Waldenström’s macroglobulinemia:Similar but Different to Myeloma?

Waldenström’s macroglobulinemia:Similar but Different to Myeloma?

Steve Treon MD, MA, PhD

Dana Farber Cancer Institute

Harvard Medical School

Boston, Massachusetts, United States

Advances in the Biology of Waldenstrom’s Macroglobulinemia

Closing Ceremony at the Acropolis, Athens, Greece 2002Closing Ceremony at the Acropolis, Athens, Greece 2002

Second Intl Workshop on Waldenstrom’s Macroglobulinemia

Clinicopathologic Definition of WMClinicopathologic Definition of WM

• Pathologic diagnosis of lymphoplasmacytic lymphoma using REAL/WHO criteria.

• Presence of a monoclonal IgM protein, irrespective of serum level.

IWWM2, ATHENS 2002Owen RG, et al. Semin Oncol. 2003;30(2):110-115.

Lack of relationship between serum IgM levels and BM involvement in WM.

Lack of relationship between serum IgM levels and BM involvement in WM.

BM Involvement (%)

•Cells: lymphocytes, lymphoplasmacytoid cells, plasma cells excess mast cells in association with lymphoid aggregates

•BM: interstitial pattern with diffuse or nodular infiltrates excess mast cells in association with lymphoid aggregates

•LN/SP: diffuse pattern

**

LNBM BM

Lymphoplasmacytic Lymphoma

• almost always expressed: sIgM, CD19,

CD20, CD22, CD79

• usually expressed: CD25, CD27, FMC7,

BCL-2, CD52

• variable expression: CD5, CD10, CD23

• small population: CD138 (plasma cells)

San Miguel et al, Semin Oncol 2003; Hunter et al, Clin Lymphoma 2005

Immunophenotypic expression of WMImmunophenotypic expression of WM

Cytogenetics in WMCytogenetics in WM

•del 6q21-25 are commonly observed (30-50%) in WM; •Present in familial and sporadic WM cases; •Absent in IgM MGUS;•IgH (Chr.14) translocations are absent and help distinguish WM from IgM MM.

Schop, Blood 2002; Avet Loiseau , Semin Oncol 2003; Treon, Ann Oncol 2006; Ocio BJH 2007.

FISH for 6q21

Advances in the Biology of Waldenstrom’s MacroglobulinemiaMicroenvironmental Support in WM by CD40L expressing mast cells.

H

I

J

Tryptase CD40 Ligand

WM-1

WM-2

Tournilhac et al, Ann Oncol 2006

sCD27 in WM-Mast Cell InteractionssCD27 in WM-Mast Cell Interactions

Mast cells Lymphoplasmacytic cells

Soluble CD27CD70

APRIL

CD40L

TACI, BCMA

CD40

Tournilhac et al, Ann Oncol 2006; Ho et al, Blood 2008

MMP-8

CD27YSGN-70

YAlemtuzumab

CD52

Y

Alemtuzumab

CD52C-kit

Imatinib mesylateX

Clinicopathologic Manifestations of WM

Clinicopathologic Manifestations of WM

Adenopathy, splenomegaly ≤15%

HCT, PLT, WBC HyperviscositySyndrome:Epistaxis, HA,Impaired vision >4.0 CP

IgM Neuropathy (22%)Cryoglobulinemia (10%)Cold Agglutinemia (5%)Fatigue, Constitutional Sxs

Cytokinemia?

Treon SP et al. Cancer Treat Res. 2008;142:211-242.

From Dr. Marvin Stone

Funduscopic exam of a WM patient with hyperviscosity syndrome

Pre

-Phe

resi

sP

ost

-Ph

ere

sis

Cryoglobulinemia in a patient with Waldenstrom’s macroglobulinemiaCryoglobulinemia in a patient with Waldenstrom’s macroglobulinemia

IgM Related Neuropathies in WMIgM Related Neuropathies in WM

• Observed in about 22% of WM patients

• Most commonly is demyelinating and related to IgM neuropathic antibody.

