Treatment Landscape of

Waldenström’s Macroglobulinemia

Dr. Steve Treon

Insert

Photo

Dana-Farber Cancer Institute

Harvard Medical School

Treatment Landscape

of Waldenström’s Macroglobulinemia

Steve Treon MD, PhD, FACP, FRCP

Professor of Medicine

Bing Center for Waldenstrom’s Macroglobulinemia

Dana-Farber Cancer Institute

Harvard Medical School

Research Support/P.I. Abbvie/Pharmacyclics, Beigene, BMS, Eli Lilly

Consultant Janssen, Abbvie/Pharmacyclics, Beigene, BMS

This presentation may contain unregistered products or indications of investigational

drugs, please check the drug compendium or consult the company

Disclosures – Steven Treon

Manifestations of WM Disease

≤20% at diagnosis;

50-60% at relapse.

Hb>>> PLT> WBC

Hyperviscosity Syndrome:

Epistaxis, Headaches

Impaired vision

>6,000 mg/dL or >4.0 CP

Treon S., Hematol Oncol. 2013; 31:76-80.

Cold Agglutinemia (5%)

Cryoglobulinemia (10%)

IgM Neuropathy (22%)

Amyloidosis (10-15%)Hepcidin

Fe Anemia

Bone Marrow

Bing Neel

Syndrome

NCCN Guidelines for Initiation of Therapy in WM

• Hb ≤10 g/dL on basis of disease

• PLT

Primary Therapy of WM with Rituximab

Regimen ORR CR Median PFS (mo)

Rituximab x 4 25-30% 0-5% 13

Rituximab x 8 40-45% 0-5% 16-22

Rituximab/thalidomide 70% 5% 30

Rituximab/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% 5-15% 69

Reviewed in Dimopoulos et al, Blood 2014; 124(9):1404-11; Treon et al, Blood 2015 126:721-732; Rummel et al, ASH 2019

Agent WM Toxicities

Rituximab • IgM flare (40-60%)-> Hyperviscosity 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

Personal communication

Pro-Survival Signaling by Mutated MYD88

in Waldenström's Macroglobulinemia

Yang et al, Blood 2013 122(7):1222-32;

Yang et al, Blood 2016 127(25):3237-52

Munshi and Yang et al, BCJ 2020

BTK-inhibitors

ibrutinib

zanubrutinib

95-97% of WM patients have mutations in MYD88

Drug resistance

Bone Marrow Stroma

Mutated CXCR4 permits ongoing

pro-survival signaling by CXCL12

CXCR4

WM Cell

CXCR4 receptor remains

up with mutationCXCL12

Cao et al, Br J Haematol. 2015 Mar;168(5):701-7; Roccarro et al, Blood. 2014 Jun 26;123(26):4120-31

30-40% of WM patients have mutations in CXCR4

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 StatusClinicalTrials.gov Identifier: NCT01614821

R Advani L PalombaS Treon PI

All Patients MYD88MUT

CXCR4WTMYD88MUT

CXCR4MUTMYD88WT

CXCR4WT P-value

N= 63 36 22 4 N/AOverall Response Rate-no. (%) 90.5% 100% 86.4% 50%

All patients MYD88 and CXCR4 Mutation Status

Ibrutinib in Previously Treated WM: Updated PFS

5 year PFS: 54%5 year OS: 87%

MYD88 Mutated

MYD88/CXCR4

MutatedMYD88/CXCR4

Wild-Type

Treon et al, NEJM 2015; Updated JCO 2020

Long Term Toxicity Findings (grade >2)

Increased since original report. 8 patients (12.7%) with Afib, including grade 1.

7 continued ibrutinib with medical management. Treon et al, NEJM 2015; Updated JCO 2020

Responses in Innovate AB Study: Update

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

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)

Buske et al., ASH 2018; abstract 149 (oral presentation)

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

Be

st R

esp

on

se (

%)

ORR 95%

ORR 48%

MYD88L265P/CXCR4WT MYD88L265P/CXCR4WHIM MYD88WT/CXCR4WT

ORR 100%

ORR 46%

ORR 96%

ORR 57%

ORR 91%

ORR 56%

CRVGPRPR

MR

Overall

Major33%

Major79%

Major29%

Major94%

Major48%

Major73%

Major33%

Major64%

??

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

Buske et al., ASH 2018; abstract 149 (oral presentation)

Pre-

treatment

Post-

treatment

Ibrutinib induced response in

a WM patient with Bing Neel Syndrome

Mason et al, BJH 2016; ;179(2):339-341

560 mg po one a day

Covalent BTK-inhibitors in WM (Cys481)

Ibrutinib Acalabrutinib Zanubrutinib Tirabrutinib

Kaptein et al, ASH 2018; Abstract 1871.

Acalabrutinib in Treatment Naïve and

Previously Treated WM

Owen et al., Lancet Hematology 2020

Median follow-up: 27.4 months

100 mg po BID

2-year PFS 90% (TN),

82% (previously treated)

Acalabrutinib in Treatment Naïve and

Previously Treated WM

Afib: 5%

No atrial fibrillation event

led to acalabrutinib

withholding or

discontinuation.

