK inhibitor- Pirtobrutinib (if not previously
used)
• PI3K inhibitors
• CIT or Immunotherapy
NCCN. Clinical practice guidelines in oncology: CLL/SLL. v.2.2023. nccn.org. Dr Faheema Hasan
Slide credit: clinicaloptions.com
With Covalent BTK Inhibitors, Resistance Mutations
Are a Major Driver of Progression in CLL
Resistance Mutations and Progression
• BTK C481 mutations are the dominant
reasons for progressive CLL in patients
receiving therapy with covalent BTK
inhibitors
56% BTK mutants
16% BTK and
PLCG2 mutants
20% BTK and
PLCG2 not
identified
Woyach. JCO. 2017;35:1437. Lampson. Expert Rev Hematol. 2018;11:185. Burger. Leukemia. 2020;34:787. Byrd. NEJM.
2016;374:323. Hershkovitz-Rokah. Br J Haematol. 2018;181:306. Woyach. NEJM. 2014;370:2286. Woyach. Blood.
2019;134(suppl 1):504. Xu. Blood. 2017;129:2519.
Acquired Resistance to Ibrutinib in
Patients With Progressive CLL2,3
Resistance Mutations and Progression
Acquired Resistance to Covalent BTK Inhibitors
Is Generally Driven by Mutations in BTK at C481
PH TH SH3 SH2 Kinase
Y223 C481 Y551
K430 M477 D539
E475 Y476
Structure of Bruton tyrosine kinase2
Acalabrutinib Zanubrutinib
In sum, BTK resistance contributes to disease progression
and diminishes the efficacy of all covalent BTK inhibitors
BTK C481 mutations also
confer resistance to covalent
BTK inhibitors acalabrutinib,
ibrutinib, and zanubrutinib Ibrutinib
X X X
1. Woyach. NEJM 2014;370:2286. 2. Gu. J Hematol Oncol. 2021;14:40. Dr Faheema Hasan
How Non Covalent BTKi overcome resistance ?
Dr Faheema Hasan
Selectivity of Non-Covalent BTKi
Dr Faheema Hasan
Dr Faheema Hasan
Dr Faheema Hasan
Dr Faheema Hasan
ASH 2023: Select Key Abstracts for R/R
CLL/SLL
Abstract Title Presenter Time
325
Pirtobrutinib in Post-cBTKi CLL/SLL: ~30 Months Follow-up
and Subgroup Analysis With/Without Prior BCL-2i from the
Phase 1/2 BRUIN Study
Woyach
Dec 9,
4:00 PM
1737
Pirtobrutinib in Richter Transformation: Updated Efficacy and
Safety Results with 18-Month Median Survival Follow-up from the
Phase 1/2 BRUIN Study
Wierda
Dec 9,
5:30 PM
108
Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy for Richter’s
Transformation: An International Multicenter Retrospective Study
Kittai
Dec 9,
10:45 AM
Dr Faheema Hasan
SUMMARY
• The evidence confirms the efficacy of cBTKi as a frontline
option
• Optimal sequencing of BTK inhibitors and BCL-2 inhibitors is
not yet clear, but either option is effective when used
sequentially
• They are the most effective 1L option for HR patients
• Venetoclax and ncBTKi are effective in the post-covalent BTKi
setting
Dr Faheema Hasan

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BTKi in Treatment Of Chronic Lymphocytic Leukemia

  • 1. Dr Faheema Hasan, MD DM Consultant Hematologist & Associate Professor, Department of Oncology, Dr Faheema Hasan
  • 2. Paradigm Shift in treatment of CLL 2023 ERA OF CHEMOTHERAPY ERA OF TARGETED THERAPY Dr Faheema Hasan
  • 3. Targeted Therapies and current FDA approval in CLL Dr Faheema Hasan
  • 4. Indications for CLL Treatment (iwCLL Guideline 2018) Constitutional symptoms referable to CLL (disease-related symptoms) Progressive marrow failure Autoimmune anemia ± thrombocytopenia poorly responsive to steroids or other therapy Massive (≥6 cm) or progressive splenomegaly Massive (≥10 cm) or progressive lymphadenopathy Symptomatic or functional extranodal involvement Progressive lymphocytosis with ≥50% increase over 2 mo or LDT <6 mo Hallek. Blood. 2018;131:2745. NO EARLY TREATMENT, EVEN FOR HIGH-RISK PATIENTS Dr Faheema Hasan
