Andre H. Goy, MD, Richard R. Furman, MD, Krish Patel, MD, and Deborah M. Stephens, DO, prepared useful practice aids pertaining to B-cell malignancies for this CME activity titled "How I Think, How I Treat: BTK Inhibitors as a Clinical Strategy in CLL, MCL, and Beyond—Therapeutic Selection, Sequencing, and Next Steps." For the full presentation, monograph, complete CME information, and to apply for credit, please visit us at http://bit.ly/2P5FeQk. CME credit will be available until December 29, 2020.

1. Clinical Guide to Using BTK Inhibitors
in B-Cell Non-Hodgkin Lymphoma
PRACTICE AID
Access the activity,“How I Think, How I Treat: BTK Inhibitors as a Clinical Strategy in CLL, MCL, and Beyond—Therapeutic Selection, Sequencing, and Next Steps,”
at www.peerview.com/FKM40.
AEs in ≥20% of pts and DDIs
• Neutropenia, thrombocytopenia,
diarrhea, anemia,
musculoskeletal pain, rash,
nausea, bruising, fatigue,
hemorrhage, and pyrexia
• DDIs with CYP3A inhibitors and
inducers
Use in special populations
• Avoid use of ibrutinib in
patients with severe baseline
hepatic impairment
• In patients with mild or
moderate impairment,
reduce ibrutinib dose
Dosing
• MCL/MZL: 560 mg orally once daily
• CLL/SLL and WM: 420 mg orally
once daily
Monitor for
• Bleeding, infections, fever, cardiac
arrhythmias, elevated BP, TLS, and
secondary primary malignancies
Assess/advise
• CBCs monthly; TLS baseline risk
• Women to avoid pregnancy while on
drug and 1 mo after cessation, and men
to avoid fathering a child during the
same period
Kinome: Percent Inhibition5
NCCN recommendations4
• Testing for BTK and PLCG2 mutations may be useful in patients receiving ibrutinib
and suspected of having progression
• BTK and PLCG2 mutation status alone is not an indication to change treatment
Indications
• MCL with ≥1 prior therapy, CLL/SLL (single agent or in combination with obinutuzumab2
), CLL/SLL with 17p deletion, WM (single
agent or in combination with rituximab3
), MZL requiring systemic therapy and with ≥1 prior anti-CD20–based therapy
Currently available BTK inhibitors have varying mechanistic and safety profiles; this guide summarizes information on these
and other aspects, including dosing, safety monitoring, and drug interactions
Ibrutinib1
TKL
STE
CK1
AGC
CAMKCMGC
Other
TK
N
N
N
N
N
H2
N
O
O
100%
99.9%
99% to 99.9%
95% to 99%
90% to 95%
65% to 90%
<65%

2. Clinical Guide to Using BTK Inhibitors
in B-Cell Non-Hodgkin Lymphoma
PRACTICE AID
Access the activity,“How I Think, How I Treat: BTK Inhibitors as a Clinical Strategy in CLL, MCL, and Beyond—Therapeutic Selection, Sequencing, and Next Steps,”
at www.peerview.com/FKM40.
AEs in ≥20% of pts and DDIs
• Neutropenia, thrombocytopenia,
diarrhea, anemia, musculoskeletal
pain, rash, nausea, bruising, fatigue,
hemorrhage, and pyrexia
• DDIs with CYP3A inhibitors and inducers,
and gastric acid–reducing agents (PPIs,
H2-receptor antagonists, and antacids)
Use in special populations
• Advise women not to
breastfeed
Dosing
• 100 mg orally approximately every
12 h; swallow whole with water, with
or without food
• Advise not to break, open, or chew
capsule
Monitor for
• Bleeding, signs and symptoms
of infections, secondary primary
malignancies, atrial fibrillation, and
trial flutter
Assess/advise
• CBCs monthly
• Patients to use sun protection
Kinome: Percent Inhibition5
NCCN recommendations4
• NCCN also recommends acalabrutinib for relapsed/refractory CLL (except
ibrutinib-refractory CLL with BTK C481S mutations)
• Patients with ibrutinib intolerance have been successfully treated with
acalabrutinib without recurrence of these symptoms
Indications
• Adult patients with MCL who have received ≥1 prior therapy
Currently available BTK inhibitors have varying mechanistic and safety profiles; this guide summarizes information on these
and other aspects, including dosing, safety monitoring, and drug interactions
Acalabrutinib6
TKL
STE
CK1
AGC
CAMKCMGC
Other
TK
O
N
N
N
NH2
N
O NH
N
100%
99.9%
99% to 99.9%
95% to 99%
90% to 95%
65% to 90%
<65%

