SlideShare a Scribd company logo
1 of 45
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

More Related Content

What's hot

Management of metastatic colorectal cancer
Management of metastatic colorectal cancerManagement of metastatic colorectal cancer
Management of metastatic colorectal cancerMohamed Abdulla
 
Hr+ her2 neu mbc
Hr+ her2 neu   mbcHr+ her2 neu   mbc
Hr+ her2 neu mbcmadurai
 
Management of recurrent Glioblastoma and role of Bevacizumab
Management of recurrent Glioblastoma and role of BevacizumabManagement of recurrent Glioblastoma and role of Bevacizumab
Management of recurrent Glioblastoma and role of BevacizumabAjeet Gandhi
 
Advances in management of castration resistant prostate cancer
Advances in management of castration resistant prostate cancerAdvances in management of castration resistant prostate cancer
Advances in management of castration resistant prostate cancerAlok Gupta
 
Hr+ her2 neu mbc ppt
Hr+ her2 neu   mbc pptHr+ her2 neu   mbc ppt
Hr+ her2 neu mbc pptmadurai
 
CCO_HER2_Breast_Cancer_Updates_Downloadable_1.pptx
CCO_HER2_Breast_Cancer_Updates_Downloadable_1.pptxCCO_HER2_Breast_Cancer_Updates_Downloadable_1.pptx
CCO_HER2_Breast_Cancer_Updates_Downloadable_1.pptxDoQuyenPhan1
 
triple negative breast cancer
triple negative breast cancertriple negative breast cancer
triple negative breast cancerLuis Toache
 
Noa Efrat Ben Baruch : Neo-adjuvant treatment in breast cancer
Noa Efrat Ben Baruch : Neo-adjuvant treatment in breast cancerNoa Efrat Ben Baruch : Neo-adjuvant treatment in breast cancer
Noa Efrat Ben Baruch : Neo-adjuvant treatment in breast cancerbreastcancerupdatecongress
 
CCO immune checkpoint_inhibitors_in_cancer_care
CCO immune checkpoint_inhibitors_in_cancer_careCCO immune checkpoint_inhibitors_in_cancer_care
CCO immune checkpoint_inhibitors_in_cancer_careAdonis Guancia
 
Hormonal Manipulations in Early Prostate Cancer
Hormonal Manipulations  in Early Prostate Cancer Hormonal Manipulations  in Early Prostate Cancer
Hormonal Manipulations in Early Prostate Cancer Apollo Hospitals
 
V_Hematology_Forum_Dr_Pavithran
V_Hematology_Forum_Dr_PavithranV_Hematology_Forum_Dr_Pavithran
V_Hematology_Forum_Dr_PavithranEAFO1
 
Empagliflozin and Cardiovascular Outcomes
Empagliflozin and Cardiovascular OutcomesEmpagliflozin and Cardiovascular Outcomes
Empagliflozin and Cardiovascular OutcomesUyen Nguyen
 
Sequencing therapy for crcp a practical approach
Sequencing therapy for crcp  a practical approachSequencing therapy for crcp  a practical approach
Sequencing therapy for crcp a practical approachMohamed Abdulla
 
Targeted therapy and immunotherapy in lung cancer
Targeted therapy and immunotherapy in lung cancerTargeted therapy and immunotherapy in lung cancer
Targeted therapy and immunotherapy in lung cancerAlok Gupta
 

What's hot (20)

On the Cusp of the Era of Immuno-Oncology in Triple-Negative Breast Cancer: R...
On the Cusp of the Era of Immuno-Oncology in Triple-Negative Breast Cancer: R...On the Cusp of the Era of Immuno-Oncology in Triple-Negative Breast Cancer: R...
On the Cusp of the Era of Immuno-Oncology in Triple-Negative Breast Cancer: R...
 
Management of metastatic colorectal cancer
Management of metastatic colorectal cancerManagement of metastatic colorectal cancer
Management of metastatic colorectal cancer
 
Putting a Personalized Colorectal Cancer Treatment Algorithm Into Practice: N...
Putting a Personalized Colorectal Cancer Treatment Algorithm Into Practice: N...Putting a Personalized Colorectal Cancer Treatment Algorithm Into Practice: N...
Putting a Personalized Colorectal Cancer Treatment Algorithm Into Practice: N...
 