  • 5. Prognostic Testing prior to Initiation of Therapy Dr Faheema Hasan
  • 6. Del 17p: The well known major therapy deciding poor prognostic feature Dr Faheema Hasan
  • 7. BTKi Therapy was a major step forward in Del 17p/TP53 mutated CLL Why continuous BTK i? Dr Faheema Hasan
  • 8. Real world data , despite these advances Dr Faheema Hasan
  • 9. Without del(17p)/TP53 mutation Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for CLL/SLL v3.2023. © National Comprehensive Cancer Network, Inc 2022. All rights reserved. To view the most recent and complete version of the guideline, go online to nccn.org. Dr Faheema Hasan
  • 11. Major Mechanisms of Action of Current CLL Therapies p53 Apoptosis BCL-2 Cytochrome C BTK PI3K B-Cell Receptor Idelalisib, duvelisib BCR Pathway Inhibitors Covalent Ibrutinib Acalabrutinib Nemtabrutinib Zanubrutinib Noncovalent Pirtobrutinib Venetoclax BCL-2 inhibition DNA Damage Cyclophosphamide Bendamustine Fludarabine BTK inhibitors PI3K Inhibitors CD20 Antibody-Dependent Cellular Cytotoxicity NK cell Rituximab, Obinutuzumab Anti-CD20 mAb Young. Nat Rev Drug Discov. 2013;12:229. Dr Faheema Hasan
  • 12. The Discovery of Bruton Tyrosine Kinase • X-linked agammaglobulinemia :Dr Ogden Bruton. • Lack of expression of BTK, a tyrosine kinase of the Tec-family, due to mutations in a gene located on the X chromosome. • BTK is essential for maturation of pre–B cells. • Extensive molecular and cellular analyses have confirmed the critical role of BTK in multiple hematopoietic signals, which go beyond the B-cell antigen receptor pathway, and initial inhibitory agents showed preliminary activity as antileukemic agents, setting up BTK as a potential target in B-cell malignancies Dr Faheema Hasan
  • 13. Timeline showing the evolution of BTK- targeting therapies for CLL. Dr Faheema Hasan
  • 14. BTK inhibitors • Ibrutinib : 1st of its class. • Initially synthesized in 2007 and described as an irreversible BTK inhibitor with potential therapeutic value in rheumatoid arthritis • Approved based on RESONATE-2 in CLL • <70 Yrs: Ibru –R vs FCR: superior PFS and OS • Ibru-0 vs Chlorambucil 0: PFS benefit • continuous BTK inhibitor monotherapy holds potential to control TP53 aberrant CLL • Role of added anti CD 20 Ab ? Dr Faheema Hasan
  • 15. Alliance A041202: First-line Ibrutinib ± Rituximab vs Bendamustine + Rituximab • International, randomized, open-label phase III study. • Primary endpoint: PFS TN CLL ≥65 yr of age; ECOG PS 0-2; ANC ≥1000/µL; PLT ≥30,000/µL; CrClCG ≥40 mL/min; AST/ALT ≤2.5 x ULN; no heparin or warfarin (N = 547) Woyach. NEJM. 2018;379:2517. NCT01886872. Ibrutinib 420 mg QD Ibrutinib 420 mg QD + Bendamustine† + Rituximab* Until PD Until PD *375 mg/m2/wk x 4 wk starting cycle 2 Day 1; cycles 3-6 Day 1; 28-day cycles. †90 mg/m2 on cycle Days 1, 2; 28-day cycles. Rituximab* 6 cycles 6 cycles STOP STOP Dr Faheema Hasan
