new directions for oral treatment in b-cell malignancies · 2020. 8. 18. · oral therapy for the...
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New Directions for Oral Treatment in B-Cell Malignancies
Implications for Pharmacists
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This educational activity is accredited by Purdue University, sponsored by Postgraduate Healthcare Education, LLC,
and supported by educational grants from AbbVie Inc. and Janssen Pharmaceuticals Inc.
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Anthony J. Perissinotti, PharmD, BCOPClinical Team Lead, Hematology/Oncology Clinical Pharmacist Specialist, Inpatient HematologyThe University of Michigan – Michigan MedicineAdjunct Clinical Assistant ProfessorThe University of Michigan College of PharmacyAnn Arbor, MI
Dr. Perissinotti is a hematology clinical pharmacist specialist at the University of Michigan, Michigan Medicine, clinical team leader of hematology/oncology, and adjunct clinical assistant professor at the University of Michigan College of Pharmacy in Ann Arbor, Michigan. He obtained his Doctor of Pharmacy degree from Wayne State University in Detroit, Michigan. He completed his first year of postgraduate residency training at the Detroit Medical Center, Harper University Hospital in Detroit, and his second year of postgraduate residency training at The University of Texas MD Anderson Cancer Center in Houston, Texas. Dr. Perissinottti is a Board Certified Hematology/Oncology Pharmacist.
Faculty
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Victoria Nachar, PharmD, BCOPClinical Pharmacist Specialist, Ambulatory Hematology OncologyUniversity of Michigan – Michigan Medicine,Rogel Cancer CenterAdjunct Clinical Assistant ProfessorThe University of Michigan College of PharmacyAnn Arbor, MI
Dr. Nachar is a hematology/oncology clinical pharmacist specialist at the Michigan Medicine RogelCancer Center and an adjunct clinical assistant professor at the University of Michigan College of Pharmacy. She completed her Doctor of Pharmacy degree at the University at Buffalo, followed by residency training at the University of Michigan. She is a Board Certified Hematology/Oncology Pharmacist. She primarily cares for patients with both hematological and oncologic malignancies in Ann Arbor and at the Rogel Cancer Center satellite in Brighton, Michigan. Her professional interests include lymphoma, multiple myeloma, and clinical research.
Faculty
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Disclosures
Drs. Perissinotti and Nachar have disclosed that they have no actual or potential conflict of interest in relation to this program.
The clinical reviewer, Ashley Glode, PharmD, BCOP, has no actual or potential conflict of interest in relation to this program.
Susanne Batesko, RN, BSN, Robin Soboti, RPh, and Susan R. Grady, MSN, RN-BC, as well as the planners, managers, and other individuals, not previously disclosed, who are in a position to control the content of Postgraduate Healthcare Education (PHE) continuing education activities hereby state that they have no relevant conflicts of interest and no financial relationships or relationships to products or devices during the past 12 months to disclose in relation to this activity. PHE is committed to providing participants with a quality learning experience and to improve clinical outcomes without promoting the financial interests of a proprietary business.
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Accreditation
Purdue University is accredited by the
Accreditation Council for Pharmacy Education
as a provider of continuing pharmacy
education.
UAN: 0018-9999-20-020-H01-P
Credits: 1.0 hour (0.1 CEU)
Type of Activity: Application
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Learning Objectives
• Discuss the current guideline recommendations for the treatment of B-cell malignancies
• Appraise the mechanism of action, efficacy, and safety of current and emerging oral treatment options for B-cell malignancies
• Demonstrate strategies to effectively counsel patients receiving oral therapy for the treatment of B-cell malignancies, including assessment and management of adverse effects, and education for promoting safe use and adherence to treatment
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Hardy RR, Hayakawa K. B cell development pathways. Annu Rev Immunol. 2001;19:595-621.
BLOOD AND MARROW
Lymphoid progenitor
Pre-B-cell
Naïve B-cell
Activated B-Cell
Germinal center B-cell
Memory B-cell
Plasmablast
Plasma cell
SECONDARY LYMPHOID
TISSUE
BONE MARROW
Acute lymphoblastic leukemia
Mantle cell lymphoma (MCL), Marginal zone lymphoma (MZL),
Chronic lymphocytic leukemia (CLL)
Follicular lymphoma (FL)
Burkitt lymphoma, CLL
Waldenstrom’s macroglobulinemia (WM)
Multiple myeloma,Amyloidosis
Diffuse large b-cell lymphoma (DLBCL)
B-Cell Malignancy Cell of Origin
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B-Cell Non-Hodgkin Lymphoma (NHL)
MCLFL, CLL, MZL, WM
Indolent Very AggressiveFeatures of both Aggressive Very aggressive
DLBCLBurkitt
lymphomaHigh grade, NOS
(i.e., “double hit”)
Survival prognosis: years to decadesGoal: disease control
Survival prognosis: months to years Goal: cure
Survival prognosis: yearsGoal: disease control
Al-Hamadani M, et al. Am J Hematol. 2015;90(9):790-5.; Siegel RL, et al. CA Cancer J Clin. 2020;70(1):7-30.
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Therapies in B-Cell Malignancies
B-cell receptorCD20
B-cell malignancy
BAX
BAK
Cellnucleus
BCL2
BTK
PI3K
Anti-CD20 monoclonal antibodies1. Rituximab2. Obinutuzumab3. Ofatumomab
Traditional chemotherapy1. Alkylating agents
• Cyclophosphamide, chlorambucil, bendamustine
2. Purine/pyrimidine analogues• Fludarabine, bendamustine, cytarabine
3. Anthracyclines• Doxorubicin
4. Vinca alkyloids (microtubule inhibitor)• Vincristine
BTK inhibitors1. Ibrutinib2. Acalabrutinib3. Zanubrutinib
BCL2 inhibitor1. Venetoclax
PI3K inhibitors1. Idelalisib2. Duvelisib3. Copanlisib
Ongoing studies to determine optimal sequence or combinations
Variety of standard regimens
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas v1.2020.
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Regimen Definitions
FCR
Clb + Obi
BR
HiDAC
Nordic regimen
CHOP
Hyper-CVAD
Fludarabine, cyclophosphamide, rituximab
Chlorambucil, obinutuzumab
Cyclophosphamide, doxorubicin, vincristine, prednisone
High-dose cytarabine
Maxi-CHOP alternating with HiDAC
Bendamustine, rituximab
Cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with HiDAC, methotrexate
CVP
DRC
VR-CAP
BDR
Bortezomib, rituximab, cyclophosphamide, doxorubicin, prednisone
Cyclophosphamide, vincristine, prednisone
Dexamethasone, rituximab, cyclophosphamide
Bortezomib, dexamethasone, rituximab
CVP Cyclophosphamide, vincristine, prednisone
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Chronic Lymphocytic Leukemia (CLL)
• Indolent lymphoma
• Incidence:• Estimated 21,040 Americans in
2020
• Deaths:• 4060 in 2020
• Median age: 70 years
National Cancer Institute. seer.cancer.gov/statfacts/html/clyl.html. Accessed June 2nd, 2020.; National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma v4.2020.; Siegel RL, et al. CA Cancer J Clin. 2020;70(1):7-30.
