Waldenstrom’sMacroglobulinemia

Heme Fellows 24.7.20Gilad Itchaki, MD

Rabin Medical Center

1מקרה

עובר בירור נוירולוגי בשל נוירופתיה פריפרית70בן •

מחלה ראומטולוגית או מחלת כלי דם, לא ידוע על סכרת-ברקע•

ללא עדות לשינויים גרמיים ניווניים משמעותיים•

IgMמסוג מונוקלונליבין בדיקותיו נמצא מקטע •

gr/dl 1מוערך ב המונוקלוןגודל •

mg/dL 2000מוצאת אימונוגלובוליניםבדיקת •

ללא ממצא בבדיקה. אתסמיני•

Case 1 – monoclone assessment

Immunofixation Nephelometry

Case 1 – IgM monoclone – DD:

• IgM-MGUS

• WM/SWM

• Other LPD

• IgM MM

• Amyloidosis

• (Reactive)

WM - Diagnostic criteria

• IgM monoclonal gammopathy of ANY size

• ≥10% of BMBx MUST demonstrate infiltration by small lymphocytes that exhibit plasmacytoid or plasma cell differentiation with an intertrabecular pattern

• May be interstitial, nodular or diffuse

• Purely paratrabecular pattern is unusual.

• Mast cells

• LP component CD138-

• plasmacytic component -

CD138+, CD38+ and CD45- or dim

Same LC restriction

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

ibrutinibzanubrutinib

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

Mutated CXCR4 permits ongoing

pro-survival signaling by CXCL12

MYD88 and CXCR4 mutations are determinants of

clinical presentation in WM

IgM MGUS

• IgM <3.0 g/dL

• No anemia, HSM, LAN, systemic symptoms

• Minimal or no LP infiltration of BM (< 10%)

• MYD88 L265P mutation in up to 50%

IgM MGUS - progression

• 210 pts followed for 1893 person years

• 34 pts (15%) progressed• NHL 17• WM 11• CLL 3• AL amyloidosis 3• MM 0

• Risk factors: IgM>1.5gr/dl, abnormal FLC ration, immunoparesis

Kyle, NEJM 2018

2%/y in first 10y; 1%/y beyond that

DD - pearls

• MZL – MYD88 5-10%, usually IgM < 1000 mg/dl• No plasmacytic differentiation

• Intra-sinusoidal infiltration

• CLL – CD5/23+, CD20dim, abnormal FISH in 80%

• MCL – CD5+, cyclin D1, t11;14

• IgM MM – rare! Lytic lesions, t11;14 in most, always MYD88 WT

DD - pearls

Clinical features

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

WM - Essential diagnostics

Castillo, IWWM8, BJH 2016

Fatigue, lack of energy Anaemia

Constitutional symptoms Disease progression

Recurrent sinus and bronchial infections Hypogammaglobulinaemia

Headaches, blurry vision or visual loss, confusion, epistaxis

Hyperviscosity

Easy bruising, bleeding diathesis Thrombocytopenia; acquired VWD; acquired coagulation factor deficiency

Progressive symmetrical numbness, tingling, burning, pain feet and hands

IgM‐related neuropathy; amyloidosis

Raynaud‐like symptoms, acrocyanosis, ulcerations on extremities

Cryoglobulinaemia; cold agglutinaemia

Diarrhoea, gastrointestinal cramping Malabsorption

Foamy urine, bipedal oedema Kidney dysfunction

Urticaria, papules, dermatitis Schnitzler syndrome, IgM or tumor cell infiltration, amyloid deposition

Castillo, IWWM8, BJH 2016

IgM monoclone & Neuropathy - DD

• IgM-related neuropathy

• Amyloidosis

• Bing-Neel syndrome

• POEMS

• Other cause

D’Sa, IWWM8, BJH 2017

IgM-related neuropathy

• The prevalence of PN in IgM MGUS may be up to 30-50% (selection bias?)