3. AE: adverse event; BTK: Bruton's tyrosine kinase; CAMK: calcium/calmodulin-dependent protein kinase; CBC: complete blood count; CK1: casein kinase 1; CLL: chronic lymphocytic leukemia; CYP3A: cytochrome P450 3A; DDI: drug–drug interaction; MCL: mantle cell lymphoma;
MZL: marginal zone B-cell lymphoma; NCCN: National Comprehensive Cancer Network; PPI: proton pump inhibitor; SLL: small lymphocytic lymphoma; STE: sulfotransferase, estrogen-preferring; TK: tyrosine kinase; TKL: tyrosine kinase–like; TLS: tumor lysis syndrome;
WM: Waldenström’s macroglobulinemia.
1. Imbruvica (ibrutinib) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205552s002lbl.pdf. Accessed November 12, 2019. 2. http://www.ascopost.com/News/59690. Accessed November 12, 2019. 3. http://www.ascopost.com/News/59204.
Accessed November 12, 2019. 4. NCCN Clinical Practice Guidelines in Oncology. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Version 2.2020. 5. Kaptein A et al. 60th American Society of Hematology Meeting and Exposition (ASH 2018). Abstract 1871.
6. Calquence (acalabrutinib) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/210259s000lbl.pdf. Accessed November 12, 2019. 7. Brukinsa (zanubrutinib) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/
label/2019/213217s000lbl.pdf. Accessed November 12, 2019.
Clinical Guide to Using BTK Inhibitors
in B-Cell Non-Hodgkin Lymphoma
PRACTICE AID
Access the activity,“How I Think, How I Treat: BTK Inhibitors as a Clinical Strategy in CLL, MCL, and Beyond—Therapeutic Selection, Sequencing, and Next Steps,”
at www.peerview.com/FKM40.
AEs in ≥20% of pts and DDIs
• Neutropenia, thrombocytopenia,
upper respiratory tract infection,
decreased white blood cells,
decreased hemoglobin, rash,
bruising, diarrhea, and cough
• DDIs with CYP3A inhibitors and
inducers
Use in special populations
• In patients with severe
hepatic impairment, reduce
zanubrutinib dose
• Advise women not to
breastfeed
Dosing
• 160 mg orally twice daily or 320 mg
orally once daily; swallow whole
with water, with or without food
• Advise not to break, open, or
chew capsule
Monitor for
• Bleeding, signs and
symptoms of infections,
secondary primary
malignancies, atrial
fibrillation,
and atrial flutter
Assess/advise
• CBCs
• Avoid use during pregnancy
Indications
• Adult patients with MCL who have received ≥1 prior therapy
Currently available BTK inhibitors have varying mechanistic and safety profiles; this guide summarizes information on these
and other aspects, including dosing, safety monitoring, and drug interactions
TKL
STE
CK1
AGC
CAMKCMGC
Other
TK
Zanubrutinib7
N
N
N
HN
H2
N
O
O
O
Kinome: Percent Inhibition5
100%
99.9%
99% to 99.9%
95% to 99%
90% to 95%
65% to 90%
<65%