• Usually sensory and related to antibodies targeting:– Myelin Associated Glycoprotein (MAG)

– Ganglioside M1 (GM1)

– Sulfatide

Courtesy Todd Levine, MD MAG antibody staining

Genetic PredispositionGenetic Predisposition

Familial disease predisposition in WMFamilial disease predisposition in WM

• N=1076 consecutive patients with clinicopathological diagnosis of WM

• 26.1% of WM patients have a first or second degree relative with a B-cell LPD.

0%

5%

10%

15%

20%

25%

30%

35%

40%

ALL CLL HCL HD MM MGUS NHL WM

Distribution of B-cell LPD in relatives of 281 Familial WM patients.

Treon et al, ICML 2011.

Familial Associations in other B-cell LPD

Familial Associations in other B-cell LPD

• Prospective study of 1,948 pts with B-cell LPD

• First/Second Degree Relatives

• CLL (17.5%)

• NHL (12.6%)

• Hodgkin’s (11.9%)

Brown et al, BJH 2008DFCI

Relative Risk of other B-cell LPD in patients with CLL, MM, and WM Relative Risk of other B-cell LPD

in patients with CLL, MM, and WM

Swedish Registry Data

1st degree Relatives

CLL WM/LPL MM

CLL 8.5 3.4 NS

NHL* 1.9 3.0 NS

MM NS NS 2.1

WM/LPL *Included 20.0 NS

MGUS NS 5.0 2.1

Kristinsson, Int J Cancer 2009; Blood 2009; Goldin, Haematologica 2009.

GWAS: Copy Number Polymorphisms in GSTM1 and GSTT1 in WM Patients Varies by Family History

GWAS: Copy Number Polymorphisms in GSTM1 and GSTT1 in WM Patients Varies by Family History

* P <0.01 vs. Mixed B-Cell History

GSTM1(-/-) GSTT1(-/-) GSTM1(-/-) & GSTT1(-/-) GSTT1 CN >2WM Only 1/6 (17%)* 1/6 (17%) 1/6 (17%) 1/6 (17%)Mixed B-Cell 9/10 (90%) 4/10 (40%) 4/10 (40%) 0/10 (0%)Sporadic WM 2/5 (40%) 1/5 (20%) 1/5 (20%) 2/5 (40%)

Analysis of GSTM1/T1 Copy Number in WM Patients

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

GSTM1(-/-) GSTT1(-/-) GSTM1(-/-) & GSTT1(-/-) GSTT1 CN >2

WM Only

Mixed B-Cell

Sporadic WM

Hunter et al, ASH 2009

Impact of familial status in rituximab-naïve patients receiving a rituximab containing regimen.

Impact of familial status in rituximab-naïve patients receiving a rituximab containing regimen.

Response to Therapy

93.974.8

23.2

7555.6

16.70

102030405060708090

100

Overall Major VGPR/CR

SporadicFamilial

p=0.032

P<0.001

p=0.029

Treon et al, ASH 2011

Familial Disease Is Associated with shorter PFS and Time to Next Therapy

Familial Disease Is Associated with shorter PFS and Time to Next Therapy

0

10

20

30

40

50

60

70

80

90

100

Per

cen

t w

ith

ou

t p

rog

ress

ion

No familial diseaseFamilial disease

PFS

0 10 20 30 40 50 60 70 80 90 100Months

0

10

20

30

40

50

60

70

80

90

100

Per

cen

t w

ith

ou

t p

rog

ress

ion

No familial diseaseFamilial disease

TTNT

0 10 20 30 40 50 60 70 80 90 100Months

Treon et al, ASH 2011

p=0.015p=0.024

Parameter DFParameterEstimate

StandardError Chi-Square Pr > ChiSq

HazardRatio

Fam Disease 1 -0.59016 0.27386 4.6438 0.0312 0.554

Age 1 -0.02276 0.01320 2.9712 0.0848 0.977

sIgM 1 0.0000498 0.0000573 0.7538 0.3853 1.000

sB2M 1 0.13171 0.05077 6.7293 0.0095 1.141

Hgb 1 0.08309 0.07579 1.2018 0.2730 1.087

  

Parameter DFParameterEstimate

StandardError Chi-Square Pr > ChiSq

HazardRatio

Fam Disease 1 -0.66490 0.26764 6.1717 0.0130 0.514

IPSS 1 0.20736 0.15232 1.8531 0.1734 1.230

  

Familial Disease Status in WM is an Independent Prognostic for PFS

Does the type treatment impact response for familial patients?Does the type treatment impact response for familial patients?

