We Can Cure Chronic Lymphocytic Leukemia with Current / Soon to be Approved Agents: CON ARGUMENT Danielle M. Brander, MD Duke University Division of Hematologic Malignancies & Cell Therapy CLL & Indolent Lymphomas Duke Cancer Institute danielle.brander@dm.duke.edu 2017 Duke Debates 22 April 2017
CLL: Incidence & Mortality Cancer Epidemiol Biomarkers Prev. 2016;25:174.
What does CURE mean? Cure means that there are no traces of your cancer after treatment and the cancer will never come back. STANLEY RIDDELL, MD It depends on the cancer you are treating, but in general we don t like to use the word cure until patients are several years out from their treatment. We know that many times, cancers can come back years later. https://www.cancer.gov/about-cancer/diagnosis-staging/prognosis http://www.fredhutch.org/en/news/center-news/2016/07/when-do-we-saycancer-cure.html
What does CURE mean? TIME Leukemia: Not all the same not even close Thomas et al. Blood. 1977; 49: 511.
What does CURE mean? TIME Benchmarks in time are not perfect (even at 5 years), and depend on the study population Van Gelder et al. Bone Marrow Transplantation. 2017; 52: 372.
What does CURE mean? DETECTION x Bottcher et al. Leukemia. 2004; 18: 1637
FCR: Durable, long term remissions 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 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.
Chemoimmunotherapy (CIT): FCR toxicities Cytopenias Infections Autoimmune complications Second Malignancies MDS/AML Annals of Internal Medicine.1992;117:466. British Journal of Hematology. 1999;105:445 JCO. 1998;16:1885 Hematol Cell Therapy. 1996;38:359 Clin Lab Haem. 2006;22:175 Blood. 2008;111:1820 Annals of Oncology. 2010; 21: 331 Clin Oncol. 1995; 13:2431 Blood. 2008; 112: 975 American Journal of Hematology.1995;49:135 J Clin Oncol.1995;13:2431
CLL: Evidence on early therapy Also no difference with FCR vs watch & wait in CLL7 Trial (Schweighofer. ASH 2013.) CLL12 trial: safety Cost JNCI. 1999;91:861-8.
Response rates with novel agents and TP53 dysregulation Rossi et al. Leukemia & Lymphoma, DOI: 10.1080/10428194.2016.1250264
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.
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; 370:2286 Maddocks et al. JAMA Oncol. 2015;1:80. Burger et al. Nat. Commun. 7:11589
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 Thompson et al. Cancer. 2015; 121:3612. Maddocks et al. JAMA Oncol. 2015;1:80.
Risks for ibrutinib acquired resistance Mutations detected up to 15 mos b/f progression Could time to best response matter? Ahn et al. Blood. doi:10.1182/blood-2016-06-719294
Kinase Inhibitors: toxicity Mato et al. Blood. 2016;128:2199
targeted inhibitors: toxicities ibrutinib idelalisib venetoclax 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 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. 2014;371:213. Blood. 2014;124:3829. Blood. 2015;125:2497 Leukemia & Lymphoma. 2015;56:277. NEJM. 2016;374:311.
Richter s Up to 10% of CLL patients Across several series time to RS is 2-5 yrs Survival: 8-14 months Parikh et al. Blood. 2014;123:1647. Br J Haematol 2013;162:774-782 Rossi et al. Blood. 2011;117(12):3391-3401.
RS Risks in CLL patients: somatic mutations Fabbri.Nature Reviews Cancer. 2016;16:147.
RS: Somatic Genetic Changes genome-wide DNA profiling: 315 CLL 28 CLL phase of RS 59 Richter s 127 de novo DLBCL Parikh et al. Blood. 2014;123:1647.. Chingrinova et al. Blood 2013; 122: 2673.
Recurrent mutations: increasing the numbers Guieze and Wu. Blood. 2015;126:445.
Genetic Drivers in CLL Landau, Wu et al. Nature. 2015; 526: 525.
CLOSING STATEMENTS Questions Danielle M. Brander, MD Duke University Division of Hematologic Malignancies & Cellular Therapy danielle.brander@dm.duke.edu