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Waldenstrom’sMacroglobulinemia
Heme Fellows 24.7.20Gilad Itchaki, MD
Rabin Medical Center
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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•
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Case 1 – monoclone assessment
Immunofixation Nephelometry
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Case 1 – IgM monoclone – DD:
• IgM-MGUS
• WM/SWM
• Other LPD
• IgM MM
• Amyloidosis
• (Reactive)
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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
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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
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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
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Mutated CXCR4 permits ongoing
pro-survival signaling by CXCL12
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MYD88 and CXCR4 mutations are determinants of
clinical presentation in WM
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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%
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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
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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
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DD - pearls
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Clinical features
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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
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WM - Essential diagnostics
Castillo, IWWM8, BJH 2016
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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
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IgM monoclone & Neuropathy - DD
• IgM-related neuropathy
• Amyloidosis
• Bing-Neel syndrome
• POEMS
• Other cause
D’Sa, IWWM8, BJH 2017
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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
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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
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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
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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)
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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
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IgM-related neuropathy - Treatment
• Corticosteroids
• IVIG
• Plasmapheresis
• Rituximab
• Cyclophosphamide-based regimens
• Consider bendamustine
• Supportive care
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Case 1
• IgM-MGUS
• IgM-related neuropathy
• Amyloidosis r/o
• CS + IVIG > progressed
• Rituximab
• BR
• Needed R maintenance
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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•
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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.
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International prognostic scoring system for WM (ISSWM)
Morel, Blood 2009
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Progression Risk Stratification of SWM
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Progression Risk Stratification of SWM
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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
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Hyperviscosity syndrome
• Serum viscosity > 4 CP
• Does NOT happen < 4 gr/dL IgM
• More prevalent > 6 gr/dL IgM
Gustine, BJH 2017
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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
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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 •
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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•
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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
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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
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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
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BR in WM
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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
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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.
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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%
??
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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)
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Covalent BTK-inhibitors in WM (Cys481)
Ibrutinib Acalabrutinib Zanubrutinib Tirabrutinib
Kaptein et al, ASH 2018; Abstract 1871.
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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)
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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
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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%
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Data Cut-off: August 31, 2019
Median Follow-up: 19.4 months
Tam et al, ASCO 2020
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Tam et al, ASCO 2020
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Tam et al, ASCO 2020
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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
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First line approaches
Gerz, AJH 2019
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First line approaches
Dimopoulus, Blood 2019
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First line approaches
Treon, JCO 2020
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Relapsed refractory WM
Dimopoulus, Blood 2019
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Thank you