Median follow-up: 27.4 months

Overall Response Rate (ORR) Progression Free Survival (PFS)

Zanubrutinib in WM: Phase 2 data in TN and previously treated pts.

21

Best Response in

WMzanubrutinib

Overall TN RR

Evaluable for

efficacy, n73 24 49

Median Follow-up 23.9 mo 12.3 mo 24.8 mo

Response CriteriaMod. 6th IWWM

(IgM decreases only, and not extramedullary disease)

Median Prior Lines of

Therapy 0 2 (1-8)

ORR 92% 96% 90%

MRR 82% 87% 78%

CR/VGPR1 42% 29% 49%

PR 40% 58% 31%

No. of patients at risk

95% CI

Trotman et al, EHA 2019; Updated Blood 2020

2 -Year PFS: 81%

Zanubrutinib 320 mg qd to 160 mg BID

Data Cut-off: August 31, 2019

Median Follow-up: 19.4 months

Tam et al, ASCO 2020; Updated Blood 2020

*Post-hoc

analysis:

28% CXCR4

mutated*

Tam et al, ASCO 2020; Updated Blood 2020

*CXCR4 mutated

patients had lower

VGPR responses in

both arms in post-hoc

analysis

using NGS:

Mut WT

Zanu (18% v. 34%)

Ibru (10% v. 24%)

Tam et al, ASCO 2020; Updated Blood 2020

Tam et al, ASCO 2020

Overall

Zanubrutinib

(N = 102)

Ibrutinib

(N = 99)

AEs of Interest, n, %

Atrial fibrillation/flutter (all grades) 2 (2.0%) 15 (15.3%)

Minor bleeding

(bruising, contusion, petechiae)

49 (48.5%) 58 (59.2%)

Major hemorrhage* 6 (5.9%) 9 (9.2%)

Diarrhea (all grades) 21 (20.8%) 31 (31.6%)

Infection

Pneumonia/Lower respirtory

tract infections

67 (66.3%)

9 (8.9%)

66 (67.3%)

19 (19.4%)

Hypertension 11 (10.9%) 17 (17.3%)

Hematologic

Neutropenia

Anemia

Thrombocytopenia

30 (29.7%)

12 (11.9%)

10 (9.9%)

13 (13.3%)

10 (10.2%)

12 (12.2%)

* Bleeding > grade 3, or CNS bleeding of any grade

ASPEN: Adverse Events of Special Interest

Press release, January 2020Tam et al, ASCO 2020

Strategies to Enhance

BTK Inhibitors

Phase I/II Trial of Ulocuplumab and Ibrutinib in

CXCR4 mutated patients with symptomatic WM

IbrutinibUntil PD or

Intolerance

Weekly Ulo

4 weeks

Biweekly Ulo

20 weeks

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

ClinicalTrials.gov Identifier: NCT03225716

0

20

40

60

80

100

120

140

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

IgM

% R

elat

ive

to B

asel

ine

Cycle

IgM % Reduction

#1

#3

#4

#5

#6

#7

#8

#9

#10

#11

Responses to Ibrutinib and CXCR4 Inhibitor Ulucuplomab

in Symptomatic CXCR4 mutated WM patients

DFCI Unpublished Data

Cohort 1

Cohort 2

Cohort 3

Median prior therapies: 0 (range 0-1)

Median time to major

response in

CXCR4 mutated frontline

WM pts on ibrutinib

(Treon et al, JCO 2018)

50% 70%

Mavorixafor in combination with ibrutinib

in CXCR4 mutated WM

Gβ

GαG

γ G-Protein

subunits

PLC

PIP2

Ca2+

Chemotaxis,Migration

StemnessSurvival

TranscriptionGene

Expression

SurvivalProliferation

Chemotaxis,Proliferation

DAG

PKC

IP2

IP3

Intracellular

Ca-stores

MAP

K

FA

KPyk

2

Paxilli

n

CR

K

Cdc4

2R

ac

Rh

o

A

kt

NFk

B

BAD

STA

TJA

K

PI3

KRAS

RAF

ERK1

/2

P

P

CXCL12

CXCR4

▪ Non-competitive, allosteric,

small molecule antagonist of

CXCR4

▪ Orally Bioavailable;

mean t1/2 of ~23 hours

▪ High volume of distribution

Mavorixafor

Venetoclax (ABT-199) augments

ibrutinib induced apoptosis

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

Cao et al, BJH 2015; 168(5): 701–7

Response n=31

Overall (≥Minor) 27 (90%)

Major (≥Partial) 25 (83%)

Very good partial 6 (20%)

Partial 19 (63%)

Minor 2 (7%)

Time to response 1.9 months

No (n=15) Yes (n=16)

14 (93%) 13 (81%)

13 (87%) 12 (75%)

5 (33%) 1 (6%)

8 (54%) 11 (69%)

