waldenström’s macroglobulinemia: genomic based treatment...

Waldenström’s Macroglobulinemia:

Genomic Based Treatment Advances

Steve Treon MD, PhD, FACP, FRCP

Professor of Medicine

Bing Center for Waldenstrom’s Macroglobulinemia

Dana Farber Cancer Institute

Harvard Medical School

Discovery of the MYD88 Mutationin 2011 in WM -2012-

93-97% of WM patientsTreon et al, ASH 2011; NEJM 2012

Pro-Survival Signaling Driven by Mutated MYD88

in Waldenström's Macroglobulinemia

Yang et al, Blood 2013

Yang et al, Blood 2016

Degradation

TLRs IL-6

IL-6

IL-6

IL-6R

gp-130

growth survival

IL-6

mTOR

ERK1/2

HCK

NFKB

MYD88

BTKIRAK1/4

AKT

ibrutinib

1 CopyNumber20.9

0.8 20%0.7

0.6 40%0.5

0.4 60%0.3

0.2 80%0.1

0 CopyNumber1

34

56

78

910

Chromosome 6

Num

ber

of

Affe

cte

d P

atie

nts

p25

.3

p25

.2

p25

.1

p24

.3

p24

.1

p2

3

p22

.3

p22

.1

p21

.31

p21

.2

p21

.1

p12

.3

p12

.1

p11

.2

q1

2

q1

3

q14

.1

q14

.3

q1

5

q16

.1

q16

.3

q2

1

q22

.1

q22

.31

q22

.33

q23

.2

q23

.3

q24

.1

q24

.2

q24

.3

q25

.1

q25

.2

q25

.3

q2

6

q2

7

Detection Threshold

HIVEP2

BCLAF1HLA-DQA/B ARID1B

FOXO3

TNFAIP3PRDM1

IBTK

BACH2

CD83 EEF1A1

PLEKHG1

CCR6MAN1A1

COL19A1

Chr. 6q clonal loss is common in WM and impacts

BTK, BCL2, and NFKB regulatory genes

Guerrera et al,

Haematologica

2018

IBTK FOXO3 BCLAF1 TNFAIP3 HIVEP2WM1 0.5 0.52 0.4 1 0.46 0.5 5

WM2 0.56 0.49 0.4 2 0.55 0.4 9

WM3 0.49 0.94 0.4 4 0.51 0.5 5

WM4 0.51 0.53 0.4 8 0.56 0.5

WM5 0.56 0.49 0.5 3 0.47 0.4 3

WM6 0.43 0.54 0.5 4 0.58 0.4 9

WM7 0.58 0.55 0.5 8 0.62 0.5 6

WM8 0.53 0.57 0.6 4 0.66 0.6

WM9 0.69 0.89 0.6 4 0.9 0.8 1

WM10 0.83 0.77 0.7 0.64 0.8 3

WM11 0.82 0.74 0.7 7 0.8 0.8 1

WM12 0.92 0.93 0.7 8 0.97 0.9 8

WM13 0.9 0.93 0.8 1 0.97 0.9

WM14 0.9 1 0.8 4 0.75 0.8 1

WM15 0.83 0.89 0.8 4 0.86 0.8 5

WM16 1.08 0.99 0.8 5 1.06 1.0 1

WM17 0.97 0.82 0.8 7 0.84 0.9 1

WM18 1.01 0.85 0.8 9 0.87 1.0 1

WM19 0.85 0.89 0.8 9 0.9 0.9 1

WM20 1 0.97 0.9 0.9 0.9 9

WM21 0.97 1.1 0.9 0.96 0.9 7

WM22 0.93 0.98 0.9 3 0.89 1.0 6

WM23 1.02 1.04 0.9 4 0.87 1.0 8

WM24 0.93 1.05 0.9 7 1.05 1.0 5

WM25 0.93 0.95 1.0 7 1.15 0.9 7

IBTKFOXO3BCLAF1TNFAIP3HIVEP2

Hunter,

et al.