MANAGEMENT OF EARLY OPERABLE HER2+ BREAST CANCER.pptx
MANAGEMENT OF EARLY OPERABLE HER2+ BREAST CANCER.pptxMANAGEMENT OF EARLY OPERABLE HER2+ BREAST CANCER.pptx
MANAGEMENT OF EARLY OPERABLE HER2+ BREAST CANCER.pptx
 
Hr+ her2 neu mbc
Hr+ her2 neu   mbcHr+ her2 neu   mbc
Hr+ her2 neu mbc
 
Management of recurrent Glioblastoma and role of Bevacizumab
Management of recurrent Glioblastoma and role of BevacizumabManagement of recurrent Glioblastoma and role of Bevacizumab
Management of recurrent Glioblastoma and role of Bevacizumab
 
Herceptin
HerceptinHerceptin
Herceptin
 
Advances in management of castration resistant prostate cancer
Advances in management of castration resistant prostate cancerAdvances in management of castration resistant prostate cancer
Advances in management of castration resistant prostate cancer
 
Hr+ mbc
Hr+ mbc Hr+ mbc
Hr+ mbc
 
Hr+ her2 neu mbc ppt
Hr+ her2 neu   mbc pptHr+ her2 neu   mbc ppt
Hr+ her2 neu mbc ppt
 
CCO_HER2_Breast_Cancer_Updates_Downloadable_1.pptx
CCO_HER2_Breast_Cancer_Updates_Downloadable_1.pptxCCO_HER2_Breast_Cancer_Updates_Downloadable_1.pptx
CCO_HER2_Breast_Cancer_Updates_Downloadable_1.pptx
 
triple negative breast cancer
triple negative breast cancertriple negative breast cancer
triple negative breast cancer
 
Noa Efrat Ben Baruch : Neo-adjuvant treatment in breast cancer
Noa Efrat Ben Baruch : Neo-adjuvant treatment in breast cancerNoa Efrat Ben Baruch : Neo-adjuvant treatment in breast cancer
Noa Efrat Ben Baruch : Neo-adjuvant treatment in breast cancer
 
CCO immune checkpoint_inhibitors_in_cancer_care
CCO immune checkpoint_inhibitors_in_cancer_careCCO immune checkpoint_inhibitors_in_cancer_care
CCO immune checkpoint_inhibitors_in_cancer_care
 
Hormonal Manipulations in Early Prostate Cancer
Hormonal Manipulations  in Early Prostate Cancer Hormonal Manipulations  in Early Prostate Cancer
Hormonal Manipulations in Early Prostate Cancer
 
V_Hematology_Forum_Dr_Pavithran
V_Hematology_Forum_Dr_PavithranV_Hematology_Forum_Dr_Pavithran
V_Hematology_Forum_Dr_Pavithran
 
Empagliflozin and Cardiovascular Outcomes
Empagliflozin and Cardiovascular OutcomesEmpagliflozin and Cardiovascular Outcomes
Empagliflozin and Cardiovascular Outcomes
 
Sequencing therapy for crcp a practical approach
Sequencing therapy for crcp  a practical approachSequencing therapy for crcp  a practical approach
Sequencing therapy for crcp a practical approach
 
Rcc in 2021
Rcc in 2021Rcc in 2021
Rcc in 2021
 
Targeted therapy and immunotherapy in lung cancer
Targeted therapy and immunotherapy in lung cancerTargeted therapy and immunotherapy in lung cancer
Targeted therapy and immunotherapy in lung cancer
 

Similar to BTKi in Treatment Of Chronic Lymphocytic Leukemia

Update on treatment for lymphoma, Lymphoma Support Ireland meeting - feb 2011...
Update on treatment for lymphoma, Lymphoma Support Ireland meeting - feb 2011...Update on treatment for lymphoma, Lymphoma Support Ireland meeting - feb 2011...
Update on treatment for lymphoma, Lymphoma Support Ireland meeting - feb 2011...Lymphoma Support Ireland
 
