we can cure chronic lymphocytic leukemia with current ... · we can cure chronic lymphocytic...

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

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t N

RM

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100

10y REL 55% (43, 67)

Months from HCT

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t p

rog

ressiv

e

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100

10y EFS 31% (21, 41)

Months from HCT

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t E

FS

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10y OS 51% (40%-62%)

Months from HCT

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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