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Waldenström’s Macroglobulinemia Biology and Management

Steven P. Treon, MD, MA, MS, PhD, FRCP, FACP Professor of Medicine, Harvard Medical School Director, Bing Center for WM Dana Farber Cancer Institute Chair, WM Clinical Trials Group

Waldenström’s Macroglobulinemia – first described by Jan Gosta Waldenström in 1944.

Manifestations of WM Disease Bone Marrow ¯Hb>>> ¯PLT> ¯WBC Hyperviscosity Syndrome: Epistaxis, Headaches Impaired vision >6,000 mg/dL or >4.0 CP

Bing Neel Syndrome

≤20% at diagnosis;; 50-­60% at relapse.

Hepcidin ¯Fe Anemia

Cold Agglutinemia (5%) Cryoglobulinemia (10%) IgM Neuropathy (22%) Amyloidosis (10-­15%) Treon S., Hematol Oncol. 2013;; 31:76-­80.

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

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-­‐66

90%

30-­‐40%

69

Rituximab/thalidomide

Rituximab/bendamustine

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

WM–centric toxicities with commonly used therapies 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%)

B-­cell CD19+CD20+CD38-­

Plasma cell CD19-­CD20-­CD38+

LPC cell CD19+CD20+CD38+/-­

From Dr. Marvin Stone

WHO Classification: IgM secreting lymphoplasmacytic lymphoma

Targeting the Entire WM Clone with Monoclonal Antibodies Rituximab

Rituximab

Daratumumab

CD20 CD20 CD38

IgM B-­cells

Lymphoplasmacytic Cells

WM Clone

Plasma Cells

Phase II Study of Daratumumab in Relapsed/Refractory WM Patients Screening Informed Consent and Registration

Progressive Disease or Unacceptable Toxicity

Daratumumab Weekly X 4 Biweekly X 4 Monthly X 12 SD or Response Continue

Stop Daratumumab Event Monitoring Event Monitoring

DFCI, MSKCC, Stanford

MYD88 L265P Somatic Mutation in WM C to G at position 38186241 at 3p22.2

• MYD88L265P confirmed by AS-­PCR in 93-­97% WM pts;; • 50-­80% IGM MGUS pts;; • Usually heterozygous

Acquired UPD at 3p22.

Treon et al, NEJM 367:826, 2012

MYD88 L265P in WM/IGM MGUS METHOD

TISSUE

WM

IGM MGUS

Treon

WGS/Sanger

BM CD19+

91%

10%

Xu

AS-­‐PCR

BM CD19+

93%

54%

Gachard

PCR

BM

70%

Varettoni

AS-­‐PCR

BM CD19+

100%

Landgren

Sanger

BM

Jiminez

AS-­‐PCR

BM

86%

Poulain

PCR

BM CD19+

80%

Argentou

PCR-­‐RFLP

BM

92%

Willenbacher

Sanger

BM

86%

Mori

AS-­‐PCR/BSiE1

BM

80%

Ondrejka

AS-­‐PCR

BM

100%

Ansell

WES/AS-­‐PCR

BM CD19+

97%

Patkar

AS-­‐PCR

BM

85%

47% 54% 87% 1/1 MGUS

11

>50 CONFIRMATIONAL STUDIES PUBLISHED

MYD88 L265P by AS-­PCR can help distinguish WM from overlapping entities -­-­-­-­MGUS-­-­-­-­ HD IGG IGM CLL MM MZL WM

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

Xu et al, Blood 2013

High risk of transformation and poorer survival accompany MYD88WT WM >18 years

Transformation risk for MYD88 WT (Odds ratio 23·3;; 95% CI 4·2-­233·8;; p<0·001).

Treon et al, BJH 2017

MYD88 mutations transactivate NFKB MYD88 Inhibitor

BCWM.1

MWCL-1

Control

Ngo et al, Nature 2011 Treon et al, NEJM 2012 MYD88 L265P mutated WM cells

Signaling Pathways Driven by Mutated MYD88 in Waldenström's Macroglobulinemia IL-­6R

TLRs/IL-­1R

IL-­6

IL-­6

MYD88

Ibrutinib ACP196 BTK CC-­292 BGB-­3111

IRAK4

BTK

IL-­6

gp-­130

HCK PIK3R2

Ibrutinib

PLCγ

PI3K

IRAK1 TRAF6

PKC

TAK1

AKT NEMO IKKα

ERK1/2

HCK

IKKβ mTOR

IL-­6

Degradation

NFKB

growth survival

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

9

PLEKHG1

8

HIVEP2

7

HLA-DQA/B

BCLAF1

6

COL19A1

4

5

CD83

BACH2

ARID1B

FOXO3

EEF1A1

PRDM1

MAN1A1

TNFAIP3

CCR6

IBTK

Detection Threshold

Hunter, et al.

