overview target audience agenda learning ......target audience this activity is designed to meet the...

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

• 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

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

• 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 -

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.

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.

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

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)


Acalabrutinib ±obinutuzumab


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

All Patients

PreferredIbrutinib


Acalabrutinib ± obinutuzumab

Other recommended regimensAlemtuzumab ± rituximab

HDMP + rituximab

Obinutuzumab


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

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.

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.

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


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



Preferred Acalabrutinib(category 1)

Ibrutinib(category 1)

Venetoclax + rituximab

(category 1)

Idelalisib + rituximab

Duvelisib


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


PreferredAcalabrutinib (category 1)

Ibrutinib (category 1)


(category 1)


Duvelisib


alemtuzumab ± rituximab, BR, FC + ofatumumab, FCR,

HDMP + rituximab, idelalisib, lenalidomide ±

rituximab, obinutuzumab, ofatumumab, PCR,

venetoclax, BR + ibrutinib, or BR + idelalisib


R/R Treatment without del(17p)/TP53 Mutation




Venetoclax + rituximab (category 1)


DuvelisibVenetoclax

Other recommended regimensalemtuzumab ± rituximab, HDMP + rituximab, idelalisib, lenalidomide ±

rituximab, or ofatumumab

R/R Treatment with del(17p)/TP53 Mutation


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

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.

• 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

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

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


Acalabrutinib ± obinutuzumab

Other recommended regimensAlemtuzumab ± rituximab

HDMP + rituximab

Obinutuzumab


What are the treatment options for this treatment-naïve, del(17p)+ patient?

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.

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.

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.

2nd occurrence

1st occurrence

4th occurrence

3rd occurrence

Ibrutinib Dosing and Modifications


Starting dose 420 mg PO once daily

After recovery, resume at 420 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

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.

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



Preferred Acalabrutinib(category 1)

Ibrutinib(category 1)


(category 1)


Duvelisib


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





(category 1)


Duvelisib


alemtuzumab ± rituximab, BR, FC + ofatumumab, FCR,

HDMP + rituximab, idelalisib, lenalidomide ±

rituximab, obinutuzumab, ofatumumab, PCR,

venetoclax, BR + ibrutinib, or BR + idelalisib


R/R Treatment without del(17p)/TP53 Mutation

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


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 BID

2nd occurrence

1st occurrence

3rd occurrence

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


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)

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

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

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.

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