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OVERVIEW This initiative is targeted to addressing the professional practice of oncology pharmacists caring for patients with chronic lymphocytic leukemia. Attendees of this symposium will gain insight into the latest clinical and scientific advances in the treatment and management of patients with chronic lymphocytic leukemia (CLL) using BTK inhibitors (BTKis), including the latest approvals, the most current safety and efficacy data, and expert insights into addressing challenges of CLL treatment using BTKis. Using a case-based approach, discussion on anticipating and managing adverse events, therapy selection, and improving adherence will be incorporated into this cutting-edge symposium.
TARGET AUDIENCE This activity is designed to meet the educational needs of hospital and health-system pharmacists, pharmacy directors, and pharmacy residents.
AGENDA 5 min Welcome and Introductions/Pre-test 10 min The BCR Pathway: A Potential Game-Changing Target in CLL 20 min Addressing Challenges in CLL Treatment: BTK Inhibition-the
Past, Present, and Future 15 min Pharmacist Perspectives: Exploring Current Challenges in CLL
Management and Integrating BTKis into Practice 10 min Q&A/Post-test
LEARNING OBJECTIVES At the conclusion of this knowledge-based activity, participants will be able to: 1. Describe the role of the BCR (B-cell receptor) pathway in malignant B-cell survival.2. Explore the therapeutic rationale for targeting the BCR pathway in CLL and other B-cell malignancies.3. Assess the latest safety and efficacy data for BTKis (BTK inhibitors) in TN (treatment-naïve) and R/R (relapsed/refractory) CLL and
examine strategies to overcome resistance seen in these agents.4. Using a case-based approach, appraise effective strategies to integrate BTK inhibitors into the CLL treatment paradigm, recognize
and appropriately manage adverse events, and answer challenging clinical issues pharmacists may encounter in their practice
FACULTY BIO
Emily Dotson received her PharmD from St. Louis College of Pharmacy. She completed a PGY1 resi-dency at the Richard L. Roudebush VA Medical Center in Indianapolis, IN and then a PGY2 residency at The James Cancer Hospital in Columbus, OH. After completion, she stayed at The James where she serves as a Clinical Pharmacist, rotating between outpatient and inpatient services. Dr. Dotson’s area of practice is with CLL, NHL, and HL patients and she also serves as the Hematology Lead Pharmacist. She is actively involved in research projects with the lymphoma and CLL teams and is a preceptor to pharmacy students and pharmacy residents.
Emily K. Dotson, PharmD, BCOP Clinical Pharmacist Specialist–Hematology Lead Hematology Inpatient/Outpatient The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at The Ohio State University Columbus, Ohio
PLANNER AND FACULTY DISCLOSURES In accordance with the Food and Drug Administration, the speakers have disclosed that there is the potential for discussions concerning off-label uses of a commercial product/device during this educational activity. Any person who may contribute to the content of this continuing education activity must disclose relevant relationships (and any known relationships of their spouse/partner) with commercial interests whose products or services are discussed in educational presentations. A commercial interest is defined as an entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on patients. Relevant relationships include receiving from a commercial interest research grants, consultant fees, travel, other benefits, or having a self-managed equity interest in a company. Disclosure of a relationship is not intended to suggest or condone any bias in any presentation but is made to provide participants with information that might be of potential importance to their evaluation of a presentation. PLANNERS Vanessa Carranza, PharmD, has no relevant financial relationships to disclose in relation to the content of this activity. PRESENTERS Emily K. Dotson, PharmD, BCOP–has disclosed that she is a consultant for AstraZeneca. Kathy Hogan Edwards, PharmD, BCPS, BCOP–has disclosed that she is a consultant for Genzyme Corporation. Rebecca J. Nelson, PharmD, BCOP–has disclosed that she is a consultant for AbbVie, BTG, and Stemline. Jeannie Patrick, PharmD, BCOP–has no relevant financial relationships to disclose in relation to the content of this activity. PEER REVIEWER Benyam Muluneh, PharmD, BCOP, CPP–has no relevant financial relationships to disclose in relation to the content of this activity.
ACCREDITATION
Pharmacy (ACPE) This application-based activity is approved for 1.0 contact hour (.10 CEUs) of continuing pharmacy education credit (JA0007101-0000-20-018-H01-P).). Upon completion of a CE request form, statements of credit for physicians, physician assistants, and nurses will be issued within 30 business days. Pharmacy credit will be reported directly to the National Association of Boards of Pharmacy® (NABP®) CPE Monitor electronic CE tracking system.
In support of improving patient care, Creative Educational Concepts is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Presented by Creative Educational Concepts, Inc. Supported by an independent educational grant from AstraZeneca
Page 1
• This slide deck in its original and unaltered format is for educational purposes and is current as of the date of this presentation. All materials contained herein reflect the views of the faculty, and not those of Creative Educational Concepts, Inc. or the commercial supporter(s).
• Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for specific patient management.
• Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review or any applicable manufacturer’s product information, and comparison with recommendations of other authorities.
• Usage Rights: This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published or distributed in print or electronic format without prior written permission from Creative Educational Concepts, Inc. Additional terms and conditions may apply.
Disclaimer
1. Describe the role of the BCR (B-cell receptor) pathway in malignant B-cell survival.
2. Explore the therapeutic rationale for targeting the BCR pathway in CLL and other B-cell malignancies.
3. Assess the latest safety and efficacy data for BTKis (BTK inhibitors) in TN (treatment-naïve) and R/R (relapsed/refractory) CLL and examine strategies to overcome resistance seen in these agents.
4. Using a case-based approach, appraise effective strategies to integrate BTK inhibitors into the CLL treatment paradigm, recognize and appropriately manage adverse events, and answer challenging clinical issues pharmacists may encounter in their practice.
