ONS BTK 5.11.18 HANDOUT - ceconcepts.com BTK HANDOUT 5.11.pdf · CLL, % TP53 mutation ~5–10% ~40% del(11q) ~11% ~20% ... 0 6 12 213 9 15 2418 0 20 40 60 80 100 Months 10 30 50 70

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Learning Objectives

1. Discuss the role of the B‐cell receptor (BCR) pathway in the survival and proliferation of cancer cells.

2. Evaluate clinical efficacy data for first‐ and second‐generation BTK inhibitors in select B‐cell malignancies (e.g., CLL/SLL, MCL) and explore the rationale for combination therapy with other antineoplastic agents.

3. Assess potential toxicities that may arise with the use of BTK inhibitors and explore evidence‐based strategies to ensure the timely recognition and proper management of these adverse events.

4. Using a case‐based approach, examine effective strategies that oncology nurses can employ to optimize therapy, anticipate and manage adverse events, improve adherence to oral chemotherapy, and promote collaborative discussion with other members of the oncology care team to ensure optimal patient outcomes.

BCR=B‐cell receptor; BTK=Bruton’s tyrosine kinase; CLL=chronic lymphocytic leukemia; MCL=mantle cell lymphoma; SLL=small lymphocytic lymphoma.

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Disclaimer

• This slide deck in its original and unaltered format is for educational purposes and is current as of May

18, 2018. 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

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Introduction to the BCR Pathway and its Role in B‐cell Malignancies

Nina Wagner, BSN, MDAssociate Professor of OncologyJohns Hopkins Sidney KimmelComprehensive Cancer Center

Baltimore, Maryland

Page 3

Objectives

• Discuss the role of the BCR pathway in the survival and proliferation of cancer cells

• Evaluate clinical efficacy data for BTK inhibitors in select B‐cell malignancies

• Explore the rationale for combination therapy

Outline

• Overview of the BCR pathway• Pathogenesis

• BTK, SYK, PI3K

• BTK inhibitors in B‐cell lymphomas• Efficacy as single agents

• Rationale for combination

• Resistance mechanisms

SYK=spleen tyrosine kinase; PI3K=phosphoinositide 3‐kinase.

Page 4

• Located on outer surface of B lymphocytes

• Extends above/below the plasma membrane

• Controls B‐cell activation

• Required for antibody production

What is the B‐cell Receptor?

Rye C, et al. Biology. 2017.Ig=immunoglobulin.

Antigen binding site

Disulfidebridge

Light chain

Heavy chain

Variableregion

Constantregion

Signal transduction region

B‐cell plasmamembrane

IgαIgβ

Critical Enzymes Control BCR Pathway

Choi MY, Kipps TJ. Cancer J. 2012.

Page 5

Recurrent Mutations in BCR Pathway Identified in Lymphoma

Krysiak K, et al. Blood. 2017.

Inhibitors of Critical Enzymes in the BCR Pathway

Choi MY, Kipps TJ. Cancer J. 2012; FDA Prescribing Information; Clinicaltrials.gov.

Fostamatinib

IbrutinibAcalabrutinib

IdelalisibCopanlisibDuvelisib

TemsirolimusEverolimus

Page 6

Bruton’s Tyrosine KinaseCritical Kinase for Lymphoma Cell Survival and Proliferation

Davids M, et al. Future Oncol. 2014.

Cytogenetics Drive CLL Biology

Zenz T, et al. Blood. 2009; Stilgenbauer S, et al. J Clin Oncol. 2009; Rossi D, et al. Clin Cancer Res. 2009; Zenz T, et al. J Clin Oncol. 2010; Gonzalez D, et al. J Clin Oncol. 2011; Badoux XC, et al. Blood. 2011; Zainuddin N, et al. Leuk Res. 2011; Hernandez JA, et al. PLoS One. 2015.

del(17p)Complex karyotypedel(11q)Trisomy 12del(13q)Others

Months

PFS (probab

ility)

1.0

0.8

0.6

0.4

0.2

0.0

0 24 48 84 10812 36 60 9672

PFS in Cytogenetic SubgroupsPhase II Study of ≥2 line Chemoimmunotherapy

LesionPrevalence at CLL Diagnosis, %

Prevalence in Relapsed/refractory

CLL, %

TP53 mutation ~5–10% ~40%

del(11q) ~11% ~20%

del(17p) alone ≤5% ~30%

PFS=progression‐free survival.

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IbrutinibBTK Inhibitor, Highly Active in CLL

Byrd JC, et al. N Engl J Med. 2013; O’Brien S, et al. Blood. 2018.

ORR: 71%ORR: 89% PR with lymphocytosis

ORR=objective response rate; PR=partial response.

