Breaking News from the WM Front

Steve Treon MD, PhD, FRCP, FACPProfessor of Medicine, Harvard Medical School

Dana Farber Cancer Institute

WM ROADMAP 2019

Why are complete responses so uncommon in WM even with targeted therapy?

Bone Marrow Biopsy from a WM Patient

From Dr. Marvin Stone

B-cellCD19+CD20+CD38-

LPC cellCD19+CD20+CD38+/-

Plasma cellCD19-CD20-CD38+

Primary Therapy of WM with Rituximab

Regimen ORR CR TTP (mo)

Rituximab x 4 25-30% 0-5% 13 Rituximab x 8 40-45% 0-5% 16-22Rituximab/thalidomide 70% 5% 30Rituximab/cyclophosphamidei.e. CHOP-R, CVP-R, CPR, CDR

70-80% 5-15% 30-36

Rituximab/nucleoside analoguesi.e. FR, FCR, CDA-R

70-90% 5-15% 36-62

Rituximab/Proteasome Inhibitori.e. BDR, VR, CaRD

70-90% 5-15% 42-66

Rituximab/bendamustine 90% 15-20% 69

Reviewed in Dimopoulos et al, Blood 2014; 124(9):1404-11; Treon et al, Blood 2015; How I Treat WM

Depth of response in treatment naïve WM patients treated with rituximab based therapy

N=159 Treon et al, BJH 2011

Agent WM Toxicities

Rituximab • IgM flare (40-60%)-> Hyperiscosity crisis, Aggravation of IgM related PN, CAGG, Cryos.

• Hypogammaglobulinemia-> infections, IVIG • Intolerance (10-15%)

Fludarabine • Hypogammaglobulinemia-> infections, IVIG• Transformation, AML/MDS (15%)

Bendamustine • Prolonged neutropenia, thrombocytopenia(especially after fludarabine)

• AML/MDS (5-8%)

Bortezomib • Grade 2+3 Peripheral neuropathy (60-70%); High discontinuation (20-60%)

WM–centric toxicities with commonly used therapies

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

Discovery of MYD88 Mutation in WM-2011-

P. Bing

Ngo et al, Nature 2011Treon et al, NEJM 2012

MYD88 mutations transactivate the pro-survival factor NFKB

MYD88 L265P mutated WM cells

Pro-Survival Signaling Driven by Mutated MYD88 in Waldenström's Macroglobulinemia

Degradation

TLRs

growth survival

NFKB

STAT3

MYD88

BTKIRAK1/4 Loss of IBTKdel 6q21-25

Loss of HIVEP2, TNFAIP3del 6q21-25

Yang et al, Blood 2013; Hunter et al, Blood 2013; Guerrera et al, Haematologica 2016

Bacteria, Viruses

Pro-Survival Signaling Driven by Mutated MYD88 in Waldenström's Macroglobulinemia

Yang et al, Blood 2013Yang et al, Blood 2016

Degradation

TLRs IL-6IL-6

IL-6

IL-6R

gp-130

growth survival

IL-6

mTOR

ERK1/2

HCK

NFKB

MYD88

BTKIRAK1/4

AKT

ibrutinib

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

Drug resistance

Bone Marrow Stroma

CXCR4 mutations permit ongoing pro-survival signaling by CXCL12, the stimulant for CXCR4 receptor.

CXCR4

WM Cell

CXCR4 receptor remainsup with mutation

CXCL12

Cao et al, Leukemia 2014; Rocarro et al, Blood 2014.

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.

ALL MYD88MutCXCR4WT

MYD88MutCXCR4Mut

MYD88WTCXCR4WT

P-value

N= 63 36 21 5*ORR 91% 100% 85.7% 60% 0.005Major (>PR) 78% 97% 67% 0%

OIbrutinib in Previously Treated WM: Updated Progression Free Survival

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

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

CXCR4WTMYD88MUTCXCR4MUT 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

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 15 617 23 9

27 22

53

29 56 23

58

44

3633

25

3

38

6

1527

14

0102030405060708090

100

Ibrutinib-RTX

Placebo-RTX

Ibrutinib-RTX

Placebo-RTX

Ibrutinib-RTX

Placebo-RTX

Ibrutinib-RTX

Placebo-RTX

Impact of CXCR4 on WM responseB

est

Res

pons

e (%

) 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%

CRVGPRPRMR

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

Major33%

Major79%

Major29%

Major94%

Major48%

Major73%

Major33%

Major64%

??

