Oncology Conference Advances in CLL: Key Elements for Todays - - PowerPoint PPT Presentation

2020 Spring Oncology Conference

Advances in CLL: Key Elements for Today’s Clinics

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• Analyze the efficacy and safety of treatment options as well as molecular features
• f CLL and patient characteristics/preferences to aid in the successful delivery of

individualized therapy to patients with newly diagnosed and relapsed/refractory CLL

• Consider the optimal treatment for patients with newly diagnosed and

relapsed/refractory CLL based on available clinical data, guidelines, and expert recommendations

• Develop team-based strategies to address challenges to optimal treatment,

including the identification and management of AEs, to ensure treatment compliance as well as improved clinical outcomes and quality of life

Learning Objectives

AE = adverse event; CLL = chronic lymphocytic leukemia.

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• More than 21,000 estimated new cases in 2020 in the United States alone[1]

‒ Most common type of leukemia in adults (37%)

• Median age at diagnosis: 70 years[2]
• SLL and CLL considered the same B-cell malignancy[3]

‒ CLL: > 5000 clonal B cells in peripheral blood ‒ SLL: presence of lymphadenopathy and/or splenomegaly and < 5000 clonal B cells in peripheral blood

• Historical 5-year survival: 66% (range: few mos to normal life span)[4]

‒ Current (2009-2015) 5-year survival: 85%[2]

CLL/SLL: Background

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SLL = small lymphocytic lymphoma.

• 1. Siegel. CA Cancer J Clin. 2020;70:7. 2. SEER Cancer Stat Facts. Chronic lymphocytic leukemia.
• 3. American Cancer Society. Chronic lymphocytic leukemia. 4. Nabhan. JAMA. 2014;312:2265.

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CLL: Prognostic Value of FISH

• Dohner. NEJM. 2000;343:1910. Dohner. Leukemia. 1997;11(suppl 2):S19. Oscier. Haematologica. 1999;84(suppl EHA-4):88.
• Jarosova. Onkologie. 2001;24:60. Dewald. Br J Haematol. 2003;121:287. Sindelárová. Cancer Genet Cytogenet. 2005;160:27.

Probability of OS From Diagnosis, by Genetic Aberration

100 80 60 40 20

Patients Surviving (%) Months

17p deletion 11q deletion 12q trisomy Normal 13q deletion as sole abnormality

FISH Lesion Patients With Abnormality (%)

Dohner et al 1997 Oscier et al 1999 Jarosova et al 2001 Dewald et al 2003 Sindelarava et al 2005

del(13q) 45 36 18 47 54 Trisomy 12 15 15 13 25 16 del(17p) 10 8 11 8 16 del(11q) 20 17 11 15 12

FISH Abnormalities Present in 268/325 Patients (82%) Lesion

% Median OS, Mos del(13q) 55 133 del(11q) 18 79 Trisomy 12 16 114 del(17p) 7 32 del(6q) 6 N/A Normal 18 111

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9 8 7 6 5 4 3 2 1

• OS effect of TP53 wild type:

‒ vs TP53 mut only: P = .013 ‒ vs TP53 del only: P = .006 ‒ vs TP53 mut + del: P < .001

• Analysis based on cases referred to the Munich Leukemia Laboratory between August 2005 and May 2013

CLL: Impact of TP53 Mutations and TP53 Deletion on OS (N = 1148)

• Stengel. Leukemia. 2017;31:705.

Frequency of TP53 Alterations in Relation to Total Size of Each Cohort (%) CLL TP53 mut only TP53 del only TP53 mut + del

Years

100

OS (%)

80 60 40 20 TP53 wt TP53 alteration P < .001 10 1 2 3 4 5 6 7 8 9

Years

100

OS (%)

80 60 40 20 TP53 wt TP53 mut only 10 1 2 3 4 5 6 7 8 9 TP53 del only TP53 mut + del

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Survival in CLL According to IGHV Mutational Status

All Patients (n = 84) Binet Stage A Patients (n = 62) Surviving (%) Surviving (%) P = .0008 P = .001 Mutated Unmutated Unmutated Mutated Months

50 100 150 200 250 300 20 40 60 80 100

Months

50 100 150 200 250 300 20 40 60 80 100

• Hamblin. Blood. 1999;94:1848.

Previously Untreated CLL

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Case Study 1: An Elderly Patient With del(17p) and a TP53 Mutation

• 75-year-old female patient who presented in 2013 with WBC 13K, ALC 9,

Hgb 13, PLTs 160K

• Flow: typical CLL pattern
• FISH: no mutations
• She was observed for 5 years
• In 2018, progressive weight loss, splenomegaly, bulky lymphadenopathy, WBC

310K, Hgb 9 ‒ IGHV unmutated, TP53 mutation ‒ FISH: del(17p)

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• An international, randomized phase III trial
• Primary endpoint: PFS
• Secondary endpoints: OS, ORR, EFS, rate of hematologic improvement, and safety

Phase III RESONATE-2: Ibrutinib vs Chlorambucil in Patients 65 Years of Age or Older With Untreated CLL/SLL

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Ibrutinib 420 mg/day until PD or unacceptable toxicity (n = 136)

Patients 65 years of age

• r older with treatment-

naive CLL/SLL; no del(17p); no warfarin use (N = 269)

Crossover upon PD (n = 43)

Chlorambucil 0.5 mg/kg (up to maximum of 0.8 mg/kg)

• n Days 1, 15 of 28-day cycle

for up to 12 cycles (n = 133)

• Burger. NEJM. 2015;373:2425.

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RESONATE-2: 5-Year Follow-up Results

• Burger. Leukemia. 2020;34:787.