Progression‐free survival, %

Months from Initiation of Study Treatment

0 12 24 42 546 18 30 4836 66 787260

0

20

40

60

80

100

del(17p)

del(11q)Trisomy 12

del(13q)No abnormality

Patients with a Response (%)

Month

Complete response plus partial response

Partial response with lymphocytosis

Stable disease

Phase II Study of Ibrutinib in Mantle Cell Lymphoma

Comparison with previously available agents for mantle cell

• Bortezomib

• ORR: 33%; CR: 8%

• Lenalidomide

• ORR: 28%; CR: 7.5%

Fisher RI, et al. J Clin Oncol. 2006; Goy A, et al. J Clin Oncol. 2013; Wang ML, et al. N Engl J Med. 2013.CR=complete response.

Median 3 prior treatmentsORR: 68%CR: 21%Median PFS: 13.9 mo

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Acalabrutinib—Second Generation BTK Inhibitor Developed to Minimize Off‐target Activity

Byrd JC, et al. N Engl J Med. 2016.

In Vivo Thrombosis Formation Model

Platelet aggregation is induced by TEC phosphorylation

Ibrutinib irreversibly binds to TECAcalabrutinib does not bind to TEC

TEC=tyrosine kinase expressed in hepatocellular carcinoma.

0 20050 1500

8,000 Healthy Adults (n=5)

Acalabrutinib(n=3)

Ibrutinib(n=5)

Time (seconds)

100

2,000

4,000

6,000

Thrombus size (µm

2)

• N=61

• 3 median prior treatments

• Incidence of 17p13.1 deletion: 31% (18/59)

• ORR: 95%

• PR: 85%; PR with lymphocytosis: 10%

• ORR: 100% in 17p13.1 deletion

Phase I/II of Acalabrutinib in Relapsed CLL


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• Excluded prior BCR pathway inhibitors or BCL‐2 inhibitors

• Median 2 prior therapies

• ORR: 81%; CR: 40%

• Median PFS not reached at median follow‐up of 15.2 months

• 12 month PFS: 67%

Phase II Study of Acalabrutinib in Mantle Cell Lymphoma

Wang ML, et al. Lancet. 2018.BCL=B‐cell lymphoma.

• Tirabrutinib (ONO‐4059/GS‐4059)

• Phase I data reported in relapsed/refractory B‐cell/NHL

• Phase II studies underway in CLL

• Zanubrutinib (BGB‐3111)

• Phase I data reported in advanced B‐cell/NHL

• No related bleeding or Afib in early evaluation

• Phase III studies underway in CLL/SLL, WM

BTK InhibitorsInvestigational Agents

Morschhauser F, et al. ICML. 2017. Abstract 276; Clinicaltrials.gov; Tam CS, et al. ASH. 2017. Abstract 152.

WM=Waldenstrom macroglobulinemia;Afib=atrial fibrillation; NHL=non‐Hodgkin lymphoma.

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Comparison of Single Agent Ibrutinib to Ibrutinib + Rituximab

ALC=absolute lymphocyte count. Adapted from Burger JA, et al. ASH. 2017. Abstract 427.

ORRIbrutinib: 98% Ibrutinib + Rituximab: 100%

0 2 4 16 361 3 8 2412 60 847248 96 120 144

0

50

100

150Ibrutinib

Ibrutinib + Rituximab

Time, weeks

ALC (K/µL)

363024181260

02849728495102

12850688292104

No. at RiskIbrutinib

Ibrutinib + Rituximab

MonthsProportion Progression‐free

0.00

0.25

0.50

0.75

1.00

Ibrutinib: 102 (9) 94% (87‐98)Ibrutinib + Rituximab: 104 (10) 93% (84‐97)

N (Deaths) 2 year (95% CI)

P=0.788

Ibrutinib Interferes with Cell‐mediated Anti‐tumor Activities of Anti‐CD20 Antibodies

Da Roit F, et al. Haematologica. 2015.

ADCC=antibody‐dependent cell‐mediated cytotoxicity;NK=natural killer (cells); OBZ=obinutuzumab; OFA=ofatumumab; PBMC=peripheral blood mononuclear cells; RTX=rituximab; TRZ=trastuzumab.

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Phase III Study of Bendamustine and Rituximab ± Ibrutinib in Relapsed CLL

Chanan‐Khan A, et al. Lancet Oncol. 2016.

Less Lymphocytosis

OR=overall response; PD=progressive disease; CRi=complete remission with incomplete hematologic recovery; PR+L=partial response with lymphocytosis; SD=stable disease.

Progression‐free survival (%)

Time (months)

Ibrutinib, bendamustine, and rituximab

Placebo, bendamustine, and rituximab

0 8 16 284 12 20 32240

20

40

60

80

100OR 82.7% vs 67.8% (P<0.0001)

Proportion of patients (%)

0

20

40

60

80

100

Ibrutinib, bendamustine,and rituximab

Placebo, bendamustine,and rituximab

CRCRiPR

CRCRiPR

PR+L PR+L SDSD PD PD

72.3%

10.4%

2.8%

23.9%

2.1%

8.7%

65.1%

0.7% 0.3% 0.0%

Arguments For/Against Chemotherapy Combinations

FOR• BTK gene modulation may overcome chemo resistance (bortezomib)

AGAINST• BTK inhibition arrests G1 phase of cell cycle which may decrease activity of chemo that works at later cell cycle phases

Is it Rational to Combine BTK Inhibitors with Cytotoxic Agents?