Optimizing the Management of Metastatic TNBC: Diagnostics, Treatments and Hop...
Optimizing the Management of Metastatic TNBC: Diagnostics, Treatments and Hop...Optimizing the Management of Metastatic TNBC: Diagnostics, Treatments and Hop...
Optimizing the Management of Metastatic TNBC: Diagnostics, Treatments and Hop...bkling
 
6 frederick
6 frederick6 frederick
6 frederickspa718
 
Recurrent/Metastatic HNSCC: Harnessing Immunotherapy in Comprehensive Care
Recurrent/Metastatic HNSCC: Harnessing Immunotherapy in Comprehensive CareRecurrent/Metastatic HNSCC: Harnessing Immunotherapy in Comprehensive Care
Recurrent/Metastatic HNSCC: Harnessing Immunotherapy in Comprehensive Carei3 Health
 
Ash 2014 update
Ash 2014 updateAsh 2014 update
Ash 2014 updatemadurai
 
MON 2011 - Slide 7 - G. Curigliano - Joint medics and nurses spotlight sessio...
MON 2011 - Slide 7 - G. Curigliano - Joint medics and nurses spotlight sessio...MON 2011 - Slide 7 - G. Curigliano - Joint medics and nurses spotlight sessio...
MON 2011 - Slide 7 - G. Curigliano - Joint medics and nurses spotlight sessio...European School of Oncology
 
MCO 2011 - Slide 9 - G. Curigliano - Joint medics and nurses spotlight sessio...
MCO 2011 - Slide 9 - G. Curigliano - Joint medics and nurses spotlight sessio...MCO 2011 - Slide 9 - G. Curigliano - Joint medics and nurses spotlight sessio...
MCO 2011 - Slide 9 - G. Curigliano - Joint medics and nurses spotlight sessio...European School of Oncology
 
Triple Negative Breast Cancer
Triple Negative Breast CancerTriple Negative Breast Cancer
Triple Negative Breast CancerMohamed Abdulla
 
4 ΟΓΚΟΛΟΓΙΚΟ ΣΥΝΕΔΡΙΟ ΡΟΔΟΥ
4 ΟΓΚΟΛΟΓΙΚΟ ΣΥΝΕΔΡΙΟ ΡΟΔΟΥ4 ΟΓΚΟΛΟΓΙΚΟ ΣΥΝΕΔΡΙΟ ΡΟΔΟΥ
4 ΟΓΚΟΛΟΓΙΚΟ ΣΥΝΕΔΡΙΟ ΡΟΔΟΥisrodoy isr
 
BALKAN MCO 2011 - F. Cardoso - Chemotherapy options/management issues in meta...
BALKAN MCO 2011 - F. Cardoso - Chemotherapy options/management issues in meta...BALKAN MCO 2011 - F. Cardoso - Chemotherapy options/management issues in meta...
BALKAN MCO 2011 - F. Cardoso - Chemotherapy options/management issues in meta...European School of Oncology
 
Hodgkin's Lymphoma: Treatment Update
Hodgkin's Lymphoma: Treatment UpdateHodgkin's Lymphoma: Treatment Update
Hodgkin's Lymphoma: Treatment Updatespa718
 
Pd 1 inhibitors (review and role in lymphoma)
Pd 1 inhibitors (review and role in lymphoma)Pd 1 inhibitors (review and role in lymphoma)
Pd 1 inhibitors (review and role in lymphoma)Mary Ondinee Manalo Igot
 
advances in head neck cancers.pptx
advances in head neck cancers.pptxadvances in head neck cancers.pptx
advances in head neck cancers.pptxShahidShaikh615046
 
TREATMENT OF NON-HIDGKIN'S LYMPHOMA IN ELDERLY PATIENTS
TREATMENT OF NON-HIDGKIN'S LYMPHOMA IN ELDERLY PATIENTSTREATMENT OF NON-HIDGKIN'S LYMPHOMA IN ELDERLY PATIENTS
TREATMENT OF NON-HIDGKIN'S LYMPHOMA IN ELDERLY PATIENTSspa718
 
esmo breast chemotherapy curigliano 02.05.2022.pptx
esmo breast chemotherapy curigliano 02.05.2022.pptxesmo breast chemotherapy curigliano 02.05.2022.pptx
esmo breast chemotherapy curigliano 02.05.2022.pptxClaudiaMartnez362809
 
