we can cure chronic lymphocytic leukemia with current ......we can cure chronic lymphocytic leukemia...
TRANSCRIPT
We Can Cure Chronic Lymphocytic
Leukemia with Current / Soon to be
Approved Agents: CON ARGUMENT
Danielle M. Brander, MDDuke University
Division of Hematologic Malignancies & Cell Therapy
CLL & Indolent Lymphomas
Duke Cancer Institute
2017 Duke Debates
22 April 2017
Cancer Epidemiol Biomarkers Prev. 2016;25:174.
CLL: Incidence & Mortality
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What does CURE mean?
“Cure means that there are no traces
of your cancer after treatment and the
cancer will never come back.”
“It depends on the cancer you aretreating, but in general we don’t like touse the word cure until patients areseveral years out from their treatment.We know that many times, cancers cancome back years later.”
https://www.cancer.gov/about-cancer/diagnosis-staging/prognosishttp://www.fredhutch.org/en/news/center-news/2016/07/when-do-we-say-cancer-cure.html
STANLEY RIDDELL, MD
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What does CURE mean? TIME
Thomas et al. Blood. 1977; 49: 511.
• Leukemia: Not all the same – not even close
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What does CURE mean? TIME
Van Gelder et al. Bone Marrow Transplantation. 2017; 52: 372.
• Benchmarks in time are not perfect (even at 5 years), and depend on the study population
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What does CURE mean? DETECTION
Bottcher et al. Leukemia. 2004; 18: 1637
• x
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MDACC: 300pts with FCR• Plateau in PFS: no relapses beyond 10.4 years in 42 patients
• Similar plateau in CLL8 and Rossi et al FCR studies
FCR: Durable, long term remissions
Blood. 2008;112: 975-980.Blood. 2015;126(16):1921.Blood. 2016;127(3):303.Blood. 2016;127(2):208.Blood. 2015;126(16):1921.Please do not copy or utilize slides for anything other than personal use without written permission from the author.
Chemoimmunotherapy (CIT): FCR toxicities
• Cytopenias
• Infections
• Autoimmune complications
• Second Malignancies
▫ MDS/AML
Annals of Oncology. 2010; 21: 331Clin Oncol. 1995; 13:2431Blood. 2008; 112: 975American Journal of Hematology.1995;49:135J Clin Oncol.1995;13:2431
Annals of Internal Medicine.1992;117:466.British Journal of Hematology. 1999;105:445JCO. 1998;16:1885Hematol Cell Therapy. 1996;38:359Clin Lab Haem. 2006;22:175Blood. 2008;111:1820
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JNCI. 1999;91:861-8.
CLL: Evidence on early therapy
• Also no difference with FCR vs watch & wait in CLL7 Trial (Schweighofer. ASH 2013.)
• CLL12 trial: safety
• CostPlease do not copy or utilize slides for anything other than personal use without written permission from the author.
Response rates with novel agents and TP53 dysregulation
Please do not copy or utilize slides for anything other than personal use without written permission from the author. Rossi et al. Leukemia & Lymphoma, DOI: 10.1080/10428194.2016.1250264Please do not copy or utilize slides for anything other than personal use without written permission from the author.
ibrutinib in CLL: extended follow up• Responses continuous
▫ Time to best response, median: 7.4 mo (1.7-42.5 mo)
▫ Time to CR, median: 21.2 mo (4.6-42.5)
• ORRs very high ▫ TN: 84% (23% CR)
▫ R/R: 90% (7% CR)
• Discontinuations
Blood. 2015;125:2497.Please do not copy or utilize slides for anything other than personal use without written permission from the author.
ibrutinib progression: secondary resistance
• Acquired resistance in 6 patients (2 had obtained CR)▫ cysteine-to-serine in BTK at the binding site of ibrutinib (5)
▫ three distinct mutations in PLCγ2 (2pts): gain of function
• Evidence of other pathway escapes/clonal evolution
Woyach et al. N Engl J Med .2014; 370:2286Maddocks et al. JAMA Oncol. 2015;1:80.Burger et al. Nat. Commun. 7:11589Please do not copy or utilize slides for anything other than personal use without written permission from the author.
Risks for ibrutinib acquired resistance
• Complex karyotype more important than del17p in progression AND outcomes (OS)
Normal karyotype stratified by FISH
Del17p stratified by karyotype
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Thompson et al. Cancer. 2015; 121:3612.
Maddocks et al. JAMA Oncol. 2015;1:80.
• Mutations detected up to 15 mos b/f progression
• Could time to best response matter?
Risks for ibrutinib acquired resistance
Ahn et al. Blood. doi:10.1182/blood-2016-06-719294Please do not copy or utilize slides for anything other than personal use without written permission from the author.
Kinase Inhibitors: toxicity
Mato et al. Blood. 2016;128:2199 Please do not copy or utilize slides for anything other than personal use without written permission from the author.
targeted inhibitors: toxicities
bleeding risks
▫ phase I/II Studies:
ICH: 2%
▫ followup (3yr):
7% gr 3
cardiovascular risks
▫ a fib:
Thompson et al: 16%
▫ HTN, edema, other
other considerations
▫ GI/diarrhea
▫ rash
▫ migratory arthritis
▫ infections
NEJM. 2014;371:213.
Blood. 2014;124:3829.
Blood. 2015;125:2497
Leukemia & Lymphoma. 2015;56:277.
ibrutinib idelalisib venetoclax
• blackbox warnings
• LFT abnormalities
• colitis
• pneumonitis
• drug-drug (CYP3A)
• infections
tumor lysis
▫ 2 deaths
▫ dose ramp up & hospitalization needs
cytopenias (gr ¾)
▫ neutropenia (41%)
▫ anemia (12%)
▫ thrombocytopenia (12%)
other (all grades)
▫ diarrhea (52%)
▫ nausea (47%)
▫ fatigue (40%)
NEJM. 2016;374:311.
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Parikh et al. Blood. 2014;123:1647.
Br J Haematol 2013;162:774-782
Rossi et al. Blood. 2011;117(12):3391-3401.
Richter’s• Up to 10% of CLL patients
• Across several series time to RS is 2-5 yrs
• Survival: 8-14 months
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RS Risks in CLL patients: somatic
mutations
Fabbri.Nature Reviews Cancer. 2016;16:147.
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Parikh et al. Blood. 2014;123:1647..
Chingrinova et al. Blood 2013; 122: 2673.
RS: Somatic Genetic Changes
• genome-wide DNA profiling:
▫ 315 CLL
▫ 28 CLL phase of RS
▫ 59 Richter’s
▫ 127 de novo DLBCL
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Recurrent mutations: increasing the numbers
Guieze and Wu. Blood. 2015;126:445.Please do not copy or utilize slides for anything other than personal use without written permission from the author.
Genetic Drivers in CLL
Landau, Wu et al. Nature. 2015; 526: 525.Please do not copy or utilize slides for anything other than personal use without written permission from the author.
CLOSING STATEMENTS
Questions…
Danielle M. Brander, MDDuke University
Division of Hematologic Malignancies & Cellular Therapy