  • 16. Woyach. ASH 2021. Abstr 639. Events, n/N Median PFS, Mo (95% CI) 4-Yr PFS, % (95% CI) Ibrutinib 48/182 NR 76 (69-82) Ibrutinib + R 47/182 NR 76 (69-82) BR 94/183 44.9 (0-0) 47 (39-55) 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Mo 0 0.2 0.4 0.6 0.8 1 PFS Probability Patients at Risk, n BR I IR 183 148 139 132 114 97 87 76 63 39 20 7 1 0 182 168 158 152 142 135 131 122 114 86 52 23 4 0 182 168 156 148 142 134 130 127 117 82 44 21 2 0 • PFS significantly improved with ibrutinib vs BR and ibrutinib + R vs BR (P <.001) • HR for ibrutinib vs BR: 0.36 (95% CI: 0.26-0.52) • HR for ibrutinib + R vs BR: 0.36 (95% CI: 0.25-0.51) • No significant difference for ibrutinib + R vs ibrutinib • HR: 0.99 (95% CI: 0.66-1.48) Phase III A041202: Ibrutinib ± R vs BR in Untreated Older Patients With CLL Dr Faheema Hasan
  • 18. Implications of BTKi selectivity for off target effects Dr Faheema Hasan
  • 19. ELEVATE-RR: PFS With Acalabrutinib vs Ibrutinib in Previously Treated CLL Byrd. ASCO 2021. Abstr 7500. Byrd. JCO. 2021;39:3441. Dr Faheema Hasan
  • 20. ELEVATE-RR: Ibrutinib vs Acalabrutinib AEs Byrd. JCO. 2021;39:3441. 51 46 20 21 23 23 18 16 14 13 13 12 0 38 35 35 29 16 9 12 9 8 8 6 4 3 0 10 20 30 40 50 60 Most Common AEs Occurring (%) Ibrutinib Acalabrutinib Dr Faheema Hasan
  • 21. ELEVATE-TN: PFS and OS With Acalabrutinib (Indefinite Therapy) ± Obinutuzumab vs CIT (Time Limited) Dr Faheema Hasan
  • 22. Phase I/II ACE-CL-001 Trial: Acalabrutinib in Ibrutinib-Intolerant Cohort • Among 33 patients who could not tolerate ibrutinib, 23 remained on acalabrutinib • No acalabrutinib dose reductions occurred • Of 61 ibrutinib-related AEs, 72% did not recur, and 13% recurred at lower grade with acalabrutinib • ORR: 76% • Median PFS: not reached • 1-yr PFS: 83.4% Awan. Blood Adv. 2019;3:1553. Did not recur 72% Lower grade 13% Same grade 11% Higher grade 3% Recurred 28% Recurrence of Ibrutinib-Related AEs (n = 61) During Acalabrutinib Treatment Dr Faheema Hasan
  • 23. ALPINE: Zanubrutinib vs Ibrutinib in Relapsed/Refractory CLL/SLL • International, open-label, randomized phase III trial • Preplanned interim analysis performed at data cutoff ~12 mo after randomizing 415 patients Hillmen. EHA 2021. Abstr LB1900. NCT03734016.  Primary endpoint: noninferiority and superiority of investigator-assessed ORR  Secondary endpoints: DoR, PFS, OS, TTF, rate of PR-L or higher, PROs, atrial fibrillation, safety Patients with R/R CLL/SLL; ≥1 prior systemic tx for CLL/SLL; measurable lymphadenopathy; no Richter transformation, prior BTKi, warfarin, other vitamin K antagonists; ECOG PS 0-2 (N = 652; interim analysis: n = 415) Until PD or unacceptable toxicity Zanubrutinib 160 mg PO BID (interim analysis: n = 207) Ibrutinib 420 mg PO QD (interim analysis: n = 208) Dr Faheema Hasan
  • 24. ALPINE: PFS With Zanubrutinib vs Ibrutinib in Relapsed/Refractory CLL/SLL Brown. ASH 2022. Abstr LBA-6 Dr Faheema Hasan
  • 25. ALPINE: AEs of Special Interest Hillmen. EHA 2021. Abstr LB1900. AE of Special Interest in Safety Analysis Population, n (%) Zanubrutinib (n = 204) Ibrutinib (n = 207) Any Grade Grade ≥3 Any Grade Grade ≥3 Cardiac disorders 28 (13.7) 5 (2.5) 52 (25.1) 14 (6.8) Atrial fibrillation and flutter 5 (2.5) 2 (1.0) 21 (10.1) 4 (1.9) Hemorrhage  Major hemorrhage* 73 (35.8) 6 (2.9) 6 (2.9) 6 (2.9) 75 (36.2) 8 (3.9) 6 (2.9) 6 (2.9) Hypertension 34 (16.7) 22 (10.8) 34 (16.4) 22 (10.6) Infections 122 (59.8) 26 (12.7) 131 (63.3) 37 (17.9) Neutropenia 58 (28.4) 38 (18.6) 45 (21.7) 31 (15.0) Thrombocytopenia 19 (9.3) 7 (3.4) 26 (12.6) 7 (3.4) Secondary primary malignancies  Skin cancers 17 (8.3) 7 (3.4) 10 (4.9) 3 (1.5) 13 (6.3) 10 (4.8) 4 (1.9) 2 (1.0) *Includes serious or grade ≥3 hemorrhage or any-grade CNS hemorrhage. Dr Faheema Hasan