Dr Michelle Poon - Prevention of relapse Following Allogeneic Transplant
Dr Michelle Poon - Prevention of relapse Following Allogeneic Transplant Dr Michelle Poon - Prevention of relapse Following Allogeneic Transplant
Dr Michelle Poon - Prevention of relapse Following Allogeneic Transplant Singapore Society for Haematology
 
Mantenimiento ca pulmón 2013-05
Mantenimiento ca pulmón 2013-05Mantenimiento ca pulmón 2013-05
Mantenimiento ca pulmón 2013-05Martín Lázaro
 

Similar to BTKi in Treatment Of Chronic Lymphocytic Leukemia (20)

Update on treatment for lymphoma, Lymphoma Support Ireland meeting - feb 2011...
Update on treatment for lymphoma, Lymphoma Support Ireland meeting - feb 2011...Update on treatment for lymphoma, Lymphoma Support Ireland meeting - feb 2011...
Update on treatment for lymphoma, Lymphoma Support Ireland meeting - feb 2011...
 
Optimizing the Management of Metastatic TNBC: Diagnostics, Treatments and Hop...
Optimizing the Management of Metastatic TNBC: Diagnostics, Treatments and Hop...Optimizing the Management of Metastatic TNBC: Diagnostics, Treatments and Hop...
Optimizing the Management of Metastatic TNBC: Diagnostics, Treatments and Hop...
 
6 frederick
6 frederick6 frederick
6 frederick
 
Cáncer de pulmón
Cáncer de pulmónCáncer de pulmón
Cáncer de pulmón
 
Recurrent/Metastatic HNSCC: Harnessing Immunotherapy in Comprehensive Care
Recurrent/Metastatic HNSCC: Harnessing Immunotherapy in Comprehensive CareRecurrent/Metastatic HNSCC: Harnessing Immunotherapy in Comprehensive Care
Recurrent/Metastatic HNSCC: Harnessing Immunotherapy in Comprehensive Care
 
Ash 2014 update
Ash 2014 updateAsh 2014 update
Ash 2014 update
 
CRPC management
CRPC managementCRPC management
CRPC management
 
MON 2011 - Slide 7 - G. Curigliano - Joint medics and nurses spotlight sessio...
MON 2011 - Slide 7 - G. Curigliano - Joint medics and nurses spotlight sessio...MON 2011 - Slide 7 - G. Curigliano - Joint medics and nurses spotlight sessio...
MON 2011 - Slide 7 - G. Curigliano - Joint medics and nurses spotlight sessio...
 
MCO 2011 - Slide 9 - G. Curigliano - Joint medics and nurses spotlight sessio...
MCO 2011 - Slide 9 - G. Curigliano - Joint medics and nurses spotlight sessio...MCO 2011 - Slide 9 - G. Curigliano - Joint medics and nurses spotlight sessio...
MCO 2011 - Slide 9 - G. Curigliano - Joint medics and nurses spotlight sessio...
 
Triple Negative Breast Cancer
Triple Negative Breast CancerTriple Negative Breast Cancer
Triple Negative Breast Cancer
 
Bendamustine Vs R-CHOP/R-CVP-Bright study
Bendamustine Vs R-CHOP/R-CVP-Bright studyBendamustine Vs R-CHOP/R-CVP-Bright study
Bendamustine Vs R-CHOP/R-CVP-Bright study
 
4 ΟΓΚΟΛΟΓΙΚΟ ΣΥΝΕΔΡΙΟ ΡΟΔΟΥ
4 ΟΓΚΟΛΟΓΙΚΟ ΣΥΝΕΔΡΙΟ ΡΟΔΟΥ4 ΟΓΚΟΛΟΓΙΚΟ ΣΥΝΕΔΡΙΟ ΡΟΔΟΥ
4 ΟΓΚΟΛΟΓΙΚΟ ΣΥΝΕΔΡΙΟ ΡΟΔΟΥ
 
BALKAN MCO 2011 - F. Cardoso - Chemotherapy options/management issues in meta...
BALKAN MCO 2011 - F. Cardoso - Chemotherapy options/management issues in meta...BALKAN MCO 2011 - F. Cardoso - Chemotherapy options/management issues in meta...
BALKAN MCO 2011 - F. Cardoso - Chemotherapy options/management issues in meta...
 
