we can cure chronic lymphocytic leukemia with current ... · we can cure chronic lymphocytic...
TRANSCRIPT
We CAN cure chronic lymphocytic leukemia with current / soon to be
approved agents
The Duke Debates
Mato et al, AJH 2015
Is BMT the “only known cure” for CLL….
0 60 120 1800
50
100
10y NRM 25% (15, 36)
Months from HCT
Perc
en
t N
RM
0 60 120 1800
50
100
10y REL 55% (43, 67)
Months from HCT
Perc
en
t p
rog
ressiv
e
0 60 120 1800
50
100
10y EFS 31% (21, 41)
Months from HCT
Perc
en
t E
FS
0 60 120 1800
50
100
10y OS 51% (40%-62%)
Months from HCT
Perc
en
t S
urv
ival
NRM
EFS
REL
OS
Overall outcome (n=90)f/u 9.7y (0.7-15.2)
Data cut-off 06.10.2016Dreger, ASH 2016
Mato and Porter, Blood 2015
SCT = CURE, BUT AT WHAT COST?
• Highly selected YOUNG patient population
• Inferior outcomes with bulky and refractory disease
• HIGH TRM 16- 23%
• Chronic extensive GVHD 49 – 65%
• Limited data in era of novel agents
Mato and Porter, Blood 2015
EBMT SCT Criteria Revised in Era of Novel Agents
Are newer agents active enough in poor risk disease that the need for SCT is negated or pushed back in the treatment algorithm?
If SCT is reserved for KI failures, are outcomes compromised or enhanced?
Dreger, Blood, 2007 & 2014
The risks of allogeneic SCT are no longer justifiable in MOST CLL patients in the
current novel agents era.
Is cure still possible (and less toxic) in select patients with current (and future)
therapies?
What can the SCT experience teach us?
Ritgen et al, Leukemia 2008, Bottcher et al, Blood Reviews 2011
No obvious tail on the PFS curve but…
Hallek et al, Lancet 2010
Outcomes are extremely poor in del17p and TP53 mutated CLL
Hallek et al, Lancet 2010
Mato et al, BJH 2016
Methods• Multicenter,
prospective observational cohort study of treated CLL patients
• Descriptive, KM survival and regression analyses
• 199 centers / 1494 pts
Can we identify patient subsets that optimally benefit from CIT (even cure)?
Can we minimize CIT exposure to minimize both short and long term
toxicities in “cured” patients?
Data for BR and long term disease free survival?
Fisher et al, Blood 2015
With median follow up 5.9 years, median PFS NOT reached in IGHV mutated patients with FCR!
Overall survival with FCR
Mutated IGHV FCR patients have superior OS (tail on curve)Patients age < 65 are best candidates for FCR
Fisher et al, Blood 2015
PFS stratified by genetic subgroup in IGHV mutated patients
NGS?
Thompson et al, Blood 2016
MDACC and GCLLSG confirm superior outcomes based on IGHV status
Early achievement of MRD-negativity in IGHV-mutated (IGHV-M) Patients Portends Highly Favorable Outcomes
after First-Line Treatment of CLL with FCR. Serial Monitoring for MRD in Blood Predicts Clinical Progression.
Philip A. Thompson,1 Paolo Strati, 1 Jeff Jorgensen,2 Michael J. Keating, 1 Susan M. O’Brien,3 Alessandra Ferrajoli, 1 Jan A. Burger, 1
Stefan Faderl,4 Zeev Estrov,1 Nitin Jain, 1 Tapan M. Kadia,1 GautamBorthakur,1 Courtney DiNardo,1 Naval Daver,1 Elias Jabbour1 and
William G. Wierda.1
Thompson, P et al. MRD analysis after FCR
Departments of 1 and 2Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 3Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange, CA 4John Theurer Cancer Center, Hackensack, NJ
MRD-negative status @EOT strongly associated with PFS but modified by IGHV mutation status
Thompson, P et al. MRD analysis after FCR
Patients with mutated IGHV have very favorable outcomes, even with only 3 courses of FCR
Thompson, P et al. MRD analysis after FCR
CIT personalization 1. FCR can cure select patients with CLL in the front line
setting2. Testing FISH, NGS and IGHV is mandated when
considering CIT as front line therapy.3. For younger fit (age < 65) patients FCR is preferred to BR
although BR is effective in IGHV mutated CLL (age > 65).4. FCR candidates should be IGHV mutated and not harbor
del17p or TP53 mutations (NGS)5. MRD (validated flow) should be tested after 3 cycles and
therapy limited if MRD negative in BM6. Responding MRD positive patients should receive 6 cycles
of FCR and MRD reassessed following treatment
A word of caution…“Back to cure but at what cost”
Mato et al, AJH 2015
Can these excellent CIT outcomes be replicated in the era of novel
agents?
