Chronic Lymphocytic Leukemia (CLL)...3 Chronic Lymphocytic Leukemia • Most common adult leukemia...
Transcript of Chronic Lymphocytic Leukemia (CLL)...3 Chronic Lymphocytic Leukemia • Most common adult leukemia...
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Chronic Lymphocytic Leukemia(CLL)
Joseph M. Tuscano, M.D.UCD Cancer Center
17th Annual Advances in OncologySeptember 30-October 1, 2016
Sacramento, CA
Joseph Tuscano, M.D.Chronic Lymphocytic Leukemia: Novel Therapeutics.
Relevant financial relationships in the past twelve months by presenter or spouse/partner:
Consultant: Celgene, MilleniumSpeakers Bureau: Celgene, Amgen, Seattle Genetics
The speaker will directly disclosure the use of products for which are not labeled (e.g., off label use) or if the product is still investigational.
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Chronic Lymphocytic Leukemia
• Most common adult leukemia (~ 15,000 cases per year)
• Median age at diagnosis 72 years • Causes ~ 4400 deaths per year• Absolute survival has increased over last
3 decades
1980-1984 2000-2004 2005-20115-year 54.2% 60.2% 81.7
American Cancer Society. Cancer Facts & Figures 2008; Rai K, et al. Blood. 1975;46:219-234;Brenner H, et al. Blood. 2008;111:4916-4921. SEER 2012
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Initial Presentation• Frequently asymptomatic
o Identified by absolute lymphocyte count on routine CBC
• Lymphadenopathy, hepatosplenomegaly, or both in 40%-50%
• “B” symptoms uncommono Fever, weight loss, or night sweats
• Laboratory abnormalitieso Coombs-positive autoimmune hemolytic anemiao Hypogammaglobulinemiao Hypergammaglobulinemia
DiVita VT, et al. Cancer Principles & Practice of Oncology. 6th ed. 2001:2451.
Staging
Diagnosis and Staging:• CLL/SLL
o Defined as > 5x109/L +/- lymphadenopathyo Rai Staging System
Stage Description Risk Status0 Lymphocytosis, peripheral lymphocyte count
>15,000/mcL and >40% lymphocytes in bone marrowLow
I Stage 0 disease with enlarge lymph node(s) IntermediateII Stage 0-I with splenomegaly and/or hepatomegaly IntermediateIII Stage 0-II with Hgb <11 g/dL or Hct <33% HighIV Stage 0-III with platelet count <100,000/mcL High
Diagnosis:
7Strati, et al. Blood; 2015.
CLL Phenotype
CD5 +CD10 -CD19 +
CD20 dimCD23 +sIg dim
Prognosis
Prognostic InformationPrognosticMarker
Molecular Significance Low Risk High Risk
IgVH mutation Somatic hypermutation Mutated (>2%) Unmutated(≤2%)
Zap-70 Cell activation tyrosine kinase
Negative (<20%)
Positive (≥20%)
CD38 Cell activation signaling Negative (<30%)
Positive (≥30%)
Molecular Study and Flow Cytometry Analysis
Favorable Normal Unfavorabledel13q – sole abnormality
Normal del11q (ATM gene)
trisomy12
del17p (p53 gene)
UnfavorableComplex karyotype = ≥3 unrelated chromosome abnormalities
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Impact of Adverse Cytogenetics on Survival
Dohner, et al. NEJM; 2000.
When to Initiate Treatment
• Role of Active Surveillanceo No benefit to early treatment
• Indications for treatment:o Significant disease-related symptomso Progressive bulky diseaseo Threatened end-organ functiono Progressive cytopenia’so ALC doubling time < 6 months (?)
Treatment
Evolution of Treatment for CLL/SLL
Before 1985Single-agent alkylators
1985-1990Single-agent purine analogs
1990-2000Combinations of purine analogs with alkylators
2000-2013Chemoimmunotherapy
After 2014Small molecule inhibitors of critical survival pathways
Advances in Treatment• 2014 was a blockbuster year…
Modern ImmunotherapyPassive Immunotherapy• Engineering of B or T-cell receptors targeting a
desired antigen and infused into the patient.