Hodgkin's Lymphoma: Treatment Update
Hodgkin's Lymphoma: Treatment UpdateHodgkin's Lymphoma: Treatment Update
Hodgkin's Lymphoma: Treatment Update
 
Pd 1 inhibitors (review and role in lymphoma)
Pd 1 inhibitors (review and role in lymphoma)Pd 1 inhibitors (review and role in lymphoma)
Pd 1 inhibitors (review and role in lymphoma)
 
advances in head neck cancers.pptx
advances in head neck cancers.pptxadvances in head neck cancers.pptx
advances in head neck cancers.pptx
 
TREATMENT OF NON-HIDGKIN'S LYMPHOMA IN ELDERLY PATIENTS
TREATMENT OF NON-HIDGKIN'S LYMPHOMA IN ELDERLY PATIENTSTREATMENT OF NON-HIDGKIN'S LYMPHOMA IN ELDERLY PATIENTS
TREATMENT OF NON-HIDGKIN'S LYMPHOMA IN ELDERLY PATIENTS
 
esmo breast chemotherapy curigliano 02.05.2022.pptx
esmo breast chemotherapy curigliano 02.05.2022.pptxesmo breast chemotherapy curigliano 02.05.2022.pptx
esmo breast chemotherapy curigliano 02.05.2022.pptx
 
Dr Michelle Poon - Prevention of relapse Following Allogeneic Transplant
Dr Michelle Poon - Prevention of relapse Following Allogeneic Transplant Dr Michelle Poon - Prevention of relapse Following Allogeneic Transplant
Dr Michelle Poon - Prevention of relapse Following Allogeneic Transplant
 
Mantenimiento ca pulmón 2013-05
Mantenimiento ca pulmón 2013-05Mantenimiento ca pulmón 2013-05
Mantenimiento ca pulmón 2013-05
 

Recently uploaded

How to Manage Website in Odoo 17 Studio App.pptx
How to Manage Website in Odoo 17 Studio App.pptxHow to Manage Website in Odoo 17 Studio App.pptx
How to Manage Website in Odoo 17 Studio App.pptxCeline George
 
e-Sealing at EADTU by Kamakshi Rajagopal
e-Sealing at EADTU by Kamakshi Rajagopale-Sealing at EADTU by Kamakshi Rajagopal
e-Sealing at EADTU by Kamakshi RajagopalEADTU
 
The Story of Village Palampur Class 9 Free Study Material PDF
The Story of Village Palampur Class 9 Free Study Material PDFThe Story of Village Palampur Class 9 Free Study Material PDF
The Story of Village Palampur Class 9 Free Study Material PDFVivekanand Anglo Vedic Academy
 
會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文
會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文
會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文中 央社
 
FICTIONAL SALESMAN/SALESMAN SNSW 2024.pdf
FICTIONAL SALESMAN/SALESMAN SNSW 2024.pdfFICTIONAL SALESMAN/SALESMAN SNSW 2024.pdf
FICTIONAL SALESMAN/SALESMAN SNSW 2024.pdfPondicherry University
 
ANTI PARKISON DRUGS.pptx
ANTI         PARKISON          DRUGS.pptxANTI         PARKISON          DRUGS.pptx
ANTI PARKISON DRUGS.pptxPoojaSen20
 
會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽
會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽
會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽中 央社
 
An overview of the various scriptures in Hinduism
An overview of the various scriptures in HinduismAn overview of the various scriptures in Hinduism
An overview of the various scriptures in HinduismDabee Kamal
 