2014

q27

q26

q25.3

q25.2

q25.1

q24.3

q24.2

q24.1

q23.3

q23.2

q22.33

q22.31

q22.1

q21

q16.3

q16.1

q15

q14.3

q14.1

q13

q12

p11.2

p12.1

p12.3

p21.1

p21.2

p21.31

p22.1

p22.3

p24.1 p23

p24.3

p25.1

p25.3 p25.2

3

Number of Affected Patients

10

Chr. 6q clonal loss is common in WM and impacts BTK, BCL2, and NFKB regulatory genes

Chromosome 6

IBTK%%%%%%%%%FOXO3%%%%%%%%BCLAF1%%%%%%%TNFAIP3%%%%%HIVEP2% IBTK FOXO3 BCLAF1 TNFAIP3 HIVEP2 WM1 WM2 WM3 WM4 WM5 WM6 WM7 WM8 WM9 WM10 WM11 WM12 WM13 WM14 WM15 WM16 WM17 WM18 WM19 WM20 WM21 WM22 WM23 WM24 WM25

0.5

0.52

0.41

0.46

0.55

0.56

0.49

0.42

0.55

0.49

0.49

0.94

0.44

0.51

0.55

0.51

0.53

0.48

0.56

0.5

0.56

0.49

0.53

0.47

0.43

0.43

0.54

0.54

0.58

0.49

0.58

0.55

0.58

0.62

0.56

0.53

0.57

0.64

0.66

0.6

0.69

0.89

0.64

0.9

0.81

0.83

0.77

0.7

0.64

0.83

0.82

0.74

0.77

0.8

0.81

0.92

0.93

0.78

0.97

0.98

0.9

0.93

0.81

0.97

0.9

1

Copy Number 2

0.9

0.8

20%

0.7

0.6

40%

0.5

0.9

1

0.84

0.75

0.81

0.83

0.89

0.84

0.86

0.85

1.08

0.99

0.85

1.06

1.01

0.97

0.82

0.87

0.84

0.91

1.01

0.85

0.89

0.87

1.01

0.85

0.89

0.89

0.9

0.91

0.4

0.3

0.2

0.1

0.97

0.9

0.9

0.99

0.97

1

1.1

0.9

0.96

0.97

0.93

0.98

0.93

0.89

1.06

1.02

1.04

0.94

0.87

1.08

0.93

1.05

0.97

1.05

1.05

0.93

0.95

1.07

1.15

0.97

0

60%

Guerrera et al, Haematologica 2018

Trojani-­Morra WGS Copy Number 1 IGM MGUS 80%

CXCR4 C-­tail mutations in WM • • • • •

B

Hunter et al, Blood 2013;; Rocarro et al, Blood 2014: Poulain et al, Blood 2016;; Cao et al, Leukemia 2014;; Cao et al, BJH 2015

30-­40% of WM patients;; v. rare in other LPD >30 Nonsense, Frameshift Mutations Accompany MYD88 mutations High serum IgM levels/Hyperviscosity Promote ibrutinib resistance through enhanced AKT/ERK signaling.

Multicenter study of Ibrutinib in Relapsed/Refractory WM (>1 prior therapy) Screening

Study O

Registration

Opened May 2012

R. Advani L. Palomba

R. Advani L. Palomba

420 mg po qD Ibrutinib

R

Progressive Disease (PD) or Unacceptable Toxicity

Stable Disease or Response Continue

Stop Ibrutinib Event Monitoring

Event Monitoring

www.clinicaltrials.gov NCT01614821

✔

MYD88, CXCR4 Mutation Status

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

ALL

MYD88Mut CXCR4WT

MYD88Mut CXCR4Mut

MYD88WT CXCR4WT

63

36

21

5

ORR

90.4%

100%

85.7%

60%

0.005

Major (>PR)

77.7%

97.2%

66.6%

0%

<0.001

VGPR

27.0%

44.4%

9.5%

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

N=

Treon et al, ASH 2017

P-­value

O

Ibrutinib in Previously Treated WM: PFS All patients

Median PFS > 5 years Treon et al, ASH 2017

Ibrutinib Related Adverse Events in previously treated WM patients Toxicities >1 patient;; N=63 Neutropenia Anemia Thrombocytopenia Arrythmia Lung Infection Skin Infection Diarrhea Post-procedure bleed Epistaxis Dehydration Pre/Syncope Hypertension Mucositis

★

Grade 2

★

Grade 3 Grade 4

Number of Subjects with Toxicity 0 5 10 15 20 # of patients with toxicity

• No impact on IGA and IGG immunoglobulins

★10% incidence with larger WM Experience;; earlier presentation for those patients with prior Afib history.