Ibrutinib (n = 136) Chlorambucil (n = 133) mPFS, mos NE 15 HR (95% CI) 0.146 (0.098-0.218) 5-year PFS rate, % 70 12 Ibrutinib Chlorambucil mOS, mos NE NE HR (95% CI) 0.450 (0.266-0.761) 5-year OS rate, % 83 68

100 80 60 40 20 0 3 6 9 121518 2124 27303336 394245 48 5154 57 606366 69

PFS (%) Months

Ibrutinib Chlorambucil 100 80 60 40 20 3 6 9 12 15 18 21 24 27 30 3336 39 42 45 48 51 54 57 60 63 66 69

OS (%) Months

Ibrutinib Chlorambucil

• Ibrutinib was generally well tolerated with no new safety signals reported with long-term follow-up

(many AEs decreased over time)

• More than one half (58%) of patients remained on ibrutinib at the 5-year follow-up

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• Primary analysis of randomized, open-label phase III trial (data cutoff: October 24, 2018)

Phase III E1912 Trial of Ibrutinib + Rituximab vs FCR in Patients ≤ 70 Years of Age With Previously Untreated CLL

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• Shanafelt. NEJM. 2019;381:432. Shanafelt. ASH 2019. Abstr 33.
• Primary endpoint: PFS

⎻ Study has 80% power to detect PFS HR for IR vs FCR of 0.67 using stratified log-rank test, with prespecified boundary of 2.87 for first PFS interim analysis corresponding to 1-sided P = .0025

• Secondary endpoints: OS, safety

Patients with previously untreated CLL requiring treatment per IWCLL 2008, ≤ 70 years of age, ECOG PS 0-2, CrCl > 40 mL/min, ability to tolerate FCR, no del(17p) by FISH (N = 529) Ibrutinib maintenance until PD Ibrutinib 420 mg PO daily for cycles 1-7 + Rituximab 50 mg/m2 IV on Day 1, cycle 2, then 325 mg/mg2 on Day 2, cycle 2, then 500 mg/m2 on Day 1, cycles 3-7 (n = 354) Fludarabine 25 mg/m2 IV on Days 1-3 for cycles 1-6 + Cyclophosphamide 250 mg/m2 IV on Days 1-3 for cycles 1-6 + Rituximab 50 mg/m2 IV on Day 1, cycle 1, then 325 mg/mg2 on Day 2, cycle 1, then 500 mg/m2 on Day 1, cycles 2-6 (n = 175) Stratified by age (< vs ≥ 60 yrs), ECOG PS (0/1 vs 2), stage (III-IV vs I-II), del(11q22.3) vs other 28-day cycles

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1.0 0.8 0.6 0.4 0.2

E1912: PFS (Primary Endpoint)

• Shanafelt. ASH 2019. Abstr 33.

1 2 3 4 5

Probability Years

Median follow-up: 48 months

Number at risk 175 354 145 338 123 321 82 280 31 121 8 HR: 0.39 (95% CI: 0.26-0.57) P < .0001 3-year rates: 89%, 71%

FCR (52 events/175 cases) Ibrutinib + rituximab (58 events/354 cases)

FCR Ibrutinib + R

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E1912: PFS by IGHV Status

• Shanafelt. ASH 2019. Abstr 33.

Median follow-up: 48 months

1.0 0.8 0.6 0.4 0.2 1 2 3 4 5

Probability Years Number at risk

71 210 63 202 50 193 31 165 8 72 7 Ibrutinib + rituximab (36 events/210 cases)

HR: 0.28 (95% CI: 0.17-0.48) P < .0001 3-year rates: 89%, 65%

IGHV Unmutated

1.0 0.8 0.6 0.4 0.2 1 2 3 4 5

Probability Years Number at risk

44 70 38 67 34 64 25 54 11 20 1

HR: 0.42 (95% CI: 0.16-1.16) P = .086 3-year rates: 88%, 82%

IGHV Mutated

FCR (8 events/44 cases) Ibrutinib + rituximab (10 events/70 cases) FCR (29 events/71 cases) FCR Ibrutinib + R FCR Ibrut + R

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E1912: OS

• Shanafelt. ASH 2019. Abstr 33.

1.0 0.8 0.6 0.4 0.2 1 2 3 4 5

Probability Years

Median follow-up: 48 months

Number at risk

175 354 155 347 143 343 131 355 69 193 9 37

Ibrutinib + rituximab (11 events/354 cases) HR: 0.34 (95% CI: 0.15-0.79) P = .009 3-year rates: 99%, 93% FCR (12 events/175 cases)

FCR Ibrutinib + R

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• Multicenter, randomized, double-blind phase III study (data cutoff: October 4, 2018)

First-line Ibrutinib vs Ibrutinib + Rituximab vs Bendamustine + Rituximab in CLL/SLL (A041202): Study Design

• Woyach. NEJM. 2018;379:2517.
• Primary endpoint: PFS

‒ 2 primary comparisons of ibrutinib vs BR and ibrutinib + R vs BR with 90% power to detect HR of 0.586 (estimated 2-yr PFS rates: ibrutinib, 75%; BR, 61%) and overall 1-sided α = 0.025 for each comparison ‒ If both primary comparisons significant, third planned comparison of ibrutinib + R vs ibrutinib

Untreated patients with CLL meeting IWCLL 2008 criteria for tx initiation; ≥ 65 years of age; ECOG PS 0-2; ANC ≥ 1000 unless due to BM involvement; PLT ≥ 30; CrClCG ≥ 40; AST/ALT ≤ 2.5 x ULN; no heparin or warfarin (N = 547) Ibrutinib 420 mg daily (n = 182) Ibrutinib 420 mg daily + Rituximab 375 mg/m2 weekly x 4 weeks starting cycle 2 Day 1; cycles 3-6 Day 1* (n = 182) Bendamustine 90 mg/m2 on Days 1, 2 + Rituximab 375 mg/m2 on cycle 1 Day 1; 500 mg/m2 on cycles 2-6 Day 1* (n = 183) Stratified by Rai stage (high vs intermediate risk), del(11q22.3) or del(17p13.1) (presence vs absence), ZAP-70 methylation (< vs ≥ 20%) Until PD Crossover to ibrutinib within 1 year of PD allowed Ibrutinib until PD *28-day cycles.

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• PFS significantly improved with

ibrutinib vs BR and ibrutinib + R vs BR (both 1-sided P < .001)

‒ HR for ibrutinib vs BR: 0.39 (95% CI: 0.26-0.58) ‒ HR for ibrutinib + R vs BR: 0.38 (95% CI: 0.25-0.59)

• No significant difference for ibrutinib +

R vs ibrutinib only (1-sided P = .49)

‒ HR: 1.00 (95% CI: 0.62-1.62)

A041202: PFS of Eligible Patients* (Primary Endpoint)

• Woyach. NEJM. 2018;379:2517.