Particularly using BTK, BCL2 inhibitors and CART cells?
MRD, use in earlier LOT and combination therapies may be the
keys to CURE!
BTK Inhibitors
Ibrutinib, Acalabrutinib and BGB3111
Five-Year Experience With Single-Agent Ibrutinib in Patients With Previously Untreated and
Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia
Susan O’Brien, MD1,2, Richard R. Furman, MD3, Steven Coutre, MD4, Ian W. Flinn, MD, PhD5, Jan Burger, MD, PhD1, Kristie Blum, MD6,
Jeff Sharman, MD7, William Wierda MD, PhD1, Jeffrey Jones MD, MPH6, Weiqiang Zhao, MD, PhD6, Nyla A. Heerema, PhD6, Amy J. Johnson, PhD6,
Ying Luan, PhD8, Danelle F. James, MD, MAS8, Alvina D. Chu, MD8, John C. Byrd, MD6
1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX; 2University of California, Irvine, CA;
3Department of Medicine, Weill Cornell Medical College, New York, NY; 4Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA;
5Sarah Cannon Research Institute, Nashville, TN; 6The Ohio State University, Columbus, OH;
7Willamette Valley Cancer Institute and Research Center, Springfield, OR; 8Pharmacyclics, LLC, an AbbVie Company, Sunnyvale, CA.
ACP 196
Venetoclax MRD Data Will add this in later
Anti CD 19 directed CART cells
Targeting CD19+ CLL with CAR-Modified T cells
• CARs combine an antigen recognition domain of antibody with intracellular signaling domains into a single chimeric protein
• Gene transfer (lentiviralvector) to stably express CAR on T cells confers novel antigen specificity
CAR, chimeric antigen receptor; TCR, T-cell receptor.
Lentiviral
T cell
CD19
Native TCR
Tumor cell
CTL019 cell
Dead tumor cell
Anti-CD19 CAR construct
Clinical Response (04409-Pilot trial, n=14)
UPN Blood Marrow Nodes Expansion Comments Max Resp
01 NED NED NED >3 log MRD* neg CR 39 mo+
02 NED NED NED >3 log MRD* neg CR 38 mo+
03 PR PR PR 2 log PR 4 mo
05 PR PR PR 2 log PR 4 mo
06 NR NR NR <2 log NR
07 NR NR NR <2 log NR
09 NED NED NED >3 log MRD* neg CR 18 mo+
10 NED NED PR 2 log Bulky nodes CR 15 mo +
12 NED NED PR 2 log Bulky nodes PR 6 mo +
14 NR NR NR - NR (10 mo)
17 NR NR NR - NR (8 mo)
18 NR NR NR min NR at 8 wk NR (7 mo)
22 NED NED PR >2 log Bulky nodes PR 9 mo +
25 NR NR NR NR (8 mo)
Clinical ResponseUPN Blood Marrow Nodes Expansion Comments Max Resp
01 NED NED NED >3 log MRD* neg CR 39 mo+
02 NED NED NED >3 log MRD* neg CR 38 mo+
03 PR PR PR 2 log PR 4 mo
05 PR PR PR 2 log PR 4 mo
06 NR NR NR <2 log NR
07 NR NR NR <2 log NR
09 NED NED NED >3 log MRD* neg CR 18 mo+
10 NED NED NED 2 log Bulky nodes CR 15 mo +
12 NED NED PR 2 log Bulky nodes PR 6 mo +
14 NR NR NR - NR (10 mo)
17 NR NR NR - NR (8 mo)
18 NR NR NR min NR at 8 wk NR (7 mo)
22 NED NED PR >2 log Bulky nodes PR 9 mo +
25 NR NR NR NR (8 mo)
IGH deep sequencing analysis:eradication of malignant CLL clone
Subject
numberSource Timepoint
Total reads of
IgH
Total unique
IgH reads
Tumor clone
reads
CLL clone
% of total
01
PB
baseline 408,579 48 407,592 99.76%
mo 6 285,305 7362 0 0.00%
yr 1 41 12 0 0.00%
yr 3 174 6 0 0.00%
yr 3.5 123 8 0 0.00%
BM
mo 1 179 3 0 0.00%
mo 6 202,535 4451 0 0.00%
mo 12 18,506 231 0 0.00%
mo 24 88 2 0 0.00%
02PB
baseline 1,385,340 4544 1,285,862 92.82%
mo 6 25,041 38 0 0.00%
mo 32 88 8 0 0.00%
yr 3 160 8 0 0.00%
yr 4 212 10 0 0.00%
BMyr 1 5 2 0 0.00%
yr 2 601 25 0 0.00%
Durable anti-tumor activity
Mato et al, Manuscript under review
Promising novel combinations
TBD
Ibrutinib + CART
Conclusions
TBD