Waldenström’s Macroglobulinemia

Steven T. Rosen, M.D.Provost and Chief Scientific Officer

Director, Comprehensive Cancer Center and

Beckman Research Institute

Irell & Manella Cancer Center Director’s Distinguished Chair

March 15, 2018

Disclosures

Consultant for:

Celgene; AbbVie; Novartis; Seattle Genetics; Bristol

Myers Squibb and Company; Exicure

On the Speaker’s Bureau for:

Celgene; Pharmacyclics ▪ Imbruvica; Prime Oncology;

Exicure; NeoGenomics,

Waldenström’s Macroglobulinemia – first

described by Jan Gosta Waldenström in 1944.

• 72 year old W.M. – history of fatigue,

malaise, anemia (Hgb 10.7 gm/dl) and

thrombocytopenia (108 k/ul)

– Splenomegaly without adenopathy

– Dx with CLL and hemolytic anemia seven

years before – treated with rituximab,

cytoxan and prednisone

Case

Case continued

• PET/CT Scan Splenomegaly

• Bone Marrow: lymphoplasmacytic infiltrate; IgM kappa,

CD20+, CD5-, CD23-

– MYD88 mutated p.L265P, c. 794T>C

CXCR4 mutated p.5338, c. 1013G>C

– IgM: 674mg/dl (38-271mg/dl) LDH: 512 U/L (WNL)

Case continued

Treatment:

– Ibrutinib 420 mg daily + Rituximab 325 mg/m2 monthly q 2 months

Results:

– Clinical CR at 3 months. Remission>3 years

Complications:

– Reactivation of Hepatitis

– Ecchymosis and Epistaxis

– Carbuncles

– Atrial Fibrillation

Bone Marrow, Left Posterior Iliac Crest, Aspirate

Smears, Touch Imprints, Core Biopsy and Clot Sections:

Bone Marrow, Left Posterior Iliac Crest, Aspirate

Smears, Touch Imprints, Core Biopsy and Clot Sections:

Differential Diagnosis of WM

• Lymphoplasmacytic lymphoma – small B cell lymphoma

with plasmacytic differentiation which does not meet

criteria for other small B neoplasms

– Waldenstrom macroglobulinemia is LPL with marrow

involvement and IgM paraprotein

• Marginal zone lymphoma – abundant, clear cytoplasm

• CLL/SLL – usually CD5+, proliferation centers

• IgM MGUS 1.8-2% annual progression rate: 40-90%

progress to WM

Relative Frequencies of B-cell Lymphoma Subtypes:

LPL 1.4%

LP L

Manifestations of WM Disease

Adenopathy,

splenomegaly

≤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.

IgM Neuropathy (22%) - (anti-MAG, anti-GM1)

Cryoglobulinemia (10%)

Cold Agglutinemia (5%)

Acquired von Willebrand Disease

Schnitzler Syndrome

Hepcidin

Fe Anemia

Bone Marrow

Hyperviscosity Related Retinal Changes in WM

• Retinal vein dilatation seen IgM >3,000 mg/dL

• Retrograde flow and hemorrhages >6,000 mg/dL

Stone and Bogen, Blood 2012: 119(10):2205-8; Menke et al,

Arch Opthal 2006; 124(11):1601-6.

Photomicrograph (Left) courtesy of Marvin Stone M.D.

Genetics

• No specific chromosomal or oncogene abnormalities are

recognized in LPL

• Deletion of 6q21-q23 (40-70%) most common

aberration; trisomy 4

• Multiple other reported abnormalities including

translocations, trisomies etc.

• Familial predisposition (20-25%)

• Ashkenazi Jews (20%)

• Rare in African Americans (5%)

Kyle et al, Blood 2003; 102(10): 3759-64; Treon et al,

Ann Oncol 2006; 17(3): 488-94; Hanzis et al,

Clin Lymph Myeloma 2011; 11(1):88-92.

Overall Survival Trends in WM (SEER)

N=5,784

2001-2010 Median OS 8.2 y

1991-2000 Median OS 6.0 y

long-rank P<0.001

Castillo et al, BJH 2015; 169:81-89.; Olszlewski et al, ASH 2015; Abstract 882

NCCN Guidelines for Initiation of Therapy in WM

• Hb ≤10 g/dL on basis of disease

• PLT <100,000 mm3 on basis of disease

• Symptomatic hyperviscosity

• Moderate/severe peripheral neuropathy

• Symptomatic cryoglobulins, cold agglutinins,

autoimmune-related events, amyloid.