Blood

2014

Discovery of CXCR4 mutations in WM -2013-

30-40% of WM patients

Mutations impact the “tail” of the CXCR4 receptor

Adapted from Kahler et al, AIMS Biophysics, 2016S338X

352

Most common

mutation is S338X

MYD88 and CXCR4 Mutation Status Impacts

Clinical Presentation of WM Patients

MYD88WT

MYD88 WT L265P L265P L265P

CXCR4 WT WT FS NS

MYD88 WT L265P L265P L265P

CXCR4 WT WT FS NS

BM (%) sIGM (mg/dL

Treon et al, Blood 2014; 123(18):2791-6.

Drug resistance

Bone Marrow StromaCXCR4

WM Cell

Mutated CXCR4 receptor fails to downregulate after

binding its ligand CXCL12 and remains active

CXCL12

Cao et al; Leukemia 2014; Roccaro et al, Blood 2014

Study O

Opened May 2012 R. Advani L. Palomba

420 mg po qD

Ibrutinib

Progressive Disease (PD) or

Unacceptable Toxicity Stable Disease or Response

Continue

Stop Ibrutinib

Event Monitoring

Event Monitoring

Screening

Registration

www.clinicaltrials.gov

NCT01614821

Multicenter study of Ibrutinib in

Relapsed/Refractory WM (>1 prior therapy)

✔ MYD88, CXCR4

Mutation StatusNCT01614821

R Advani L PalombaS Treon PI

FDA MEETING JUNE 2014

First Drug Approval for Waldenstrom’s Macroglobulinemia

Update of Pivotal Study

• The median time on treatment was19.1 months at time of original studyreporting (NEJM, 2015).

• The median time on treatment forupdated study: 47 months (EHA, 2018)

• Last patient follow-up: October, 2018.

Baseline Characteristics for Study Participants (n=63)

Median Range

Age (yrs) 63 44-86

Prior therapies 2 1-9

Refractory to prior therapy 25 (40%) N/A

Hemoglobin (mg/dL) 10.5 8.2-13.8

Serum IgM (mg/dL) 3,520 724-8,390

B2M (mg/dL) 3.9 1.3-14.2

BM Involvement (%) 60 3-95

Adenopathy >1.5 cm 37 (59%) N/A

Splenomegaly >15 cm 7 (11%) N/A

Treon et al, NEJM 372: 1430, 2015

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

Basel

ine

Cyc

le 2

Cyc

le 3

Cyc

le 6

Cyc

le 9

Cyc

le 1

2

Cyc

le 1

5

Cyc

le 1

8

Cyc

le 2

1

Seru

m I

gM

(m

g/d

L)

BestIgMResponse:3,520to880mg/dL;p<0.001

N=63

Serum IgM and Hb Levels Following Ibrutinib

BestHemoglobinResponse:10.5to13.8;p<0.001

8

9

10

11

12

13

14

15

16

Bas

eline

Cyc

le 2

Cyc

le 3

Cyc

le 6

Cyc

le 9

Cyc

le 1

2

Cyc

le 1

5

Cyc

le 1

8

Cyc

le 2

1

N=63

He

mo

glo

bin

(g

/dL

)

Serum IgM Hb

Best Hemoglobin Response:10.5 to 13.8; p<0.001

Best IgM Response: 3,520 to 880 mg/dL; p<0.001

Treon et al, N Engl J Med. 2015; EHA 2018

Updated:

Best Hemoglobin Response:10.5 to 14.2; p<0.001

Best IgM Response: 3,520 to 821 mg/dL; p<0.001

ALL MYD88Mut

CXCR4WT

MYD88Mut

CXCR4Mut

MYD88WT

CXCR4WT

P-value

N= 63 36 21 5*

ORR 91% 100% 85.7% 60% 0.005

Major (>PR) 78% 97% 67% 0% <0.001

VGPR 29% 44% 10% 0% 0.007

Time to Minor Response (mos.)