• Most prevalent leukemia
• Prognostic factors:• del(17p)/TP53 mutation, unmutated
IGHV, complex karyotype
• CLL and SLL (same malignancy)• CLL: > 5000 clonal lymphocytes in blood
• SLL: < 5000 clonal lymphocytes in blood but presence of lymphadenopathy and/or splenomegaly
IGHV, immunoglobulin heavy chain variable.
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First-Line Treatment in CLL:Pre-BTK Inhibitors
New standardOld standardPopulation
Young/fit
Older/fit
Elderly/comorbidities
Mutated IGHV: FCR Unmutated IGHV: FCR
or BR
Chlorambucil + Obi
Bendamustine + rituximab
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BTK Inhibitor Mechanism of Action
Marini BL, et al. J Oncol Pharm Pract. 2017;23(7):502-17.
BCR
LYN
SYK
CD
79
a
CD
79
b
BTK
PLCγ2
PKC
MAPK/MEK/ERKpathway
NF-kβpathway
BTK inhibitor
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ECOG 1912 Trial: Study Schema
Shanafelt TD, et al. N Engl J Med. 2019;381(5):432-43.
Ibrutinib + rituximabIbrutinib 420 mg PO daily cycles 1-7
Rituximab cycles 2-7
FCRx 6 cycles
Standard CLL dosing
n = 354
n = 175
Population• Treatment-naïve CLL• Age ≤ 70 years,
ECOG 0-2• Del(17p) excluded
Ibrutinib maintenance
Randomized 2:1
Study design
• Phase III, multicenter, open-label, randomized controlled trial (RCT)
Primary outcome
• Progression-free survival (PFS)
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ECOG 1912 Trial: ResultsIbrutinib + Rituximab (IR) vs. FCR
IR improved PFS vs. FCR, especially in IGHV unmutated CLLConclusions
PFS
Years40 1 2 3
PFS
(%
)
1.0
0.8
0.6
0.4
0.2
0
P < 0.001
Ibrutinib + RituximabFCR
89.4%
72.9%
40 1 2 3
PFS
(%
)
1.0
0.8
0.6
0.4
0.2
0
Years
PFS (IGHV unmutated)
P < 0.001
90.7%
62.5%
Ibrutinib + RituximabFCR
Shanafelt TD, et al. N Engl J Med. 2019;381(5):432-43.
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Mutated IGHV: FCR Unmutated IGHV: FCR
or BR
Chlorambucil + Obi
Bendamustine + rituximab
First-Line Treatment in CLL:Changing Landscape
New standardOld standardPopulation
Young/fit
Older/fit
Elderly/comorbidities
Ibrutinib + rituximab*
*Mutated IGHV without del(17p)/TP53 mutation can consider FCR.
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Alliance A041202 Trial: Study Schema
Study design
• Phase III, multicenter, open-label, RCT
Primary outcome
• PFS
Ibrutinib + rituximabIbrutinib 420 mg PO daily cycles 1-6
Rituximab cycles 2-6
Bendamustine/rituximab(BR) x 6 cyclesStandard CLL dosing
n = 182
n = 183
Population• Treatment-naïve CLL• Age ≥ 65 years• ECOG 0-2• Del(17p) NOT excluded
Ibrutinib maintenance
Randomized 1:1:1
IbrutinibIbrutinib 420 mg PO daily
Ibrutinib maintenance
Cross-over allowed
n = 182
Woyach JA, et al. N Engl J Med. 2018;379(26):2517-28.
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Alliance A041202 Trial: ResultsIbrutinib + Rituximab (IR) vs. Ibrutinib Alone vs. Bendamustine + Rituximab (BR)
Median PFS 2-Yr PFS
Ibrutinib Not reached 87%
Ibrutinib + R Not reached 88%
BR 43 months 74%
PFS
(%
)
100
80
60
40
20
0
Months
0 6 12 18 24 30 36 42 48
Ibrutinib ± rituximab improved PFS vs. BR
Conclusions
Vast majority of patients with CLL no longer need chemotherapy
No improvement with adding rituximab to ibrutinib
P < 0.001
Woyach JA, et al. N Engl J Med. 2018;379(26):2517-28.
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Mutated IGHV: FCR Unmutated IGHV: FCR
or BR
Chlorambucil + Obi
Bendamustine + rituximab
New standardOld standardPopulation
Young/fit
Older/fit
Elderly/comorbidities
Ibrutinib + rituximab*
Ibrutinib
*Mutated IGHV without del(17p)/TP53 mutation can consider FCR; can consider no rituximab with ibrutinib based on ALLIANCE trial (but now FDA approved).
First-Line Treatment in CLL:
Changing Landscape
FDA, United States Food and Drug Administration.
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BTK Inhibitors Not Created Equal
IC50/EC50 (nM)
Kaptein A, et al. Blood. 2018;132(Suppl 1):1871.
Kinase Ibrutinib Acalabrutinib Zanubrutinib
BTK 1.5 5.1 0.5
TEC 10 126 44
ITK 4.9 > 1000 50
BMX 0.8 46 1.4
EGFR 5.3 > 1000 21
ERBB4 3.4 16 6.9
JAK3 32 > 1000 1377
BLK 0.1 > 1000 2.5
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ELEVATE-TN Trial: Study Schema
Study design
• Phase III, multicenter, open-label, RCT
Primary outcome
• PFS
Acalabrutinib + obinutuzumab
Acalabrutinib 100 mg PO q12hObinutuzumab cycles 2-6
Obinutuzumab +chlorambucil
Standard CLL dosing
n = 179
n = 177
Population• Treatment-naïve CLL• Age ≥ 65 or < 65 years
with comorbidities
Acalabrutinibmaintenance
Randomized 1:1:1
AcalabrutinibAcalabrutinib 100 mg PO q12h
Acalabrutinibmaintenance
Cross-over allowed
n = 179
Sharman JP, et al. Lancet. 2020;395(10232):1278‐91.
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Sharman JP, et al. Lancet. 2020;395(10232):1278‐91.
100
80
60
40
20
0
PFS
(%
)
0 6 12 18 24 30 36
Months
Acalabrutinib + obininutuzumabAcalabrutinibChlorambucil + obinutuzumab
40
Acalabrutinib ± Obi improved PFS vs. chlorambucil + Obi
Conclusions
Higher ORR with adding Obi to acalabrutinib (94% vs. 79%; p<0.0001)
No significant PFS improvement with adding Obi to acalabrutinib
90%
82%
34%
ORR, overall response rate.
ELEVATE-TN Trial: ResultsAcalabrutinib + Obinutuzumab vs. Acalabrutinib Alone vs. Chlorambucil + Obinutuzumab
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BCL2 Inhibitor Mechanism of Action
BAK
BAX
BAX
BAK
Caspase-dependent apoptosis
BCL-2
BCL-2
Anderson MA, et al. Semin Hematol. 2014;51(3):219-27.
BH3 proteins(e.g., BIM, BAD, PUMA, NOXA) Venetoclax
Anti-apoptotic proteins(BCL-2, MCL1, BCLXL, etc.)