Buske et al, ASH 2018

Importance of CXCR4 in PFS

• 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

Prog

ress

ion-

Free

Sur

viva

l (%

)

Months

MYD88WT/CXCR4WT

MYD88L265P/CXCR4WHIM

MYD88L265P/CXCR4WHIM

MYD88WT/CXCR4WTMYD88L265P/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

Pro-Survival Signaling Driven by Mutated MYD88 in Waldenström's Macroglobulinemia

Yang et al, Blood 2013Yang et al, Blood 2016Munshi et al, ASH 2018

Degradation

TLRs IL-6IL-6

IL-6

IL-6R

gp-130

growth survival

IL-6

mTOR

ERK1/2

HCK

NFKB

BCR

CD79

SYK

LYN

STAT3

MYD88

BTKIRAK1/4

AKT

AKT

Targeting Pro-Survival Signaling Driven by Mutated MYD88 with extended HCK inhibitors

Yang et al, Blood 2013Yang et al, Blood 2016Munshi et al, ASH 2018

Degradation

TLRsIL-6

IL-6IL-6

IL-6R

gp-130

growth survival

IL-6

mTOR

ERK1/2

HCK

NFκB

BCR

CD79

SYK

LYN

STAT3

MYD88

BTKIRAK1/4

AKTAKT

Targets of KIN-8194

Targeting BCL-2 in WM

BCL-2

DIE

Chang et al, Leukemia 2006; Cao et al, BJH 2015

29

The role of BCL2 and other anti-apoptotic proteins in WM

Cao et al, BJH 2015

Higher BCL2 levels in MYD88 mutated WM

Screening

Informed Consent and Registration

Venetoclax200 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

Venetoclax400 mg/day

Observation

4 weeks 4 weeks 22 months Follow to PDor 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

L265P positive cells

with BTK C481ST>A

L265P positive cells

with BTK C481SG>C

L265P positive cells

with BTK C481YG>A

L265P positive cells with PLCG2

Y495HT>C

L265P positive cells

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%

P4 None None None None None None

P5 None None None None None None

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

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

Y

Y

Y Y

Y

Y

YY

Y

YY

YY

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

IL6IL10

IL6IL10

+ibrutinib +ibrutinib

Ibrutinib

+ ERK-inhibitor

DFCI/ELI LILLY COLLABORATIONPhase I/II Clinical Trial of the oral ERK inhibitor LY3214996 in

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

Acalabrutinib in Treatment Naïve and Previously Treated WM

Owen et al, ASCO 2018; EHA 2018

Zanubrutinib in WM

Trotman et al, EHA 2018

Phase I/II Data51 patients out of 67 evaluable for efficacyGenotyping unknown for many patients91% PFS at 1 year

Phase IIII Study of Zanubrutinib vs. Ibrutinib in WM

Incorporating Novel Treatments to eradicate residual or resistant disease

Syk inhibitors (fostamatinib, entospletinib, R406)BCL2, MCL-1, BCLXL inhibitors (ABT199, AZD5991) IRAK4 inhibitors (CA 4948, PF-06650833)HCK inhibitors (Dasatinib, KIN8194)CXCR4 inhibitors (Ulocuplomab, X4)ERK inhibitors (LY3214996)Other MoAbs (CD38, CD27, CD70)Bispecific Antibodies (CD3/BCMA)CAR-T cells (CD19, CD38)ASCT

What are the knowledge gaps for developing more effective treatments for WM patients without MYD88 mutations?

High risk of transformation and poorer survival accompany MYD88WT WM

Transformation risk for MYD88 WT(Odds ratio 23·3; 95% CI 4·2-233·8; p

New Driver Mutations Identified in MYD88 WT WM

Principal component analysis of top 500 high variance genes.