Kyle RA, et al. Semin Oncol. 2003;30(2):116-120;

Anderson et al, JNCCN 2012; 10(10):1211-9.

NCCN Guidelines Version 2.2016 Waldenström’s Macroglobulinemia/Lymphoplasmacytic Lymphoma

Primary Therapy of WM with Rituximab

Regimen ORR VGPR/CR TTP (mo)

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

Rituximab x 8 40-45% 5-10% 16-22

Rituximab/thalidomide 70% 10% 30

Rituximab/cyclophosphamide

i.e. CHOP-R, CVP-R, CPR,

CDR

70-80% 20-25% 30-36

Rituximab/nucleoside analogues

i.e. FR, FCR, CDA-R

70-90% 20-30% 36-62

Rituximab/Proteasome Inhibitor

i.e. BDR, VR, CaRD

70-90% 20-40% >42-48

Rituximab/bendamustine 90% 30-40% 69

Reviewed in Dimopoulos et al, Blood 2014; 124(9):1404-

11; Treon et al, Blood 2015; How I Treat WM

Rituximab induced IgM Flare in WM Patients

Treon SP, et al. Ann Oncol. 2004;15(10):1481-1483.

P denotes patient-required plasmapheresis

for hyperviscosity.

14,000

12,000

00 2 4 6 8 10

Weeks

Seru

m I

gM

(m

g/d

L)

10,000

8000

6000

4000

2000

12 14

WM 1WM 2WM 3WM 4WM 5WM 6WM 7WM 8WM 9WM 10WM 11

P

P

P

PP

P

P

Bendamustine-R vs. CHOP-R: Subset Analysis

Rummel et al, Lancet. 2013 Apr 6;381(9873):1203-10.

WM

Nucleoside Analogues in WM

• Risk of Transformation or MDS/AML is 10-15%;

• Risk of secondary malignant events in 1/3 patients

with FCR;

• Stem cell collection impacted by nucleoside

analogues: avoid in ASCT candidates;

• Consider Impact on future therapy (Bendamustine)

Treon et al, Blood 2008; 113(16):3673-8; Leleu et al, JCO 2009; 27(2):

250-5; Thomas et al, Proc. 5th International Workshop on WM 2008; Treon

et al, Clin Lymphoma 2011; 11(1):133-5. Tdeschi et al, ASH 2015; Abstract

3958.; Vos et al, BJH 2015.

100

0

25

50

75

Aliv

e o

r w

ith

ou

t p

rog

ress

ion

(%

)

0 20 40 60 80 100

Time from treatment initiation (months)

120

Observation vs. Maintenance Rituximab in WM

No Rituximab Maintenance

Rituximab Maintenance

PFS100

0

25

50

75

Aliv

e (

%)

0 20 40 60 80 100

Time from treatment initiation (months)

120

OS

No Rituximab Maintenance

Rituximab Maintenance

N = 248

Observation Maintenance p=

Median OS

116 months >120 months 0.0095

Observation Maintenance p=

Median PFS

28.6 months 56.3 months 0.0001

Treon et al, BJH 2011;154(3):357-362.

N=246

Comparative outcomes of immunochemotherapy

regimens in Waldenström macroglobulinaemia

British Journal of Haematology, 2017, 179, 106-115

Comparative outcomes of immunochemotherapy

regimens in Waldenström macroglobulinaemia

British Journal of Haematology, 2017, 179, 106-115

Comparative outcomes of immunochemotherapy

regimens in Waldenström macroglobulinaemia

British Journal of Haematology, 2017, 179, 106-115

Dexamethasone, rituximab and cyclophosphamide for

relapsed and/or refractory and treatment‐naïve patients

with Waldenström macroglobulinemia

British Journal of Haematology, 2017, 179, 98-105

NCCN Guidelines Version 2.2016 Waldenström’s Macroglobulinemia/Lymphoplasmacytic Lymphoma

MYD88 L265P Somatic Mutation in WM

MYD88L265P confirmed by AS-

PCR in 95% WM patients, 50-

80% IGM MGUS.