71

100

48.4

100

6.5

80

0

20

40

60

80

100

120

Non-Bortezomib Bortezomib

ORR

Major

VGPR/CR

p=0.0006

p=0.05N=36

Treon et al, ASH 2011

Impact of Bortezomib-based therapy on PFS in Familial and Sporadic WM Patients.

Impact of Bortezomib-based therapy on PFS in Familial and Sporadic WM Patients.

Familial WM Sporadic WM Familial WM Sporadic WM

Treon et al, ASH 2011

p=0.08p=0.68

Consensus Panel Recommendations for Initiation of Therapy in WM

Consensus Panel Recommendations for Initiation of Therapy in WM

• Hb ≤10 g/dL on basis of disease

• PLT <100,000 mm3 on basis of disease

• Symptomatic hyperviscosity (>4.0 cp)

• Moderate to severe peripheral neuropathy

• Symptomatic cryoglobulinemia, cold agglutinemia, amyloidosis, or symptomatic autoimmune-related events on the basis of disease

Kyle RA, et al. Semin Oncol. 2003;30(2):116-120.

Fab

Fc

Fc receptorNatural Killer Cell

CD20WM cell

CD20-Directed RituximabMonoclonalAntibody

Serum IgM Levels Following Rituximab in Patients With WM

Serum IgM Levels Following Rituximab in Patients With WM

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

P denotes patient-required plasmapheresis for hyperviscosity.

14,000

12,000

00 2 4 6 8 10

Wks

Ser

um

IgM

(m

g/d

L)

10,000

8000

6000

4000

2000

12 14

WM 1WM 2WM 3WM 4WM 5WM 6WM 7WM 8WM 9WM 10WM 11

P

P

P

PP

P

P

Bystander Release of IL-6 by Monocytes May Account for the Rituximab IgM Flare

1200

1400

1600

1800

2000

2200

2400

2600

IgM

(n

g/m

l)

+mon

ocyt

es+m

onoc

ytes

+

ritu

xim

ab+m

onoc

ytes

+ritu

xim

ab

+an

ti-IL

6 be

ads

IL-6IL-6

MonocytesMonocytes

FcγRIIAFcγRIIA

RituximabRituximab

WM-LPCWM-LPC

IL-6RIL-6R

IgMIgM

IVIgIVIg

Primary Therapy of WM with Rituximab-Based Options

Regimen ORR CR

Rituximab x 4 25-30% 0%

Rituximab x 8 40-45% 0%

Rituximab/cyclophosphamide i.e. CHOP-R, CVP-R, CPR, RCD

70-80% 8-10%

Rituximab/nucleoside analoguesi.e. FR, FCR, CDA-R

70-90% 5-10%

Rituximab/thalidomide 70% 5%

Rituximab/bortezomib i.e. BDR, VR

70-90% 10-25%

Rituximab/bendamustine 90% NA

Disease Transformation and MDS/AML Following Nucleoside Analogues in WM

Study Population N Median F/U (mo) Outcome

Leleu et al, JCO 20091

Prev treated with NA vs. non-NA or untreated

439 60 Histologic

Transformation (8%)MDS/AML (5%)

Tamburini et al, Leukemia 20052

Firstline with Fludara/Cyclo 49 41 Histologic

Transformation (10%)

Leblond, JCO 19983

Previously treated with

Fludara71 34 Histologic

Transformation (10%)

Rakkhit et al, ASH 20084

Untreated; 2CDA based

therapy111 NA Histologic

Transformation (9%)

1. Leleu X, et al.J Clin Oncol. 2009;27(2):250-255. 2. Tamburini J, et al. Leukemia. 2005;19(10):1831-1834. 3. Leblond V, et al. J Clin Oncol. 1998;16:2060-2064. 4. Rakkhit R, et al. Blood. 2008;112: Abstract 3065.