Learning Objectives
Page 2
The BCR PathwayA Potential Game-changing Target in CLL
Chronic Lymphocytic LeukemiaOverview
• Most common leukemia in the Western world
• >20,000 new cases/year in the United States with ~4,000 deaths
• Median age at diagnosis = 70
• Heterogeneous disease with wide-ranging clinical course
• Strongest tendency of leukemias for family aggregation
• Incurable with standard chemotherapy
• Small, mature lymphocytes accumulated in peripheral blood and/or bonemarrow (CLL) or primarily in lymph nodes and bone marrow (SLL)
Brown JR. Expert Rev Hematol. 2008; Nosari A. Mediterr J Hematol Infect Dis. 2012; https://seer.cancer.gov/statfacts/html/clyl.html; NCCN. CLL/SLL Guidelines. v4.2020.
Pre-test - https://www.surveymonkey.com/r/BTKIL
Page 3
• In the absence of symptoms, “watch and wait” approachlow-intermediate risk CLL, with treatment being beneficial ifsymptomatic or showing disease progression.– Severe fatigue– Night sweats– Weight loss– Fever without infection– Progressive anemia/thrombocytopenia– Progressive bulky disease
Brown JR. Expert Rev Hematol. 2008; Nosari A. Mediterr J Hematol Infect Dis. 2012; NCCN. CLL/SLL Guidelines. v4.2020.
Chronic Lymphocytic LeukemiaSigns, Symptoms and Treatment
“B symptoms”
• Flow cytometry of blood adequate for diagnosis of CLL/SLL– Monoclonal B lymphocytes ≥5 x 109/L in peripheral blood
NCCN. CLL/SLL Guidelines. v4.2020.
Chronic Lymphocytic LeukemiaDiagnostic Markers
• Immunophenotyping identifies surface markers– Distinguishes CLL/SLL from other B-cell malignancies
– Typically: CD5+, CD23+, CD43+/-, CD10-, CD19+, CD20 dim, and cyclin D -
Page 4
Genetic Abnormalities in CLL/SLLGuiding Prognosis & Treatment Modalities
Genomic aberration PrognosisDeletions in 13q14 Favorable
Deletions in 14q32.33 Favorable
IGHV mutation Favorable
Del(6q) Intermediate
Trisomy 12 Intermediate
Deletion in 17p13 Unfavorable
Deletions in 11q22 (ATM) Unfavorable
Complex karyotypes Unfavorable
Elevated beta-2 microglobulin Unfavorable
TP53 mutation (vs wild-type) Unfavorable
Yeung CC, Shadman M. Curr Oncol Rep. 2019; NCCN. CLL/SLL Guidelines. v4.2020; Gentile M, et al. Haematologica. 2009.
CLL is a Complex Disease
Burger JA, O’Brien S. Nat Rev Clin Oncol. 2018.
Page 5
The B-cell Receptor Pathway
ten Hacken E, et al. Biochimica et Biophysica Acta. 2016; Davids NS, Brown JR. Leuk Lymphoma. 2012; Burger JA, Chiorazzi N. Trends Immunol. 2013.
• Normal BCR activation appropriate cell proliferation, differentiation, and antibody production.
• ↑ BCR activation = CLL cell survival and proliferation– Mechanisms of BCR stimulation are typically heterogenous – May be caused by ligand independent (tonic) signaling
(IGVH, ZAP-70 associated with auto-antigen binding)
How can we exploit this increased activation to treat CLL?
New Model• Inhibit the BCR pathway• Immune based therapy• Target bcl-2• Spare the DNA
Treatment in 2020
Acalabrutinib
Venetoclax, ABT-737, obatoclax, oblimersen
IdelalisibDuvelalisib
IbrutinibAcalabrutinib
IdelalisibDuvelisib
Copanlisib
Venetoclax
Adapted from Hallek M. Blood. 2013; FDA Prescribing Information; Clinicaltrials.gov.
Page 6
Addressing Challenges in CLL TreatmentBTK Inhibition—the Past, Present, and Future
• ↑ BCR activation = ↑ BTK proteins in CLL • BTK inhibitors bind to these proteins and hinder the BTK’s downstream effects
Bruton’s Tyrosine Kinase (BTK) Inhibitors
ten Hacken E, et al. Biochimica et Biophysica Acta. 2016; Davids NS, Brown JR. Leuk Lymphoma. 2012; Burger JA, Chiorazzi N. Trends Immunol. 2013.
Regulation of cellular survival, proliferation
and differentiation
Nucleus
Cell death
Nucleus
Irreversible binding
= Irreversible inhibition
Irreversible BTK
InhibitorBTK
BTK
Without BTK Inhibition With BTK Inhibition
Page 7
FDA Prescribing Information.
BTK Inhibitors for the Treatment of CLL/SLL
Therapy FDA-approved CLL Indication
Ibrutinib • Approved for CLL/SLL with or without del(17p)• 420 mg tablet PO once daily
Acalabrutinib • Approved for CLL/SLL• 100 mg tablet PO Q12H
Zanubrutinib • Under investigation
Tirabrutinib • Under investigation
Vecabrutinib • Under investigation
Age and Comorbidities Evaluated
Frail w/ significant comorbidities or ≥65 or younger w/ significant comorbidities
PreferredIbrutinib (category 1)
Venetoclax + obinutuzumab
Acalabrutinib ±obinutuzumab
Other recommended regimens
Bendamustine + anti-CD20 mAb (not
recommended for frail patients), chlorambucil + obinutuzumab, HDMP +
rituximab, ibrutinib + obinutuzumab, obinutuzumab,
chlorambucil, rituximab
<65 and without significant comorbidities
PreferredIbrutinib
(category 1)
Venetoclax + obinutuzumab
Acalabrutinib ±obinutuzumab
Other recommended regimens
Bendamustine + anti-CD20 mAb, FCR (preferred for IGHV-mutated
CLL), FR, HDMP + rituximab,
ibrutinib + rituximab, PCR
NCCN. CLL/SLL Guidelines. v4.2020.BR, bendamustine + rituximab; FCR, fludarabine, cyclophosphamide, rituximab; HDMP, high-dose methylprednisolone; PCR, pentostatin, cyclophosphamide, rituximab.