4. Selected Studies With BTK Inhibitors
Clinical Trial Landscape of B-Cell Non-Hodgkin Lymphoma1
PRACTICE AID
Access the activity,“How I Think, How I Treat: BTK Inhibitors as a Clinical Strategy in CLL, MCL, and Beyond—Therapeutic Selection, Sequencing, and Next Steps,”
at www.peerview.com/FKM40.
Ibrutinib
Zanubrutinib
(BGB-3111)
Key: ˜ Active, not recruiting ˜ Currently recruiting
Phase 3 Clinical
Trials
Phase 3 Clinical
Trials
PFS
NCT01776840 (SHINE)
Ibrutinib + bendamustine + rituximab in patients with newly diagnosed MCL
CR, VGPR
NCT03053440 (BGB-3111-302 ASPEN)
Zanubrutinib vs ibrutinib in patients with WM
PFS
NCT02947347 (PERSPECTIVE)
Ibrutinib + rituximab in patients with treatment-naïve FL
PFS
NCT03112174 (SYMPATICO)
Ibrutinib + venetoclax in previously treated patients with MCL
PFS
ISRCTN01844152 (FLAIR)2
Ibrutinib monotherapy vs ibrutinib + rituximab vs ibrutinib + venetoclax vs
FCR in patients with treatment-naïve CLL/SLL
TLS, DLT, PFS, CR
NCT03462719 (GLOW/CLL 3011)
Ibrutinib + venetoclax vs chlorambucil + obinutuzumab for patients with newly diagnosed CLL/SLL
PFS
NCT03336333 (BGB-3111-304 SEQUOIA)
Zanubrutinib vs bendamustine + rituximab in patients with previously untreated CLL/SLL
Approved BTK inhibitors currently include ibrutinib, acalabrutinib,
and zanubrutinib
Primary
Endpoint(s)
Primary
Endpoint(s)

5. BTK: Bruton's tyrosine kinase; CLL: chronic lymphocytic leukemia; CR: complete response; DLT: dose-limiting toxicities; FCR: fludarabine, cyclophosphamide, and rituximab; FL: follicular lymphoma; MCL: mantle cell lymphoma; MRD-CR: minimal residual disease–negative
complete response; R/R: relapsed/refractory; SLL: small lymphocytic lymphoma; TLS: tumor lysis syndrome; TN: treatment naïve; VGPR: very good partial response; WM: Waldenström’s macroglobulinemia.
1. https://clinicaltrials.gov/ct2/home. Accessed November 19, 2019. 2. https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-ibrutinib-rituximab-chronic-lymphocytic-leukaemia-flair#undefined. Accessed November 19, 2019.
3. Sharman JP et al. 61st Annual Meeting & Exposition of the American Society of Hematology (ASH 2019). Abstract 31. 4. NCCN Clinical Practice Guidelines in Oncology. B-Cell Lymphomas. Version 5.2019. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf.
Accessed November 19, 2019.
Selected Studies With BTK Inhibitors
Clinical Trial Landscape of B-Cell Non-Hodgkin Lymphoma1
PRACTICE AID
Access the activity,“How I Think, How I Treat: BTK Inhibitors as a Clinical Strategy in CLL, MCL, and Beyond—Therapeutic Selection, Sequencing, and Next Steps,”
at www.peerview.com/FKM40.
PFS
Results available (ASH 2019): Acalabrutinib
± obinutuzumab significantly improved
PFS vs obinutuzumab + chlorambucil3
NCT02475681 (Elevate CLL TN)
Acalabrutinib monotherapy vs acalabrutinib + obinutuzumab vs obinutuzumab + chlorambucil
in patients with previously untreated CLL/SLL
PFS
NCT02972840 (ACE-LY-308)
Acalabrutinib + bendamustine/rituximab vs bendamustine/rituximab
in patients with previously untreated MCL
PFS
NCT02970318 (ACE-CL-309)
Acalabrutinib vs investigator's choice of idelalisib + rituximab
or bendamustine + rituximab in R/R CLL/SLL
MRD- CR, time to first therapy
NCT03516617 (Phase 2)
Acalabrutinib ± obinutuzumab in patients with early stage CLL/SLL
MRD- CR
NCT03580928 (AVO; Phase 2)
Venetoclax + obinutuzumab + acalabrutinib in patients with newly diagnosed CLL/SLL
PFS
NCT02477696 (Elevate CLL R/R)
Acalabrutinib vs ibrutinib in previously treated patients with high-risk CLL/SLL
Key: ˜ Active, not recruiting ˜ Currently recruiting
Acalabrutinib
Primary
Endpoint(s)
Approved BTK inhibitors currently include ibrutinib, acalabrutinib,
and zanubrutinib
Phase 3 Clinical
Trials
NCCN Recommendation4
The NCCN believes that the best management for any patient with cancer is in a clinical trial. Participation in a clinical trial is especially encouraged.