Murray MY, et al. Cell Cycle. 2015; Yue C, et al. J Exp Clin Cancer Res. 2017.

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• Horizontal BCR Inhibitor Combinations• PI3K• SYK

• Downstream Combinations• Resistance due to activation of transcription downstream or outside of PI3K (e.g., MYC amplification)

• BET inhibitor → downregulates transcrip on of MYC• CDK4/6 inhibitor (palbociclib)• BCL‐2 inhibitor (venetoclax)

What are Potential Rational Combinations with BTK inhibitors?

Ilic N, et al. Proc Nat Acad Sci USA. 2011; Chiron D, et al. Cancer Discov. 2014; Boi M, et al. Clin Cancer Res. 2015;

Barr PM, et al. Blood. 2016; Kuo HP, et al. Mol Cancer Ther. 2017; Bernasconi E, et al. Br J Haematol. 2017; Tam CS, et al. N Engl J Med. 2018.

BTKi is mostly cytostatic“Apoptotic Priming” with BTKi

CDK=cyclin‐dependent kinase;BTKi=Bruton’s tyrosine kinase inhibitor;BET=bromodomain and extraterminal motif.

• Historically, each produces CR rates of 21%

• At week 16, ORR: 71%, CR: 62%

• Overall CR rate: 71%

Phase II Study of Ibrutinib and Venetoclax(BCL‐2 inhibitor) for Mantle Cell Lymphoma

Tam CS, et al. N Engl J Med. 2018.

Estimated 18 mo PFS: 57%

0 6 12 213 9 15 24180

20

40

60

80

100

Months

10

30

50

70

90

24 18 18 121 18 10 17No. at Risk

Patients Alive an

d Free

from Progression (%)

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• BTK structure has cysteine in ATP‐binding pocket. BTK inhibitors bind covalently to Cys481.

• Mutations of the cysteine residue (Cys481) where binding occurs identified in ibrutinib and acalabrutinib.

• Mutations of PLCγ2 and CARD11 immediately downstream of BTK.

Resistance Mechanisms for BTK Inhibitors

Woyach JA, et al. N Engl J Med. 2014; Byrd JC, et al. N Engl J Med. 2016; Xu L, et al. Blood. 2017.

ATP=adenosine triphosphate; CARD11=caspase recruitment domain‐containing protein 1; PLCγ2=phospholipase C gamma 2

Ibrutinib (nM)

1.0

0.8

0.6

0.4

0.2

0.0

‐0.2

Kinase Activity

(norm

alized to activity in untreated control)

0 1 10 100 1000 10,000

Mutant BTK

Non‐mutant BTK

Dismal Outcomes in MCL Patients Who Progress After Ibrutinib

Adapted from Martin P, et al. Blood. 2016.

Median OS following ibrutinibcessation was 2.9 mo

3111473

0 10 20 30 40

24038

01818

1010

66

44

33

11

00

Overall Survival (Month)

Survival Probab

ility

Group

Did not receive subsequent treatment

Received subsequent treatmentOverall

1.0

0.8

0.6

0.4

0.2

0.0123

+ CensoredLog rank P<0.0001

OS=overall survival.

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• BTK is an integral component of the BCR pathway

• BTK inhibitors are highly effective as single agents in CLL and MCL

• Resistance, while rare, is a well‐recognized phenomena with poor prognosis

Conclusions

BTK Inhibitor Toxicities

Mollie E. Moran, MSN, CNP, AOCNPOncology Nurse Practitioner

Division of Hematology and OncologyArthur G. James Cancer Hospital

The Ohio State UniversityColumbus, Ohio

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Potential Toxicities with BTK Inhibitors

• Understand how BTK inhibitor off‐target activity can lead to the formation of certain toxicities

• Differences between first‐ and second‐generation inhibitors (selectivity, off target effects, monitoring considerations)

• Therapy management considerations based on patient specific factors (age, prior treatments, comorbidities, tolerability)

aPatients in the ibrutinib arm had a >50% longer AE reporting period than those on ofatumumab (median of treatment duration 8.6 vs. 5.3 months, respectively); there was no adjustment for exposure duration; bTEAEs reported in all patients who received study drug.

Ibrutinib Side Effects—RESONATE Trial Safety Adverse Events (≥15%) Regardless of Attributiona

Ibrutinib(N=195)

Ofatumumab(N=191)

Any Grade Grade 3/4 Any Grade Grade 3/4

Any TEAE, % 99 51 98 39

Diarrhea 48 4 18 2

Fatigue 28 2 30 2

Nausea 26 2 18 0

Pyrexia 24 2 15 1

Anemia 23 5 17 8

Neutropenia 22 16 15 14

Cough 19 0 23 1

Thrombocytopenia 17 6 12 4

Arthralgia 17 1 7 0

Upper respiratory tract infection 16 1 10 2

Constipation 15 0 9 0

Infusion‐related reaction 0 0 28 3

Byrd JC, et al. N Engl J Med. 2014.AE=adverse event; TEAE=treatment‐emergent adverse event.