Frontline Treatment without del(17p)/TP53 Mutation
Page 8
All Patients
PreferredIbrutinib
Venetoclax + obinutuzumab
Acalabrutinib ± obinutuzumab
Other recommended regimensAlemtuzumab ± rituximab
HDMP + rituximab
Obinutuzumab
NCCN. CLL/SLL Guidelines. v4.2020.
Frontline Treatment with del(17p)/TP53 Mutation
Ibrutinib Monotherapy in TN CLLData from the RESONATE-2 Trial (PCYC-1115/1116)
Ibrutinib Monotherapy in Frontline CLL: Phase III RESONATE-2 Trial after 5 Years• Randomized to ibrutinib
or chlorambucil (N=269)• ≥65 years old (median
age 73)• Excluded del(17p)
Burger JA, et al. Leukemia. 2019.
Ibrutinib
Chlorambucil
Page 9
Woyach JA, et al. N Engl J Med. 2018.
Months
BRIbrutinibIR
20/18324/18222/182
# of Events/# of PtsNE (NE-NE)NE (NE-NE)NE (NE-NE)
Median (95% CI) mo
OS
(%)
IR
Ibrutinib
BR
• Ibrutinib >BR• No significant difference in PFS or OS between ibrutinib +/-
rituximab
IzR
Ibrutinib
BR
BRIbrutinibIR
68/17634/17832/170
# of Events/# of Pts
43 (38-NR)NRNR
Median (95% CI) mo
Ibrutinib Regimens vs ChemotherapyTN CLL in ≥65-Year-Old Patients: Alliance A041202
BR, bendamustine and rituximab; IR, ibrutinib and rituximab; OS, overall survival; PFS, progression-free survival.
Arm 2 (n=179)• Acalabrutinib 100 mg PO BID until disease progression • Obinutuzumab 100 mg IV day 1, 900 mg day 2• Obinutuzumab 1000 mg day 8, and 15 of cycle 1• Obinutuzumab 1000 mg day 1 of cycles 2–6, every 28 days
Arm 3 (n=177)• Chlorambucil 0.5 mg/kg PO days 1 and 15 of each 28-day cycle for 6 cycles• Obinutuzumab 100 mg IV day 1, 900 mg day 2• Obinutuzumab 1000 mg day 8, and 15 of cycle 1• Obinutuzumab 1000 mg day 1 of cycles 2–6, every 28 days
Acalabrutinib CombinationPhase III, ELEVATE-TN Trial
Sharman JP, et al. ASH. 2019. Abstract 31.
Patient Population• Randomized 1:1:1• Median age = 71• 69% have high CLL-
IPI score, 12% have very high CLL-IPI score
≥65 years or older or <65 years + coexisting conditionsArm 1 (n=179)• Acalabrutinib 100 mg PO BID until disease progression
IPI, international prognostic index.
Page 10
Acalabrutinib CombinationPhase III, ELEVATE-TN Trial
Sharman JP, et al. ASH. 2019. Abstract 31.
Acala Acala + obin Obin + clb
Median PFS, mo NR NR 22.6
30 mo PFS*, % 82% 90% 34%
30 mo OS**, % 94% 95% 90%
ORR, % 85% 94% 79%
*Consistent across all subgroups, including del(17p)
PFS
Acala + obin
Acala
Obin + clb
Months
Prog
ress
ion-
free
Sur
viva
l (%
)
**Median OS has not been reached in any arm
Arm B: FCR (n= 175)• Cycles 1–6
• Fludarabine 25 mg/m2 IV, days 1–3• Cyclophosphamide 250 mg/m2 IV, days 1–3
• Cycle 1• Rituximab 50 mg/m2 IV, day 1, cycle 1• Rituximab 325 mg/m2 IV, day 2, cycle 1
• Cycles 2–6• Rituximab 500 mg/m2 IV, day 1, cycles 2–6
Fit Patients—Phase III E1912FCR vs IR in <70, without del(17p) CLL
Shanafelt TD, et al. N Engl J Med. 2019.
Arm A: Ibrutinib + Rituximab (n=354)• Cycle 1
• Ibrutinib 420 mg PO daily, days 1–28 • Cycle 2
• Ibrutinib 420 mg PO daily, days 1–28 • Rituximab 50 mg/m2 IV, day 1• Rituximab 325 mg/m2 IV, day 2
• Cycles 3–7 • Ibrutinib 420 mg PO daily, days 1–28 • Rituximab 500 mg/m2 IV, day 1
• Cycle 8+• Ibrutinib 420 mg PO daily, days 1–28
Randomized2:1
Patient Population• Median age 58• ECOG 0–2• CrCl >40 • Able to tolerate FCR• No del(17p) by FISH
CrCl, creatinine clearance; FISH, fluorescence in situ hybridization.
Page 11
FCR
IRIntent to Treat OS
HR=0.17 (95% CI 0.05-0.54)One sided P<0.0003
Years0 1 2 3 4
FCR
IR
Intent to Treat PFS
HR=0.35 (95% CI 0.22-0.5)One sided P<0.00001
0 1 2 3 4
Years
0
0.2
0.4
0.6
0.8
1.0
0
0.2
0.4
0.6
0.8
1.0
IR (37 events/354 cases)FCR (40 events/175 cases)
IR (4 events/354 cases)FCR (10 events/175 cases)
• Improved efficacy• Less AEs
Adapted from Shanafelt TD, et al. N Engl J Med. 2019.
Perc
enta
ge o
f Pat
ient
s
Perc
enta
ge o
f Pat
ient
s
AE, adverse event; HR, hazard ratio.