*524 of 547 randomized patients.

Events, n/N Median PFS, Mos (95% CI) 2-Yr PFS, % (95% CI) Ibrutinib 34/178 NR 87 (81-92) Ibrutinib + R 32/170 NR 88 (81-92) BR 68/176 43 (38-NR) 74 (66-80)

PFS (%)

Number at risk Ibrutinib Ibrutinib + R BR

Months

178 170 176 165 159 140 154 145 129 147 138 122 78 74 57 136 132 103 120 115 88 45 40 26 22 20 11

100 80 60 40 20 6 12 18 24 30 36 42 48

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• PFS benefit with ibrutinib-containing regimens vs BR observed in all cytogenetic factor–related subgroups, with

del(17p13.1) being most pronounced

A041202: PFS by del(17p) and del(11q) Status

Events, n/N Median PFS, Mos (95% CI) Ibrutinib 2/9 NE Ibrutinib + R 3/11 NE BR 10/14 7 (4-23) Events, n/N Median PFS, Mos (95% CI) Ibrutinib 4/35 NE Ibrutinib + R 7/37 NE BR 15/33 41 (36-NE) Events, n/N Median PFS, Mos (95% CI) Ibrutinib 27/137 NE Ibrutinib + R 25/132 NE BR 45/134 51 (43-NE)

• Woyach. NEJM. 2018;379:2517.

del(17p) del(11q) Neither del(17p) or del(11q) PFS Probability

0.8 0.6 0.4 0.2 1.0

Months

6 12 18 24 30 36 42 48 52 0.8 0.6 1.0

Months

6 12 18 24 30 36 42 48 52 0.4 0.2 0.8 0.6 1.0

Months

6 12 18 24 30 36 42 48 52 0.4 0.2

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A041202: PFS by IGHV Mutation Status

• No significant interaction between IGHV mutation status and PFS benefit by regimen

‒ Increased PFS among patients with mutated vs unmutated IGHV disease (HR: 0.51; 95% CI: 0.32-0.81)

Events, n/N Median PFS, Mos (95% CI) Ibrutinib 7/45 NE Ibrutinib + R 6/45 NE BR 12/52 51 (51-NE) Events, n/N Median PFS, Mos (95% CI) Ibrutinib 16/77 NE Ibrutinib + R 20/70 NE (48-NE) BR 31/71 39 (32-NE)

Mutated IGHV PFS Probability 0.8

0.6 0.4 0.2 1.0

Months

6 12 18 24 30 36 42 48 52

Months Unmutated IGHV PFS Probability

0.8 0.6 0.4 0.2 1.0 6 12 18 24 30 36 42 48 52

• Woyach. NEJM. 2018;379:2517.

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A041202: Safety

Grade 3-5 AEs During Treatment or Follow-up,* n (%) Ibrutinib (n = 180) Ibrutinib + R (n = 181) BR (n = 176) P Value

Any hematologic

• Anemia
• Neutropenia
• Thrombocytopenia

74 (41) 21 (12) 27 (15) 12 (7) 70 (38) 11 (6) 39 (22) 9 (5) 107 (61) 22 (13) 71 (40) 26 (15) < .001 .09 < .001 .008 Any nonhematologic

• Bleeding
• Infections
• Febrile neutropenia
• Atrial fibrillation
• Hypertension

133 (74) 3 (2) 37 (21) 3 (2) 17 (9) 53 (29) 134 (74) 5 (3) 37 (20) 1 (1) 10 (6) 61 (34) 111 (63) 26 (15) 13 (7) 5 (3) 25 (14) .04 .46 .62 < .001 .05 < .001 Death

• Unexplained/unwitnessed
• During active treatment + 30 days
• During active treatment + 30 days, up to 6 cycles

7 (4) 13 (7) 3 (2) 4 (2) 13 (7) 6 (3) 2 (1) 2 (1) 2 (1) .24

• Woyach. ASH 2018. Abstr 6. Woyach. NEJM. 2018;379:2517.

*Excludes crossover.

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• Primary endpoint: PFS by IRC with acalabrutinib + obinutuzumab vs obinutuzumab + chlorambucil
• Key secondary endpoints: PFS of acalabrutinib vs obinutuzumab + chlorambucil, ORR by IRC and investigators,

time to next treatment, OS, safety

Phase III ELEVATE TN (ACE-CL-007): Study Design

Patients with treatment- naive CLL who are ≥ 65 years or < 65 years with CIRS score > 6 or CrCl < 70 mL/min (N = 535) Acalabrutinib 100 mg PO BID + Obinutuzumab* (n = 179) Obinutuzumab† + Chlorambucil 0.5 mg/kg PO D1, 15 (n = 177) Acalabrutinib 100 mg PO BID (n = 179)

Crossover allowed to acalabrutinib after IRC- confirmed progression

• Sharman. ASH 2019. Abstr 31.

*1000 mg IV on D1, 2, 8, 15 of 28-day cycle 2; Day 1 of subsequent cycles for total of 6 cycles.

†1000 mg IV on D1, 2, 8, 15 of 28-day cycle 1; Day 1 of cycles 2-6.

Stratified by del(17p) status, ECOG PS 0/1 vs 2, geographic region

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ELEVATE TN: Progression-Free Survival (IRC Assessed)

• Sharman. ASH 2019. Abstr 31.