Treon et al, NEJM 2015;; Gustine et al, AJH 2016

FDA News Release FDA expands approved use of Imbruvica for rare form of non-Hodgkin lymphoma First drug approved to treat Waldenstrom’s January 29, 2015 EMA Approval for symptomatic previously treated and chemoimmunotherapy unsuitable frontline WM First ever for Waldenstrom’s May 22, 2015 July 8, 2015

Ibrutinib in Rituximab-Refractory WM Patients: Multicenter, Open-Label Phase 3 Substudy (iNNOVATE™) Median Prior Therapies: 4 (range 1-­7) Median follow-up: 18.1 (range 6.3-21.1 months)

ORR: 90% Major RR (> PR): 71%

VGPR PR MR

(N=) 4 18 6

Median time to > MR: 4 weeks Median time to best response: 8 weeks

(%) 13 58 19 18 mo PFS: 86% 18 mo OS: 97%

Dimopoulos et al, IWWM9 2016;; Lancet Oncol 2017.

Impact of CXCR4 Mutation Status on IgM and HgB Response

Dimopoulos et al, IWWM9;; Lancet Oncology, 2017

Primary Therapy of WM with Ibrutinib N= Overall Response Rate-no. (%) Major Response Rate-no. (%) Categorical responses Minor responses-no. (%) Partial responses-no. (%) Very good partial responses-no. (%) Median time to response (months) Minor response (≥Minor response) Major response (≥Partial response)

All Patients 30 30 (100%) 25 (83%)

MYD88MUT CXCR4WT 16 16 (100%) 15 (94%)

MYD88MUT CXCR4MUT 14 14 (100%) 10 (71%)

5 (17%) 19 (63%) 6 (20%)

1 (6%) 10 (63%) 5 (31%)

4 (29%) 9 (64%) 1 (7%)

0.16 1.00 0.18

1.0 1.9

0.9 1.8

1.7 7.3

0.07 0.01

P-value N/A 1.00 0.16

Median on treatment duration of 13.4 (range 1.8-­21.1 months)

18 mo: PFS 92%;; OS 100%. PD patients were CXCR4 mutated.

Treon et al, ASH 2017;; Submitted 2018

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

Mason et al, BJH 2016

Strategies to Enhance BTK Inhibitors in WM

Phase II Study of Ibrutinib plus Ulucuplomab in CXCR4WHIM WM Patients Screening Informed Consent and Registration

Progressive Disease or Unacceptable Toxicity

Ibrutinib 420 mg po daily + Ulucuplomab weekly x 4 then biweekly X 20 weeks

SD or Response Continue

Stop Ibrutinib/Ulucuplomab Event Monitoring Event Monitoring

S. Treon PI

BCL-­2 is overexpressed in primary WM patient cells by transciptome analysis in MYD88 mutated patients Donor B-Cells, WMregardless of CXCR4 mutation status.

Cell Lines, and Primary Patient Samples

CL1

PB B-Cell Memory B-Cell WM L265P+ Healthy Donor Healthy Donor WM CD19+ CD19+CD27-­ CD19+CD27+ MYD88L265P CXCR4WT

WM L265P+WHIM+

WM CD19+ MYD88L265P CXCR4WHIM

WM WT

WM CD19+ MYD88WT CXCR4WT

p<0.001 for healthy donor samples versus any MYD88L265PCXCR4WT or WHIM Hunter et al, BLOOD 2016

Ibrutinib

BCL2

Venetoclax (ABT-­199) enhances Ibrutinib killing in MYD88 mutated WM Cells.

Untreated

BCWM.1'

ABT/IB/CXCL12/AMD

ABT/IB/CXCL12

ABT/IB

ABT

IB

DMSO

ABT/IB/CXCL12/AMD

80 70 60

DMSO

50

IB

40 30

ABT

20

ABT+IB

10

Cleaved'' PARP'

0 WM1

*

WM2

*

WM3

WM4

Ibrutinib >6 mo.

Cleaved'' Caspase3'

50 45 40 35 30 25 20 15 10 5 0

GAPDH'

MWCL)1'

90

CXCR4S338X ABT/IB/CXCL12

ABT/IB

ABT

IB

DMSO

CXCR4WT

Cleaved'' PARP' Cleaved'' Caspase3' GAPDH'

Cao et al, BJH 2015

DMSO IB ABT ABT+IB WM5 *

WM6 *

WM7

*CXCRWHIM

Activity of the anti-­‐BCL2 agent Venetoclax (ABT-­‐199) in previously treated NHL Patients

Davids et al, JCO 2017

Phase I/II Study of Venetoclax (ABT-­‐199) in Previously Treated WM Screening Informed Consent and Registration ABT-­199 200è 800 mg a Day Progressive Disease or Unacceptable Toxicity

SD or Response Continue

Stop ABT-­199 Event Monitoring Event Monitoring

Very Active!! EHA 2018

Bing Center for WM

WM Clinic Time

WM Case 1 66 year old female swimmer was experiencing progressive fatigue, as well as shortness of breath while swimming her normal laps. She went to urgent care clinic, and had a hemoglobin of 5 g/dL with normal platelet and leukocyte counts. The reticulocyte count was elevated at 10.4%, and haptoglobin low consistent with autoimmune hemolysis. Cold-­‐agglutinins were negative. She was started on steroids with modest improvement. There was no further benefit with IVIG. Her total protein was elevated, and further workup revealed an IgM kappa monoclonal protein, and total serum IgM level of 2525 mg/dL. Bone marrow biopsy showed 25% involvement with lymphoplasmacytic lymphoma.