1.0 1.0 1.0 1.0 0.10

Time to Major response (mos.)

2.0 2.0 6.0 N/A 0.05

Responses to ibrutinib are impacted by MYD88 (L265P and non-L265P) and CXCR4 mutations.

*2 patients at initial reporting with major responses were discovered subsequently

to have MYD88 mutated disease (S243N, L265P). One patient at initial reporting

was subsequently found to CXCR4 mutated disease upon genotyping of CD19-

selected WM cells.

Treon et al, EHA 2018

OIbrutinib in Previously Treated WM:

Updated PFS

5 year PFS: 60% (95% CI 46-71%).

All patients MYD88 and CXCR4 Status

MYD88 MUTATED ONLY

BOTH MYD88 AND CXCR4 MUTATED

NO MYD88 OR CXCR4 MUTATIONS

Treon et al, EHA 2018

R

Study O

Opened May 2012 R. Advani L. Palomba

420 mg po qD

Ibrutinib

Progressive Disease (PD) or

Unacceptable Toxicity Stable Disease or Response

Continue

Stop Ibrutinib

Event Monitoring

Event Monitoring

Screening

Registration

www.clinicaltrials.gov

NCT01614821

Ibrutinib Monotherapy in

Symptomatic Treatment Naive WM

✔ MYD88, CXCR4

Mutation Status

Treon et al, JCO 2018NCT02604511

Time to and depth of response to ibrutinib

are impacted by CXCR4 mutations.

All Patients MYD88MUT

CXCR4WT

MYD88MUT

CXCR4MUT P-value

N= 30 16 14 N/A

Overall Response Rate-no. (%)

30 (100%) 16 (100%) 14 (100%) 1.00

Major Response Rate-no. (%)

25 (83%) 15 (94%) 10 (71%) 0.16

Categorical responsesMinor responses-no. (%)

5 (17%) 1 (6%) 4 (29%) 0.16

Partial responses-no. (%)

19 (63%) 10 (63%) 9 (64%) 1.00

Very good partial responses-no. (%)

6 (20%) 5 (31%) 1 (7%) 0.18

Median time to response (months)Minor response (≥Minor response)

1.0 0.9 1.7 0.07

Major response (≥Partial response)

1.9 1.8 7.3 0.01

Median f/u: 14.6 (range 1.8-21.6 months) Data cutoff: Jan. 22, 2018

OIbrutinib Monotherapy in Frontline WM: PFS

18 mo: PFS 92%;

All patients alive.

PD patients were both

CXCR4 mutated.

Median f/u: 14.6 (range 1.8-21.6 months) Data cutoff: Jan. 22, 2018

Ibrutinib (560 mg/day) induced response in a WM patient with Bing Neel Syndrome

Mason et al, BJH 2016

Phase IIII Study of Zanubrutinib vs. Ibrutinib in WM

Strategies to Enhance BTK Inhibitors in WM

ARM B: Placebo

+ Rituximab 375mg/m2 x 8 infusions (weeks 1,2,3,4,17,18,19, and 20)

ARM A: ibrutinib 420mg

+ Rituximab 375mg/m2 x 8 infusions (weeks 1,2,3,4,17,18,19, and 20)

1:1

Randomization

N = 150

ARM C: ibrutinib 420mgSubjects considered

refractory to prior rituximab

N=31

iNNOVATE Study in WMTreatment Naïve + Previously Treated

45 centers in 9 countries

ABC patients genotyped for MYD88 and CXCR4

16 156

17 239

27 22

53

2956

23

58

44

3633

25

3

38

6

15

27

14

0102030405060708090

100

Ibrutinib-RTX

Placebo-RTX

Ibrutinib-RTX

Placebo-RTX

Ibrutinib-RTX

Placebo-RTX

Ibrutinib-RTX

Placebo-RTX

Responses in Innovate AB Study: UpdateB

est

Resp

on

se (

%)

ORR 95%

ORR 48%

aFollowing modified 6th IWWM Response Criteria (NCCN 2014); required two consecutive assessments.