Advances in the Biology of Waldenstrom’s Macroglobulinemia

Lenalidomide-Induced Anemia in WM

Decreased Hct observed in 10/12 pts following first week of lenalidomide monotherapy

Median Hct decrease: 3.9% (31.9% to 28.0%; P = .003)

No evidence for hemolysis; concurrent thrombocytopenia observed in 1 pt

4 patients hospitalized for anemia related complications (Afib, syncope, CHF)

Afib, atrial fibrillation, CHF, congestive heart failure, Hct, hematocrit.Treon SP, et al. Clin Cancer Res 2008

20

22

24

26

28

30

32

34

36

38

1 2 3 4 5 6 7 8 9 10 11 12

Pretherapy Posttherapy

Hem

ato

crit

(%

)

Patient

Phase I Study of Pomalidomide, Dexamethasone, and Rituximab

(PDR) in WM

Agent Dose Schedule

Pomalidomide 1, 2, 3, 4 mg QD 52 weeks

Dexamethasone 40 mg wkly IV Pre-rituximab

Rituximab 375 mg/m2/wk W1-4; W12-15

•Aggravated Anemia less pronounced•IgM Flare potentiated•CR in Dose Level -1

Proteasome Inhibitors

Bortezomib Combination Therapy in WMBortezomib Combination Therapy in WM

• PrimaryBortezomib (1.3 mg/m2/biwkly)/Dexamethasone/Rituximab

ORR 95%; CR 22%; TTP >4 yrs; 30% Grade 3 PN

Bortezomib (1.6 mg/m2/wk)/Rituximab

ORR 92%; CR 8%; 80% 1 Y PFS; No Grade 3 PN

• SalvageBortezomib (1.6 mg/m2/wk)/Rituximab

ORR 81%; CR 5%; TTP 12 months; 5% Grade 3 PN.

Bortezomib (randomized wkly vs biwkly)/Rituximab

ORR 80%; CR 0%; TTP ?; 0% Grade 3 PN.

Treon SP, et al. J Clin Oncol. 2009;27(23):3830-383. Ghobrial IM, et al. Blood. 2010;116: Abstract 832. Ghobrial IM, et al. J Clin Oncol. 2010; 28(8):1422-1428. Agathocleous A, et al. Blood. 2007;110: Abstract 2559.Treon SP, et al. J Clin Oncol. 2009;27(23):3830-383. Ghobrial IM, et al. Blood. 2010;116: Abstract 832. Ghobrial IM, et al. J Clin Oncol. 2010; 28(8):1422-1428. Agathocleous A, et al. Blood. 2007;110: Abstract 2559.

vs. 10-12% in MM!

Bortezomib-Based Rituximab TherapyBortezomib-Based Rituximab Therapy

Twice A Week Once A Week

CR/VGPR

PFS (?)

Time to Response

Rituximab IgM Flare

Neuropathy

Primary Therapy of WM with Carfilzomib, Rituximab, Dex (CARD)

Primary Therapy of WM with Carfilzomib, Rituximab, Dex (CARD)

Induction Cycle 1 q21 daysDays 1,2,8,9 Carfilzomib 20 mg/m2 IV; Dexamethasone 20 mg IV.Days 2,9 Rituximab 375 mg/m2

Induction Cycle 2-6 q21 daysDays 1,2,8,9 Carfilzomib 36 mg/m2 IV; Dexamethasone 20 mg IV.Days 2,9 Rituximab 375 mg/m2

Maintenance Cycles 1-8 q 2 monthsDays 1,2 Carfilzomib 36 mg/m2 IV; Dexamethasone 20 mg IV.Days 2 Rituximab 375 mg/m2

2 months

N

N

CH3

COOHN

ClH2C

ClH2C

BendamustineBendamustine

N

N

N

N

NH2

Cl

O

OH

HOCH2

CladribineCladribine

Benzimidazole ringBenzimidazole ring

NCl

Cl

N

P

OO

H

CyclophosphamideCyclophosphamide

Nitrogen mustardNitrogen mustard

Carboxylic acidCarboxylic acid

Bendamustine in WM

CHOP plus Rituximab (CHOP-R)

Randomization

Bendamustine plus Rituximab (B-R)

B = Bendamustine 90 mg/m2 day 1+2 29+30 57+58 85+86 113+114 141+142 R = Rituximab 375 mg/m2 day 0 29 57 85 113 141

0 1 29 57 85 113 141

RB B-R B-R B-R

Tag

B-R B-R

0 1 22 43 64 85 106

RCHOP CHOP-R CHOP-R CHOP-R

Tag

CHOP-R CHOP-R

CHOP day 1 22 43 64 85 106 Rituximab 375 mg/m2 day 0 22 43 64 85 106

Rummel MJ, et al. Blood. 2008;112: Abstract 2596.Rummel MJ, et al. Blood. 2008;112: Abstract 2596.