BCL2 overexpression:
binds to BAX and BAK
preventing apoptosis
BAX
BAK
BAX
BAKVenetoclax
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CLL14 Trial: Study Schema
Venetoclax + obinutuzumabVenetoclax ramp-up day 22 of cycle 1 (continue until
cycle 12 complete)Obinutuzumab x 6 cycles
Chlorambucil + obinutuzumabChlorambucil 0.5 mg/kg days 1, 15
x 12 cyclesObinutuzumab x 6 cycles
n = 216
n = 216
Population• Treatment-naïve CLL• Patients with significant
comorbidities (a total score of > 6 on the Cumulative Illness Rating Scale) or CrCl < 70 mL/min
Randomized 1:1
Study design
• Phase III, multicenter, open-label, RCT
Primary outcome
• PFS
Fischer K, et al. N Engl J Med. 2019;380(23):2225‐36. CrCl, creatinine clearance.
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CLL14 Trial: ResultsVenetoclax + Obinutuzumab vs. Chlorambucil + Obinutuzumab
Venetoclax ± Obi improved PFS vs. chlorambucil + Obi
Conclusions
Low rate of tumor lysis; no different between the 2 groups
Provides a targeted therapy option with a fixed duration (1 year then stop)P
FS (
%)
100
80
60
40
20
00 6 12 18 24 30 36
Months
64%
88%
Venetoclax + obinutuzumabChlorambucil + obinutuzumab
Fischer K, et al. N Engl J Med. 2019;380(23):2225‐36.
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Mutated IGHV: FCR Unmutated IGHV: FCR
or BR
Chlorambucil + Obi
Bendamustine + rituximab
Ibrutinib + rituximab*
Ibrutinib
New standardOld standardPopulation
Young/fit
Older/fit
Elderly/comorbiditiesAcalabrutinib +/- Obi
IbrutinibVenetoclax + Obi
*Mutated IGHV without del(17p)/TP53 mutation can consider FCR; can consider no rituximab with ibrutinib based on ALLIANCE trial (but now FDA approved).
First-Line Treatment in CLL:
Changing Landscape
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Mantle Cell Lymphoma (MCL)
• Hallmark: • t(11;14)
• Prognostic factors:• p53 mutations, ATM, CCND2 or 3, SOX11, IGHV
• Cytologic variants• Classic, small-cell, blastoid, pleomorphic
Armitage JO, Weisenburger DD. J Clin Oncol. 1998;16(8):2780-95.; Eskelund CW, et al. Blood. 2017;130(17):1903-10.; Herrmann A, et al. J Clin Oncol. 2009;27(4):511-8.; Hoster E, et al. Blood. 2008;111(2):558-65.; Jain P, Wang M. Am J Hematol. 2019;94(6):710-25.; National Cancer Institute. seer.cancer.gov/statfacts/html/nhl.htm. Accessed June 2, 2020.; National Comprehensive Cancer Center. NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas v1.2020.; Tiemann M, et al. Br J Haematol. 2005;131(1):29-38.
• Indolent with aggressive features
• Incidence: 6% of NHL
• Deaths:• Low risk: 5-year OS 60%
• Intermediate risk: median 51-month OS
• High risk: median 29-month OS
• Median age: 63 years
OS, overall survival.
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MCL Treatment 2020
NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas v1.2020.
First-line therapy
Transplant eligible Non-transplant eligible
Intensive therapyR-CHOP/HiDAC-based
therapy (i.e., Nordic, Hyper-CVAD)
Less intensive therapyBR, R-CHOP, VR-CAP,
R-lenalidomide
Autologous stem cell transplant
Maintenance rituximab
“Watch and wait”/observation
Relapsed/refractory therapy
Second line:• R-chemotherapy• Bortezomib ± R• Lenalidomide ± R• BTK inhibitors:
• Ibrutinib ± R• Acalabrutinib• Zanubrutinib
• Venetoclax ± ibrutinib
Third line:• Treatment based on prior
therapiesFactors to consider: response and duration of response to previous therapy, patient age, and comorbidities.
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Ibrutinib Pooled Analysis: Relapsed/Refractory (R/R) MCL
Rule S, et al. Haematologica. 2019;104(5):e211-4.
Phase 2 PCYC-1104
Phase 2 SPARK
Phase 3 RAY
Ibrutinib 560 mg PO daily became an option for R/R MCL
Led to FDA approval in
MCL
PFS100
80
60
40
20
00 4 12 20 28 36 44 52 60 68 76
Months
PFS
(%
)
Median: 25.4 months
Median: 10.3 months1 prior line> 1 prior line
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ACE-LY-004 Trial: Study Schema
Study design
• Phase II, multicenter, open-labeI
Primary endpoint
• ORR
Wang M, et al. Lancet. 2018;39(10121)1:659-67.
Acalabrutinib100 mg PO BID in 28-day cycles
Until progression or unacceptable toxicity
*class 3/4 cardiac disease per NYHA Functional Classification, CHF or MI within 6 months of screening, QTc > 480 ms, uncontrolled/symptomatic arrhythmias.
n = 124
Population• R/R MCL• 1-5 prior lines of therapy• No notable CVD*• No concurrent use of
warfarin/equivalent vitamin K antagonists
• No prior BTK or BCL-2 inhibitors
CHF, congestive heart failure; CVD, cardiovascular disease; MI, myocardial infarction; NYHA, New York Heart Association.
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ACE-LY-004 Trial:Acalabrutinib for R/R MCL Results
Wang M, et al. Lancet. 2018;391(10121):659-67.; Wang M, et al. Leukemia. 2019;33(11):2762‐6.
81% ORR
0
20
40
60 43% CR
38% PR
80
100
Median duration of response: 26 monthsEstimated 24-month OS: 72.4% (median OS not reached)
1.0
0.8
0.6
0.4
0.2
0
PFS
%
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Led to FDA approval in MCL
Median PFS: 20 months
Months
Res
po
nse
(%
)
Ibrutinib or acalabrutinib now options for R/R MCL
CR, complete response; PR, partial response.
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BCG-3111-206 Trial: Study Schema
Song Y, et al. Clin Cancer Res. 2020;clincanres.3703.2019.
Zanubrutinib160 mg PO BID in 28-day cycles
Until progression or unacceptable toxicity
*Clinically significant CVD; patients with history of cardiac arrythmia that was adequately controlled at time of enrollment were eligible
n = 86
Population• R/R MCL• 1-4 prior lines of
treatment• No notable CVD*• No prior BTK inhibitors
Study design
• Phase II, multicenter, open-labeI
Primary endpoint
• ORR
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BCG-3111-206 Trial:Zanubrutinib for R/R MCL Results
83.7% ORR
0
20
40
60
68.6% CR
15.1% PR
80
100
Re
spo
nse
(%
)
Led to FDA approval in MCL
Ibrutinib, acalabrutinib, or zanubrutinibnow options for R/R MCL
0 6 12 18 24
Months
PFS
(%
)
Median PFS: 22.1 months
100
80
60
40
20
0
Song Y, et al. Clin Cancer Res. 2020;clincanres.3703.2019.