Molecular diagnostic studies showed MYD88 L265P mutation, but no CXCR4 mutation. CT scans showed prominent mesenteric, retroperitoneal and inguinal adenopathy but no splenomegaly. Viral studies are unremarkable (HCV, HBV, HIV). She is requiring supportive transfusions with packed red blood cells.

WM Case 1 At this time you decide to: 1.Administer rituximab 2.Administer rituximab with an alkylator drug 3.Administer rituximab with a proteasome inhibitor 4.Administer rituximab with fludarabine 5.Start ibrutinib 6.Consider plasmapheresis

WM  Case  1 The patient was started on ibrutinib at 420 mg a day. Over the next 10 months the IgM declined to 60 mg/dL. Immunofixation studies showed a faint spike not apparent on the electropherogram. Her reticulocytosis resolved, and haptoglobin normalized. Her hemoglobin rose 14.9 g/dL, and she did not require transfusions. Repeat bone marrow biopsy showed 5% LPL involvement. CT scans show scattered subcentimeter lymph nodes that did not meet pathological criteria.

Hemoglobin g/dL 16 14 12 10 8 6 4 2 0

0 1 2 3 4 5 6 7 8 9 10

Months

WM Case 2 A 42 year-­‐old male presented with blurry vision and nosebleeds.

Physical examination revealed retinal hemorrhages, adenopathy and splenomegaly. Laboratories revealed a hematocrit of 18% (normal 34.8-­‐43.6%), platelets of 50,000/mm3 (normal 155,000-­‐ 410,000/mm3), and leukocyte count of 1,500/mm3 (normal 3,800-­‐ 9,200/mm3).

Serum total protein was high prompting a workup that revealed an IgMλ monoclonal protein and serum IgM level of 12,400 mg/dL. CT scans showed bulky adenopathy, and a bone marrow biopsy revealed that 80% of the intertrabecular space was involved with lymphoplasmacytic lymphoma.

Immunohistochemistry demonstrated CD20 expressing bone marrow disease, and the MYD88L265P mutation was present.

WM Case 2

Case Presentation I

WM Case 2 Which of the following is the best next step in the care of this patient?

1. Initiate rituximab therapy 2. Initiate proteasome inhibitor based therapy 3. Initiate alkylator (bendamustine or cyclophosphamide) based therapy 4. Initiate nucleoside analogue based therapy 5. Initiate ibrutinib 6. Initiate plasmapheresis

WM Case 2 The patient undergoes emergent plasmapheresis, and his vision and energy improved. His retinal exam improved, and repeat serum IgM level was 3,892 mg/dL. Genotyping shows that the patient has also a CXCR4 nonsense mutation. What intervention would you now recommend?

1. Initiate rituximab therapy 2. Initiate proteasome inhibitor based therapy 3. Initiate alkylator (bendamustine or cyclophosphamide) based therapy 4. Initiate nucleoside analogue based therapy 5. Initiate ibrutinib

WM Case 3 A 46 year-­‐old male was diagnosed with WM after presentation with fatigue and a hematocrit of 28.6% (normal 34.8-­‐43.6%). A bone marrow biopsy showed 90% involvement with lymphoplasmacytic lymphoma. CT scans were unremarkable, and the serum IgM was 2,780 mg/dL. Treatment with bortezomib, dexamethasone and rituximab was started. After 3 cycles, no treatment response was observed. The patient then received 2 cycles of cyclophosphamide-­‐ based (CDR) therapy without response. Bendamustine was then initiated, and after two cycles the serum IgM and hemoglobin levels remained unchanged. A repeat bone marrow biopsy confirmed unchanged tumor burden, and molecular diagnostics showed the patient to have MYD88 L265P mutation. The patient continues to be symptomatic.

WM Case 3 Which of the following is the best therapeutic intervention at this time?

1. Initiate fludarabine 2. Initiate ibrutinib 3. Initiate everolimus 4.Initiate treatment with high dose chemotherapy and autologous stem cell transplantation.

10th International Workshop on Waldenstrom’s Macroglobulinemia New York City, NY October 10-­13, 2018

Patient Symposium October 13-­14, 2018

www.waldenstromsummit.org