2020thth Aug 2008 Aug 2008 Bendamustine-RBendamustine-R CHOP-RCHOP-R

40 evaluable pts.40 evaluable pts. (n = 23) (n = 17)(n = 23) (n = 17)

Age (median)Age (median) 65 yrs65 yrs 64 yrs64 yrs

Stage IVStage IV 100 %100 % 100 % 100 %

Beta-2 Microglobulin Beta-2 Microglobulin 3,23,2 3,43,4

IgM (median, mg/dl)IgM (median, mg/dl) 2.7902.790 1.6901.690

Range IgM (mg/dl)Range IgM (mg/dl) 11.220 - 1.10011.220 - 1.100 8.510 - 900 8.510 - 900

Hb (median, g/dl)Hb (median, g/dl) 10,210,2 9,99,9

Toxicity treatment associatedToxicity treatment associated

Neuropathy (patients)Neuropathy (patients) 11 33

Waldenström Patient Characteristics: B-R vs CHOP-R

Rummel M, et al. Presented at: Third International Pt Physic Summit on WM; May 1-3, 2009; Boston, Massachusetts, United States.

PFS: Benda-R vs CHOP-R in Frontline WM

0 12 24 36 48 60 72

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

months

Pro

bab

ility

Bendamustine-R

CHOP-R

Rummel M, et al. Presented at: Third International Pt Physic Summit on WM; May 1-3, 2009; Boston, Massachusetts, United States.

Advances in the Biology of Waldenstrom’s Macroglobulinemia

Bendamustine in Relapsed/Refractory WM

0

5

10

15

20

25

30

35

40

sIgM (g/L) Hematocrit (%)

Pre-Rx

Post-Rx

P<.0001 P = .0002P<.0001 P = .0002

Treon S, et al. Clin Lymphoma Myeloma Leuk. 2011;11(1):133-135.Treon S, et al. Clin Lymphoma Myeloma Leuk. 2011;11(1):133-135.

•ORR 83%•PFS 13.2 mos.

PFS is impacted by Depth of Response in WM Pts Treated With Rituximab-Based Therapy.

CRCR

VGPRVGPR

PRPR

MRMR

NRNR

P < .00010.00

0.25

0.50

0.75

1.00

Wit

ho

ut

pro

gre

ss

ion

(%

)

0 10 20 30 40 50 60 70 80 90 100Time from treatment initiation (months)

CR/VGPRCR/VGPR

MR/PRMR/PR

P = 0.040.00

0.25

0.50

0.75

1.00

Wit

ho

ut

pro

gre

ss

ion

(%

)

0 10 20 30 40 50 60 70 80 90 100Time from treatment initiation (months)

Treon S, et al. Br J Haematol. 2011 May 12 [Epub ahead of print].

Response Estimated PFS (mos)

CR >90

VGPR >75

PR 42.6

MR 30.8

NR/SD 10.6 N=159

Treon S, et al. Clin Lymph Myeloma. 2010;10(5):347-352.

VAL/VAL 10-12%VAL/PHE 35-40%PHE/PHE 40-50%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Non-Responders Minor Responders Partial Responders VGPR/CR Responders

FcγRIIIA158-VV or VF

P = .03 P = .02

P = .04

P-values vs VGPR/CR

FcγRIIIA-158 Polymorphisms Predict Response in WM

Treon S, et al. Br J Haematol. 2011 May 12 [Epub ahead of print].

•Glycoengineered Fc domain Enhanced ADCC effect

•Modified elbow hingeApoptosis induction

Mossner E, et al. Blood. 2010;115(22):4393-4402.