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M12-175 Trial: Study Schema
VenetoclaxDose escalation study (3+3
design) to target daily dose of 200-1200 mg orally daily
Until progression or unacceptable toxicity
n = 28
Population• R/R MCL• 1-7 prior lines of
treatment (median 3)• No prior BTK inhibitors or
lenalidomide
Study design
• Phase I multicenter, open-labeI
Primary endpoint
• Safety
Davids MS, et al. J Clin Oncol. 2017;35(8):826-33.
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Venetoclax: R/R MCL
75% ORR
0
20
40
60 21% CR
54% PR
80 100
75
50
25
6 12 18 24 30 36 42 48P
FS (
%)
Time (months)
Estimated median PFS: 14 months
Davids MS, et al. J Clin Oncol. 2017;35(8):826-33.
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Future Directions: AIM TrialIbrutinib + Venetoclax for R/R MCL
Ibrutinib560 mg PO daily
for 4 weeksUntil
progression or
unacceptable toxicity
n = 24
Population• R/R MCL or treatment-
naïve not candidate for chemoimmunotherapy
• No notable CVD*• No prior BTK inhibitors
*Uncontrolled or symptomatic arrhythmias, CHF, or MI within 6 months of screening, or any class 3/4 cardiac disease per NYHA Functional Classification.
Study design
• Phase 2, multicenter, open-labeI
Primary endpoint
• CR at week 16
Ibrutinib560 mg PO daily
Venetoclax400-800 mg PO
daily
50 mg
100 mg
200 mg
400 mg
800 mg
Dose increased weekly to 400 mg; increased to 800 mg if no CR by week 16.
Tam CS, et al. N Engl J Med. 2018;378(13):1211-23.
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AIM Trial:Ibrutinib + Venetoclax for R/R MCL Results
Handunnetti SM, et al. Blood. 2019;134(suppl 1):756.; Tam CS, et al. N Engl J Med. 2018;378(13):1211-23.
100
90
80
70
60
50
40
30
20
10
00 6 12 18 24 30 36
Months
100
90
80
70
60
50
40
30
20
10
00 6 12 18 24 30 36
Months
Median PFS: 29 months Median OS: 32 months
PFS
%
OS
%
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Waldenström Macroglobulinemia (WM)
American Cancer Society. cancer.org/cancer/waldenstrom-macroglobulinemia/about/key-statistics.html. Published July 19, 2018. Accessed June 2, 2020.; Castillo JJ, Treon SP. Leukemia. 2019;33(11):2555-62.; National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma v1.2020.
• Indolent lymphoma
• Incidence:• < 1% of NHL; 100-1500 new cases/year
• Deaths:• 60% OS at 5 years
• Median age: 63 years
• Hallmark: • MYD88L265P (> 90%), high IgM
• Prognostic factors:• MYD88WT and CXCR4 mutations
• Presentation• Hyperviscosity, neuropathy, adenopathy or
organomegaly, amyloidosis, cryoglobulinemia, cold agglutin disease, and cytopenias
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WM Treatment 2020
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: WaldenströmMacroglobulinemia/Lymphoplasmacytic Lymphoma v1.2020.; Vaxman I, Gertz M. Leuk Lymphoma. 2020;1-13.
• Bulky disease• Profound cytopenias• Constitutional symptoms• Hyperviscosity symptoms
Hyperviscosity symptoms
Yes No
Plasmapheresis
BRIbrutinib ± ritixumab*
DRC (if no need for fast response)BDR (no baseline neuropathy)
PN, peripheral neuropathy.
^Patients with MYD88WT and/or CXCR4 mutations have lower and slower responses.
First line:Significantly symptomatic
Relapsed/refractory> 3 years from previous therapy
Yes No
Repeat originaltherapy
BTK inhibitor*^• Ibrutinib• AcalabrutinibBDR if baseline PN < grade 2*BR*DRC*
*If not previously received
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Revisited: Pathophysiology and Mechanism of Action in WM
Adapted from Baron M, et al. Curr Oncol Rep. 2019;21(3):27.; Marini BL, et al. J Oncol
Pharm Pract. 2017;23(7):502-17.; Munshi M, et al. Blood Cancer J. 2020;10(1):12.
BCR
CD
79
a
CD
79
b
BTKPLCγ2
PKC
MAPK/MEK/ERKpathway
NF-kβpathway
LYN
SYK
TLRs
IL-6R
Microenvironment releases IL-6CXCR12/CXCR4
MYD88
HCK
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iNNOVATE Trial: Study Schema
Dimopoulos MA, et al. N Engl J Med. 2018;378(25):2399-410.
Study design
• Phase III, multicenter, placebo-controlled, RCT
Primary outcome
• PFS
Ibrutinib + rituximabIbrutinib 420 mg PO daily
Rituximab 375 mg/m2 IV on day 1 of weeks 1-4 and 17-20
Rituximab + placeboRituximab 375 mg/m2 IV on day 1 of
weeks 1-4 and 17-20
n = 75
n = 75
Population• Patients with WM• Serum IgM > 0.5 g/dL• Not refractory to
rituximab or no rituximab in 12 months before study
Randomized 1:1
Cross-over allowed
Ibrutinib/placebo until progression
IgM, immunoglobulin M.
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iNNOVATE Trial: ResultsIbrutinib + Rituximab vs. Rituximab for First-Line WM
0102030405060708090
100
Pat
ien
ts R
esp
on
din
g (%
)
20%
47%
Ibrutinib-R(n = 75)
92% ORR
Rituximab(n = 75)
15%
27%
47% ORR
4%
23%
3%
1%
IgM Levels
Months
Me
an Ig
M (
g/lit
er)
12106420 80
10
20
30
40
Rituximab
Ibrutinib + Rituximab
Minor responsePartial response
Very good partial responseComplete response
Dimopoulos MA, et al. N Engl J Med. 2018;378(25):2399-410.
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iNNOVATE Trial: ResultsIbrutinib + Rituximab vs. Rituximab for First-Line WM
PFS
Ibrutinib-RPlacebo-Rituximab
0
Months
36302418126
PFS
(%
)
100
80
60
40
20
0
Led to FDA approval in WM
Ibrutinib + rituximab improves PFS over rituximab alone• Median PFS: NR vs. 20.3 months; HR
0.2 (95% CI, 0.11-0.38); p < 0.001
Conclusions
Patients with mutations in CXCR4 or MYD88WT have lower and slower responses
• 30-month PFS: 82% vs. 28%• 30-month OS: 94% vs. 92%
HR, hazard ratio; NR, not reached. Dimopoulos MA, et al. N Engl J Med. 2018;378(25):2399-410.
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ACE-WM-001 Trial: Study Schema
Study design
• Phase II, multicenter, open-labeI
Primary endpoint
• ORR
Owen RG, et al. Lancet Haematol. 2020;7(2):e112-21.
Acalabrutinib100 mg PO BID in 28-day cycles
Until progression or unacceptable toxicity
n = 14 (TN)n = 92 (R/R)
Population• R/R WM*• No notable CVD**• No prior BTK inhibitors
*Or treatment-naïve patients who declined or had comorbidities that would preclude treatment with chemoimmunotherapy, such as symptomatic hyperviscosity with ≥ IgM 5000 mg/dL, or disease-related neuropathy
**Uncontrolled or symptomatic arrhythmias, CHF, or MI within 6 months of screening; any class 3 or 4 cardiac disease as defined by the NYHA Functional Classification; or QTc > 480 ms; patients with previous or concurrent atrial fibrillation could participate.