C to G at position 38186241

at 3p22.2Acquired UPD at 3p22.

Treon et al, NEJM 367:826, 2012

MYD88 L265P by AS-PCR is a Useful

Molecular Diagnostic Marker for WM

WM WM

HD IGG IGM CLL MM MZL WM ----MGUS----

0% 0% 54% 4% 0% 10% 93%

Xu et al, Blood 2013; 121 (11): 2051-8.

MYD88

Treon et. Al. “MYD88 L265P Somatic Mutation in

Waldenstrom’s Macroglobulinemia.” N Engl Med 2012.

WHIM-like CXCR4 C-tail Mutations in WM

Warts, Hypogammaglobulinemia, Infection,

and Myelokathexis

B • 30-40% of WM

patients

• > 30 Nonsense and

Frameshift Mutations

• Almost always occur

with MYD88L265P

Hunter et al, Blood 2013; Rocarro et al, Blood 2014; Poulain et al,

ASH 2014; Schmidt et al, BJH 2014.

MYD88 and CXCR4 Mutation Status Impacts

Clinical Presentation of WM Patients

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

MYD88 WT L265P L265P L265P

CXCR4 WT WT FS NS

MYD88 WT L265P L265P L265P

CXCR4 WT WT FS NS

Summary of key findings by MYD88 and CXCR4 mutation

status

Summary of key findings by MYD88 and CXCR4 mutation

status

Summary of key findings by MYD88 and CXCR4 mutation

status

Multicenter study of Ibrutinib in

Relapsed/Refractory WM (>1 prior therapy)

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

Baseline Characteristics for Study Participants (n=63)

Median Range

Age (yrs) 63 44-86

Prior therapies 2 1-9

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 2015; 372:1430

Serum IgM and Hb Levels Following Ibrutinib

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

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; 372(15):1430-40.

Best Clinical Responses to Ibrutinib

Median duration of treatment: 19.1 (range 0.5-29.7) months

(N=) (%)

VGPR 10 16

PR 36 57

MR 11 17

ORR: 91% Major RR (> PR): 73%

Median time to > MR: 4 weeks

Median time to > PR or better: 8 weeks

Treon et al, N Engl J Med. 2015; 372(15):1430-40.

Progression-free and Overall Survival for 63

Previously WM Patients Treated with Ibrutinib

2 yrs (69%) 2 yrs (95%)

PFS OS

Treon et al, N Engl J Med. 2015; 372(15):1430-40.

Ibrutinib Related Adverse Events in Previously

Treated WM Patients

0 5 10 15 20

Mucositis

Hypertension

Pre/Syncope

Dehydration

Epistaxis

Post-procedure bleed

Diarrhea

Skin Infection

Lung Infection

Arrythmia

Thrombocytopenia

Anemia

Neutropenia

Grade 2

Grade 3

Grade 4

Toxicities >1 patient; N=63

Treon et al, N Engl J Med. 2015; 372(15):1430-40.

Responses to Ibrutinib are Impacted by MYD88

(L265P and non-L265P) and CXCR4 Mutations

MYD88MUT

CXCR4WT

MYD88MUT

CXCR4WHIM

MYD88WT

CXCR4WT

p-value

N= 36 21 5

OverallRR

100% 85.7% 60% <0.01

MajorRR

91.7% 61.9% 0% <0.01

2 patients subsequently found to have other MYD88 mutations not picked up by AS-PCR

Treon et al, N Engl J Med. 2015; 372(15):1430-40;

NEJM 2015; Letter, August 6, 2015.