Number at risk Acalabrutinib Acalabrutinib + O Chlorambucil-O

PFS (%) Months

179 179 177 176 166 162 170 161 157 168 157 151 159 148 102 163 153 136 160 150 113 46 43 13 41 40 13 4 4 3

100 80 60 40 20 6 12 18 24 30 36 42

155 147 86 109 103 46 104 94 41 2 3 2

Acalabrutinib + Obinutuzumab Acalabrutinib Chlorambucil + Obinutuzumab (Median PFS: 22.6 months; 95% CI: 20.2-27.6) HR (95% CI)

Acala-O vs Chl-O Acalabrutinib vs Chl-O Acala-O vs Acalabrutinib 0.10 (0.06-0.17) P < .0001 0.20 (0.13-0.30) P < .0001 0.49 (0.26-0.95)

93% 87% 47%

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ELEVATE TN: Progression-Free Survival Across Patient Subgroups

• Sharman. ASH 2019. Abstr 31.
• No. of Events/No. of Patients

Bulky disease < 10 cm ≥ 10 cm del(17)(p13.1) and/or TP53 mutation Yes No del(11)(q22.3) Yes No IGHV mutation status Unmutated Mutated Complex karyotype Yes No Acala-O Acala Acala-O Acala Acala-O Acala Acala-O Acala Acala-O Acala Acala-O Acala Acala-O Acala Acala-O Acala Acala-O Acala Acala-O Acala 14/173 0/4 3/25 11/154 4/31 10/146 11/103 3/74 3/29 9/126

Acala-O

21/160 4/15 6/23 20/156 3/31 23/148 16/119 10/58 3/31 20/117

Acala

81/167 81/167 11/14 11/14 16/25 16/25 77/152 77/152 26/33 26/33 66/143 66/143 78/116 78/116 14/59 14/59 20/32 20/32 59/121 59/121

Chl-O HR (95% CI)

0.11 (0.04-0.19) 0.18 (0.11-0.30) NE (NE-NE) 0.22 (0.07-0.71) 0.10 (0.03-0.34) 0.23 (0.09-0.61) 0.10 (0.05-0.18) 0.19 (0.11-0.31) 0.09 (0.03-0.26) 0.07 (0.02-0.22) 0.10 (0.05-0.20) 0.26 (0.16-0.41) 0.08 (0.04-0.16) 0.11 (0.07-0.19) 0.15 (0.04-0.52) 0.69 (0.31-1.56) 0.09 (0.03-0.29) 0.10 (0.03-0.33) 0.11 (0.05-0.21) 0.27 (0.15-0.46) 0.01 0.1 1 Favor Acala-O or acalabrutinib Favor Chl-O

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ELEVATE TN: Safety (Most Common AEs)

• Sharman. ASH 2019. Abstr 31.

AEs in ≥ 15% of Patients in Any Treatment Arm, % Acalabrutinib + Obinutuzumab (n = 178) Acalabrutinib (n = 179) Obinutuzumab + Chlorambucil (n = 169)

Any Grade Grade ≥ 3 Any Grade Grade ≥ 3 Any Grade Grade ≥ 3 Any 96.1 70.2 95.0 49.7 98.8 69.8 Headache 39.9 1.1 36.9 1.1 11.8 Diarrhea 38.8 4.5 34.6 0.6 21.3 1.8 Neutropenia 31.5 29.8 10.6 9.5 45.0 41.4 Fatigue 28.1 1.7 18.4 1.1 17.2 0.6 Contusion 23.6 15.1 4.1 4.1 Arthralgia 21.9 1.1 15.6 0.6 4.7 1.2 Cough 21.9 18.4 0.6 8.9 URTI 21.3 2.2 18.4 8.3 0.6 Nausea 20.2 22.3 31.4 Dizziness 18.0 11.7 5.9 Infusion-related reaction 13.5 2.2 39.6 5.3 Pyrexia 12.9 6.7 0.6 20.7 0.6

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ELEVATE TN: AEs of Clinical Interest for Acalabrutinib

• Sharman. ASH 2019. Abstr 31.

AE, n (%) Acalabrutinib + Obinutuzumab (n = 178) Acalabrutinib (n = 179) Obinutuzumab + Chlorambucil (n = 169)

Any Grade Grade ≥ 3 Any Grade Grade ≥ 3 Any Grade Grade ≥ 3 Atrial fibrillation 6 (3.4) 1 (0.6) 7 (3.9) 1 (0.6) Hypertension 13 (7.3) 5 (2.8) 8 (4.5) 4 (2.2) 6 (3.6) 5 (3.0) Bleeding

• Major bleeding

76 (42.7) 5 (2.8) 3 (1.7) 3 (1.7) 70 (39.1) 3 (1.7) 3 (1.7) 3 (1.7) 20 (11.8) 2 (1.2) Infection 123 (69.1) 37 (20.8) 117 (65.4) 25 (14.0) 74 (43.8) 14 (8.3) Second primary malignancy* 10 (5.6) 6 (3.4) 5 (2.8) 2 (1.1) 3 (1.8) 2 (1.2)

*Excluding non melanoma skin cancer.

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First-line Venetoclax + Obinutuzumab vs Chlorambucil + Obinutuzumab in CLL (CLL14): Study Design

• Fischer. NEJM. 2019;380:2225. NCT02242942.

Patients with previously untreated CLL and coexisting medical conditions (CIRS > 6 and/or CrCl < 70 mL/min) (N = 432) Venetoclax PO 5-wk ramp up from 20 to 400 mg/day starting

• n Day 22 of cycle 1, then 400 mg/day until end of cycle 12

+ Obinutuzumab IV 1000 mg Days 1, 8, 15 of cycle 1, then 1000 mg Day 1 of cycles 2-6 (n = 216) Chlorambucil PO 0.5 mg/kg Days 1, 15 of cycles 1-12 + Obinutuzumab IV 1000 mg Days 1-2, 8, 15 of cycle 1, then 1000 mg Day 1 in cycles 2-6 (n = 216)

• Open-label, multicenter, randomized phase III trial
• Primary endpoint: investigator-assessed PFS
• Secondary endpoints: IRC-assessed PFS, ORR, MRD negativity, OS, safety

Total 28-day cycles

• Venetoclax: 12
• Chlorambucil: 12
• Obinutuzumab: 6

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CLL14: Investigator-Assessed PFS (Primary Endpoint)

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• Fischer. NEJM. 2019;380:2225.

100 PFS (%)

HR: 0.35 (95% CI: 0.23-0.53; P < .001)

80 60 40 20 6 12 18 24 30 36 Months Venetoclax + obinutuzumab (n = 216) Chlorambucil + obinutuzumab (n = 216) 64% 88%

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CLL14: PFS by IGHV Mutation and TP53 Status

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• Fischer. NEJM. 2019;380:2225.