1 (6%) 1 (6%)

1.1 months 3.8 months

Prior BTK inhibitorAll patients

No (n=14) Yes (n=17)

13 (93%) 14 (82%)

12 (86%) 13 (76%)

4 (29%) 2 (12%)

8 (54%) 11 (69%)

1 (6%) 1 (6%)

1.3 months 2.1 months

CXCR4 mutations

Phase II Study of Venetoclaxin Previously Treated WM

Multicenter Study: Cornell (John Allan, Rick Furman); City of Hope (Tanya Siddiqi)

J. Castillo

Castillo et al, 17th IMW 2019

18-month PFS: 82%

Phase II Study of Venetoclax

in Previously Treated WM

Castillo et al, 17th IMW 2019

Median 18 months. Range 1-30 months.

Treon et al, April 2020

Table 2. Clinical characteristics of 6 patients with Waldenstrom’s Macroglobulinemia on ibrutinib with

COVID-19 infection. WM, Waldenstrom’s Macroglobulinemia; HC, hydrochloroquine; AZ, azithromycin;

TOCI, tocilizumab. Taken from Treon et al, Ref. 26.

Demographics Pt-1 Pt-2 Pt-3 Pt-4 Pt-5 Pt-6

Age (years) 65 61 72 67 71 58

Gender M/F M M F F M M

Time since B-cell Diagnosis (months)

39 54 95 202 52 107

Received treatment prior to Ibrutinib for WM

N N Y Y N Y

Time on Ibrutinib (months) 39 54 83 50 47 85

Dose of Ibrutinib (mg/day) 420 420 420 420 420 140-HELD-420

COVID-19 Symptoms

Time with symptoms prior to COVID-19 diagnostic testing (days)

5 2 6 7 10 5

Time since COVID-19 diagnostic testing (days)

24 20 17 28 13 29

Cough Y Y Y Y Y Y

Fever Y Y Y Y Y Y

Dyspnea N N N N N Y

Sore throat Y N N N N Y

Taste loss N N Y N Y N

Smell loss N N Y N Y N

Hospitalization N N N N N Y

Required Intensive Care Unit

Y N N N N Y

Required Supplemental O2

N N N N N Y

Required Mechanical Ventilation

N N N N N Y

Other COVID-19 symptoms

N Anorexia Diarrhea Headache N N

Other Meds for COVID-19

HC, AZ NA N NA N HC, AZ, TOCI

Disposition

COVID-19 Symptoms Resolved

N Y Y Y Y N

COVID-19 Symptoms Persist

Y N Y Y N Y

COVID-19 Symptoms Improved

Y Y Y Y Y Y

Clinical characteristics of WM patients on ibrutinib who contracted COVID-19

Treon et al, Blood 2020

MYD88

CXCR4

Genotypi

ng

MYD88Mut

CXCR4Mut

MYD88Mut

CXCR4WT

MYD88WT

CXCR4WT

Rapid Response

Required

Rapid Response

Not Required

Plasmapheresis for

severe HV, CAGG, CRYOS,

rapidly progressing IGM PN

BTK-I plus rituximab

Alternative: Benda-R, PI based regimen

Benda-R

or PI based regimen

BTK-inhibitor (monotherapy)

Alternatives: Benda-R, PI based regimen

Benda-R, PI based regimen

Genomic Based Treatment Approach

to Symptomatic Treatment Naïve WM

• Rituximab should be held for serum IgM >4,000 mg/dL

• Benda-R for bulky adenopathy or extramedullary disease.

• PI based regimen for symptomatic amyloidosis, and possible ASCT as consolidation.

• Rituximab alone, or with ibrutinib if MYD88Mut or bendamustine for IgM PN depending on severity

and pace of progression.

• Maintenance rituximab may be considered in patients responding to rituximab based regimens.

Treon et al, JCO 2020

MYD88

CXCR4

Genotyping

MYD88Mut

CXCR4Mut

MYD88Mut

CXCR4WT

MYD88WT

CXCR4WT

Plasmapheres

is if

severe HV,

CAGG,

CRYOS,

rapidly

progressing

IGM PN

First and second

relapse or refractory

BTK-inhibitor plus

rituximab (if BTK-I naïve)

Alternative: Benda-R,

PI based regimen

First and second relapse or refractory

BTK-inhibitor alone (if BTK-I naïve)

Alternatives: Benda-R, PI based regimen

Benda-R, PI based regimen

Third or later relapse or refractory

BTK-inhibitor alone (if BTK-I naïve)

Alternatives: venetoclax, NA1, everolimus

Third or later

relapse or

refractory

BTK-inhibitor +

Rituximab

(if BTK-I naïve)

Alternatives:

venetoclax, NA1,

everolimus

Genomic Based Treatment Approach

to Symptomatic Relapsed or Refractory WM

• Nucleoside analogues (NA) should be avoided in younger patients, and candidates for ASCT.1

• ASCT may be considered in patients with multiple relapses, and chemosensitive disease.

Treon et al, JCO 2020