Treatment of CLL in the eara of targeted therapy

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

10. With del(17p)/TP53 mutation
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

17. Challenges with Ibrutinib
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

33. 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

41. Dr Faheema Hasan

42. Dr Faheema Hasan

43. 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