IRFCR
IR
FCR
Intent to Treat PFS Intent to Treat OS
Fit Patients—Phase III E1912FCR vs IR in <70, without del(17p) CLL
• Ibrutinib plays a crucial role in frontline treatment in NCCN Guidelines• Regardless of high-risk features• With or without comorbidities
• BTK combinations require more research• IR combination has not demonstrated benefit over monotherapy in those ≥65 yo• Acalabrutinib and ibrutinib combinations with obinutuzumab seem promising
• Alternative combinations such as venetoclax + obinutuzumab have similar PFS• Fixed duration may impact preference• May also be preferred over ibrutinib in those with cardiac comorbidities or
predisposition for AEs
Patient Selection for Frontline Treatment
NCCN. CLL/SLL Guidelines. v3.2020.
Page 12
www.clinicaltrials.gov; Tam CS, et al. ASH. 2019. Abstract 499;Lampson BL, et al. ASH. 2019. Abstract 32; Fischer K, et al. N Engl J Med. 2019; Jain N, et al. ASH. 2019. Abstract 34.
Ongoing and Future Trials for Frontline CLL
Trial Patients Study Arms Available Data
SEQUOIAPh III (NCT03336333)
≥65 years old or younger if comorbidities
• Zanubrutinib• Zanubrutinib + venetoclax• Bendamustine + rituximab
• At median f/u of 7 months: ORR of 92%
ASSUREPh III (NCT04008706)
TN cohort (further stratified by concomitant warfarin use) • Acalabrutinib -
EA9161Ph III (NCT03701282) All comers, no del(17p) • Ibrutinib + venetoclax + obinutuzumab
• Ibrutinib + obinutuzumab -
GLOWPh III (NCT03462719)
≥65 years old or younger if comorbidities
• Ibrutinib + venetoclax• Obinutuzumab + chlorambucil -
AVO Ph II (NCT03580928) All comers • Acalabrutinib + venetoclax +
obinutuzumab• Interim TN cohort data:
• 100% PR; 75% CR
Age and Comorbidities Evaluated
Frail w/ significant comorbidities or ≥65 or younger w/ significant comorbidities
Preferred Acalabrutinib(category 1)
Ibrutinib(category 1)
Venetoclax + rituximab
(category 1)
Idelalisib + rituximab
Duvelisib
Other recommended regimens
alemtuzumab ± rituximab, chlorambucil + rituximab, reduced-dose FCR or PCR,
HDMP + rituximab, idelalisib, lenalidomide ± rituximab,
obinutuzumab, ofatumumab, venetoclax, dose-dense
rituximab, BR, BR + ibrutinib, or BR + idelalisib
<65 and without significant comorbidities
PreferredAcalabrutinib (category 1)
Ibrutinib (category 1)
Venetoclax + rituximab
(category 1)
Idelalisib + rituximab
Duvelisib
Other recommended regimens
alemtuzumab ± rituximab, BR, FC + ofatumumab, FCR,
HDMP + rituximab, idelalisib, lenalidomide ±
rituximab, obinutuzumab, ofatumumab, PCR,
venetoclax, BR + ibrutinib, or BR + idelalisib
NCCN. CLL/SLL Guidelines. v4.2020.BR, bendamustine + rituximab; FCR, fludarabine, cyclophosphamide, rituximab; HDMP, high-dose methylprednisolone; PCR, pentostatin, cyclophosphamide, rituximab.
R/R Treatment without del(17p)/TP53 Mutation
Page 13
Age and Comorbidities Evaluated
PreferredAcalabrutinib (category 1)
Ibrutinib (category 1)
Venetoclax + rituximab (category 1)
Idelalisib + rituximab
DuvelisibVenetoclax
Other recommended regimensalemtuzumab ± rituximab, HDMP + rituximab, idelalisib, lenalidomide ±
rituximab, or ofatumumab
R/R Treatment with del(17p)/TP53 Mutation
NCCN. CLL/SLL Guidelines. v4.2020.
Ibrutinib Significantly Extended PFS Compared with Ofatumumab
(RESONATE ~6-year Update)
Byrd JC, et al. Blood. 2019; Munir T, et al. Am J Hematol. 2019.
Median PFS (months)
All (ibrut vs ofatu) 44.1 vs 8.11
Del(17p) 40.6
Del(11q) 60.7
No Del(17p)/Del(11q) 42.5
IGHV mutated 48.4
Unmutated IGHV 49.7
TP53 40.7
No TP53 56.9
Ibrutinib
Ofatumumab
Page 14
Ghia P, et al. EHA. 2019. Abstract LB2606.
Phase III ASCEND (ACE-CL-309)Acalabrutinib in R/R CLL
Arm 1 (n=155)• Acalabrutinib 100 mg PO
twice daily until PD or unacceptable toxicityPatient population• ≥1 prior therapy for CLL• ECOG PS ≤2• Interim analysis planned after
~79 PFS eventsArm 2 (n=155)• Rituximab + physician’s choice
• Idelalisib 150 mg PO twice daily (n=119)
• Bendamustine 70 mg/m2 IV (n=36)Median follow-up, 16.1 monthsMost common AEs (any-acalabrutinib)• Headache 22%• Neutropenia 19%• Diarrhea 18%• Anemia 15%• Cough 15%
Randomized2:1
Ghia P, et al. ASCO. 2020. Abstract 8015.
Phase III ASCEND (ACE-CL-309)Acalabrutinib in R/R CLL
Improved PFS (including high-risk subgroups)
Acalabrutinib
IdR/BR
IdR, idealisib and rituximab.
Page 15
• Ibrutinib and acalabrutinib both covalently bind to BTK at the cysteine 481 (C481) amino acid
• Acquired resistance occurs due to this binding site mutation (cysteine to serine change so BTKi can no longer bind)
• If C481S mutation develops, resistance will occur with both ibrutinib and acalabrutinib. Do not use acalabrutinib when there is resistance to ibrutinib.