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1Ibrutinib Prescribing Information. 2Leong DP, et al. Blood. 2016. 3Byrd JC, et al. Blood. 2015. 4Lipsky AH, et al. Haemotolgica. 2015. 5Mato AR, et al. Blood. 2016. 6Byrd JC, et al. N Engl J Med. 2013. 7Bitar C, et al. JAMA Dermatol. 2016.

Adverse Effect Incidence

Afib1,2~5x increase with ibrutinib

3.3 events per 100 person‐years; RR: 3.9 vs. comparator; (P<0.0001)

Bleeding3,461% (53% grade 1/2)

55% (all grade 1/2)

Hypertension1 6%–17% (Median time to onset: ~5 months)

Pneumonitis5 Not yet defined

Skin (rash)6 27%

Hair/Nail Changes7 67% nail, 26% hair

Diarrhea1 43% all grades (Median time to onset: ~10 days; ~74 days for ≥grade 3)

Lymphocytosis1CLL: 66% all grades (Median time to onset: ~4 weeks)MCL: 33% all grades (Median time to onset: first few weeks)

RR=relative risk.

IbrutinibSafety

IbrutinibSafety

Hypertension (HTN)• Increases in patients on ibrutinib over time and often requires initiation or increase

of anti‐hypertensive therapy (monitor patients for new onset HTN that is not adequately controlled)

• The ≥grade 3 incidence is 4%–13% at years 1–2 but rises to 25%–32% with 5‐year follow‐up in clinical trials. However, frequency has been found to be relatively constant after second year of therapy.

• Note: Over 60% of patients who experienced ≥grade 3 HTN had pre‐existing HTN

• Across trials, ibrutinib discontinuation/dose reduction was infrequent, suggesting that with appropriate management, patients can remain on therapy.

• “2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines”

FDA Prescribing Information; Byrd JC, et al. N Engl J Med. 2013; Burger JA, et al. N Engl J Med. 2015; Byrd JC, et al. Blood. 2015; O’Brien S, et al. Lancet Oncol. 2016; Coutre SE, et al. Clin Cancer Res. 2017;

Whelton PK, et al. J Am Coll Cardiol. 2017; O’Brien S, et al. Blood. 2018; Brown JR, et al. Leukemia. 2018.

Page 17

• MCL and MZL: 560 mg PO once daily

• CLL/SLL, WM, and cGVHD: 420 mg PO once daily

• Take with a glass of water

• Do not open, break, or chew capsules or tablets

• Missed dose: Take as soon as possible on same day, returning to normal schedule following day. Extra doses should not be taken.

Ibrutinib Dose and Administration

FDA Prescribing Information.cGVHD=chronic graft versus host disease; MZL=marginal zone lymphoma.

• New formulation ibrutinib tablets are available in 140 mg, 280 mg, 420 mg, and 560 mg dosage strengths

• Now comes in a 28‐day blister pack

• Ibrutinib 140 mg capsules no longer available after May 15, 2018

• Be sure that patients are aware of the change to the number of pills they will be taking on a daily basis

Ibrutinib Dose and Administration

FDA Prescribing Information.

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Second‐Generation BTKis

• Up to 20% of patients discontinue ibrutinib due to toxicities• Next‐generation agents have thus far been associated with comparable efficacy

to ibrutinib but with greater tolerability in R/R MCL. Studies in MCL and other B‐cell malignancies (e.g., CLL/SLL) are ongoing.

• Compared to ibrutinib, newer agents associated with reduction or elimination of:• Atrial fibrillation• Skin toxicity• Pneumonitis• Bleeding complications

• Acalabrutinib indicated for the treatment of adult patients with mantle cell lymphoma who have received at least one prior therapy

Walter HS, et al. Blood. 2017; FDA Prescribing Information.R/R=relapsed and/or refractory.

• Second‐generation, selective, irreversible inhibitor of BTK

• Improved pharmacologic features

• Favorable plasma exposure

• Rapid oral absorption

• Short half‐life

• Absence of irreversible targeting to alternative kinases (greater selectivity for BTK leads to fewer off‐target effects)

• EGFR (epidermal growth factor receptor)

• TEC (tyrosine kinase expressed in hepatocellular carcinoma)

• ITK (interleukin‐2–inducible T‐cell kinase)


AcalabrutinibAgent Overview

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• Well tolerated• Most common AEs: headache, diarrhea, weight gain

• Compared to ibrutinib• Overlapping toxicities: mild diarrhea, infections

• New toxicities: headache, weight gain

• Less commonly seen with acalabrutinib: Afib, significant skin toxicity, pneumonitis, major hemorrhage

AcalabrutinibSafety

Byrd JC, et al. N Engl J Med. 2016; Wang M, et al. Lancet. 2018; FDA Prescribing Information.