  • 26. SEQUOIA: Frontline Zanubrutinib (Indefinite) vs Bendamustine/Rituximab (Time Limited) • Multicenter, multicohort, open-label, part-randomized phase III trial • Primary endpoint (cohort 1): IRC-assessed PFS Tam. Lancet Oncol. 2022;23:1031. Patients with untreated CLL/SLL meeting iwCLL criteria for treatment; aged ≥65 yr or ≥18 yr with comorbidities; unsuitable for FCR treatment; anticoagulation and CYP3A inhibitors permitted Zanubrutinib 160 mg BID Bendamustine + Rituximab Cohort 1 without del(17p) by central FISH (planned n ~450) Cohort 2 with del(17p) (planned n ~100) Cohort 3 with del(17p) (planned n ~80) *Bendamustine 90 mg/m2 on Days 1 and 2 + rituximab 375 mg/m2 in cycle 1, then 500 mg/m2 in cycles 2-6. Until PD/ intolerable toxicity 6 cycles STOP Dr Faheema Hasan
  • 27. SEQUOIA: PFS With Zanubrutinib vs BR in Treatment-Naive CLL/SLL Without del(17p) Kahl. Pan Pacific Lymphoma Conference 2022. Tam. Lancet Oncol. 2022;23:1031. TN CLL/SLL without del(17p), ≥65 yr of age or unsuitable for FCR treatment HR: 0.42 (95% CI: 0.28-0.63; 2-sided P <.0001) 100 80 60 40 20 0 PFS Probability (%) Mo 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 241 238 237 218 230 210 224 200 222 187 214 176 208 164 195 150 123 89 79 54 31 20 17 8 2 1 1 0 0 Zanubrutinib BR Censored 24-mo PFS 85.5% (95% CI: 80.1-89.6) 69.5% (95% CI: 62.4-75.5) Zanubrutinib BR Dr Faheema Hasan
  • 28. Phase II Trial of Zanubrutinib in R/R B-Cell Malignancies Intolerant to Ibrutinib/Acalabrutinib Shadman. Lancet Haematol. 2022;S2352. Intolerance Events: Ibrutinib* Patients, n Intolerance Events: Acalabrutinib† Fatigue Arthralgia Hemorrhage Hypertension Stomatitis Constipation Nausea Insomnia Rash Headache Myalgia Diarrhea Atrial Fibrillation Muscle Spasms Dizziness Lymphedema AST increased ALT increased Pain in extremity Neutropenia Myalgia Arthralgia 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Recurred at same grade Recurred at a lower grade Did not recur *18 additional ibrutinib-related intolerance events occurred in 1 patient and did not recur on zanubrutinib (not shown). †11 additional acalabrutinib-related intolerance events occurred in 1 patient and did not recur on zanubrutinib (not shown). Dr Faheema Hasan
  • 29. Should we prefer Zanubrutinib upfront ? • It is important to recognize the ‘dead-kinase’ mutations at codon L528 of BTK which have been observed with disease progression on Zanu and pirtobrutinib • These have been described at lower frequency with Ib or Acala. • They may have important implications for double class-refractory disease for whom effective treatment options are limited. • Dead-kinase L528 mutations following Zanu may induce cross-resistance to Pirto. • However, the precise incidence of L528 BTK mutations arising following Zanu therapy is presently undefined and should not currently influence selection of initial BTKi until more data are available. Dr Faheema Hasan
  • 30. The Overall Safety Experience with BTKi Dr Faheema Hasan
  • 31. When using BTKi , which is the preferred BTKi? Dr Faheema Hasan
  • 32. When using a BTKi, should you add an anti‐CD20 monoclonal antibody? • ILLUMINATE and E1912 studies demonstrate that IbO and IbR: uMRD did not associate clearly with improved PFS outcomes. • Ibru may impair rituximab-induced ADCC due to inhibition of ITK, which may explain lack of PFS benefit with the combination. • ELEVATE-TN, the addition of Obi to Acala (AO) appeared to improve rates of CR/CRi in TP53 aberrant CLL and umIGHV • Greater incidence of hematological adverse events was observed following AO versus A, including all-grade neutropenia and thrombocytopenia. • RITUXIMAB • OBINUTUZUMAB Dr Faheema Hasan