Hunter et al, Blood. Adv 2018

NFKB signaling cascades in MYD88 Wild-Type WM

Hunter et al, Blood Adv. 2018

Beyond MYD88 and CXCR4:Are there other targetable mutations or alterations in WM?

48

Variants and Copy Number Alterations in WM

Hunter et al, Blood 2014

Sequence 300 Symptomatic Untreated WM Patients

-Determine mutations in the DNA by Whole Exome Seq.-Determine transcriptional (RNA) changes, incl. aberrant splicing-Map epigenome and its regulatory changes-Understand impact on disease presentation, course, survival-Develop targeted therapies based on mutation profile for individual patients

Homozygous mutated MYD88 (ibrutinib and other)BTK Cys 481 (ibrutinib)PLCG2 (ibrutinib)6q (ibrutinib and others)8p (ibrutinib)

What about clonal evolution?

Detection of MYD88 and CXCR4:-What is the best platform?-Is CD19 selection needed?-Is cell free DNA testing feasible?-Can PB be used? -Do we need to develop testing to identify all MYD88 and CXCR4 mutations?

Blue=TreatedRed=UntreateddCT>9.5 called as negative

Circulating WM Cells by Treatment StatusIn untreated patients, allele specificPCR for MYD88 L265P is roughlycomparable between DNA derivedfrom CD19+ peripheral blood orCD19+ bone marrow cells. Inpreviously treated samples thereappears to be a subset of patientsfor whom the WM cells stopcirculating making the PB negativefor MYD88 in spite of a strong signalfrom the BM. Higher dCT valuesindicate a weaker signal.

Xu et al, Blood 2013

NGS versus PCR: Cell sorting and MYD88 Mutation Detection in BM Biopsies

Distribution and discrepancy between techniques:Lower levels of WM bone marrow involvement wasfound to be associated with the discordance betweenNGS panel data and AS-PCR. Tumor enrichment fromCD19+ selection may play an important role in theincreased sensitivity of the AS-PCR assay.

For 319 unique biopsies collected from 295 WM patients, both NGS panel data and AS-PCRwere available. The finding between the NGS and AS-PCR studies were largely concordant.Discrepancies were observed in 82 (25.7%) cases where targeted NGS gave false negativeresults for c.978T>C. Median sequencing read depth at p.Leu265Pro was 229 (range 120-922).Modeling these false negative results by age, previous treatment and bone marrow involvementrevealed only bone involvement to be significant (p < 0.0001).

Kofides et al, ASH 2018

Role of Nonsense vs. Frameshift CXCR4 mutations in Ibrutinib Response

Castillo et al, EHA 2018

All patientsPreviously Treated

Untreated

Special Patient Populations in WM:Bing Neel Syndrome

What are the knowledge gaps for treating BNS?

What trials should we prioritize for. BNS?

Current Treatments used for BNS

Ibrutinib (high dose 560 mg/day)FludarabineBendamustineIT MTX High Dose MTXIT Rituximab

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

Mason et al, BJH 2016

Special Patient Populations in WM:Peripheral Neuropathy

What are the knowledge gaps for treating PN?

What trials should we prioritize for WM-related PN?

Treatment Outcome of WM-related PN

• Plasmapheresis 29/42 (69%) had symptomatic improvement;

• IVIG 1/8 (12.5%) had symptomatic improvement;

• Chemotherapy71/151 (47%) had symptomatic improvement;

→8/151 (5.3%) had complete resolution of PN.

Treon et al, ASCO 2010.

Symptomatic Improvement following therapy of WM related PN

p=0.04

p24 months< 24 vs. >24 months

Combination vs. MonotherapyCombination vs. Monotherapy

Series 1

Series 2

48.5

15.4

79

35.5

57.3

42.5

59.3

37

Sheet1

Series 1Series 2

IgM vs. Amyloid PN48.515.4

Major vs. Minor Response7935.5

< 24 vs. >24 months57.342.5

Combination vs. Monotherapy59.337

To resize chart data range, drag lower right corner of range.