PFS by IGHV Mutation PFS by TP53 Status

Venetoclax + obinutuzumab and IGHV mutated Venetoclax + obinutuzumab and IGHV unmutated Chlorambucil + obinutuzumab and IGHV mutated Chlorambucil + obinutuzumab and IGHV unmutated Venetoclax + obinutuzumab and TP53 deletion and/or mutation Venetoclax + obinutuzumab and wild-type TP53 Chlorambucil + obinutuzumab and TP53 deletion and/or mutation Chlorambucil + obinutuzumab and wild-type TP53

PFS (%) 100 80 60 40 20 6 12 18 24 30 36 Months PFS (%) 100 80 60 40 20 6 12 18 24 30 36 Months

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CLL14: Response and OS

• Fischer. NEJM. 2019;380:2225.

HR: 1.24 (95% CI: 0.64-2.40; P = .52)

OS (%) 100 80 60 40 20 6 12 18 24 30 36 Months Venetoclax + obinutuzumab Chlorambucil + obinutuzumab

Patients With Response (%) 100 80 60 40 20 Chlorambucil + Obinutuzumab (n = 216) Venetoclax + Obinutuzumab (n = 216) P < .001 49.5 35.2 23.1 48.1 PR CR

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CLL14: MRD Negativity

MRD Status, % Venetoclax + Obinutuzumab (n = 216) Chlorambucil + Obinutuzumab (n = 216) P Value Peripheral blood

• Negative (< 10-4)*

76 35 < .001

• Negative (< 10-6)†

42 7 Bone marrow

• Negative (< 10-4)*

57 17 < .001

• Fischer. NEJM. 2019;380:2225.

*MRD status assessed by ASO-PCR 3 months after completion of treatment.

†MRD status assessed by NGS 3 months after completion of treatment.

• MRD negativity (< 10-4) with venetoclax + obinutuzumab occurred early and was

durable

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CLL14: Safety

Grade 3/4 AE, % Venetoclax + Obinutuzumab (n = 212) Chlorambucil + Obinutuzumab (n = 214)

Hematologic AEs 60 55

• Neutropenia

53 48

• Thrombocytopenia

14 15

• Anemia

8 7

• Febrile neutropenia

5 4 Injury, poisoning, procedural complications 12 14

• Infusion-related reaction

9 10 Infections and infestations 18 15

• Pneumonia

4 4 Metabolism, nutrition disorders* 12 6

Grade 5 AE, % Venetoclax + Obinutuzumab (n = 212) Chlorambucil + Obinutuzumab (n = 214)

Total events 8 4 Events during therapy 2 2

• Infections and

infestations 2 1

• Neoplasms

< 1 < 1 Events after therapy completion 5 2

• Cardiac disorders

1 < 1

• Infections and

infestations 2

• Neoplasms

< 1 < 1

• Other reasons

< 1 < 1

• Fischer. NEJM. 2019;380:2225.

*P = .02

Previously Treated CLL

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Case Study 2: A Normal-Risk Patient Relapsing on Chemoimmunotherapy

• A 78-year-old female diagnosed with CLL (mutated IGHV and trisomy 12)

‒ Treated with obinutuzumab and chlorambucil ‒ She tolerated 4 cycles of treatment before developing prolonged cytopenias ‒ On exam, there was no adenopathy or splenomegaly

• You chose to observe and initially cytopenias gradually resolved
• However, over the next 12 months, the patient had a rising ALC and developed

progressive anemia and thrombocytopenia ‒ Repeat FISH showed trisomy 12; TP53 status was negative

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• At time of interim analysis, median time on study was 9.4 months

Phase III RESONATE: Ibrutinib vs Ofatumumab in Previously Treated CLL/SLL

Protocol amended for crossover with support of data monitoring committee and discussion with health authorities.

Enrollment dates: June 2012 - April 2013 Patients with CLL/SLL diagnosis; ≥ 1 prior therapy; ECOG PS 0/1; measurable nodal disease (N = 391) Ibrutinib 420 mg/day PO until PD or unacceptable toxicity (n = 195) Ofatumumab IV starting dose of 300 mg followed by 2000 mg x 11 doses for 24 weeks (n = 196) Crossover to Ibrutinib 420 mg/day following PD (n = 122)

Stratified by refractory to purine analogue chemoimmunotherapy (no response

• r relapsed within 12 months); presence or absence of 17p13.1 (17p del)
• Byrd. NEJM. 2014;371:213.

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142 121 105 5 110 5 131 115

Median OS, mo (95% CI) HR (95% CI) Ibrutinib (n = 195) 67.7 (61.0-NE) Ofatumumab (n = 196) 65.1 (50.6-NE) 0.810 (0.602-1.091)

RESONATE: Final Analysis of PFS (Primary Endpoint) and OS

• Munir. Am J Hematol. 2019;94:1353.

Median follow-up: 65.3 months

20 40 60 80 100

3 6 9 12 15

Mos PFS (%)

Number at risk Ibrutinib Ofatumumab 195 196 189 159 179 120 171 67 161 34

18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72

154 22 149 19 146 14 138 10 123 9 115 6 99 4 92 4 84 4 82 4 80 4 77 3 70 3 65 3 56 3 33 5

Median PFS, mo 95% CI HR (95% CI) Ibrutinib (n = 195) 44.1 (38.5-55.2) Ofatumumab (n = 196) 8.1 (7.8-8.3) 0.148 (0.113-0.195) 20 40 60 80 100

3 6 9 12 15

Mos OS (%)

Number at risk Ibrutinib Ofatumumab 195 196 191 183 184 165 180 154 174 148

18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72

166 142 164 138 160 135 156 130 147 128 132 112 122 109 120 107 117 103 112 101 110 96 108 93 106 91 100 87 84 74 50 43 11 16

Ibrutinib Ofatumumab

75

1

Ibrutinib Ofatumumab

36

Most Common AEs (≥ 20% of Patients), % Any Grade Grade 3/4

Diarrhea 48 4 Fatigue 28 2 Nausea 26 2 Pyrexia 24 4

RESONATE Trials: Summary of AEs in the Ibrutinib Arm

AEs of Interest

• Infection (all grade): 70%

̶ Grade ≥ 3: 24% (8% pneumonia)