  • 34. Is there still a role forchemoimmunotherapy as first line therapy? • Time limited • FCR : Young , fit, Ig HV mutated, No Del 17p or TP53 unmutated. • BR, Chl/O: Older, unfit, Ig HV mutated, NON TP53 aberrant CLL • FCR :hematological toxicity and infection, risk of secondary myeloid malignancies, lymphoid clonal evolution, • Appealing when financial toxicity is considered Dr Faheema Hasan
  • 35. What About BTKi and BCL2 combinations ? Dr Faheema Hasan
  • 36. Current Treatment Landscape in R/R CLL Therapy for R/R Disease After Prior BTKi- and Venetoclax-Based Regimens • Non-covalent (reversible) BTK inhibitor- Pirtobrutinib (if not previously used) • PI3K inhibitors • CIT or Immunotherapy NCCN. Clinical practice guidelines in oncology: CLL/SLL. v.2.2023. nccn.org. Dr Faheema Hasan
  • 37. Slide credit: clinicaloptions.com With Covalent BTK Inhibitors, Resistance Mutations Are a Major Driver of Progression in CLL Resistance Mutations and Progression • BTK C481 mutations are the dominant reasons for progressive CLL in patients receiving therapy with covalent BTK inhibitors 56% BTK mutants 16% BTK and PLCG2 mutants 20% BTK and PLCG2 not identified Woyach. JCO. 2017;35:1437. Lampson. Expert Rev Hematol. 2018;11:185. Burger. Leukemia. 2020;34:787. Byrd. NEJM. 2016;374:323. Hershkovitz-Rokah. Br J Haematol. 2018;181:306. Woyach. NEJM. 2014;370:2286. Woyach. Blood. 2019;134(suppl 1):504. Xu. Blood. 2017;129:2519. Acquired Resistance to Ibrutinib in Patients With Progressive CLL2,3 Resistance Mutations and Progression
  • 38. Acquired Resistance to Covalent BTK Inhibitors Is Generally Driven by Mutations in BTK at C481 PH TH SH3 SH2 Kinase Y223 C481 Y551 K430 M477 D539 E475 Y476 Structure of Bruton tyrosine kinase2 Acalabrutinib Zanubrutinib In sum, BTK resistance contributes to disease progression and diminishes the efficacy of all covalent BTK inhibitors BTK C481 mutations also confer resistance to covalent BTK inhibitors acalabrutinib, ibrutinib, and zanubrutinib Ibrutinib X X X 1. Woyach. NEJM 2014;370:2286. 2. Gu. J Hematol Oncol. 2021;14:40. Dr Faheema Hasan
  • 39. How Non Covalent BTKi overcome resistance ? Dr Faheema Hasan
  • 40. Selectivity of Non-Covalent BTKi Dr Faheema Hasan
  • 44. ASH 2023: Select Key Abstracts for R/R CLL/SLL Abstract Title Presenter Time 325 Pirtobrutinib in Post-cBTKi CLL/SLL: ~30 Months Follow-up and Subgroup Analysis With/Without Prior BCL-2i from the Phase 1/2 BRUIN Study Woyach Dec 9, 4:00 PM 1737 Pirtobrutinib in Richter Transformation: Updated Efficacy and Safety Results with 18-Month Median Survival Follow-up from the Phase 1/2 BRUIN Study Wierda Dec 9, 5:30 PM 108 Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy for Richter’s Transformation: An International Multicenter Retrospective Study Kittai Dec 9, 10:45 AM Dr Faheema Hasan
  • 45. SUMMARY • The evidence confirms the efficacy of cBTKi as a frontline option • Optimal sequencing of BTK inhibitors and BCL-2 inhibitors is not yet clear, but either option is effective when used sequentially • They are the most effective 1L option for HR patients • Venetoclax and ncBTKi are effective in the post-covalent BTKi setting Dr Faheema Hasan