TN=Treat Naive
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ACE-WM-001 Trial: ResultsAcalabrutinib for WM
0102030405060708090
100
Pat
ien
ts R
esp
on
din
g (%
)
14%
79%
Treatment naïve(n = 14)
93% ORR
R/R(n = 92)
13%
72%
93% ORR
Best response by line of therapy
9%
Minor responsePartial responseVery good partial response
0102030405060708090
100
Pat
ien
ts R
esp
on
din
g (%
)
14%
69%
MYD88L265P
(n = 36)
94% ORR
MYD88WT
(n = 14)
14%
64%
79% ORR
Best response by MYD88 status
11%
Owen RG, et al. Lancet Haematol. 2020;7(2):e112-21.
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Tam C, et al. J Clin Oncol. 2020;(38 suppl):abstr 8007.
ASPEN Trial: Study Schema
Zanubrutinib160 mg PO BID
n = 99
n = 26
Population• R/R WM or treatment-
naïve not candidate for chemoimmunotherapy
• ECOG 0-2• MYD88MUT
Randomized 1:1
Ibrutinib420 mg PO daily
Zanubrutinib160 mg PO BID
n = 102
Cohort 2• MYD88WT
Untilprogression
Study design
• Phase III, multicenter, open-label, RCT
Primary outcome• Complete response or very good partial response (superiority)
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Future Directions: ASPEN TrialZanubrutinib vs. Ibrutinib for WM
Minor responsePartial responseVery good partial response
0
10
20
30
40
50
60
70
80
90
100
Pat
ien
ts R
esp
on
din
g (%
)
16.7%
49%
Zanubrutinib(n = 102)
94.1% ORR
Ibrutinib(n = 99)
15.2%
58.6%
92.9% ORR
19.2%28.4%
First randomized trial comparing 2 BTK inhibitors
No significant differences in ORR, PFS, or OS
Look for Future FDA Guidance
Conclusions
Improved toxicity profile with zanubrutinib (not shown)
Tam C, et al. J Clin Oncol. 2020;(38 suppl):abstr 8007.
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Follicular Lymphoma (FL)
Al-Hamadani M, et al. Am J Hematol. 2015;90(9):790-5.; Federico M, et al. .J Clin Oncol. 2009;27(27):4555-62.; Junlen HR, et al. Leukemia. 2015;29(3):668-76.; National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: B-cell Lymphomas v1.2020.; Solal‐Celigny P, et al. Blood. 2004;104:1258-65.; Swerdlow SH, et al. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. 2008. IARC Press.
• Indolent lymphoma
• Incidence:• 22% of NHL
• Deaths:• 60% OS at 10 years
• Median age: 60 years
• Hallmark: • BCL2 translocation; t(14;18)
• Prognostic factors:• FLIPI Score, Grade 3 histology
• Presentation• Heterogenous (can be asymptomatic)
• B-symptoms, diffuse lymphadenopathy, bone marrow involvement, splenomegaly, other extra nodal sites
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Current Treatment Landscape in FL
Diagnosis
Asymptomatic /No indication
“Watch and wait”Anti-CD20 mAbISRT
Mild symptoms Low tumor burden
High tumor burden
Anti-CD20 mAbISRT
Anti-CD20 mAb +• Bendamustine• CHOP• CVP• Lenalidomide+/- anti-CD20 mAb maintenanceRadioimmunotherapy
Factors to consider: patient preference and tumor burden
Factors to consider: patient age and comorbidities
Factors to consider: patient age and comorbidities
Relapsed/Refractory *Rule out histologic transformation to DLBCL
Factors to consider: response and duration of response to previous therapy, patient age, and comorbidities
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. B-cell Lymphomas v1.2020.
Anti-CD20 mAb +• Bendamustine• CHOP• CVP
+/- anti-CD20 mAb maintenanceRadioimmunotherapyLenalidomide +/- anti-CD20 mAbPI3K inhibitors (2 or more prior therapies)• Idelalisib, copanlisib, duvelisib
ISRT, involved-site radiation therapy.
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PI3K Inhibitor Mechanism of Action
PI3K
AKT
mTOR
NF-kβpathway
PI3K Inhibitors
p110Isoform
Function1-4 Idelalisib
(IC50, nM)5
Duvelisib
(IC50, nM)6
Copanlisib
(IC50, nM)7
α Glucose homeostasis 820 1602 0.5
β Platelet aggregation 565 85 3.7
γT-cell and granulocyte
function89 27.4 6.4
δB and T lymphocyte
function2.5 2.5 0.7
1. Sopasakis VR, et al. Cell Metab. 2010;11(3):220-30.; 2. Jackson SP, et al. Nat Med. 2005;11(5):507-14.; 3. Sasaki T, et al. Science. 2000;287(5455):1040-6.; 4. Okkenhaug K, et al. Science. 2002;297(5583):1031-4.; 5. Lannutti BJ, et al. Blood. 2011;117(2):591-4.; 6. Göckeritz E, et al. Int J Cancer. 2015;137(1):2234-42.; 7. Marini BL, et al. J Oncol Pharm Pract. 2017;23(7):502-7.
BCR
CD
79
a
CD
79
bLYN
SYK
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PI3K Inhibitor Pivotal Trial Design
Double refractory NHL (failed to respond or relapsed within 6
months following rituximab and an alkylator)
Idelalisib 150 mg PO BID (N = 72 FL) Primary endpoint: ORR
Single-arm, open-label, phase 2 study
Refractory to both rituximab and chemotherapy or RIT
Previously received an alkylating agent or purine analogue
Continuous until disease progression or unacceptable toxicity
Duvelisib 25 mg PO BID (N = 83 FL) Primary endpoint: ORR
Single-arm, open-label, phase 2 study
Relapsed or refractory after 2 or more lines of therapy
Copanlisib 60 mg IV over 60 minutes on days 1, 8, and 15 of 28-day cycle (N = 104 FL)
Primary endpoint: ORR
Single-arm, open-label, phase 2 study
Dreyling M, et al. J Clin Oncol. 2017;35(35):3898-905.; Dreyling M, et al. Am J Hematol. 2020;1-10.; Flinn IW, et al. J Clin Oncol. 2019;37(11):912-22.; Gopal AK, et al. N Engl J Med. 2014;370(11):1008-18.; Salles G, et al. Haematologica. 2017;102(4):e156-9.
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Efficacy Outcomes: PI3K Inhibitors R/R FL
0
20
40
60
14% CR
42% PR
17% CR
44% PR
1.2% CR
41% PR
Idelalisib DuvelisibCopanlisib
Re
spo
nse
Rat
es
56% ORR61% ORR
42.2% ORR
Dreyling M, et al. J Clin Oncol. 2017;35(35):3898-905.; Dreyling M, et al. Am J Hematol. 2020;1-10.; Flinn IW, et al. J Clin Oncol. 2019;37(11):912-22.; Gopal AK, et al. N Engl J Med. 2014;370(11):1008-18.; Salles G, et al. Haematologica. 2017;102(4):e156-9.