When the Binding Site ChangesMutation Concerns
Adapted from Wiestner A. Haematologica. 2015; NCCN CLL/SLL Guidelines. v4.2020; Byrd JC, et al. Oncotarget. 2018; Wu J, et al. J Hematol Oncol. 2016; Byrd JC, et al. N Engl J Med. 2016; Woyach JA, et al. N Engl J Med. 2014; Woyach JA. Blood. 2018.
Irreversible BTK Inhibitor (e.g., ibrutinib, acalabrutinib)
Cysteine
Irreversible (covalent)
binding
Persistent/irreversible inhibitionATP binding pocket
Reiff SD, et al. Cancer Discov. 2018;Woyach JA, et al. EHA. 2018. Abstract PF355; Bond DA, Woyach JA. Curr Hematol Malig Rep. 2019.
BTK inhibitor Mechanism Selectivity for BTK Phase of developmentZanubrutinib Covalent, Irreversible Moderate II/III
Tirabrutinib Covalent, Irreversible High I/II
Vecabrutinib Non-covalent, Reversible Moderate I/II
LOXO-305 Non-covalent, Reversible High I
ARQ-531 Non-covalent, Reversible Low I
What Is Next?Overcoming Inhibition
Reversible, non-covalent BTKis may mitigate resistance• Trial with ARQ 53, found cytotoxicity at 72 hours against ibrutinib resistant cell lines• Activity in heavily pretreated patients with BTK mutations• Well tolerated
Page 16
www.clinicaltrials.gov; Jain N, et al. ASH. 2019. Abstract 359; Furman RR, et al. ASH. 2019. Abstract 3039.
Ongoing and Future Trials for R/R CLLTrial Patients Study Arms Available Data
ALPINEPh III (NCT03734016) Relapsed/refractory • Zanubrutinib
• Ibrutinib —
ACE-CL-006Ph III (NCT02477696) Previously treated, high-risk • Acalabrutinib
• Ibrutinib —
Ph II (NCT04169737) Relapsed after and/or refractory to ≥1 prior therapy
• Acalabrutinib + obinutuzumab + venetoclax• Acalabrutinib + early obinutuzumab +
venetoclax—
Ph II (NCT02029443) Relapsed/refractory, ≥1 prior therapy • Acalabrutinib
• ORR: 94%• CR: 4%• PR: 84%• PD: 1%
Ph II (NCT04116437) Previously treated, ibrutinib intolerant • Zanubrutinib —
Ph II (NCT02756897) Relapsed/refractory, ≥1 prior therapy (cohort 1) • Ibrutinib + venetoclax
• After 24 cycles, 67% achieved BM uMRDremission
CR, complete response; PR, partial response; PD, progressive disease; BM uMRD, bone marrow undetectable minimal residual disease.
Pharmacist PerspectivesExploring Current Challenges
in CLL Management and Integrating BTKis into Practice
Page 17
Case 1KT is a 71-year-old male diagnosed with CLL 2 years ago. He now presents with progressive symptoms (bulky disease, B symptoms) that meet iWCLL criteria for treatment.
Disease: del(17p), del(13q), IGHV unmutatedPMHx: atrial fibrillation, GERD, osteoarthritisMeds: metoprolol, pantoprazole, aspirin, fish oil supplements
Labs: CrCl 58 mL/min, WBC 86,000/μL, ANC 1100/μL, platelets 96,000/μL, LDH 380 U/L, uric acid 6.5 mg/dLEKG: HR 82 bpm, NSR, QTc 450 msec, BP 128/72 mmHg
ANC, absolute neutrophil count; GERD, gastroesophageal reflux disease; iWCLL, International Workshop on CLL; NSR, normal sinus rhythm; QTc, corrected QT interval; WBC, white blood cell.
All Patients
PreferredIbrutinib
Venetoclax + obinutuzumab
Acalabrutinib ± obinutuzumab
Other recommended regimensAlemtuzumab ± rituximab
HDMP + rituximab
Obinutuzumab
NCCN. CLL/SLL Guidelines. v4.2020.
What are the treatment options for this treatment-naïve, del(17p)+ patient?
Page 18
Case 1Ibrutinib Considerations
Does a history of atrial fibrillation prohibit use of ibrutinib?• Pooled long-term safety from RESONATE, RESONATE-2, and phase 1b/2
PCYC-1102/1103 (total of 330 ibrutinib patients—41% previously untreated)
Adverse Event Any Grade (%)
Grade 1(%)
Grade 2(%)
Grade 3(%)
Grade 4(%)
Grade 5(%)
Atrial fibrillation 11 2 4 5 0 0
Hypertension 21 3 10 7 0 0
Bleeding/bruising 55 39 11 4 1 <1
Infection 83 7 45 25 4 2
Diarrhea 52 35 13 5 0 0
Rash 35 22 10 3 0 0
Arthralgia 22 14 7 2 0 0
Coutre SE, et al. Blood Adv. 2019; Wiczer TE, et al. Blood Adv. 2017.
CTCAEToxicity Grading Examples
Adverse Event Grade 1 Grade 2 Grade 3 Grade 4 Grade 5
Atrial fibrillationAsymptomatic, intervention not indicated
Non-urgent medical intervention indicated
Symptomatic, urgent intervention indicated; device (e.g., pacemaker); ablation; new onset
Life-threatening consequences;embolus requiring urgent intervention
Death
Infections(specific criteria—based on type/site of infection)
Asymptomatic, or mild symptoms;intervention generally not indicated
Generally localintervention or oral therapy (e.g., topical or oral antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or antiviralintervention indicated; radiologic, endoscopic, or operative intervention indicated
Life-threatening consequences; urgent intervention indicated
Death
HypertensionSystolic BP (SBP) 120–139 mmHg ordiastolic BP (DBP) 80–89 mmHg
SPB 140–159 mmHg orDBP 90–99 mmHg, medical intervention indicated
SBP ≥160 mmHg or DBP ≥100 mmHg, medical intervention indicated
Life-threatening consequences Death
Hemorrhage/Bleeding/Bruising
Mild symptoms; intervention not indicated
Moderate symptoms; intervention indicated
Transfusion indicated: invasive intervention indicated; hospitalization
Life-threatening consequences; urgent intervention indicated
Death
Diarrhea↑ of <4 stools/day over baseline
↑ 4–6 stools/day over baseline ↑ ≥7 stools/day over baseline
Life-threatening consequences Death
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf.