GA101: Novel Humanized CD20 MAB

0

20

40

60

80

100

120

0.00001 0.00010 0.00100 0.01000 0.10000 1.00000

GA101

Rituximab

Log Ab concentration (ug/ml)

% T

ota

l C

yto

tox

icit

y

WM patient

FcγRIIIA-158 V/V

GA101

Rituximab

Log Ab concentration (ug/ml)

% T

ota

l C

yto

tox

icit

y

0

10

20

30

40

50

60

70

80

90

0.00001 0.00010 0.00100 0.01000 0.10000 1.00000

WM patient

FcγRIIIA-158 F/F

V/V

F/F

Yang G, et al. J Clin Oncol. 2010;28(15S): Abstract 8112.

ADCC Against WM Cells for GA101 is Greater Among Autologous NK Cells

Genotyped for FCGRIIIA-158 F/F

GA101 Demonstrates Greater Direct Killing vs Rituximab in BCWM.1 WM Cells

Untreated

GA101

Rituximab

20.2% 31.4%

45.6% 77.6%

17.1% 23.6%

To Maintain or Not to Maintain?

Untreated, ObservationUntreated, MaintenancePrev Treated, ObservationPrev Treated, Maintenance

N=248

PFS in rituximab naïve WM patients who were observed or given maintenance rituximab therapy.

100

75

50

25

00 10 20 30 40 50 60 70 80 90 100 110 120

Time from treatment initiation (months)

Aliv

e o

r w

ith

ou

t p

rog

fres

sio

n (

%)

With Maintenance

No Maintenance

Treon S, et al. Br J Haematol. 2011 May 25 [Epub ahead of print].

Infectious Events in WM Patients Who Underwent Observation or Maintenance

Rituximab Therapy

0% 10% 20% 30% 40% 50%

Grade > 3

InfectiousEvents(Any

Grade)

Maintenance Rituximab

Observation

P = .0064

P = .718

Treon S, et al. Br J Haematol. 2011 May 25 [Epub ahead of print].

Salvage OptionsSalvage Options

• N = 50 (DFCI and Mayo)

• 10 mg QD

• Reduce to 5 mg for AE

• Median prior therapies: 3

• Median IgM: 3330 mg/dL

• ORR: 72%

• Median response:

• NR (3-22+ mos)

• Grade >3 thrombocytopenia, pneumonitis, mucositis, and hyperglycemia.

Everolimus in Relapsed/Refractory WM

Ghobrial IM, et al. J Clin Oncol. 2010;28(8):1408-1414.

RAD001RAD001

RAD001 for Primary Therapy of WM

• N = 60

• Eligibility: symptomatic, untreated WM

• Dose: 10 mg QD

• Reduction to 7.5, 5.0 mg for AE

• Duration: 4 yrs to progression

• Primary endpoints: safety, ORR, and 2- and 4-yr PFS

IgM Discordance to WM BM Disease Involvement is Common With RAD001

7 non-responders by serial BM biopsies despite reductions in sIgM.

Advances in the Biology of Waldenstrom’s Macroglobulinemia

“Medicine is not only a science; it is also an art. It does not consist of compounding pills and plasters; it deals with the very processes of life, which must be understood before they may be guided.”

Phillipus Aureolus Paracelsus

Advances in the Biology of Waldenstrom’s MacroglobulinemiaResponse Assessment can be complicated by differential impact of targeted therapies on WM clonal populations.

Varghese et al, Clin Lymph Myeloma 2009Varghese et al, Clin Lymph Myeloma 2009Post-Rituximab

Alemtuzumab in WMAlemtuzumab in WM•CD52 widely expressed on WM and BM Mast cells.

•UK Study (n=7):

-ORR 86%; 1 CR;

-2 deaths due to Opportunistic Infections.

•Multicenter study by WMCTG (n=28):

-ORR 75%; Major RR: 36% (1 CR);

-TTP 14.5 months ;

-Cytopenias, CMV (3 deaths); Late ITP (1 death).

Owen et al, ASH 2003; Treon, Blood 2011.