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Efficacy Outcomes: PI3K Inhibitors R/R FL
Idelalisib Duvelisib Copanlisib
10.8 months (range, 0-26.9)
2.6 months (range, 1.6-11)
Median time to response
Median duration of response
1.7 months (range, 1.3-9.7)
1.87 months (range, 1.4-11.7)
14.1 months (range, 0-42.5)
10 months (range, 6.3-10.5)
1686420 10 12 14Months
Dreyling M, et al. J Clin Oncol. 2017;35(35):3898-905.; Dreyling M, et al. Am J Hematol. 2020;1-10.; Flinn IW, et al. J Clin Oncol. 2019;37(11):912-22.; Gopal AK, et al. N Engl J Med. 2014;370(11):1008-18.; Salles G, et al. Haematologica. 2017;102(4):e156-9.
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Adverse Effect Management and Patient Monitoring Plans
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0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
Diarrhea(All grades)
Diarrhea(Grade ≥ 3)
Atrial fibrillation(All grades)
Hypertension(Grade ≥ 3)
Bleeding(Grade ≥ 3)
Arthralgia/Myalgia(All grades)
Infection(Grade ≥ 3)
Headache (Allgrades)
Ibrutinib Acalabrutinib Zanubrutinib
Adverse EffectBrukinsa (zanubrutinib) [prescribing information]. 2019.; Calquence (acalabrutinib) [prescribing information]. 2019.; Imbruvica (ibrutinib) [prescribing information]. 2020.;Rule S, et al. Haematologica. 2019;104(5):e211-e4.; Tam CS, et al. Hematol Oncol; 2019;37:245-7.; Wang M, et al. Lancet. 2018;391(10121):659-67.
*Data are comparisons from separate trials in patients with MCL
Inci
de
nce
BTK Inhibitors: Select Adverse Events (AEs) Across Pivotal Trials*
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Off-Target Effects
Berglӧf A, et al. Scand J Immunol. 2015;82(3):208.; Bose P, et al. Expert Opin Drug Metab Toxicol. 2016;12(11):1381-92.; Bye AP, et al. Blood Adv. 2017;1(26):2610-23.; Ghez D, et al. Blood. 2018;131(17):1955-9.; Rogers K. Blood. 2018;131(17):1882-4.; Rogers KA, et al. Leukemia. 2019;33(10):2527-30.; Ruchlemer R, et al. Mycoses. 2019;62(12):1140-7.; Shatzel JJ, et al. J Thromb Haemost. 2017;15(5):835-47.; Woyach JA. Blood. 2018;132(18):1869-70.
EGFR
SRC
TEC
ITK
JAK3
BMX
ERBB4
Rash, cardiac toxicity, diarrhea
Platelet effects
Cardiac toxicity
Antibody-dependent cellular cytotoxicity, migration of PMN
Immune effects
Platelet effects, T-cell priming
Cardiac toxicity
PMN, polymorphonuclear leukocyte.
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ASPEN Trial: Adverse EffectsOnly Randomized Trial Comparing BTK inhibitors
0%
10%
20%
30%
40%
50%
60%
70%
80%
Atrial Fibrillation(All Grades)
MinorBleeding
MajorBleeding
Diarrhea(All Grades)
Infection Pneumonia Hypertension Neutropenia Thrombocytopenia
Zanubrutinib Ibrutinib
Inci
de
nce
(%
)
Tam C, et al. J Clin Oncol. 2020;38(suppl):abstr 8007.
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BTK Inhibitors: Hypertension and Atrial Fibrillation
Hypertension
• Risks include cardiac risk factors, acute infections, prior history of AF
• Educate patient on risk for AF and what to do in the event of abnormal heart rhythm
• AF is not an absolute contraindication to continuing BTK inhibitors
• Be cautious of drug interactions when managing AF (i.e., diltiazem and CYP3A4)
• Anticoagulation can be used but should be used with caution
• Avoid vitamin K antagonists
• If AF persists, consider the risks and benefits of treatment and dose modification
Atrial fibrillation (AF)
• Risks include cardiac risk factors, prior history of hypertension
• Monitor blood pressure throughout treatment
• Hypertension is not an absolute indication to discontinue BTK inhibitors
• Adequate management of hypertension from BTK inhibitors mitigates cardiovascular events
• If hypertension is persistent or life threatening, consider risks and benefits of treatment and dose modification
Brukinsa (zanubrutinib) [prescribing information]. 2019.; Calquence (acalabrutinib) [prescribing information]. 2019.; Dickerson T, et al. Blood. 2019;134 (22):1919-28.; Imbruvica (ibrutinib) [prescribing information]. 2020. CYP, cytochrome P450.
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BTK Inhibitors: Mechanism of Bleeding
Bye AP, et al. Blood Adv. 2017;1(26):2610-23.
SFK
TEC/BTK
Secondary mediators
αIIbβ3 activation and
granule secretion
Ibrutinib Acalabrutinib
Aggregation, adhesion, andstable thrombus formation
CLEC-2
GPIb
• BTK, SFK (src family kinases), and TEC are involved in several platelet activation and adhesion functions:
• GPVI, CLEC-2, GPIb, integrin αIIbβ3
• TEC compensates when BTK is inhibited/dysfunctional
• BTK inhibition alone leads to mildly diminished platelet activation
• Blocking both BTK and TEC leads to significant platelet inhibition, platelet aggregation, and thrombus stability
GPVI
vWFCollagen
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Reversible impact on platelet aggregation within 1 week of discontinuation
Dose reduction may mitigate platelet aggregation and improve bruising
Recommend holding BTK inhibitor prior to and after invasive procedures for 3 (minor) to 7 days (major)
Blood thinner or antiplatelet agents (aspirin, clopidogrel, prasugrel, ticagrelor) increase bleeding risk
Anticoagulants increase bleeding risk by impacting multiple hemostatic pathways
Anticoagulants are not contraindications
Avoid concurrent vitamin K antagonists
Clinical Pearls and Management
Major bleed (grade ≥ 3) N=13
Total 18%
Antiplatelet + anticoagulant 54%
Antiplatelet alone 30%
Anticoagulant alone 8%
Interacting medication 8%
None of the above 0%
Real-world risk*
*Data represented are for ibrutinib.
Imbruvica (ibrutinib) [prescribing information]. 2020.; Kunk PR, et al. Blood. 2016;128(22):3229.
BTK Inhibitors:Bleeding and Bruising Management
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Brukinsa (zanubrutinib) [prescribing information]. 2019.; Calquence (acalabrutinib) [prescribing information]. 2019.; Imbruvica (ibrutinib) [prescribing information]. 2019.; Rule S, et al. Haematologica. 2019;104:e211-4.; Tam CS, et al. Hematolog Oncol. 2019:37:245-7.; Wang M, et al. Lancet. 2018;391:659-67.