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Risk Factors for Developing Atrial Fibrillation
• Hypertension• Heart failure• Diabetes mellitus• Age• Obesity• Excess alcohol consumption• Valvular heart disease, murmur• COPD• Hyperthyroidism• Obstructive sleep apnea• Chronic kidney disease• Acute infections
Stuhlinger MC, et al. Wien Klin Wochenschr. 2019; Wiczer TE, et al. Blood Adv. 2017;https://www.framinghamheartstudy.org/fhs-risk-functions/atrial-fibrillation-10-year-risk/.
1. Careful history and assessment—numerous risk score calculators
2. Optimize modifiable factors
3. Reassess on regular basis
4. Educate patient and caregivers
COPD, chronic obstructive pulmonary disease.
Assessing Risk for Complications
Risk Factor Score
Congestive heart failure 1
Hypertension 1
Age ≥75 years 2
Age 65–74 years 1
Diabetes mellitus 1
Stroke/TIA/Thromboembolism 2
Vascular disease 1
Female sex 1
Clinical Characteristic Points Awarded
Hypertension 1
Abnormal liver function 1
Abnormal renal function 1
Stroke 1
Bleeding 1
Labile INRs 1
Elderly (age >65 years) 1
Drugs 1
Alcohol 1
CHA2DS2-VASc for Stroke Risk HASBLED Score for Bleeding Risk
https://www.chadsvasc.org.
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Case 1 Patient Considerations
• Thorough history and physical, medication reconciliation, and cardiac assessment/consult• Atrial fibrillation controlled, okay to cautiously begin on ibrutinib • Not on anticoagulation at this time, if required, consider other therapy options
• Avoid warfarin, may consider LMWH or DOAC using caution with drug interactions• Bleeding risk
• Use antiplatelet agents with caution, alternative agents if possible, avoid dual antiplatelet agents, if aspirin required, use lowest dose (81 mg) possible
• Avoid use of concurrent anticoagulation and antiplatelet therapy• Ibrutinib may control disease for long duration, must consistently assess, prevent, and
treat common side effects to avoid unnecessary discontinuation
Brown JR. Blood. 2018; Salem JE, et al. J Am Coll Cardiol. 2019; Shatzel JJ, et al. J Thromb Haemost. 2017; Stephens DM, et al. Blood. 2019.
How to counsel this patient?• Discontinue/avoid unnecessary medications that may contribute to bleeding risk
(e.g., aspirin, fish oil, NSAIDS, vitamin E)• Educate on inadvertent use in combination products
• Educate/report symptoms of cardiac arrhythmias (e.g., palpitations, lightheadedness, syncope, chest pain, new onset dyspnea)
• Management of common adverse effects• Diarrhea – rule out infection, loperamide• Arthralgia – acetaminophen, short course corticosteroid if severe• Fatigue, inability to concentrate – review meds, physical therapy, optimize sleep/nutrition• Rash – topical steroids, antihistamines if pruritic• Minimize infection risk – consider prophylaxis based on patient factors (VZV, PCP, IgG)
• Encourage compliance at full dose if possible (maintain full BTK occupancy)
Brown JR. Blood. 2018; Shatzel JJ, et al. J Thromb Haemost. 2017; Stephens DM, et al. Blood. 2019.
Page 21
2nd occurrence
1st occurrence
4th occurrence
3rd occurrence
Ibrutinib Dosing and Modifications
FDA Prescribing Information.
Starting dose 420 mg PO once daily
After recovery, resume at 420 mg PO once daily
After recovery, resume at 280 mg PO once daily
After recovery, resume at 140 mg PO once daily
Discontinue ibrutinib
Interrupt therapy for• ≥Grade 3 non-
hematological toxicities
OR• ≥Grade 3 neutropenia
with infection or fever
OR• Grade 4
hematological toxicities
Key Considerations1. Continuous dosing2. Transient lymphocytosis
(on-target effect, not progression)
3. Toxicity assessments4. Patient education5. Drug interactions6. Renal and liver
dysfunction7. Impact of drug holidays
• Most AEs decrease over time except hypertension• 8% during first year• 15% in year 2• 20% in year 3• 19% in years >3
Outcomes AnalysisIbrutinib and Hypertension
O’Brien SM, et al. Am J Hematol. 2019; NCCN. CLL/SLL Guidelines. v4.2020.
Hypertension
Medically manage with anti-hypertensives and
closely monitor
Discontinue ibrutinib for uncontrollable HTN
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Toxicity ManagementIbrutinib Intolerance
Stephens DM, et al. Blood. 2019; NCCN. CLL/SLL Guidelines. v4.2020.
Arthralgia
APAP or short pulses of prednisone therapy
• Hold ibrutinib for up to 1 week and reduce dose by one level (e.g., 420 mg to 280 mg)
• Transition to alternative BTK inhibitor such as acalabrutinibcan diminish or resolve this toxicity.
Pneumonitis
Permanent D/C of ibrutinib and alternate
CLL therapy
Atrial Fibrillation
• Rate/rhythm control• Assess CHA2DS2 VASc Score
• If ≥2, anticoagulation is recommended
• D/C ibrutinib and consider alternate CLL therapy
Patient still unable to tolerate arthralgia
Previous diagnosis of Afib is not a contraindication to ibrutinib initiation.