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Active Immunotherapy• Enabling the patient’s own immune system to re-
engage and re-establish immune surveillance. Concept of avoiding “tumor escape”.
CD20 Monoclonal Antibodies
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Drug Antibody
Type
Structure Mechanism of Action
ADCC/CDC/PCD
FDA Approval
Rituximab I Chimeric IgG1 ++ / ++ / + 1997Ofatumumab I Human IgG1
Kappa+++ / ++++ / ++ 2014
Obinutuzumab II Humanized IgG1, glycol-engineered ++++ / - / ++++ 2014
Veltuzumab I Humanized IgG1 ++ / ++ / + Phase I/IIPRO131921 I Humanized IgG1 ++ / ++ / + discontinued
ADCC: Antibody-dependent cell-mediated cytotoxicityCDC: Complement-dependent cytotoxicityPCD: Programmed cell death
Obinutuzumab: CLL11 Trial
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Chlorambucil 0.5 mg/kg PO on Days 1, 15 x 6 cycles(n = 118)
Obinutuzumab 1000 mg IV cycle 1 Days 1, 8, 15; cycles 2-6 Day 1 +
Chlorambucil 0.5 mg/kg PO on Days 1, 15 x 6 cycles(n = 333)
Rituximab 375 mg/m2 IV cycle 1 Day 1; 500 mg/m2 cycles 2-6 Day 1 +
Chlorambucil 0.5 mg/kg PO on Days 1, 15 x 6 cycles(n = 330)
28-day cycleRandomized 1:2:2
• Front-line therapy• CLL patients w/
comorbidities– CIRS score >6 – CrCl <70
• Median age 73• CIRS score 8• Unmutated IgHV –
60%• del17p – 8%
(N=781)
Crossover to obinutuzumab + chlorambucil arm at progression on chlorambucil monotherapy
Obinutuzumab
CLL11 Results
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ORR: 78%CR: 22%PFS: 26.7 moImproved OS
Goede, et al. NEJM; 2014
26.7 mo
11.1 mo
Ofatumumab: Complement 1 Trial
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Chlorambucil 10 mg/m2 PO on Days 1-7 x 12 cycles(n = 226)
Ofatumumab 1000 mg IV cycle 1 Days 1 (300 mg), 8; cycles 2-12 Day 1 +
Chlorambucil 10 mg/m2 PO on Days 1, 15 x 6 cycles(n = 221)
28-day cycleRandomized 1:1
• Front-line therapy• CLL patients w/
comorbidities• Median age 70• CIRS score 9• Unmutated IgHV –
56%• del17p – 6%
(N=447)
No crossover allowed; minimum 3 cycles w/ maximum of 12 cycles
Ofatumumab
Complement 1 Results
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ORR: 82%CR: 14%PFS: 22.4 moOS: not reached
Hillmen, et al. Lancet; 2015
22.4 mo
13.1 mo
Ofatumumab: PROLONG Trial• Phase III trial• CLL in CR/PR following
2 or 3 lines of therapy• No prior maintenance• 1:1 randomization• Median age 65• IgHV unmutated – 50%• del17p – 2%
21van Oers, et al. Lancet; 2015.
29.4 mo
15.2 mo
Ofatumumab 1000 mg IVCycle 1 Day 1 (300 mg) and Day 8
then Q8 wks
CD20 Antibody: Take Home Points
• For older/frail patients with favorable/normal risk cytogeneticso Combination w/ chlorambucilo Favor obinutuzumab or ofatumumab
• Role for maintenance ofatumumab in R/R disease that has reached a CR/PR
• Front-line therapy in del11q CLL/SLL for older/frail patients
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Alemtuzumab• CD52 antibody• Still in the guidelines• Still available
23Hillmen, et al. JCO; 2007.