• Bleeding/bruising (all grade): 44%

̶ Grade ≥ 3: 1% (no grade 5)

• Cardiac (all grade): 8%

̶ Grade ≥ 3 cardiac: 3% (afib) ̶ 5% atrial fibrillation (all grades)

Most Common Grade ≥ 3 Hematologic AEs, % Grade 3/4

Neutropenia 16 Thrombocytopenia 6 Anemia 5

• Byrd. NEJM. 2014;371:213. Munir. Am J Hematol. 2019;94:1353.
• Treatment-emergent AEs generally decreased over time (except HTN and bruising)

37

• Multicenter, randomized, open-label phase III trial

Phase III Trial of Venetoclax + Rituximab vs BR in Previously Treated CLL/SLL (MURANO): Study Design

• Seymour. NEJM. 2018;378:1107. NCT02005471.

Adult patients with R/R CLL, 1-3 prior tx lines (with ≥ 1 CT-containing regimen), prior bendamustine permitted if DoR ≥ 24 months (N = 389) Venetoclax monotherapy until PD, unacceptable toxicity, or maximum of 2 years from Day 1 of cycle 1 Venetoclax dose ramp-up 20-400 mg PO daily for 5 wks then 400 mg PO daily for cycles 1-6 + Rituximab 375 mg/m2 on Day 1 of cycle 1, then 500 mg/m2 Day 1 of cycles 2-6 (n = 194) Bendamustine 70 mg/m2 on Days 1, 2 of cycles 1- 6 + Rituximab 375 mg/m2 on Day 1 of cycle 1, then 500 mg/m2 Day 1 of cycles 2-6 (n = 195)

Stratified by del(17p), prior tx response,* geographic region *High-risk CLL defined as: del(17p); no response to first-line CT-containing tx; or relapsed in ≤ 12 months after CT or in ≤ 24 months after chemoimmunotherapy.

• Primary endpoint: investigator-assessed

PFS

• Secondary endpoints: IRC-assessed PFS

and MRD negativity, IRC-assessed CR → ORR → OS (hierarchical testing), safety

28-day cycles

38

MURANO: Four-Year Analysis of PFS (Primary Endpoint) and OS

• Seymour. ASH 2019. Abstr 355.

20 40 60 80 100

Months PFS (%)

Number at risk BR VenR 195 194 178 190 165 185 143 179 129 176

0 3 6 9 12 15 1821 24 27 30 3336 39 42 4548 515457 60

104 174 85 170 80 167 66 161 56 150 45 141 40 134 32 130 23 118 14 101 9 55 3 40 2 14 7 2

EOCT EOT

Treatment VenR (n = 194) BR (n = 195) 4-Year PFS, % (95% CI) 57.3 (49.4-65.3) 4.6 (0.1-9.2) Median follow-up: 48 months

20 40 60 80 100

Months OS (%)

Number at risk BR VenR 195 194 181 190 175 185 167 183 162 182

0 3 6 9 12 15 1821 24 27 30 3336 39 42 4548 515457 60

155 179 152 178 150 176 147 173 141 168 140 166 138 165 134 164 130 163 116 154 94 110 58 84 29 34 7 15 6

EOCT EOT

Treatment VenR (n = 194) BR (n = 195) 4-Year OS, % 85.3 66.8 Median follow-up: 48 months

1

39

MURANO: Safety

Grade 3/4 AE With ≥ 2% Difference Between Arms, n (%) Venetoclax + Rituximab (n = 194) Bendamustine + Rituximab (n = 188)

Neutropenia 114 (58.8) 75 (39.9) Anemia 22 (11.3) 26 (13.8) Thrombocytopenia 11 (5.7) 19 (10.1) Febrile neutropenia 7 (3.6) 18 (9.6) Pneumonia 10 (5.2) 15 (8.0) Infusion-related reaction 4 (2.1) 10 (5.3) TLS 6 (3.1) 2 (1.1) Hypotension 5 (2.7) Hyperglycemia 4 (2.1) Hypogammaglobulinemia 4 (2.1)

• Seymour. ASH 2019. Abstr 355.

40

• Phase III trial in patients with relapsed CLL after at least 1 prior line of tx

‒ Primary study 116 with idelalisib/rituximab followed by extension study 117 with single- agent idelalisib

Phase III Trial of Idelalisib + Rituximab in Relapsed CLL: Final Results of PFS (Primary Endpoint) and OS

• Sharman. JCO. 2019;37:1391.

100

90 80 70 60 50 40 30 20 10

Probability of PFS (%) Months Since Treatment Assignment

24 2 4 6 8 10 12 14 16 18 20 22 IDELA/R Placebo/R PFS, median mos (95% CI) IDELA/R (n = 110) 19.4 (12.3-NR) Placebo/R (n = 110) 6.5 (4.0-7.3)

100

90 80 70 60 50 40 30 20 10

Probability of OS (%) Months Since Treatment Assignment

56 4 8 12 16 20 24 28 32 40 44 52 IDELA/R (to IDELA in the extension study) Placebo/R (to IDELA in the extension study) OS, median mos (95% CI) IDELA/R (n = 110) 40.6 (28.5-57.3) Placebo/R (n = 110) 34.6 (16.0-NR) 60 64 68

41

• Duvelisib is a dual inhibitor of

PI3K delta and PI3K gamma[1]

• Administered orally twice daily[1]
• Prolonged PFS compared with
• fatumumab in the DUO study[2]
• FDA approved for patients with

R/R CLL/SLL and ≥ 2 previous therapies in September 2018

Phase III DUO Trial of Duvelisib vs Ofatumumab in R/R CLL

• 1. Flinn. Blood. 2018;131:877. 2. Flinn. Blood. 2018;132:2446.