Muscle cramps
Oral magnesium supplements
Arthralgias/myalgias
Acetaminophen, prednisone, tonic water
Reduce dose of BTK inhibitor or therapy discontinuation
Leg lymphedema
Therapy discontinuation
Fatigue
Reduce dose of BTK inhibitor or therapy discontinuation
Headaches
Acetaminophen, caffeine, hydration
Rash
Topical emollients or corticosteroids can alleviate symptoms
Diarrhea
If no evidence of infection, antidiarrheals as needed
Infection
Monitor and treat as needed
For all grade 3/4 non-hematologic AEs: hold BTK inhibitor until resolution to baseline or grade 1
Resume at original dose for first recurrence, refer to package insert for specific dose reductions for second recurrence
BTK Inhibitors: Miscellaneous AE Management
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Venetoclax: AEs and Management
Wk 1
Wk 2
Wk 3
Wk 4
Wk 5Pertinent AEs: Diarrhea (all grade): 43% Nausea (all grade): 42% Neutropenia (grade ≥ 3): 45% Tumor lysis syndrome (TLS)
20 mg 50 mg 100 mg 200 mg 400 mg
Assess risk: inpatient for first dose of first 2 ramp-up doses if high risk (i.e., bulky adenopathy per PI)
Monitor: TLS labs per PIPrevention: hydration, antihyperuricemic agents
Treatment: per institutional guideline
Ven
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.
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Venetoclax: TLS Management
TLS risk Disease characteristics
Low risk No bulky adenopathyALC < 25 x 109/L
Intermediate risk Bulky adenopathy: ≥ 5 cm and < 10 cmorALC: ≥ 25 x 109/L
High risk Bulky adenopathy: ≥ 10 cmorBulky adenopathy: ≥ 5 cm and ALC ≥ 25 x 109/L
Additional factors to consider: baseline uric acid, LDH, potassium, phosphorous, SCr, calcium
Assess Risk
TLS risk Management plan
Low risk Outpatient: • Oral hydration (1.5-2 L per day) and allopurinol• Lab monitoring: pre-dose and 6 to 8 hours & 24
hours after first dose of 20 mg and 50 mg and then pre-dose at subsequent ramp-up doses
Intermediate risk Outpatient: • Oral hydration (1.5-2 L per day), IV (PRN), and
allopurinol• Lab monitoring: pre-dose, 6 to 8 hours & 24 hours
after first dose of 20 mg and 50 mg and then pre-dose at subsequent ramp-up doses
• If creatinine clearance < 80 mL/min, consider inpatient admission for first 2 dose escalations
High risk Inpatient for first dose of first 2 ramp-up doses:• Oral hydration and IV as tolerated• Allopurinol (consider rasburicase based on
baseline uric acid)
Develop a Management Plan2
Venclexta (venetoclax) [prescribing information]. 2019.
1
ALC, absolute lymphocyte count; LDH, lactate dehydrogenase; PRN, as needed; SCr, serum creatinine.
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0
10
20
30
40
50
60 Idelalisib Duvelisib Copanlisib
*Data are comparisons from separate trials in patients with FL
Dreyling M, et al. J Clin Oncol. 2017;35(35):3898-905.; Flinn IW, et al. J Clin Oncol. 2019;37(11):912-22.; Gopal AK, et al. New Engl J Med. 2014;370(11):1008-18.
Inci
den
ce (
%)
PI3K Inhibitors:Select Grade ≥ 3 AEs Across Pivotal Trials*
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Immune-related toxicity mechanism: decrease in T-regulatory cells (due to PIK3δ inhibition)
HepatotoxicityDiarrhea and colitisIntestinal perforationInfectionPneumonitis
Diarrhea and colitisInfectionPneumonitisCutaneous reactions
None
Idelalisib Duvelisib Copanlisib
PI3K Inhibitors:Black Box Warnings
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• Febrile neutropenia: 3%• 21% experienced a fatal
or serious infection• Pneumocystis jirovecii
pneumonia (PJP) orcytomegalovirus (CMV): < 1% of patients
• Pneumonitis: 2%
• Febrile neutropenia: 9.3%• 31% experienced a fatal or
serious infection• PJP or CMV: 1% of patients,
1 case of bronchopulmonary aspergillosis
• Pneumonitis: 5%
• Neutropenia (including febrile neutropenia): 32%
• 19% experienced a fatal or serious infection
• PJP: < 1% of patients, 1 case of bronchopulmonary aspergillosis
• Pneumonitis: 5%
Idelalisib Duvelisib Copanlisib
Aliqopa (copanlisib) [prescribing information]. 2019.; Copiktra (duvelisib) [prescribing information]. 2019.; Dreyling M, et al. J Clin Oncol. 2017;35(35):3898-905.; Flinn IW, et al. J Clin Oncol. 2019;37(11):912-22.; Gopal AK, et al. New Engl J Med. 2014;370(11):1008-18.; Zydelig (idelalisib) [prescribing information]. 2018.
PI3K Inhibitors:Infectious and Respiratory Complications
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Management
PneumonitisInfection
Provide PJP prophylaxis during treatment
Clinical and laboratory monitoring for CMV infection is recommended in patients with history of CMV infection or positive CMV serology at the start of treatment
Suspected infection, CMV viremia/infection, or PJP infection: interrupt therapy until infection has resolved. Permanent discontinuation if PJP infection is confirmed, consider permanent discontinuation for all infections.
Pneumonitis: Time to onset ranged from < 1 to 15 months
Monitor for pulmonary symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on a radiologic exam, or a decline by more than 5% in oxygen saturation
Discontinue therapy with any severity symptomatic pneumonitis and initiate appropriate treatment with corticosteroids
Aliqopa (copanlisib) [prescribing information]. 2019.; Copiktra (duvelisib) [prescribing information]. 2019.; Dreyling M, et al. J Clin Oncol. 2017;35(35):3898-905.; Flinn IW, et al. J Clin Oncol. 2019;37(11):912-22.; Gopal AK, et al. New Engl J Med. 2014;370(11):1008-18.; Zydelig (idelalisib) [prescribing information]. 2018.
PI3K Inhibitors:Infectious and Respiratory Complications
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7 months (range, 0.5-29.8 months)
1.5 months (range, 0-15.2 months)
Mild to moderate diarrhea
2724211815129630 30
Severe diarrhea
*Mild: increase of < 4 stools per day over baseline; Moderate: increase of 4-6 stools per day over baseline
*Severe: increase of ≥ 7 stools per day over baseline
Patient and provider education
Mild diarrhea: initiate supportive therapy with antidiarrheal agents, monitor weekly until resolved
Mild diarrhea unresponsive to intervention and moderate diarrhea: withhold therapy, initiate supportive therapy with enteric-acting steroids (e.g., budesonide); once resolved, resume therapy at reduced dose
Severe diarrhea or abdominal pain, stool with mucus or blood, change in bowel habits, peritoneal signs: withhold therapy, initiate supportive therapy with enteric-acting steroids or systemic steroids; once resolved, consider resuming therapy at reduced dose
For any recurrent grade 3+ diarrhea or colitis, permanently discontinue therapy
Time to onset (months)
Management
Aliqopa (copanlisib) [prescribing information]. 2019.; Copiktra (duvelisib) [prescribing information]. 2019.; Coutré SE, et al. Leuk Lymphoma. 2015;56(10):2779-86.; Zydelig (idelalisib) [prescribing information]. 2018.