Adverse Events All Grades Grades 1–2 Grades 3–4

Number of patients (%)

Headache 26 (43) 26 (43) 0

Diarrhea 24 (39) 23 (38) 1 (2)

Increased weight 16 (26) 15 (25) 1 (2)

Pyrexia 14 (23) 12 (20) 2 (3)

Upper respiratory tract infection

14 (23) 14 (23) 0

Fatigue 13 (21) 11 (18) 2 (3)

Peripheral edema 13 (21) 13 (21) 0

Hypertension 12 (20) 8 (13) 4 (7)

Nausea 12 (20) 12 (20) 0

Contusion 11 (18) 11 (18) 0

Arthralgia 10 (16) 9 (15) 1 (2)

Petechiae 10 (16) 10 (16) 0

Decreased weight 10 (16) 10 (16) 0

• MCL: 100 mg PO every 12 hours

• Take with a glass of water

• Do not open, break, or chew capsules or tablets

• Missed dose: If missed by >3 hours, skip dose and take the next dose at the regularly scheduled time. Extra doses should not be taken.


Acalabrutinib Dose and Administration

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Management of Common BTK Inhibitor Toxicities

Lymphocytosis

• Usually peaks after the first few weeks of therapy (up to 19 weeks has been observed with ibrutinib therapy)

• Does not signify disease progression

• Lymphocytosis usually asymptomatic

• Resolves with continued therapy

Neutropenia

• Consider growth factor support

Byrd JC, et al. Blood. 2015; NCCN CLL/SLL Guidelines. v5.2018.

Management of Common AEs in BTKis

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Cytopenias (≥grade 3)



Monitor blood counts monthly while on therapy or per institutional protocol (i.e., weekly for the first month, monthly for 3 months, then every 3 months while on therapy).

Neutropenia

• Ibrutinib: 13%–29%

• Acalabrutinib: 23%

Thrombocytopenia

• Ibrutinib: 5–17%


Anemia

• Ibrutinib: 0%–13%


Bleeding

• Fatal bleeding events have occurred in in patients treated with BTK inhibitors.

• The risk/benefit ratio should be evaluated for patients on any anti‐platelet or anticoagulant therapies. Concomitant administration of BTKis with warfarin should be avoided.

• BTKis should be held at least 3–7 days pre‐ and post‐surgery depending on the surgery and risk of bleeding.

Cardiac Arrhythmias

• Obtain ECG for patients who are symptomatic (e.g., palpitations, light headedness, syncope, chest pain, etc.)

• Afib/flutter

• Acalabrutinib: 1% grade 3

• Ibrutinib: up to 6% ≥grade 3FDA Prescribing Information; NCCN CLL/SLL Guidelines. v5.2018.

• Ventricular tachyarrythmias

• Ibrutinib: 0%–1% ≥grade 3


Any grade (~50% of patients treated with BTKis)≥ Grade 3 (ibrutinib: 6%; acalabrutinib: 2%)

ECG=electrocardiogram.

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Nausea and Vomiting (~20% all grades)

• BTKis have minimal to low emetic risk (<30% frequency of emesis)

• 5‐HT3 receptor antagonists (dolasetron, granisetron, ondansetron), metoclopramide, and prochlorperazine

• Recommended PRN. Start before therapy and continue daily.

Diarrhea (~40% all grades)

• Generally self‐limiting, typically resolving without additional therapy

• Symptomatic management with anti‐motility agents once infectious etiologies have been ruled out


NCCN Antiemesis Guidelines. v2.2018; Byrd JC, et al. Blood. 2015; FDA Prescribing Information.

Infection• Continues to be one of the main problems in CLL/SLL patients

• Identify early and treat as indicated

• CLL/SLL has an intermediate risk of infection. NCCN recommends the following prophylactic measures during neutropenia:

• Fluoroquinolone and TMP/SMX (PCP prophylaxis)

• Fluconazole or micafungin

• Acyclovir, famciclovir, or valacyclovir (HSV prophylaxis—Consider during active therapy and possibly longer depending on degree of immunosuppression)

• While IVIG has been used as a supportive care measure in clinical trials and has been associated with a significant decrease in the occurrence of infections, there has been no demonstrable improvement in OS outcomes with its use

Byrd JC, et al. Blood. 2015; NCCN CLL/SLL Guidelines. v5.2018; NCCN Prevention and Treatment of Cancer‐related Infections Guidelines. v1.2018.


PCP=Pneumocystis pneumonia; SMX=sulfamethoxazole; TMP=trimethoprim;HSV=herpes simplex virus; IVIG=intravenous immunoglobulin.

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Toxicity Occurrence

Dose Modification

Ibrutinib 560 mg Ibrutinib 420 mg Acalabrutinib 100 mg

FirstInterrupt therapy until resolved to grade 1 or baseline. May be initiated at starting dose.

Interrupt therapy until resolved to

grade 1 or baseline level. May be

resumed at 100 mg daily.

Second

Interrupt therapy until resolved to grade 1. Restart at

420 mg daily.


280 mg daily.

Third


280 mg daily.


140 mg daily.

Fourth Discontinue

Dose Modifications Due to AEs


• Ibrutinib: ≥grade 3 non‐hematological toxicities, ≥grade 3 neutropenia with infection or fever, or grade 4 hematological toxicities.

