W ld t ö ’ M l b li iWaldenström’s MacroglobulinemiaSteven T. Rosen, M.D.Steven T. Rosen, M.D.
Provost and Chief Scientific OfficerDirector, Comprehensive Cancer Center and
B k R h I tit tBeckman Research InstituteIrell & Manella Cancer Center Director’s Distinguished Chair
March 16, 2017,
Disclosures
On the Speaker’s Bureau for:pCelgene; Pharmacyclics ▪ Imbruvica; The Scienomics Group; Xcenda ▪ AmerisourceBergen; Valeant Pharmaceuticals;Bergen; Valeant Pharmaceuticals; Prime Oncology
Waldenström’s Macroglobulinemia – first gdescribed by Jan Gosta Waldenström in 1944.
Case
• 72 year old W.M. – history of fatigue, malaise anemia (Hgb 10 7 gm/dl) andmalaise, 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 prednisonecytoxan and prednisone
Case continued
• PET/CT Scan Splenomegalyg y
• Bone Marrow: lymphoplasmacytic infiltrate; IgM kappa,
CD20+ CD5 CD23CD20+, 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
Results:Results:
– Clinical CR at 3 months. Remission>2 years
Complications:
– Reactivation of Hepatitisp
– Ecchymosis and Epistaxis
Atrial Fibrillation– Atrial Fibrillation
Bone Marrow, Left Posterior Iliac Crest, Aspirate Smears, Touch Imprints, Core Biopsy and Clot Sections:, p , p y
Bone Marrow, Left Posterior Iliac Crest, Aspirate Smears, Touch Imprints, Core Biopsy and Clot Sections:, p , p y
Differential Diagnosis of WM
• Lymphoplasmacytic lymphoma – small B cell lymphoma y p p y y p y pwith plasmacytic differentiation which does not meet criteria for other small B neoplasms
Waldenstrom macroglobulinemia is LPL with marrow– 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%
t WMprogress to WM
Relative Frequencies of B-cell Lymphoma Subtypes: LPL 1.4%
LPL
Manifestations of WM Disease
Hb>>> PLT> WBC b C
Hyperviscosity Syndrome:Epistaxis, Headachesp ,
Impaired vision>6,000 mg/dL or >4.0 CP
Bone MarrowAdenopathy,
splenomegaly IgM Neuropathy (22%) - (anti-MAG, anti-GM1)
Bone Marrow
≤20% at diagnosis;50-60% at relapse.
IgM Neuropathy (22%) (anti MAG, anti GM1)Cryoglobulinemia (10%)Cold Agglutinemia (5%)
Acquired von Willebrand DiseaseHepcidin
Treon S., Hematol Oncol. 2013; 31:76-80.
qSchnitzler SyndromeFe Anemia
Hyperviscosity Related Retinal Changes in WM
R ti l i dil t ti I M 3 000 /dL• 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 p grecognized in LPL
• Deletion of 6q21-q23 (40-70%) most common b ti t i 4aberration; trisomy 4
• Multiple other reported abnormalities including translocations, trisomies etc.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 y1991-2000 Median OS 6.0 y
long rank P<0 001long-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 y p yp y• Moderate/severe peripheral neuropathy• Symptomatic cryoglobulins, cold agglutinins,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% 13Rituximab x 4 25-30% 0-5% 13 Rituximab x 8 40-45% 5-10% 16-22Rituximab/thalidomide 70% 10% 30Rituximab/cyclophosphamide i.e. CHOP-R, CVP-R, CPR, CDR
70-80% 20-25% 30-36
CDR Rituximab/nucleoside analoguesi.e. FR, FCR, CDA-R
70-90% 20-30% 36-62
Rit i b/P t I hibit 70 90% 20 40% 42 48Rituximab/Proteasome Inhibitori.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
P denotes patient-required plasmapheresis for hyperviscosity.