• Remember! PN affects 24% of the general population, increasing to 80% with advancing

• => Causative role of the MGUS versus coincidental association??

• Consider other causes • Diabetes

• nutritional deficiencies

• Alcohol

• connective tissue disease

• drugs

• pre-existent hereditary neuropathy

IgM-related neuropathy - Investigation

• EMG/NCV

• B12, HbA1C

• Anti-MAG antibodies

• Anti-ganglioside antibodies (GQ1b, GM1, GD1a, GD1b, SGPG)

• VEGF if POEMS is suspected

• Neuroimaging to rule out infiltration if suspected

• CSF examination for protein including immunofixation

• CSF examination for cells including cytology, immunophenotyping and molecular studies –MYD88

• Workup for amyloidosis if suspected

• Nerve biopsy if indicated

IgM-related neuropathy

• Demyelinating

• Symmetrical

• Sensory > motor

• Distal > proximal

• Chronic, peak > 6 months

• Associated with anti-MAG Ab (50%)

• Other targeted neural proteins are – GM1, GD1a, GD1b, GT1b, GM2, GM3, SGPG

• In 30-40% of IgM-RN Ab tests are negative

IgM-related neuropathy

Less likely when -

• Axonal degeneration

• Time to peak < 6 mo (amyloidosis, vasculitis, other eg CIDP)

• Relapsing/remitting course

• Cranial nerve involvement (meningeal involvement, amyloid, vasculitis, CIDP, infection)

• Non-symmetrical (vasculitis, infiltration, CTS)

• Symptoms suggestive of POEMS and L-LC (also demyelinativebut motor > sensory)

IgM-related neuropathy – specific entities

• DADS• Distal, Acquired, Demyelinating, Sensory neuropathy

• Painless neuropathy, accompanied by imbalance or ataxia

• Negative Ab

• CANOMAD• Chronic ataxic neuropathy with ophthalmoplegia, M-protein, cold agglutinins and disialosyl

ganglioside (IgM Anti-GD1b/GT1b/GQ1b) antibodies

• Rare

• Mixed axonal loss and demyelinating features

IgM-related neuropathy - Treatment

• Corticosteroids

• IVIG

• Plasmapheresis

• Rituximab

• Cyclophosphamide-based regimens

• Consider bendamustine

• Supportive care

Case 1

• IgM-MGUS

• IgM-related neuropathy

• Amyloidosis r/o

• CS + IVIG > progressed

• Rituximab

• BR

• Needed R maintenance

2מקרה

64גבר בן •

בירור אנמיה קלה•

נמצא חסר ברזל ומתוקן•

IgM 5400 mg/dlנמצא גם •

•BMB– אבחנתWM ,30%תאים לימפופלזמציטרים

אתסמיני•

•IgM באופן עקבי6400עולה ל

?מה הלאה•

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.

International prognostic scoring system for WM (ISSWM)