Kinetics of Major Responses Following Ibrutinib

Therapy in Genotyped WM Patients

Treon et al, NEJM 372: 1430, 2015

MYD88L265P

CXCR4WT

MYD88L265P

CXCR4WHIM

MYD88WT

CXCR4WTMajo

r R

esp

on

ses (

%)

3 6 9 12 15 18 21 24

Cycle

Ibrutinib in Rituximab-Refractory Patients with

WM: INNOVATE Study Design

Dimopoulos M et al, ASH 2015 (abstract 2745, poster presentation)

INNOVATE: Best Response to Ibrutinib

Dimopoulos M et al, ASH 2015 (abstract 2745, poster presentation)

INNOVATE: Median Hemoglobin and IgM Levels

During Early Follow-up

Dimopoulos M et al, ASH 2015 (abstract 2745, poster presentation)

BCL-2 is overexpressed in primary WM patient cells by next generation

sequencing (RNAseq) in MYD88 and CXCR4 mutated and unmutated

patients

BCWM1 BCWM2 WMCL1 PB B-Cell Memory B-Cell WM L265P+ WM L265P+WHIM+ WM WT

BCL2 by Healthy Donor B-Cells, WM Cell Lines, and Primary Patient Samples

Nor

mal

ized

Rea

d C

ount

s

5000

1500

025

000

3500

0

Healthy Donor

CD19+CD27-

Healthy Donor

CD19+CD27+

WM CD19+

MYD88L265P

CXCR4WT

WM CD19+

MYD88L265P

CXCR4WHIM

WM CD19+

MYD88WT

CXCR4WT

p<0.001 for healthy donor samples versus any MYD88L265PCXCR4WT or WHIM

Castillo et al, ICML 2015; Hunter et al, ASH 2015; Abstract 128

Venetoclax (ABT-199) Shows Pre-clinical and

Clinical Activity in WM

Cao et al, BJH 2015; Gericitano et al, ASH 2015. Abstract 254.

N=4

ORR=100%; all

major responders

PFS: 18, 25, 38+,

40+ months.

0

5

10

15

20

25

30

35

40

45

50

WM5 WM6 WM7

DMSO

IB

ABT

ABT+IB

0

10

20

30

40

50

60

70

80

90

WM1 WM2 WM3 WM4

DMSO

IB

ABT

ABT+IB

Untreated

* *

* *

*CXCRWHIM

%

%

%

%

%

%

%

%

%

%

%

%

%

%

%

%

%

%

%

%

%

SDF-1

CXCR4

Ser346/7

Β-arrestins

GRK 2/3

CXCR4 Signaling in WM Patients with WHIM Mutations

Busillo et al, JBC 2010

Mueller et al, PLOS ONE 2013

Cao et al, Leukemia 2014

Rocarro et al, Blood 2014

Cao et al, BJH 2015

ERK

AKTSURVIVAL

DRUG RESISTANCE

Plerixafor

Ulucuplomab

Y

Peripheral Neuropathies in WM

• 20-30% of WM patients; associated with low sIgM

• Usually a sensory IgM demyelinating neuropathy related

to antibodies targeting:

– Myelin Associated Glycoprotein

– Ganglioside M1

– Sulfatide

• Amyloid neuropathy is rare and associated with axonal

degeneration

• Bing-Neel Syndrome (1%) – CNS involvement

Treon et al, ASCO 2010; Photomicrograph Courtesy Todd Levine, MD

MAG IgM

Baldini et al, Am J Hematol 1994; 45(1):25-31; Treon et al,

J Clin Oncol 2010; 28:15S (Abstract 8114).

Photomicrograph courtesy of Todd Levine, M.D.

Symptomatic Improvement of WM Related PN

Treon et al, J Clin Oncol 28:15s, 2010 (suppl; abstr 8114)

N=148

Severe Cryoglobulinemia in a WM PatientP

re-P

here

sis

Po

st-

Ph

ere

sis

Treon and Merlini, Williams Hematology 8th ed., Ch 111, 2010.

Transformed Waldenström macroglobulinaemia: clinical presentation

and outcome. A multi‐institutional retrospective study of 77 cases from

the French Innovative Leukemia Organization (FILO)

Progression‐free survival and overall survival from histological transformation (HT).

British Journal of Haematology, 2017, 179, 439-448

• WM can present with broad symptomatology. Asymptomatic

patients should be observed.

• Treatment options include rituximab alone and in combination.

Objectives as well risks of therapy should be considered when

making treatment choices.

• MYD88 and CXCR4 mutations are common in WM. MYD88

activates BTK and HCK in WM cells.

• Ibrutinib represents a novel treatment option for WM. MYD88

and CXCR4 mutation status impacts ibrutinib responses.

• Inhibitors for MYD88, CXCR4 and BCL2 pathways represent

novel treatment approaches for WM.

Summary