14 00014,000
12,000
) 10 000
WM 1WM 2WM 3WM 4
P
gM (m
g/dL 10,000
8000
WM 4WM 5WM 6WM 7WM 8
P
P
PPP
Seru
m Ig 6000
4000
WM 8WM 9WM 10WM 11P
00 2 4 6 8 10
2000
12 14
Treon SP, et al. Ann Oncol. 2004;15(10):1481-1483.
Weeks
Bendamustine-R vs. CHOP-R: Subset Analysis
WM
Rummel et al, Lancet. 2013 Apr 6;381(9873):1203-10.
Nucleoside Analogues in WM
• Risk of Transformation or MDS/AML is 10-15%;;• Risk of secondary malignant events in 1/3 patients
with FCR;with FCR;• Stem cell collection impacted by nucleoside
analogues: avoid in ASCT candidates;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.
Observation vs. Maintenance Rituximab in WM
100
)
PFS100
OS
50
75
prog
ression (%
)
50
75
(%)
N=246
25
50
Alive or with
out p
No Rituximab Maintenance
Rituximab Maintenance
25
50
Alive
No Rituximab Maintenance
Rituximab Maintenance
N = 2480A
0 20 40 60 80 100
Time from treatment initiation (months)
12000 20 40 60 80 100
Time from treatment initiation (months)
120
Observation Maintenance p=Ob ti M i t 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.
NCCN Guidelines Version 2.2016 Waldenström’s Macroglobulinemia/Lymphoplasmacytic Lymphoma
MYD88 L265P Somatic Mutation in WM
C to G at position 38186241at 3p22.2
Acquired UPD at 3p22.at 3p22.2
MYD88L265P confirmed by AS-PCR in 95% WM patients, 50-80% IGM MGUS.80% IGM MGUS.
Treon et al, NEJM 367:826, 2012
MYD88 L265P by AS-PCR is a Useful Molecular Diagnostic Marker for WM
HD IGG IGM CLL MM MZL WM----MGUS----
HD IGG IGM CLL MM MZL WM
WMWM WM
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, d M l k th iand Myelokathexis
B • 30-40% of WM patients
• > 30 Nonsense and Frameshift Mutations
• Almost always occurAlmost 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
MYD88 WT L265P L265P L265PCXCR4 WT WT FS NS
MYD88 WT L265P L265P L265PCXCR4 WT WT FS NS
Treon et al, Blood 2014; 123(18):2791-6.
CXCR4 WT WT FS NS CXCR4 WT WT FS NS
Multicenter study of Ibrutinib in Relapsed/Refractory WM (>1 prior therapy)
Study O
Screening
Study O
Opened May 2012 R. Advani L. Palomba 420 mg po qD
Registration
g p q Ibrutinib
Progressive Disease (PD) or U t bl T i it Stable Disease or ResponseUnacceptable Toxicity p
Continue
Stop IbrutinibStop IbrutinibEvent Monitoring
li i lt i lEvent Monitoring www.clinicaltrials.gov NCT01614821
Baseline Characteristics for Study Participants (n=63)
Median Range
Age (yrs) 63 44-86Prior therapies 2 1-9Hemoglobin (mg/dL) 10.5 8.2-13.8Serum IgM (mg/dL) 3,520 724-8,390B2M (mg/dL) 3.9 1.3-14.2BM Involvement (%) 60 3-95Adenopathy >1.5 cm 37 (59%) N/ASplenomegaly >15 cm 7 (11%) N/A
Treon et al, NEJM 2015; 372:1430
Serum IgM and Hb Levels Following Ibrutinib
Serum IgM Hb
5000
6000
7000
8000
9000
mg/
dL)
N=63
13
14
15
16
n (g
/dL)
Serum IgM Hb
0
1000
2000
3000
4000
5000
Ser
um Ig
M (
8
9
10
11
12
N=63
Hem
oglo
bin
0
Baseli
ne
Cycle
2 Cyc
le 3
Cycle
6 Cyc
le 9
Cycle
12
Cycle
15
Cycle
18
Cycle
21
8 Bas
eline
Cyc
le 2
Cycle
3 Cyc
le 6
Cycle
9 Cyc
le 12
Cyc
le 15
Cyc
le 18
Cyc
le 21
Best Hemoglobin Response:10 5 to 13 8; p<0 001
Best IgM Response: 3 520 to 880 mg/dL; p<0 001 10.5 to 13.8; p<0.0013,520 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
ORR 91% M j RR ( PR) 73%
(N=) (%)ORR: 91% Major RR (> PR): 73%
( ) ( )VGPR 10 16PR 36 57PR 36 57MR 11 17Median time to > MR: 4 weeksMedian 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
PFS OSPFS OS
2 yrs (69%) 2 yrs (95%)
Treon et al, N Engl J Med. 2015; 372(15):1430-40.