DUV OFA Median PFS, mos (95% CI) 13.3 9.9 (12.1-16.8) (9.2-11.3) HR: 0.52; P < .0001

PFS by ICR (%) PFS[2] Months

20 40 60 80 100 3 6 9 12 15 18 21 24 27 30 Duvelisib 25 mg BID Ofatumumab 33 36 160 159 149 126 108 95 95 77 78 43 58 15 33 7 29 6 13 3 10 2 3 1 2 1 Number at risk Duvelisib Ofatumumab

42

• Multicenter, randomized, open-label phase III trial

Phase III ASCEND Trial of Acalabrutinib vs Idelalisib + Rituximab or BR in Previously Treated CLL

• Ghia. EHA 2019. Abstr LB2606. NCT02970318.

Adult patients with R/R CLL; ≥ 1 prior systemic therapies (no prior exposure to a BCL-2 inhibitor or B-cell receptor signaling inhibitor); ECOG PS 0-2 (N = 310) Acalabrutinib (n = 155) Idelalisib + Rituximab or Bendamustine + Rituximab (n =155)

• Primary endpoint: IRC-assessed PFS

43

ASCEND: PFS (Primary Endpoint)

• Ghia. EHA 2019. Abstr LB2606.

Patients, n Median PFS, Mos 12-Mo PFS, % Acalabrutinib 155 NR 88 IdR or BR 155 16.5 68

HR: 0.31 (95% CI: 0.20-0.49; P < .0001) 100 80 60 40 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

Months PFS (%)

Acalabrutinib Idelalisib + R or BR

Number at risk

153 150 155 155 153 156 149 146 147 144 146 142 145 136 143 130 143 129 139 112 139 105 137 101 118 82 116 77 73 56 61 44 60 39 25 18 21 10 21 8 1 1 1

44

ASCEND: AEs of Clinical Interest for Acalabrutinib

• Ghia. EHA 2019. Abstr LB2606.

AEs, % Acalabrutinib (n = 154) Idelalisib + R (n = 118) BR (n = 35)

Any Grade ≥ 3 Any Grade ≥ 3 Any Grade ≥ 3 Atrial fibrillation 5 1 3 1 3 3 Bleeding 26 2 8 3 6 3 Hypertension 3 2 4 1 SPM (no NMSC) 6 3 3 3 3

AEs and Targeted Therapies in CLL

46

Case Study 3: A Patient With Relapsed CLL Planning to Start Venetoclax Therapy

• A 69-year-old male with CLL currently taking ibrutinib reports increasing fatigue during

routine follow up ‒ unmutated IGHV, trisomy 12

• PE: axillary lymphadenopathy has increased from 2 cm to 6 cm
• Normal cardiac and kidney function
• Lab results:

‒ Hgb 13.6, WBC 14K, PLT 400K, ALC 10.5, LDH normal

• CT imaging: generalized lymphadenopathy, largest 6 cm in maximal dimension.
• PET imaging: lymphadenopathy with FDG uptake slightly above hepatic reference
• After consultation, the patient decides on treatment with venetoclax

47

Case Study 3 (cont’d): Patient Presents For Second Dose of Venetoclax

• The patient presents on day 8 of cycle 2 to receive his next dose of venetoclax

(planned escalation to 100 mg)

• Lab results show normal potassium, calcium, creatinine, uric acid, ANC 600/mL

(grade 3 neutropenia)

48

• Stilgenbauer. Lancet Oncol. 2016;17:768. Venetoclax PI.

General Measures

• Identify subjects at higher risk for TLS (see below)
• Initiate prophylaxis with hydration and uric acid–reducing agent
• Initiate venetoclax with 20-mg dose for 1 week, gradual stepwise ramp-up over 5 weeks to target dose of 400 mg/day

Low Risk: Nodal Mass < 5 cm and ALC ≤ 25,000/L

• Outpatient dosing at all dose levels, if no indication to hospitalize
• Post dose 8- and 24-hour lab monitoring following initial dose and at dose increase

Medium Risk: Nodal Mass ≥ 5 cm and < 10 cm or ALC > 25,000/L

• Outpatient IV hydration at 20 and 50 mg
• Inpatient if CrCl < 80 mL/min or high tumor burden
• Post dose 8- and 24-hr lab monitoring following initial dose and at dose escalation

High Risk: Nodal Mass ≥ 10 cm or Nodal Mass ≥ 5 cm and ALC > 25,000/L

• Inpatient dosing and monitoring (4, 8, 12, and 24 hours) at 20 and 50 mg
• Outpatient IV hydration for high-risk subjects at 100 mg and above, if no indication to hospitalize
• Post dose 8- and 24-hour laboratory monitoring at 100 mg and above

Venetoclax: TLS Prophylaxis and Monitoring

49

AEs of Available BTK Inhibitors

Ibrutinib PI. Acalabrutinib PI.

Ibrutinib Acalabrutinib

Cytopenias (grade 3/4)

• Neutropenia 13% to 29% (with risk of febrile neutropenia)
• Thrombocytopenia 5% to 17%
• Anemia 0% to 13%

Cytopenias (grade 3/4)

• Neutropenia 10% to 23%
• Thrombocytopenia 5% to 8%
• Anemia 5% to 11%

Hold BTK inhibitor for grade 3 neutropenia with infection or fever or grade 4 cytopenia Infections (grade 3-5)

• 14% to 29% of patients

Infections (grade 3-5)

• 11% to 18% of patients

Consider prophylaxis in patients who are at increased risk for opportunistic infections Other notable AEs

• Cardiac arrhythmia (5% in CLL)
• Bleeding/bruising (grade 3 bleeding up to 6%)
• Rash
• Diarrhea, early self-limited, typically responds to loperamide
• Muscle cramping, late, can be very bothersome
• Pneumonitis, rare but serious, discontinue ibrutinib

Other notable AEs

• Cardiac arrhythmia (3% in CLL)
• Bleeding/bruising (grade 3 bleeding up to 3%)
• Rash
• Headaches
• Diarrhea

Future Directions in CLL

51

Select Phase III Trials in Previously Untreated CLL

Trial Phase Population Planned N Primary Endpoint Treatment Arm(s)

CLL13 (NCT02950051) III Untreated CLL (no del[17p] or TP53 mutation) 920 PFS, MRD Venetoclax + rituximab vs venetoclax +

• binutuzumab vs. venetoclax +
• binutuzumab + ibrutinib vs standard

chemoimmunotherapy A041702 (NCT03737981) III Untreated CLL (≥ 70 years) 454 PFS Ibrutinib + obinutuzumab vs ibrutinib +