• Acalabrutinib: ≥grade 3 non‐hematological toxicities, grade 3 thrombocytopenia with bleeding, grade 4 thrombocytopenia, and grade 4 neutropenia lasting longer than 7 days.

CYP3A4/5 Inhibitors*

Clarithromycin

Itraconazole

Ketoconazole

Ritonavir

Erythromycin

Diltiazem

Fluconazole

Grapefruit juice

Seville oranges

Verapamil

Cimetidine

SafetyConcomitant Medications

*Not a complete list

https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm.

• Avoid co‐administration with strong CYP3A4 inhibitors/inducers

• If CYP3A inhibitors are to be used short‐term (such as anti‐infectives for up to 7 days, interrupt therapy)

• Dose reductions are recommended when BTK inhibitor is co‐administered with moderate CYP3A inhibitors

• Acalabrutinib: Avoid co‐administration with proton pump inhibitors (e.g., omeprazole), take 2 hours before taking H2‐receptor antagonists (e.g., ranitidine), and separate dosing by at least 2 hours with antacids.

CYP3A4/5 Inducers*

Carbamazepine

Phenytoin

Rifampin

St. John’s wort

Modafinil

Rufinamide

Page 24

Shifting to a Chronic Disease Model in B‐cell Malignancies: Case‐based Treatment

Strategies for the Oncology Nurse

Katherine Stephans, MS, ANPDivision of Hematologic Malignancies

Lymphoma and Stem Cell Transplant ProgramsDana‐Farber Cancer Institute

Boston, Massachusetts

NCCN CLL Guidelines: Preferred Regimens

NCCN CLL/SLL Guidelines. v5.2018.

First‐line

Later‐line Frail w/ significant

comorbidities

≤65 w/o significant

comorbidities

Ibrutinib* FCR* Ibrutinib*

Obinutuzumab+ chlorambucil*

IbrutinibIdelalisib + rituximab*

Rituximab + chlorambucil

Bendamustine ±CD20 mAb

Venetoclax + rituximab*

Rituximab + ofatumumab

—— ——

*Category 1.

BTK InhibitorsThe “No Chemo” Era

CLL without del17p CLL with del17p

First‐line Later‐line

Ibrutinib

Ibrutinib*

Venetoclax + rituximab*

Idelalisib + rituximab

Venetoclax

FCR=fludarabine, cyclophosphamide, rituximab; mAb=monoclonal antibody.

Page 25

• New standards of oncologic therapy require new mindset for patient management• Therapy moving from the controlled, clinic setting to the home• Therapy moving from short‐term to long‐term, possibly lifetime

• With these changes, cancer care more closely follows the chronic disease model• Substantial number of patients struggle to adhere to oral anticancer regimens

• Studies of Americans with cancer suggest that most prefer learning detailed information about their disease and its prognosis in a direct and honest manner• However, many patients have little understanding of their disease prognosis,

treatment options or sources of support

AdherenceA New Challenge in Era of Targeted Therapies

Stacey D, et al. Cochrane Database Syst Rev. 2017; Greer JA, et al. Oncologist. 2016; https://www.ahrq.gov/professionals/education/curriculum‐tools/shareddecisionmaking/index.html.

• When clinician and patient work together to make a healthcare decision that is best for the patient

• Optimal decision takes into account evidence‐based information about available options, the provider's knowledge and experience, and the patient's values and preferences

• Patients who are engaged in SDM are more often satisfied with their outcomes, even when met with unexpected or unfavorable side effects

Improving Adherence Shared Decision Making (SDM)

Stacey D, et al. Cochrane Database Syst Rev. 2017;http://connect.ons.org/issue/february‐2016/up‐front/making‐treatment‐decisions‐together.

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• Barriers to effective use of SDM among healthcare providers (HCPs)• Lack of familiarity with SDM approaches• Lack of familiarity of the role of the nurse navigator • Providers feels threatened by involvement of the nurse navigator

• Time Although time is among the biggest perceived barriers, research shows that clinicians can implement SDM without increasing visit duration.

Stacey D, et al. Cochrane Database Syst Rev. 2017;http://connect.ons.org/issue/february‐2016/up‐front/making‐treatment‐decisions‐together.

Improving Adherence Shared Decision Making (SDM)

• BF is a 79‐year‐old female diagnosed in 2016 with CLL with a 17p deletion. She is married to a 72‐year‐old professor who still teaches part time at the local university.

• She is struggling with some early dementia, but still has a good quality of life, enjoying knitting, playing regular bridge games with friends, and traveling to England from time to time to visit family.

• Watchful waiting for 2 years, but she has become increasingly fatigued with recurrent infections. Hgb of 10.2 g/dL, platelet count of 82K.

• BF is originally from England; she has no family nearby and, due to her husband’s schedule, is alone from 8:00 AM–12:00 PM each day.

Case 1CLL

Hbg=hemoglobin.

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Goals of care: BF wants to have more energy, experience fewer

infections, and have as much time as she can.