Ibrutinib Related Adverse Events in Previously Treated WM Patients
Toxicities >1 patient; N=63
ArrythmiaThrombocytopenia
Anemia Neutropenia
Post procedure bleedDiarrhea
Skin Infection Lung Infection
Arrythmia
Grade 2 Grade 3
HypertensionPre/Syncope Dehydration
Epistaxis Post-procedure bleed
Grade 4
0 5 10 15 20
Mucositis Hypertension
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
CXCR4WTMYD88MUT
CXCR4WHIMMYD88WT
CXCR4WTp‐value
CXCR4WT CXCR4WHIM CXCR4WT
N= 36 21 5
Overall RR
100% 85.7% 60% <0.01
Major RR
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
MYD88L265P
CXCR4WT
es (%
)
MYD88L265P
CXCR4WHIM
Res
pons
e
MYD88WT
CXCR4WTMaj
or R
3 6 9 12 15 18 21 24Cycle
Treon et al, NEJM 372: 1430, 2015
Ibrutinib in Rituximab-Refractory Patients with WM: INNOVATE Study Designy g
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
PB B-Cell Memory B-Cell WM L265P+ WM L265P+WHIM+ WM WTHealthy DonorCD19+CD27-
Healthy DonorCD19+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
N=4708090
Untreated *CXCRWHIM
%
%
% N 4ORR=100%; all major responders30
40506070
DMSOIBABTABT IB
%
%
%
%
% major respondersPFS: 18, 25, 38+, 40 th
01020
WM1 WM2 WM3 WM4
ABT+IB
* *
%
%
%
40+ months.35404550
DMSO
%
%
%
%
51015202530 DMSO
IBABTABT+IB
%
%
%%
%
Cao et al, BJH 2015; Gericitano et al, ASH 2015. Abstract 254.
05
WM5 WM6 WM7* *%
%
CXCR4 Signaling in WM Patients with WHIM Mutations
SDF-1
Busillo et al, JBC 2010Mueller et al, PLOS ONE 2013Cao et al, Leukemia 2014
PlerixaforUlucuplomab
Y
CXCR4
Β-arrestins
Rocarro et al, Blood 2014Cao et al, BJH 2015
Ser346/7
Β-arrestins
Ser346/7
ERK
GRK 2/3
ERKAKT
SURVIVALGRK 2/3 DRUG RESISTANCE
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– Myelin Associated Glycoprotein
– Ganglioside M1 – Sulfatide
MAG IgM 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, MDBaldini 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
N=148
Treon et al, J Clin Oncol 28:15s, 2010 (suppl; abstr 8114)
Severe Cryoglobulinemia in a WM PatientPh
eres
isPr
e-P
st-P
here
sis
Post
Treon and Merlini, Williams Hematology 8th ed., Ch 111, 2010.
Summary
• WM can present with broad symptomatology. Asymptomaticpatients should be observedpatients should be observed.
• Treatment options include rituximab alone and in combination.Objectives as well risks of therapy should be considered whenObjectives as well risks of therapy should be considered whenmaking treatment choices.
• MYD88 and CXCR4 mutations are common in WM. MYD88activates BTK and HCK in WM cells.
• Ibrutinib represents a novel treatment option for WM. MYD88p pand CXCR4 mutation status impacts ibrutinib responses.
• Inhibitors for MYD88, CXCR4 and BCL2 pathways representnovel treatment approaches for WM.
