Wld tö ’ M lbli iWaldenström’s...

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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.

• 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

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%

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

g/dL 10,000

WM 4WM 5WM 6WM 7WM 8

m Ig 6000

WM 8WM 9WM 10WM 11P

00 2 4 6 8 10

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

Bendamustine-R vs. CHOP-R: Subset Analysis

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

PFS100

ression (%

Alive or with

No Rituximab Maintenance

Rituximab Maintenance

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)

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.

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

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

Baseli

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

Progression-free and Overall Survival for 63 Previously WM Patients Treated with Ibrutinib

PFS OSPFS OS

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

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

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

MYD88L265P

CXCR4WHIM

MYD88WT

CXCR4WTMaj

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

INNOVATE: Median Hemoglobin and IgM Levels During Early Follow-up

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

WM1 WM2 WM3 WM4

ABT+IB

40+ months.35404550

51015202530 DMSO

IBABTABT+IB

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

WM5 WM6 WM7* *%

CXCR4 Signaling in WM Patients with WHIM Mutations

Busillo et al, JBC 2010Mueller et al, PLOS ONE 2013Cao et al, Leukemia 2014

PlerixaforUlucuplomab

Β-arrestins

Rocarro et al, Blood 2014Cao et al, BJH 2015

Ser346/7

Β-arrestins

Ser346/7

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

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

Severe Cryoglobulinemia in a WM PatientPh

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.

Wld tö ’ M lbli iWaldenström’s...

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