Know your options at the start: Ideally, plan is developed over a few

visits. BF wants both written and verbal information about traditional IV

treatment and oral medication.

• BF lives 40 minutes from treatment facility; prefers the oral option of

ibrutinib over the IV option of obinutuzumab/chlorambucil

• She is willing to give up toast with marmalade and take her

medication daily before her husband leaves for work

Using the Shared Care Model, How Do We Help Identify the Best Treatment for BF?

After two months on ibrutinib, BF presents to the clinic…so how is she doing?

• BF and her husband keep track of her pills daily. Her fatigue and blood counts have improved, but she is experiencing 2–3 loose stools per day, as well as some arthralgias and a rash.

• Assess grade of toxicity

• Loose stool: rule out infectious etiology

• Arthralgias:

• Magnesium: yes or no?

• Oral pain medications?

Case 1Conclusion

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The SHARE ApproachCreated by the Agency for Healthcare Research and Quality (AHRQ)

to foster practitioner utilization of SDM

Seek patient's participation

Help patient explore and compare treatments

Assess patient's values and preferences

Reach a decision with your patient

Evaluate your patient’s decision

https://www.ahrq.gov/professionals/education/curriculum‐tools/shareddecisionmaking/index.html.

Improving AdherenceSHARE

https://www.ons.org/practice‐resources/toolkits/oral‐adherence.

Communication Approaches

Traditional Counseling Motivational Interviewing

• HCP is the healthcare expert• Assumes patient lacks knowledge• Tells patient what to do• Hopes patient follows instructions

• HCP develops partnership with patient• Exchanges information to facilitate an informed decision• Patient has the right to decide own care

• HCP provides definitive information• Directives are presumed to be non‐negotiable

• HCP provides information to patient for the purpose of developing discrepancy between present behavior and goal

• HCP dictates healthcare behavior • HCP and patient negotiate behavior and reach agreement

• Goal is to motivate the patient• Goal is to assess motivation and elicit patient’s

commitment to change behavior

• HCP persuades patient to change behavior • HCP understands and accepts patient’s actions

• HCP expects respect from patient • HCP must earn respect from patient

Improving AdherenceONS Toolkit

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Barriers to Adherence


Dimension Barriers

Personal and Patient Factors

• Emotional and mental status• Physical status and comorbid conditions• Social supports• Feelings about disease, self‐efficacy, and outcome expectation• Socioeconomic status

Treatment‐related Factors

• Goal of therapy• Complexity of treatment regimen• Immediacy and evidence of benefit• Short‐ and long‐term side effects• Cost of medication and copay

Healthcare System

• Relationship with providers• Communication with providers• Education of patient and caregivers• Satisfaction with care• Insurance coverage• Access to convenient and efficient clinic



A treatment regimen that is not a good lifestyle fit may result in poor adherence to therapy, and changing one’s lifestyle can be challenging. • Begin by assessing the individual’s readiness to change.• Ask patient to rate how ready he/she is for change by drawing an arrow to or

circling a number in the appropriate area on the scale. • A score >5 indicates patient is ready to work toward changing behavior.

Readiness to Change Scale

0 1 2 3 4 5 6 7 8 9 10

Not Ready Considering Change Ready

Readiness Ruler


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• The introduction of kinase inhibitors, with unique toxicities and indefinite dosing, has exponentially increased the monitoring required for a panel of CLL patients

• Collaboration between physicians, nurse practitioners, nurses, and pharmacists is essential to effectively manage these patients• APP‐run oral therapy clinics• APP‐driven toxicity monitoring and therapy• Pharmacist counseling and assistance with insurance approval

APP=advanced practice provider.

Collaborative Management of Patients Receiving Kinase Inhibitors

• AB is a 68‐year‐old female with MCL who is receiving ibrutinib 560 mg PO daily as second‐line therapy

• On treatment for 14 months with good disease control

• AB had been feeling well until 2 months ago, when she began experiencing heart palpitations

• Holter monitor demonstrated intermittent Afib with RVR

• Treatment with calcium channel blocker initiated, followed by amiodarone, without significant decrease in symptoms

• AB reports skipping ibrutinib doses because of fear she’ll have a heart attack

Case Study 2R/R MCL

RVR=rapid ventricular rate.

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• Switch to acalabrutinib

• Atrial fibrillation likely due to off‐target effects, potentially through TEC leading to PI3K/AKT inhibition

• Acalabrutinib does not appear to be associated with atrial fibrillation, so would be a good choice for this patient

McMullen JR, et al. Blood. 2014.