For del17p CLL/SLL
ORR• Alemtuzumab: 64%• Chlorambucil: 20%
PFS• Alemtuzumab: 10.7 mo• Chlorambucil: 2.2 mo
from manufacturer website
Alemtuzumab• CLL206 Trial; n=39 w/ del17p CLL/SLL• Alemtuzumab 30 mg three times weekly• Methylprednisolone 1 g/m2 days 1-5 Q4 wks• ORR – 85%; CR – 36%; PFS – 18.3 mo; OS – 23.5 mo
24Pettitt, et al. JCO 2012
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Untreated CLL:
Chlorambucil vs Bendamustine
Progression-Free Survival
Knauf WU, et al. Blood. 2007:110. Abstract 2043 and poster at American Society of Hematology Annual Meeting 2007.
Original Article
Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia
Andrew W. Roberts, M.B., B.S., Ph.D., Matthew S. Davids, M.D., John M. Pagel, M.D., Ph.D., Brad S. Kahl, M.D., Soham D. Puvvada, M.D., John F. Gerecitano, M.D., Ph.D.,
Thomas J. Kipps, M.D., Ph.D., Mary Ann Anderson, M.B., B.S., Jennifer R. Brown, M.D., Ph.D., Lori Gressick, B.S., Shekman Wong, Ph.D., Martin
Dunbar, Dr.P.H., Ming Zhu, Ph.D., Monali B. Desai, M.D., M.P.H., Elisa Cerri, M.D., Sari Heitner Enschede, M.D., Rod A. Humerickhouse, M.D., Ph.D., William G.
Wierda, M.D., Ph.D., and John F. Seymour, M.B., B.S., Ph.D.
N Engl J MedVolume 374(4):311-322
January 28, 2016
ChemoimmunotherapyFCR – fludarabine /
cyclophosphamide / rituximab
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• Fischer, et al. Blood; 2016o Update on CLL8 trial
BR – bendamustine / rituximab
• Eichhorst, et al. ASH 2014– Update on CLL10 trial
First-Line FCR-Lite for Patients With CLL
• Cyclophosphamide plus fludarabine yielded increased CR and ORR in CLL patients compared with fludarabine alone
• Rituxan plus fludarabineo Higher CR and ORR than each agent given sequentially
o Increased CR rate and PFS compared to fludarabine alone
• FCR in 224 patients with previously untreated CLL o Reported to induce a CR rate of 70% and an ORR of 95%
o Highest RR reported for the initial therapy of CLL
o Major toxicity was grade 3/4 neutropenia (52% of the 927 evaluable cycles)
• One approach to decreasing neutropenia without compromising efficacy is to reduce the doses of fludarabine and cyclophosphamide and increase the dose of Rituxan (FCR-Lite)
FCR=Fludarabine 25 mg/m2 on Days 1-3, cyclophosphamide 250 mg/m2 on Days 1-3, Rituxan 500 mg/m2 on Day 1, every 4 weeks for 6 cycles.Tarhini AA et al. Blood (ASH Annual Meeting Abstracts). 2006;108: Abstract 2844.
First-line FCR-Lite for Patients With CLL: Results
• N=28 patients (19 male, 9 female) with a median age of 58 years (range, 36-85 years) were treated
• 154 cycles of FCR-Lite were administered• Adverse events: All patients were evaluable for toxicity
Number of Cycles (%)Grade 3/4 Neutropenia 12 (8%)*
Grade 3/4 Thrombocytopenia 4 (3%)
Grade 3/4 Anemia 2 (1%)
Neutropenic Fever 1 case
Pneumonia 1 case
*52% of cycles in FCR trial
Tarhini AA et al. Blood (ASH Annual Meeting Abstracts). 2006;108: Abstract 2844.