Long Term Follow-up of Patients with MAG related IgM Neuropathy.

• N=25• Mean f/u of 8.5 yrs. • Mean duration of neuropathy was 11.8 yrs.• 17 (68%) alive ; 3/25 died from treatment

complication. No pt died from neuropathy.• 11 (46%) became disabled from their PN.

Nobile-Orazio et al. Brain. 2000;123 :710-7.

Ibrutinib in WM related PN• 9 patients with PN (3 MAG+) treated on

pivotal trial• All 9 had progressive sensory PN after

rituximab• Following ibrutinib, all 9. had IgM major

response• 5 had subjective improvement, 4 had

stabilization of PN during follow-up period.

Treon et al, NEJM 2015

10th International Workshop on WM -NYC 2018-

Giampaolo Merlini, MDRobert A. Kyle Award

Bart Barlogie, MD PHDJan Waldenstrom Award

Young Investigator Award Winners –IWWM10-

Breaking News from �the WM Front��������Steve Treon MD, PhD, FRCP, FACP�Professor of Medicine, Harvard Medical School�Dana Farber Cancer InstituteWhy are complete responses so uncommon in WM even with targeted therapy? �����Slide Number 3Slide Number 4Slide Number 5Slide Number 6Slide Number 7Slide Number 8Slide Number 9Slide Number 10Slide Number 11Slide Number 12Slide Number 13Slide Number 14Slide Number 15Slide Number 16Update of Pivotal StudyResponses to ibrutinib are impacted by �MYD88 (L265P and non-L265P) and CXCR4 mutations.Slide Number 19Slide Number 20Time to and depth of response to ibrutinib �are impacted by CXCR4 mutations.Slide Number 22Impact of CXCR4 on WM responseImportance of CXCR4 in PFSPhase I/II Trial of Ulocuplumab and Ibrutinib in CXCR4 mutated patients with symptomatic WMSlide Number 26Slide Number 27Targeting BCL-2 in WMSlide Number 29The role of BCL2 and other �anti-apoptotic proteins in WMSlide Number 31Phase II Study of Venetoclax in Previously Treated WMIbrutinib and Venetoclax in Treatment Naïve WM�BTK Cys481 Mutations accompany �CXCR4 in WM Patients on Ibrutinib.Slide Number 35Slide Number 36Slide Number 37Slide Number 38Acalabrutinib in Treatment Naïve and Previously Treated WMZanubrutinib in WMSlide Number 41Slide Number 42�What are the knowledge gaps for developing more effective treatments for WM patients without MYD88 mutations? ����High risk of transformation and poorer survival accompany MYD88WT WMNew Driver Mutations Identified �in MYD88 WT WMSlide Number 46Beyond MYD88 and CXCR4:�Are there other targetable mutations or alterations in WM?Slide Number 48Slide Number 49What about clonal evolution?Detection of MYD88 and CXCR4:�-What is the best platform?�-Is CD19 selection needed?�-Is cell free DNA testing feasible?�-Can PB be used? �-Do we need to develop testing to � identify all MYD88 and CXCR4 � mutations?�Circulating WM Cells by Treatment StatusNGS versus PCR: Cell sorting and MYD88 Mutation Detection in BM BiopsiesRole of Nonsense vs. Frameshift CXCR4 mutations in Ibrutinib ResponseSpecial Patient Populations in WM:�Bing Neel Syndrome��What are the knowledge gaps for treating BNS?�What trials should we prioritize for. BNS?Current Treatments used for BNS Ibrutinib (560 mg/day) induced response in a WM patient with Bing Neel SyndromeSpecial Patient Populations in WM:�Peripheral Neuropathy��What are the knowledge gaps for treating PN?��What trials should we prioritize for WM-related PN?Treatment Outcome of WM-related PNSymptomatic Improvement following therapy of WM related PNLong Term Follow-up of Patients with MAG related IgM Neuropathy.Ibrutinib in WM related PN10th International Workshop on WM �-NYC 2018-Slide Number 64Slide Number 65Slide Number 66