Morel, Blood 2009

Progression Risk Stratification of SWM

Progression Risk Stratification of SWM

Hyperviscosity syndrome

• Up to 30%

• Headache

• Blurring, loss of vision → Nystagmus, diplopia

• Neurological complinates

• Tinnitus, sudden deafness

• Dizziness, vertigo, ataxia

• Bleeding

• Confusion, disturbance in consciousness

• CVA

Hyperviscosity syndrome

• Serum viscosity > 4 CP

• Does NOT happen < 4 gr/dL IgM

• More prevalent > 6 gr/dL IgM

Gustine, BJH 2017

Plasmapheresis

• Indication – requirement of immediate IgM reduction

• HVS, symptomatic CG, severe CAD

• Consider blood warmers

• 2-3 plasmapheresis sessions

• Transient effect ~2-4 weeks

• Start definitive therapy

• DO NOT START RITUXIMAB – IgM flare

2מקרה

64גבר בן •

בירור אנמיה קלה•

נמצא חסר ברזל ומתוקן•

IgM 5400 mg/dlנמצא גם •

•BMB– אבחנתWM ,30%תאים לימפופלזמציטרים

אתסמיני•

•IgM באופן עקבי6400עולה ל

6500סביב IgMשנים ללא כל צורך בטיפול ו 5ממשיך מעקב כבר •

3מקרה 54גבר בן •

כ"בריא בד•

7.3המוגלובין , התקבל לבירור אנמיה•

וללא תסמינים נוספיםIgM 5.4 gr/dlעם WMנמצא •

טחול מעט מוגדל•

ללא ביטוח פרטי•

(ריתוקסימב נדחה)RCDהחל טיפול •

מחזורי טיפול4ללא תגובה לאחר •

PRוהשיג BRעבר ל •

עבר השתלה –BRלאור גילו הצעיר ומחלה רפרקטורית לקו ראשון ועם תגובה חלקיתל •VGPRהשיג –2015עצמית

התקדם בהדרגה לאורך השנים•

HVSללא , ואנמיה עמוקהIgM 6000 mg/dLשוב –2020•

Response category Description

Complete response (CR)

•Absence of serum monoclonal IgM protein by immunofixation•Normal serum IgM level•Complete resolution of extramedullary disease, ie, lymphadenopathy and splenomegaly if present at baseline•Morphologically normal bone marrow aspirate and trephine biopsy

Very good partial response (VGPR)

•Monoclonal IgM protein is detectable•≥90% reduction in serum IgM level from baseline*•Complete resolution of extramedullary disease, ie, lymphadenopathy/splenomegaly if present at baseline•No new signs or symptoms of active disease

Partial response (PR)

•Monoclonal IgM protein is detectable•≥50 but <90% reduction in serum IgM level from baseline*•Reduction in extramedullary disease, ie, lymphadenopathy/splenomegaly if present at baseline•No new signs or symptoms of active disease

Minor response (MR)•Monoclonal IgM protein is detectable•≥25 but <50% reduction in serum IgM level from baseline*•No new signs or symptoms of active disease

Stable disease

•Monoclonal IgM protein is detectable•<25% reduction and <25% increase in serum IgM level from baseline*•No progression in extramedullary disease, ie, lymphadenopathy/splenomegaly•No new signs or symptoms of active disease

Progressive disease•≥25% increase in serum IgM level*

¶from lowest nadir (requires confirmation) and/or progression in

clinical features attributable to the disease

Owen, IWWM6, BJH 2013

WM in Israel

“Health Basket”2020

• Rituximab – approved in any line of therapy • Single-agent or combination

• NOT for maintenance

• Bendamustine – approved 1st line

• Bortezomib – NOT reimbursed

• Ibrutinib – approved after 2 lines of therapy

• Venetoclax – current compassionate use program

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

BR in WM

All patients MYD88 and CXCR4 Mutation Status

Updated from Treon et al, NEJM 2015

Ibrutinib in Previously Treated WM: Updated PFS

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

MYD88 Mutated

MYD88/CXCR4

MutatedMYD88/CXCR4

Wild-Type

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.

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

1723

9

27 22

53

2956

23

58

44

3633

25

3

38

6

15

27

1

4

0

10

20

30

40

50

60

70

80

90

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%

CRVGPRPRMR

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

gre

ssio

n-F

ree

Su

rviv

al (

%)

Months

MYD88WT/CXCR4WT

MYD88L265P/CXCR4WHIM

MYD88L265P/CXCR4WHIM

MYD88WT/CXCR4WT

MYD88L265P/CXCR4WT

Ibrutinib-RTX

RTX

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

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 brillation 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.

49

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

2 -Year PFS: 81%

Data Cut-off: August 31, 2019

Median Follow-up: 19.4 months

Tam et al, ASCO 2020

Tam et al, ASCO 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

First line approaches

Gerz, AJH 2019

First line approaches

Dimopoulus, Blood 2019

First line approaches

Treon, JCO 2020

Relapsed refractory WM

Dimopoulus, Blood 2019

Thank you