However, more selective BTKis may be used instead, as there is a lower incidence of Afib
Ibrutinib Drug Interactions• Metabolized by liver, primarily CYP3A4 substrate, also inhibits P-gp• Avoid concomitant administration with CYP3A4 inhibitors/inducers and P-gp substrates, if possible• Prospective trial reported two-thirds of patients on medications that potentially interact with ibrutinib
Examples
CYP3A4 Inhibitors Clarithromycin, erythromycin, itraconazole, fluconazole, posaconazole, voriconazole, ritonavir, indinavir, nelfinavir, darunavir, fosamprenavir, diltiazem, verapamil, amiodarone, dronedarone
CYP3A4 Inducers Rifampin, carbamazepine, phenytoin, St. John’s wort
P-glycoprotein Dabigitran, digoxin, methotrexate
Management Dosing Examples
Strong CYP3A4 inhibitors If short term (<7 days), consider interrupting ibrutinib
• Voriconazole 200 mg PO BID—decrease to 140 mg PO daily
• Posaconazole 300 mg tablets daily—decrease to 70 mg PO dailyModerate CYP3A4 inhibitors Reduce ibrutinib dose to 280 mg PO daily
Finnes HD, et al. Leuk Lymphoma. 2017; FDA Prescribing Information; https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers.
BID, twice daily.
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Case 2Previously Treated
BW is a 68-year-old active male who has new symptoms of increasing cervical lymphadenopathy, fatigue, and left upper quadrant fullness.
PMH: diagnosed with CLL 5 years ago and treated with FCR, achieving a complete response; hypertension; diabetes; multivessel coronary artery disease s/p stents (requiring prolonged dual antiplatelet therapy); and GERDDisease: del(11q), unmutated IGHV, and TP53 wild typeMeds: aspirin, ticagrelor, lisinopril, hydrochlorothiazide, metformin, and pantoprazole
Labs: CrCl 52 ml/min, Hb 11.2 gm/dL, WBC 55,000/ μL, ANC 1600/μL, and Plt147,000/μL
Age and Comorbidities Evaluated
Frail w/ significant comorbidities or ≥65 or younger w/ significant comorbidities
Preferred Acalabrutinib(category 1)
Ibrutinib(category 1)
Venetoclax + rituximab
(category 1)
Idelalisib + rituximab
Duvelisib
Other recommended regimens
alemtuzumab ± rituximab, chlorambucil + rituximab, reduced-dose FCR or PCR,
HDMP + rituximab, idelalisib, lenalidomide ± rituximab,
obinutuzumab, ofatumumab, venetoclax, dose-dense
rituximab, BR, BR + ibrutinib, or BR + idelalisib
<65 and without significant comorbidities
PreferredAcalabrutinib (category 1)
Ibrutinib (category 1)
Venetoclax + rituximab
(category 1)
Idelalisib + rituximab
Duvelisib
Other recommended regimens
alemtuzumab ± rituximab, BR, FC + ofatumumab, FCR,
HDMP + rituximab, idelalisib, lenalidomide ±
rituximab, obinutuzumab, ofatumumab, PCR,
venetoclax, BR + ibrutinib, or BR + idelalisib
NCCN. CLL/SLL Guidelines. v4.2020.BR, bendamustine + rituximab; FCR, fludarabine, cyclophosphamide, rituximab; HDMP, high-dose methylprednisolone; PCR, pentostatin, cyclophosphamide, rituximab.
R/R Treatment without del(17p)/TP53 Mutation
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Case 2Acalabrutinib 100 mg PO every 12 hours is initiated.
• Selective, BTK inhibitor with minimal off-target activity
Byrd JC, et al. ASH. 2018. Abstract 692.
Adverse Event All Grades (%) Grades 3–4 (%)Headache 44 5Diarrhea 49 5Increased weight 31 3URI 40 1Fatigue 17 1Hypertension 16 6Contusion 39 0Arthralgia 33 1
• >2% of patients had Grade 3/4 neutropenia (7%), nausea (4%), pneumonia (4%), and syncope (3%)• ≤2% Grade 3/4 rash, bleeding, and Afib
Afib, atrial fibrillation; URI, upper respiratory infection.
4th occurrence
Acalabrutinib Dosing
FDA Prescribing Information.
Starting dose 100 mg PO BID
After recovery, resume at 100 mg PO BID
Discontinue acalabrutinib
Interrupt therapy for • ≥Grade 3 non-
hematologic toxicitiesOR
• Grade 3 thrombocytopenia with bleeding
OR• Grade 4
thrombocytopenia OR
• Grade 4 neutropenia lasting >7 days
Key Considerations1. Continuous dosing2. Transient
lymphocytosis (on-target effect, not progression)
3. Toxicity assessments4. Patient education5. Drug interactions
After recovery, resume at 100 mg PO once daily
After recovery, resume at 100 mg PO BID
2nd occurrence
1st occurrence
3rd occurrence
Page 25
Acalabrutinib Drug Interactions• Metabolized by liver, primarily CYP3A enzymes• Increased gastric pH decreases acalabrutinib solubility
Medication Acalabrutinib Management
Strong CYP3A4 inhibitors • Avoid concurrent use if possible• If short term use (up to 7 days), interrupt acalabrutinib
Moderate CYP3A4 inhibitors • 100 mg PO once daily
Strong CYP3A4 inducers • Avoid concurrent use if possible• If concurrent use unavoidable, increase acalabrutinib to 200 mg twice daily
Proton pump inhibitors • Avoid concomitant use
H2-receptor blockers • Take acalabrutinib 2 hours before taking H2-receptor blocker
Antacids • Separate dosing by at least 2 hours
FDA Prescribing Information.
Case 2Counseling
• BW is on dual antiplatelet therapy—assess for need, monitor for signs of bleeding
• Discontinue/avoid unnecessary medications that may contribute to bleeding risk (e.g. fish oil, NSAIDS, vitamin E)
• Monitor blood pressure, treat to goal• Discontinue proton pump inhibitor, consider H2 blocker with
detailed instructions for timing of dose • Management of common side effects
• Headache—often transient, acetaminophen, caffeine, avoid NSAIDS• Diarrhea—rule out infection, loperamide• Infections—consider prophylaxis based on patient factors (VZV, PCP,
IgG)
Page 26
BTKi and Invasive ProceduresWhat recommendations would you provide with regard to BTK inhibitor therapy?