Case Study 2Conclusion

• JK is a 65‐year‐old female with CLL who receives ibrutinib as third‐line therapy; she has been on treatment for 3 years and feels well

• On routine exam, you note that she has no palpable lymphadenopathy, but ALC has increased from 3000/mL to 6000/mL

• JK reports compliance with ibrutinib• You ask her to return in 2 months

At that time: JK’s ALC has risen to 8000/mL; she remains asymptomatic; new 1.5 cm cervical lymph nodes are noted

Case 3R/R CLL

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Patient is relapsing on ibrutinib

• Relapse evidenced by increasing WBC count and presence of new palpable adenopathy

With other agents, immediate discontinuation of therapy would be warranted

• Tempo of relapse tends to escalate when ibrutinib is discontinued

• Ibrutinib should be continued until next therapy is started

Case 3Conclusion

• CLL therapy has advanced significantly with the introduction of kinase inhibitors and venetoclax

• With the rapid approval of new agents in CLL with new toxicities and the potential for life‐long therapy, a collaborative approach is necessary to manage these increasingly complex patients

• Collaboration between RNs, APPs, and physicians is especially important during therapy transitions with these novel agents

Conclusions

Page 33

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Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP‐196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):323–332.Chanan‐Khan A, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double‐blind, phase 3 study. Lancet Oncol. 2016;17(2):200–211.

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FDA Approved Drug: Copanlisib. U.S. Food and Drug Administration website. September 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209936s000lbl.pdf. Accessed May 2018.

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ReferencesFDA Approved Drug: Everolimus. U.S. Food and Drug Administration website. April 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022334s040,203985s013lbl.pdf. Accessed May 2018.

FDA Approved Drug: Fostamatinib. U.S. Food and Drug Administration website. April 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209299lbl.pdf. Accessed May 2018.

FDA Approved Drug: Ibrutinib. U.S. Food and Drug Administration website. February 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205552Orig2lbl.pdf. Accessed May 2018.FDA Approved Drug: Idelalisib. U.S. Food and Drug Administration website. July 2014. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206545lbl.pdf. Accessed May 2018.

FDA Approved Drug: Temsirolimus. U.S. Food and Drug Administration website. March 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022088s021s023lbl.pdf. Accessed May 2018.

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Abbreviations• AAPA=American Academy of Physician

Assistants

• ABC=Association of Black Cardiologists

• ACC=American College of Cardiology

• ACPM=American College of Preventive

Medicine

• ADCC=antibody‐dependent cell‐mediated

cytotoxicity

• AE=adverse event

• Afib=atrial fibrillation

• AGS=American Geriatrics Society

• AHA=American Heart Association

• AHRQ=Agency for Healthcare Research and

Quality

• ALC=absolute lymphocyte count

• APhA=American Pharmacists Association

• APP=advanced practice provider

• ASH=American Society of Hypertension

• ASPC=American Society for Preventive

Cardiology

• ATP=adenosine triphosphate

• BCL=B‐cell lymphoma

• BCR=B‐cell receptor

• BET=bromodomain and extraterminal motif

• BTK=Bruton’s tyrosine kinase

• BTKi=Bruton’s tyrosine kinase inhibitor

• CARD11=caspase recruitment domain‐

containing protein 1

• CDK=cyclin‐dependent kinase

Abbreviations• cGVHD=chronic graft versus host disease

• CLL=chronic lymphocytic leukemia

• CR=complete response

• CRi=complete remission with incomplete

hematologic recovery

• ECG=electrocardiogram

• EGFR=epidermal growth factor receptor

• FCR=fludarabine, cyclophosphamide,

rituximab

• Hbg=hemoglobin

• HCP=healthcare provider

• HSV=herpes simplex virus

• HTN=hypertension

• Ig=immunogloblin

• ITK=interleukin‐2–inducible T‐cell kinase

• IV=intravenous

• IVIG=intravenous immunoglobulin

• mAb=monoclonal antibody

• MCL=mantle cell lymphoma

• MZL=marginal zone lymphoma

• NCCN=National Comprehensive Cancer

Network

• NHL=non‐Hodgkin lymphoma

• NK=natural killer (cells)

• NMA=National Medical Association

• N/V=nausea and vomiting

• OBZ=obinutuzumab

• OFA=ofatumumab

Page 37

Abbreviations• OR=overall response

• ORR=objective response rate

• OS=overall survival

• PBMC=peripheral blood mononuclear cells

• PCNA=Preventative Cardiovascular Nurses

Association

• PCP=Pneumocystis pneumonia

• PD=progressive disease

• PFS=progression‐free survival

• PI3K=phosphoinositide 3‐kinase

• PLCγ2=phospholipase C gamma 2

• PO=by mouth

• PR=partial response

• PR + L=partial response with lymphocytosis

• SD=stable disease

• SDM=shared decision making

• SLL=small lymphocytic leukemia

• SMX=sulfamethoxazole

• SYK=spleen tyrosine kinase

• TEAE=treatment‐emergent adverse event

• TEC=tyrosine kinase expressed in

hepatocellular carcinoma

• TMP=trimethoprim

• TRZ=trastuzumab

• UA=urinalysis

• WBC=white blood cell

• WM=Waldenstrommacroglobulinemia

Notes

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Documents

ONS BTK 5.11.18 HANDOUT - ceconcepts.com BTK HANDOUT 5.11.pdf · CLL, % TP53 mutation ~5–10% ~40% del(11q) ~11% ~20% ... 0 6 12 213 9 15 2418 0 20 40 60 80 100 Months 10 30 50 70