MYD88L265P/CXCR4WT MYD88L265P/CXCR4WHIM MYD88WT/CXCR4WT

ORR 100%

ORR 46%

ORR 96%

ORR 57%

ORR 91%

ORR 56%

CRVGPR

PR

MR

Median time to ≥PR,

months (range)2

(1–28)

6

(2–26)

2

(1–28)

5

(2–17)

3

(1–19)

11

(4–18)

6

(1–17)

6

(5–26)

Median time to ≥MR,

months (range)1

(1–18)

3

(1–24)

1

(1–18)

3

(1–24)

1

(1–11)

3

(1–8)

2

(1-17)

3

(2–17)

Overall

Major

33%

Major

79%

Major

29%

Major

94%

Major

48%

Major

73%

Major

33%

Major

64%

??

Buske et al, ASH 2018

Progression-Free Survival Benefit: Impact of MYD88/CXCR4 Genotype

• Improved PFS

with ibrutinib

• 36-month PFS

rates

▪ MYD88L265P/CXCR4WT:

84% vs 29%

▪ MYD88L265P/CXCR4WHIM:

64% vs 26%

▪ MYD88WT/CXCR4WT:

82% vs 44%

MYD88L265P/CXCR4WT

Pro

gres

sio

n-F

ree

Surv

ival

(%

)

Months

MYD88WT/CXCR4WT

MYD88L265P/CXCR4WHIM

MYD88L265P/CXCR4WHIM

MYD88WT/CXCR4WT

MYD88L265P/CXCR4WT

Ibrutinib-RTX

RTX

Innovate AB Data: Buske et al, ASH 2018.

Phase I/II Trial of Ulocuplumab and Ibrutinib in

CXCR4 mutated patients with symptomatic WM

Ibrutinib Until PD or

Intolerance

Weekly Ulo

4 weeks

Biweekly Ulo

20 weeks

ClinicalTrials.gov Identifier: NCT03225716

STOP

Dose Level Ibrutinib Ulocuplumab Cycle 1 Ulocuplumab Cycles 2-6

Level 1 –Starting dose 420mg PO DQ 400 mg weekly 800 mg every other week

Level 2 420mg PO DQ 800 mg weekly 1200 mg every other week

Level 3 420mg PO DQ 800 mg weekly 1600 mg every other week

Schema

Serial IgM Levels for Evaluable PatientsDose Level 1 (ongoing)

WM Pt

Venetoclax (ABT-199) augments

ibrutinib induced apoptosis

Cao et al, BJH 2015

BCWM.1

MWCL-1

CleavedPARP

CleavedCaspase3

CleavedPARP

CleavedCaspase3

GAPDH

DM

SO

IB

A

BT

A

BT

/IB

A

BT

/IB

/CX

CL1

2

AB

T/IB

/CX

CL1

2/A

MD

D

MS

O

IB

AB

T

AB

T/IB

A

BT

/IB

/CX

CL1

2

AB

T/IB

/CX

CL1

2/A

MD

GAPDH

CXCR4WT CXCR4S338X

Higher BCL2 levels in

MYD88 mutated WM

Screening

Informed Consent and Registration

Venetoclax

200 mg PO QD

800 mg PO QDProgressive Disease or

Unacceptable Toxicity

SD or Response →

Continue for 2 years

Stop ABT-199 Event Monitoring

www.clinicaltrials.gov: NCT02677324

Phase II Study of Venetoclax in Previously Treated WM

Selected inclusion

criteria:

• Clinicopathological

diagnosis of WM

• Serum IgM >2 x

ULN

• Previously treated

• Age ≥18 years

• Good performance

• Normal organ and

marrow function

Selected exclusion

criteria:

• Serious medical

condition

• Concurrent anti-

cancer agent

• Known CNS

lymphoma

• Active HIV, HBV,

HCV infection

• Lactating or

pregnant women

Castillo et al. EHA 2018

Phase II Study of Venetoclax in Previously Treated WM

ResponseNo prior ibrutinib

(n=15)

Prior ibrutinib

(n=15)

Overall 14 (93%) 12 (80%)

Major 13 (87%) 9 (60%)

Very good 4 (27%) 1 (7%)

Partial 9 (60%) 8 (53%)

Minor 1 (7%) 3 (20%)

Stable 1 (7%) 3 (20%)

CXCR4 WT

(n=14)

CXCR4 MUT

(n=16)

12 (86%) 14 (87%)

9 (86%) 13 (63%)

4 (29%) 1 (7%)

8 (57%) 9 (56%)

0 (0%) 4 (25%)

2 (14%) 2 (13%)

1 patient had progressive disease at 9 months (MYD88, CXCR4, TP53)

Castillo et al. EHA 2018

Median follow-up: 11 months

Ibrutinib and Venetoclax in Treatment Naïve WM

Ibrutinib

420 mg/day

x 4 weeks

Ibrutinib

420 mg/day

Add Venetoclax100 mg/day week 5

200 mg/day week 6

400 mg/day weeks 7,8

Ibrutinib

420 mg/day

And

Venetoclax

400 mg/day

Observation

4 weeks 4 weeks 22 months Follow to PD

or off study

24 months

Jorge Castillo, PI (DFCI)

BTK Cys481 Mutations accompany CXCR4 in WM Patients on Ibrutinib.

Patient*

L265P positive cells

with BTK C481RT>C


with BTK C481ST>A


with BTK C481SG>C


with BTK C481YG>A

L265P positive cells with PLCG2

Y495HT>C


with CARD11 L878FC>T

P1 None None None None None None

P2 32.4% 6.6% 5.8% 1.0% None None

P3 0.3% 34.4% 6.5% 0.3% None 0.2%



P6 None None 10.3% None 11.9% None

Targeted next-generation sequencing for MYD88, CXCR4, BTK, PLCG2, CARD11, LYN.

All patients are MYD88 Mutated.

P2, P3, P6 are CXCR4 WHIM Mutated. Xu et al, BLOOD 2017

BTK C481S cells show uniform ERK 1/2 activation

in the presence of ibrutinib.

Chen et al,

Blood 2018

Ulixertinib blocks ERK-downstream signaling and overcomes

mutated BTK Cys 481 resistance to ibrutinib.

Chen et al, BLOOD 2018

BTK mutated cells release inflammatory cytokines in the presence of

ibrutinib that can be blocked by ERK-inhibitor.

Chen et al, BLOOD 2018

Y

Y

Y Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

YYY

Y

YY

Y

Y

Y

Y

YY

Y

BTKWT

BTKWT

BTKCys481Ser

BTKWT

BTKCys481Ser

BTKWT

+anti-IL6 and -IL10 Abs

BTKCys481Ser mutated clones release cytokines that protect

BTKWT clones from ibrutinib triggered cytotoxicity

Chen et al, Blood 2018

+ibrutinib

IL6

IL10IL6

IL10

+ibrutinib +ibrutinib

BTK mutated clones.. Bad apples that spoil the bunch?

Ibrutinib

+ ERK-inhibitor

DFCI/ELI LILLY COLLABORATION

Phase I/II Clinical Trial of the oral ERK inhibitor LY3214996 in

BTK Cys 481 and PLCG2 mutated CLL, WM, MZL, MCL

S. Treon, PI

Bing Center for WM

www.IMW2019boston.org

REGULAR AND YIA

ABSTRACT DEADLINE

June 19, 2019

LATE BREAKING

July 24, 2019

waldenström’s macroglobulinemia: genomic based treatment...

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