Sternal Fractures & Dislocations - EMGuidewire Radiology Reading Room
Sternal Fractures & Dislocations - EMGuidewire Radiology Reading RoomSternal Fractures & Dislocations - EMGuidewire Radiology Reading Room
Sternal Fractures & Dislocations - EMGuidewire Radiology Reading RoomSean M. Fox
 
SPLICE Working Group: Reusable Code Examples
SPLICE Working Group:Reusable Code ExamplesSPLICE Working Group:Reusable Code Examples
SPLICE Working Group: Reusable Code ExamplesPeter Brusilovsky
 
Andreas Schleicher presents at the launch of What does child empowerment mean...
Andreas Schleicher presents at the launch of What does child empowerment mean...Andreas Schleicher presents at the launch of What does child empowerment mean...
Andreas Schleicher presents at the launch of What does child empowerment mean...EduSkills OECD
 
TỔNG HỢP HƠN 100 ĐỀ THI THỬ TỐT NGHIỆP THPT TOÁN 2024 - TỪ CÁC TRƯỜNG, TRƯỜNG...
TỔNG HỢP HƠN 100 ĐỀ THI THỬ TỐT NGHIỆP THPT TOÁN 2024 - TỪ CÁC TRƯỜNG, TRƯỜNG...TỔNG HỢP HƠN 100 ĐỀ THI THỬ TỐT NGHIỆP THPT TOÁN 2024 - TỪ CÁC TRƯỜNG, TRƯỜNG...
TỔNG HỢP HƠN 100 ĐỀ THI THỬ TỐT NGHIỆP THPT TOÁN 2024 - TỪ CÁC TRƯỜNG, TRƯỜNG...Nguyen Thanh Tu Collection
 
Personalisation of Education by AI and Big Data - Lourdes Guàrdia
Personalisation of Education by AI and Big Data - Lourdes GuàrdiaPersonalisation of Education by AI and Big Data - Lourdes Guàrdia
Personalisation of Education by AI and Big Data - Lourdes GuàrdiaEADTU
 
Basic Civil Engineering notes on Transportation Engineering & Modes of Transport
Basic Civil Engineering notes on Transportation Engineering & Modes of TransportBasic Civil Engineering notes on Transportation Engineering & Modes of Transport
Basic Civil Engineering notes on Transportation Engineering & Modes of TransportDenish Jangid
 
Major project report on Tata Motors and its marketing strategies
Major project report on Tata Motors and its marketing strategiesMajor project report on Tata Motors and its marketing strategies
Major project report on Tata Motors and its marketing strategiesAmanpreetKaur157993
 
AIM of Education-Teachers Training-2024.ppt
AIM of Education-Teachers Training-2024.pptAIM of Education-Teachers Training-2024.ppt
AIM of Education-Teachers Training-2024.pptNishitharanjan Rout
 
OSCM Unit 2_Operations Processes & Systems
OSCM Unit 2_Operations Processes & SystemsOSCM Unit 2_Operations Processes & Systems
OSCM Unit 2_Operations Processes & SystemsSandeep D Chaudhary
 
SURVEY I created for uni project research
SURVEY I created for uni project researchSURVEY I created for uni project research
SURVEY I created for uni project researchCaitlinCummins3
 

Recently uploaded (20)

How to Manage Website in Odoo 17 Studio App.pptx
How to Manage Website in Odoo 17 Studio App.pptxHow to Manage Website in Odoo 17 Studio App.pptx
How to Manage Website in Odoo 17 Studio App.pptx
 
e-Sealing at EADTU by Kamakshi Rajagopal
e-Sealing at EADTU by Kamakshi Rajagopale-Sealing at EADTU by Kamakshi Rajagopal
e-Sealing at EADTU by Kamakshi Rajagopal
 
The Story of Village Palampur Class 9 Free Study Material PDF
The Story of Village Palampur Class 9 Free Study Material PDFThe Story of Village Palampur Class 9 Free Study Material PDF
The Story of Village Palampur Class 9 Free Study Material PDF
 
會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文
會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文
會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文會考英文
 