• binutuzumab + venetoclax

EA9161 (NCT03701282) III Untreated CLL (< 70 years) 720 PFS Ibrutinib + obinutuzumab vs ibrutinib +

• binutuzumab + venetoclax

FLAIR (ISRCTN0184415 2) III Untreated CLL (≤ 75 years) 1576 PFS, MRD FCR vs ibrutinib + rituximab vs ibrutinib vs ibrutinib + venetoclax

52

• Investigator-initiated phase II trial

‒ Median follow-up: 14.8 months (range: 5.6-27.5)

Phase II Trial of Ibrutinib + Venetoclax in Previously Untreated High- Risk CLL: Study Design

• Jain. NEJM. 2019;380:2095.
• Primary endpoint: CR/CRi by 2008 IWCLL criteria

Patients ≥ 18 years of age with treatment- naive, high-risk CLL/SLL* and adequate

• rgan function†

(N = 80) Ibrutinib 420 mg daily (n = 80)

*Meeting 2008 IWCLL criteria; ≥ 1 high risk feature required: del(17p) or mutated TP53, del(11q), unmutated IGHV, or ≥ 65 years of age.

†GFR > 50 mL/min; ALT/AST ≤ 3.0 x ULN; total bilirubin ≤ 1.5 x ULN; platelets > 20 K/μL. ‡Ibrutinib stopped at cycle 24 if BM MRD negative (by flow cytometry at 10-4), or if BM MRD positive, until PD. §Week 1: 20 mg daily; Wk 2: 50 mg daily; Week 3: 100 mg daily; Week 4: 200 mg daily; Week 5-27: 400 mg daily.

Response evaluations Q3M in Yr 1, Q6M in Year 2. Any LN > 1.5 cm by CT considered PR.

Until PD

Ibrutinib‡ 420 mg daily + Venetoclax§ Dose-escalation to 400 mg daily (n = 75) 3 cycles 24 cycles

53

• Addition of venetoclax to

ibrutinib led to improved responses with ongoing therapy and rapid and deep reductions in CLL BM disease

Ibrutinib + Venetoclax in CLL: Response

3 Cycles IBR (n = 75) 3 Cycles VEN + IBR (n = 72) 6 Cycles VEN + IBR (n = 70) 9 Cycles VEN + IBR (n = 60) 12 Cycles VEN + IBR (n = 33) 18 Cycles VEN + IBR (n = 26)

Response (%)

20 40 60 80 100

PR CR/CRi BM MRD negative*

96 1 43 57 17 27 73 17 83 40 52 12 88 61 96 69 4

*By flow cytometry at 10-4 sensitivity.

• Jain. NEJM. 2019;380:2095.

54

Ongoing Phase III Clinical Trials in R/R CLL

Trial Population N Status MRD Treatment Arms UTX-IB-301 (NCT02301156) del(17p), del(11q), and/or TP53 mutation 120 Enrolled No Ublituximab + ibrutinib vs ibrutinib ELEVATE-RR (NCT02477696) del(17p) and/or del(11q) 533 Enrolled No Acalabrutinib vs ibrutinib ALPINE (NCT03734016) All 400 Recruiting No Zanubrutinib vs ibrutinib

55

• Resistance and intolerance can limit utility
• f covalent BTK inhibitors (eg, ibrutinib,

acalabrutinib)[1]

‒ BTK C481 mutations predominant reason for CLL progression after approved BTKi[1,2]

• Reversible, noncovalent BTK inhibitors in

development with activity against WT and C481-mutant BTK[2-4]

‒ LOXO-305 ‒ ARQ 531 ‒ Vecabrutinib

Overcoming Acquired Resistance With Reversible BTK Inhibitors

• Dose-escalation phase I trial of LOXO-305

(N = 28, including 16 with CLL)[2]

— ≥ 2 lines of therapy, including BTKi intolerant — 25 mg up to 200 mg daily

• Safety profile

— No DLTs reported, MTD not reached — No reported atrial fibrillation or major bleeding

• ORR (in CLL): 77%

— Tumor shrinkage reported in all pts regardless of starting dose, previous therapy, or C481S mutation — Responses deepened over time

• 1. Kipps. Nat Rev Dis Primers. 2017;3:16096. 2. Mato. ASH 2019. Abstr 501.
• 3. Allan. ASH 2019. Abstr 3041. 4. Bond. Curr Hematol Malig Rep. 2019;14:197.

56

Chimeric Antigen Receptor T-Cell Therapy

✓

2011: first case report of successful CAR T-cell therapy in CLL[1]

✓

Since then, multiple reports of sustained remissions after CAR T-cell therapy[2]

✓

Ibrutinib + anti-CD19 CAR T-cell therapy associated with 89% CR rate in CLL[3]

✓

In pts with R/R CLL previously treated with ibrutinib (> 50% received venetoclax), anti-CD19 CAR T-cell therapy induced rapid and durable responses[4] ‒ ORR: 82% (CR/CRi: 46%) ‒ MRD negativity rate (10-4): 75% in peripheral blood and 65% in bone marrow

• 1. Porter. NEJM. 2011;365:725. 2. Turtle. JCO. 2017;35:3010.
• 3. Gill. ASCO 2017. Abstr 7509. 4. Siddiqi. ASH 2019. Abstr 503.

Case Report: CAR T-Cell Therapy in CLL[1]

Bone Marrow Biopsy Specimens Day 1 (Baseline) Day 23 6 Mos Axial Coronal Before Therapy 1 Month of Treatment 3 Months of Treatment Contrast-Enhanced CT

57

PCE Action Plan

✓ Order karyotype and molecular analysis tests to identify prognostic and

predictive biomarkers that inform treatment decisions

✓ Consider targeted therapy options for all patients with newly diagnosed

• r relapsed/refractory CLL

✓ Evaluate risk of and establish recommended monitoring practices for

tumor lysis syndrome in patients being treated with venetoclax

✓ Discuss clinical trial options for patients with progression following

treatment with currently available targeted therapies for CLL

PCE Promotes Practice Change

2020 Spring Oncology Conference