PI3K Inhibitors:Diarrhea and Colitis Management
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• Peak: 5-8 hours post-infusion• Permanent BG elevation in approximately 18% of patients, 10% of patients will develop A1C > 6.5%• Optimize BG control in all patients before starting copanlisib
Pre-dose: fasting BG > 160 mg/dL OR
random/non-fasting BG > 200 mg/dL
• Withhold until FBG ≤ 160 mg/dL or a random/non-fasting BG ≤ 200 mg/dL
• Close observation with PCP or endocrinology
Pre-dose or post-dose BG ≥ 500 mg/dL or more
• Withhold until FBG ≤ 160 mg/dL or a random/non-fasting BG ≤ 200 mg/dL or less, then reduce dose
• Close observation with PCP or endocrinology• If persists at lowest dose, permanently discontinue
Management
Transient hyperglycemia
Aliqopa (copanlisib) [prescribing information]. 2019.; Cheson BD, et al. Clin Lymphoma Myeloma Leuk. 2019;19(3):135-41.
A1C, hemoglobin A1C; BG, blood glucose; FBG, fasting blood glucose; PCP, primary care physician.
PI3K Inhibitors:Hyperglycemia Management
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• Monitor BP pre- and post-dose
• BP decline starting 2 hours post-infusion but can remain elevated for 6-8 hours
• Optimal BP control should be achieved before starting each infusion
Pre-dose BP ≥ 150/90 mmHg
• Withhold until BP is < 150/90 mmHg based on 2 consecutive BP measurements at least 15 minutes apart
Post-dose BP≥ 150/90 mmHg
(non-life-threatening)
• If antihypertensive is not required, continue at previous dose
• If antihypertensive is required,* consider dose reduction
• Discontinue therapy if BP remains high (> 150/90 mmHg) despite antihypertensive
Post-dose elevated BP (life threatening)
• Permanently discontinue
ManagementTransient hypertension
*Decision to treat should be individualized on the basis of several factors, including baseline BP, severity of BP elevation, and pre-existing cardiovascular risk (diabetes, chronic kidney disease) or coronary vascular disease.
If treating during the infusion, short-acting antihypertensives should be used
Aliqopa (copanlisib) [prescribing information]. 2019.; Cheson BD, et al. Clin Lymphoma Myeloma Leuk. 2019;19(3):135-41. BP, blood pressure.
PI3K Inhibitors:Hypertension Management
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SPDlymph node size
0 1 2 3 4 5 6 7 8 9 10 11
550
450
350
250
150
50
-50
Absolute lymphocyte count
Month Month
-100
-75
-50
-25
0
25
Mea
n P
erce
nt
Ch
ange
fro
m B
asel
ine
0 1 2 3 4 5 6 7 8 9 10 11
Blood Lymphocytes Lymph Nodes
Bro
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JR
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5;1
26
(23
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95
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. New
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Transient Lymphocytosiswith PI3K Inhibitors/BTK Inhibitors?
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Summary of Novel Agents in Lymphoma
FDA approval Class Dose SuppliedRouteAgent
IbrutinibCLL (1st+), MCL (2nd+)WM (1st+), MZL (2nd+)
BTKiMCL: 560 mg dailyCLL: 420 mg daily
Oral70-, 140-, 280-, 420-, and 560-mg tablets
AcalabrutinibMCL (2nd+)CLL (1st+)
BTKi 100 mg twice daily Oral 100-mg capsule
Zanubrutinib MCL (2nd+) BTKi160 mg twice daily or320 mg daily
Oral 80-mg capsule
IdelalisibCLL (3rd+), FL (3rd+)CLL with comorbidities (2nd+)
PI3Ki (δ) 150 mg twice daily Oral100- and 150-mgtablets
Duvelisib PI3Ki (γ/δ) 25 mg twice daily Oral15- and 25-mgcapsules
Copanlisib FL (3rd+) PI3Ki (α/δ)60 mg IV over 1-hour days 1, 8, and 15 (28-day cycle)
Intravenous 60 mg vial
Venetoclax CLL (1st+) BCL2i MCL: 400-800 mg with foodCLL: 400 mg with food
Oral10-, 50-, and 100-mg tablets
CLL (3rd+), FL (3rd+)
Aliqopa (copanlisib) [prescribing information]. 2019.; Brukinsa (zanubrutinib) [prescribing information]. 2019.; Calquence (acalabrutinib) [prescribing information]. 2019.; Copiktra (duvelisib) [prescribing information]. 2019.; Imbruvica (ibrutinib) [prescribing information]. 2020.; Zydelig (idelalisib) [prescribing information]. 2018.
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Drug and Comorbidity Interactions with Novel Agents in Lymphoma
*Avoid proton pump inhibitors; take acalabrutinib 2 hrs before H2RAs and antacids (reduces acalabrutinib AUC 40% to 50%). †Idelalisib inhibits CYP3A4 (strong) and UGT1A1. Duvelisib inhibits CYP3A4 (moderate); all agents listed inhibit P-glycoprotein except for acalabrutinib, copanlisib, and duvelisib.
IbrutinibCYP3A4 (major)CYP2D6 (minor)
Voriconazole: ↓ 140 mg daily?Posaconazole: ↓ 70 mg dailyModerate: ↓ 280 mg daily
Avoid No changesChild-Pugh A: ↓ 140 mgChild-Pugh B: ↓ 70 mgChild-Pugh C: avoid
*AcalabrutinibCYP3A4 (major)P-gp, BCRP
Strong: avoidModerate: ↓ 100 mg daily
↑ 200 mgtwice daily
No changesNo changesMonitor in severe
Zanubrutinib CYP3A4 (?)Strong: ↓ 80 mg dailyModerate: ↓ 80 mg twice daily
Avoid No changesSevere: ↓ 80 mgtwice daily
**IdelalisibCYP3A4 (major)P-gp, UGT1A4
Avoid Avoid No changesCaution(1.7x increase AUC)
^Duvelisib Strong: ↓ 15 mg daily Avoid No changes No changes
CopanlisibCYP3A4 (major)P-gp, BCRP
Strong: avoid or↓ 45 mg daily
Avoid No changesChild-Pugh B: ↓ 45 mgChild-Pugh C: avoid
VenetoclaxCYP3A4 (major)P-gp
Strong: avoid during ramp-up,↓ 75% thereafterModerate: ↓ 50%
Avoid Monitor TLS Monitor toxicity
CYP3A4 (major)
Metabolism CYP Inhibitors CYP Inducers HepaticRenalAgent
AU
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rea
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H2
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, his
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TLS
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.; B
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20
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.; I
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Considerations When Selecting Therapies
Molecular mutations
Patient preference
Cytogenetics Line of therapy
Age/fitnessDrug
interactions
AE profile (including
financial toxicity)
Dosing schedule
ComorbiditiesResponse to
previous therapy
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Patient Education
Administration
Adherence
Drug-drug interactionsContact with new medications, herbals, or supplements
Create a monitoring planHighlight key adverse effects, how to self-manage, and when to report
Drug procurement
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Thank You!