First-line FCR for Patients With CLL: Response
by CharacteristicNumber of
PatientsComplete Response
Rate (%)Overall Response
Rate (%)Total 21 86% 100%Rai Stage
I/II 16 88% 100%III/IV 5 80% 100%
Age<55 years 7 86% 100%55-69 years 12 83% 100%>70 years 2 100% 100%
Chromosomal Abnormality
None 6 100% 100%13q 2 50% 100%Trisomy 12 6 100% 100%11q 3 100% 100%17p 2 0 100%Not done 2 100% 100%
Tarhini AA et al. Blood (ASH Annual Meeting Abstracts). 2006;108: Abstract 2844.
B-cell Receptor (BCR) Signaling
• Activated by antigens in tumor microenvironment
• CLL BCRs recognize:o Autoantigenso Microbial antigenso Intrinsic IgHV motifs
• BCR activation promotes CLL cell maintenance/expansion
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Hendriks, et al. Nat Rev Cancer; 2014Burger, et al. Cell Press; 2013.
BTK Pathway in CLL/SLL
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ibrutinib manufacturer slide set
BTK Inhibitors in CLL/SLL
Drug Code Drug Name Investigations
FDAApproval
PCI-32765 Ibrutinib I / II / III YESACP-196 Acalabrutinib I / II / III NOAVL/CC-292 Spebrutinib I NOONO/GS-4059 I NO
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Ibrutinib: Early Trial Experience• Phase Ib/II trial – O’brien, et al. Lancet; 2014
o Symptomatic CLL; age >65 yrs (N=31)o Ibrutinib 420 mg vs 840 mg (later discontinued)o ORR = 71% w/ 13% CR at median f/u 22.1 mo
• Phase II – Farooqui, et al. Lancet Oncol; 2015o Both untreated (n=35) and relapsed/refractory (n=16)o High risk disease with del17p o PFS and OS at 2 yrs: 82% and 80%
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Ibrutinib: RESONATE Trial
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Ibrutinib 420 mg PO daily Until progression or toxicity
(n = 195)
Ofatumumab 2000 mg IV300 mg dose 1, then 2000 mg weekly x7
then Q4wk x 16 doses(n = 196)
Randomized 1:1
• Relapsed/refractory CLL/SLL
• Median age 67• ≥3 prior therapies –
50%• CIRS score >6 – 38%• del17p – 32%
(N=391)
Primary endpoint = PFS
Crossover at progressionIbrutinib 420 mg PO daily
(n = 57)
Ibrutinib: RESONATE Trial• Met PFS endpoint
o 12 month• 84% vs 19%
• ORR: 42.6% vs 4.1%o Plus 20% PR w/ WBC ct
36Byrd, et al. NEJM; 2014.
NR
8.1 mo
90%
81%
At 12 mo
Ibrutinib: RESONATE-2 Trial
• Phase III – Berger, et al. NEJM; 2015.o Symptomatic CLL/SLL, previously untreatedo Age >65; median age 73o Randomized 1:1; ibrutinib (420 mg) vs chlorambucilo ORR 86% vs 35%o PFS: not reached vs 18.9 monthso OS at 2 yrs: 98% vs 85%
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Ibrutinib: Take Home Points• Front-line therapy for del17p CLL/SLL• Front-line alternative for del11q CLL/SLL in older/frail
patients• Excellent second-line option for all subtypes• Recent approval for consideration in all subtypes as
front-line therapy• Several studies have demonstrated poor OS after
coming of ibrutinib*• Commitment to long-term therapy should be
considered carefully
38*Jain et al Blood 2015, Maddoks JAMA Oncol 2015
PI3K Pathway in CLL/SLL
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Ortiz-Maldonado, et al. Ther Adv Hematol; 2015.