FICTIONAL SALESMAN/SALESMAN SNSW 2024.pdf
FICTIONAL SALESMAN/SALESMAN SNSW 2024.pdfFICTIONAL SALESMAN/SALESMAN SNSW 2024.pdf
FICTIONAL SALESMAN/SALESMAN SNSW 2024.pdf
 
ANTI PARKISON DRUGS.pptx
ANTI         PARKISON          DRUGS.pptxANTI         PARKISON          DRUGS.pptx
ANTI PARKISON DRUGS.pptx
 
會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽
會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽
會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽會考英聽
 
An overview of the various scriptures in Hinduism
An overview of the various scriptures in HinduismAn overview of the various scriptures in Hinduism
An overview of the various scriptures in Hinduism
 
Sternal Fractures & Dislocations - EMGuidewire Radiology Reading Room
Sternal Fractures & Dislocations - EMGuidewire Radiology Reading RoomSternal Fractures & Dislocations - EMGuidewire Radiology Reading Room
Sternal Fractures & Dislocations - EMGuidewire Radiology Reading Room
 
Mattingly "AI and Prompt Design: LLMs with NER"
Mattingly "AI and Prompt Design: LLMs with NER"Mattingly "AI and Prompt Design: LLMs with NER"
Mattingly "AI and Prompt Design: LLMs with NER"
 
SPLICE Working Group: Reusable Code Examples
SPLICE Working Group:Reusable Code ExamplesSPLICE Working Group:Reusable Code Examples
SPLICE Working Group: Reusable Code Examples
 
Andreas Schleicher presents at the launch of What does child empowerment mean...
Andreas Schleicher presents at the launch of What does child empowerment mean...Andreas Schleicher presents at the launch of What does child empowerment mean...
Andreas Schleicher presents at the launch of What does child empowerment mean...
 
TỔNG HỢP HƠN 100 ĐỀ THI THỬ TỐT NGHIỆP THPT TOÁN 2024 - TỪ CÁC TRƯỜNG, TRƯỜNG...
TỔNG HỢP HƠN 100 ĐỀ THI THỬ TỐT NGHIỆP THPT TOÁN 2024 - TỪ CÁC TRƯỜNG, TRƯỜNG...TỔNG HỢP HƠN 100 ĐỀ THI THỬ TỐT NGHIỆP THPT TOÁN 2024 - TỪ CÁC TRƯỜNG, TRƯỜNG...
TỔNG HỢP HƠN 100 ĐỀ THI THỬ TỐT NGHIỆP THPT TOÁN 2024 - TỪ CÁC TRƯỜNG, TRƯỜNG...
 
Personalisation of Education by AI and Big Data - Lourdes Guàrdia
Personalisation of Education by AI and Big Data - Lourdes GuàrdiaPersonalisation of Education by AI and Big Data - Lourdes Guàrdia
Personalisation of Education by AI and Big Data - Lourdes Guàrdia
 
Basic Civil Engineering notes on Transportation Engineering & Modes of Transport
Basic Civil Engineering notes on Transportation Engineering & Modes of TransportBasic Civil Engineering notes on Transportation Engineering & Modes of Transport
Basic Civil Engineering notes on Transportation Engineering & Modes of Transport
 
Major project report on Tata Motors and its marketing strategies
Major project report on Tata Motors and its marketing strategiesMajor project report on Tata Motors and its marketing strategies
Major project report on Tata Motors and its marketing strategies
 
AIM of Education-Teachers Training-2024.ppt
AIM of Education-Teachers Training-2024.pptAIM of Education-Teachers Training-2024.ppt
AIM of Education-Teachers Training-2024.ppt
 
OSCM Unit 2_Operations Processes & Systems
OSCM Unit 2_Operations Processes & SystemsOSCM Unit 2_Operations Processes & Systems
OSCM Unit 2_Operations Processes & Systems
 
Supporting Newcomer Multilingual Learners
Supporting Newcomer  Multilingual LearnersSupporting Newcomer  Multilingual Learners
Supporting Newcomer Multilingual Learners
 
SURVEY I created for uni project research
SURVEY I created for uni project researchSURVEY I created for uni project research
SURVEY I created for uni project research
 

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