• Both ibrutinib and acalabrutinib recommend holding for 3–7 days pre-and post-invasive procedures• For major procedures, hold ibrutinib 7 days prior to procedures and resume at
1–3 days or based on individual factors
• For urgent procedures, platelet transfusion to achieve 50% fresh plateletsManagement of bleeding?
• Low grade bleeding—supportive care• Non-CNS bleeding—hold BTKi and transfuse platelets• CNS bleeding—individualize considerations for platelet transfusion
Shatzel JJ, et al. J Thromb Haemost. 2017; Gribben JG, et al. Br J Haematol. 2018; FDA Prescribing Information.CNS, central nervous system.
Back to Case 1Ibrutinib
KT begins experiencing severe arthralgias and myalgias.Would a switch to acalabrutinib improve tolerance?
Owen C, et al. Curr Oncol. 2019.
BTK Inhibitor Selectivity
↑ off target binding = ↑ likelihood of toxici es
Ibrutinib Acalabrutinib
Page 27
Back to Case 1Ibrutinib
KT begins experiencing severe arthralgias and myalgias.Would a switch to acalabrutinib improve tolerance?
• In 33 ibrutinib-intolerant patients, 72% of adverse events did not recur while on acalabrutinib therapy and 13% recurred at a lower grade1
• Acalabrutinib safety profile in this population is similar to that reported for prior reports in BTK inhibitor naïve R/R CLL1
• Preliminary results suggest acalabrutinib is an effective option in ibrutinib intolerant patients. Direct comparative studies underway.1,2
1Awan FT, et al. Blood Adv. 2019; 2Rogers KA, et al. ASCO. 2019. Abstract 7530.
Considerations for Starting BTKi Therapy
Safe and Effective Safe and Effective BTKi Therapy
Comorbidities/Comorbidities/Risks Comprehensive
Medication History
Cardiac Assessment
Laboratory Assessment
Infection Prophylaxis
Risk of Tumor Risk of Tumor Lysis Syndrome
Combination Therapy
Medication Medication Access
Page 28
Considerations to Ensuring BTKi Therapy Success
• Continued medication access• Unfunded, private insurance, Medicare part D• Pharmaceutical company support/programs, prior authorization/appeal
support, utilization of approved compendia for off-label use
• Reinforce patient and caregiver education• Compliance• Adverse events
• Ongoing reassessment of new medications, OTC• Dosing/drug interactions
BTK Inhibitors and SARS-CoV-2 (COVID-19)
• Pulmonary failure is the main cause of mortality related to SARS-CoV-2
SARS-CoV-2 binds via the
ACE2-receptor on ATII cells
Toll ligand receptors (TLRs) on ATII cells trigger inflammatory cytokines and
chemo-attractants, recruiting macrophages and neutrophils
Acute lung injury and
pathogenesis
• Early clinical data/case studies demonstrate that BTKis can protect against lung injury and improve pulmonary function in these patients
• CALAVI (NCT04346199) – trial to assess acalabrutinib in treatment of cytokine storm associated with COVID-19 infection in severely ill patients.
BTK protein is involved in downstream signaling of inflammatory process
Treon SP, et al. Blood. 2020; https://www.astrazeneca.com/media-centre/press-releases/2020/astrazeneca-initiates-calavi-clinical-trial-with-calquence-against-covid-19.html.
1
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Copyright Statements
CLL is a Complex Disease: Reprinted by permission from Springer Nature: Nat Rev Clin Oncol; Burger JA, O'Brien S. Evolution of CLL treatment—from chemoimmunotherapy to targeted and individualized therapy; 15(8):510–527. Copyright © 2018.
CLL Treatment in 2020: From Blood: Hallek M. Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies; 122(23):3723–3734. Copyright © 2013 by the American Society of Hematology.
Bruton’s Tyrosine Kinase (BTK) Inhibitors: From Transl Cancer Res. Singh SP, Rip J, Hendricks RW. Targeting Bruton’s tyrosine kinase expression levels through microRNAs in chronic lymphocytic leukemia treatment; 6(Suppl3):S502–S507. Copyright © 2017 by Translational Cancer Research. All rights reserved.
Ibrutinib Monotherapy in TN CLL, The RESONATE-2 Trial (PCYC-1115/1116): From Leukemia: Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study; 34(3):787–798. Copyright © 2020. License available at https://creativecommons.org/licenses/by-nc/4.0/legalcode. Accessed August 2020.
Ibrutinib Regimens vs Chemotherapy, TN CLL in ≥65-Year-Old Patients: From New England Journal of Medicine; Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CL; 379(26):2517–2528. Copyright ©2018 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
Fit Patients, Phase III E1912, FCR vs IR in <70, without del(17p) CLL: From New England Journal of Medicine; Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia; 381(5):432–443. Copyright ©2019 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
Ibrutinib Significantly Extended PFS Compared with Ofatumumab in R/R CLL (Phase III, RESONATE ~6-year Update: From Am J Hematol: Munir T, Brown JR, O'Brien S, et al. Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma; 94(12):1353–1363. Copyright © 2019 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc. License available at https://creativecommons.org/licenses/by-nc/4.0/legalcode. Accessed March 2020.
Back to Case 1, Ibrutinib: From J Pharmacol Exp Ther: Leukemia: Barf T, Covey T, Izumi R, et al. Acalabrutinib (ACP-196): a covalent Bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile; 363(2):240–252. Copyright © 2017. License available at https://creativecommons.org/licenses/by-nc/4.0/legalcode. Accessed August 2020.
Post-test & Credit Form: https://www.surveymonkey.com/r/BTKPOST