PI3K inhibitors in CLL/SLL
Drug code Drug Name PI3K isotype Investigations
FDA Approval
GS1101/CAL101
Idelalisib δ I / II / III YES
IPI-145 Duvelisib δ / γ I / II / III NOTGR-1202 δ I / II / III NOBKM120 Buparlisib pan I / II NOAMG 319 δ I NOSAR245408 pan I NOGS-9820 Acalisib pan I NO
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*Patients with disease progression continued on idelalisib Extension Study 117.†Rituximab schedule: 375 mg/m2, then 500 mg/m2 every 2 wks x 4, then 500 mg/m2 every 4 wks x
Rituximab†
(6 mos)
Placebo BID(N = 110)
Idelalisib 150 mg BID(N = 110)
Disease progression*, death, or discontinuation due to AE
Primary Study 116 Extension Study 117
Rituximab†
(6 mos)
Idelalisib 300 mg BID
Idelalisib 150 mg BID
Randomized 1:1
Idelalisib: Studies 116 and 117
• Relapsed/refractory CLL/SLL
• Median age 71• Median CIRS – 8• del17p – 40% • Unmutated IgHV –
76% (N=220)
Idelalisib: Study 116 Results
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Furman R, et al. N Engl J Med; 2014.
5.5 mo
NR
92%
80%
At 12 mo
Idelalisib: Take Home Points
• Relapsed/refractory CLL/SLLo Use in combination with rituximab
• Alternative when there are contraindications to ibrutinib in relapsed/refractory disease
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Safety of Ibrutinib and IdelalisibIbrutinib Idelalisib
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• Bleeding issues:o Careful in patients on
anticoagulationo Hold drug prior to surgical
procedures
• Atrial fibrillation:o Reason for alternative?
• Hypertension:o Monitor/treat
• Toxicities:o Hepatotoxicity
• Follow LFTso Diarrhea/colitiso Pneumonitiso Intestinal perforation
• Infections:o PCP prophylaxiso CMV reactivation
Gilead drug letter 3/2016
Treatment Targets
45Hallek, et al. Blood; 2013.
SYK InhibitorsDrug Code Drug Name Investigations FDA ApprovalR788 Fostamatinib I / II NOGS-9973 Entospletinib I / II NOPRT-062070 Cerdulatinib I NO
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BCL-2 Targeted AgentsDrug Code Drug Name Investigations FDA ApprovalGDC-0199/ABT-199
Venetoclax I / II YES
SPC2996 I / II NOG3139 Oblimersen I / II NOGX15-070MS Obatoclax I NOABT-263 Navitoclax I / II NO
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Untreated CLL:Chlorambucil vs Bendamustine
Bendamustine (B)100 mg/m2 IV D1 and 2
q4w × 3 (n = 154)Previously untreated, Age ≤ 75 yrBinet B/C(n = 298)
ASSESS
Chlorambucil (Chl)0.8 mg/kg
Broca normal weight*PO D1 and 15
q4w × 3 (n = 144)
ASSESS
*Broca normal weight in kg (men) = Height in cm – 100.
Broca normal weight in kg (women) = 0.9 (height in cm – 100).
Primary endpoint: ORR and PFS
Knauf WU, et al. Blood. 2007:110. Abstract 2043.
RANDOMIZE
Stratified by stage and center
Venetoclax Schedules, Pharmacokinetic Response, and Activity against Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL).
Roberts AW et al. N Engl J Med 2016;374:311-322
Durability of Benefit with Ongoing Venetoclax Therapy.
Roberts AW et al. N Engl J Med 2016;374:311-322
Allogeneic Transplant
Treatment SummaryPreviously Untreated CLL
Meets IWCLL Criteria for Tx
Age, Functional Status, Comorbidities, FISH
<65yrs/Good FS >65yrs/Poor FS
17p
+ -FCR, FCR-liteIbrutinibBR
FCR, FCR-liteBR
FCR-lite, BR, G+Chl, O+ChlR alone (TIW) +/- Solumedrol
Relapsed CLL
Ibrutinib, Zydelig +RVenetoclax, Alemtuzumab
Allo PSCT
Ibrutinib, Zydelig +RVenetoclax
NHL Chemo
ALWAYS consider a clinical trial at any stage
** Preferred in other high risk patients
**