CharacteristicsCharacteristics No. availableNo. available No. of patients (%)No. of patients (%)

Sex: MaleSex: Male

Age at diagnosis, years [median (range)]Age at diagnosis, years [median (range)] ≥ 50 years ≥ 60 years ≥ 65 years

No. of prior therapiesNo. of prior therapies < 3 ≥ 3 IPSSWM - riskIPSSWM - riskIntermediate High

Interval diagnosis – ASCT, months [median Interval diagnosis – ASCT, months [median (range)](range)] ≤ 2 years 2 – 3 years ≥ 3years

158

158

153

158

158

99 (63%)

49 (20 – 67)74 (47%)10 (6%) 2 (1%)

104 (68%)104 (68%) 49 (32%)

58(37%)85(54%)85(54%)

20 (3 – 244)88 (88 (556%)6%)36 (23%)36 (23%)34 (21%)

Kyriakou et al, JCO 2010Kyriakou et al, JCO 2010

Autologous SCT in WM: EBMT

ASCT IN WM RELAPSE RATE AND NON-RELAPSE MORTALITY

ASCT IN WM RELAPSE RATE AND NON-RELAPSE MORTALITY

1.0

0.0

0.2

0.4

0.6

0.8

0 1 2 3 4 5 6 7 8

Time after ASCT (years)

Cu

mu

lati

ve

Inci

den

ce

NRM

Relapse or Progression

52%

4.6% 5.6%3.8%

Kyriakou et al, JCO 2010

0.0

0.1

0.2

0.3

0.4

0.5

0 2 4 6 8 10

Time after ASCT (years)

Cu

m I

nc

Se

c M

alig

nan

cy8.4%

Secondary malignancies

ADVERSE PROGNOSTIC FACTORS FOR POST ASCT OUTCOME: MULTIVARIATE ANALYSIS

ADVERSE PROGNOSTIC FACTORS FOR POST ASCT OUTCOME: MULTIVARIATE ANALYSIS

Adverse prognostic factorAdverse prognostic factor Relative riskRelative risk Confidence Confidence intervalinterval

P valueP value

Relapse / ProgressionRelapse / Progression ≥ 3 prior lines of therapy Refractory disease at ASCT

2.5 3.9

1.5 – 4.1 1.6 – 9.4

0.0010.003

Progression free survivalProgression free survival ≥ 3 prior lines of therapy Refractory disease at ASCT

2.4 4.1

1.5 – 3.9 1.8 – 9.2

0.001< 0.001

Overall survivalOverall survival Male sex ≥ 3 prior lines of therapy Age at ASCT > 60 years Refractory disease at ASCT

2.03.11.93.1

1.1 – 3.91.7 – 5.91.0. - 3.81.2 – 8.1

0.040.0010.050.03

Kyriakou et al, JCO 2010

Novel DirectionsNovel Directions

Burton’s Tyrosine Kinase (BTK)

Nat Rev Imm 2:945

• B-cell antigen receptor (BCR) signaling is required for tumor expansion and proliferation

• Bruton’s Tyrosine Kinase (Btk) is an essential element of the BCR signaling pathway

• Inhibitors of Btk block BCR signaling and induces apoptosis

IgM

IKBα-(pS32)

total IKBα

Hogan Hogan + PCI-32765

MWCL1 MWCL1 + PCI-32765

ANBL6 ANBL6 + PCI-32765

INA6 INA6 + PCI-32765

Hogan Hogan + PCI-32765

MWCL1 MWCL1 + PCI-32765

ANBL6 ANBL6 + PCI-32765

INA6 INA6 + PCI-32765

ERK1/2 - (pT202/pY204)

total ERK1/2

NFkB signaling

MAPK signaling

Impact of BTK-I on NFKB and MAPK Signaling in WM and MM

PCI-32765 Clinical Experience

N CR PR SD PD NE TETE

ORR %ITT

ORR %Eval

CLL/SLL 16 1 10 2 2 1 69% 85%

FL 16 1 3 5 4 3 25% 31%

MCL 9 3 4 1 1 78% 78%DLBCL 7 2 1 4 29% 29%

MZL/MLT 4 1 1 1 1 25% 33%

WM 4 2 1 1 50% 67%TOTAL 56 5 22 11 10 6 2 48% 56%

Advani et al. ASCO 2010

MCL (n=9)

CLL/SLL (n=13)

Indolent (n=20)

DLBCL (n=7)

Most Frequently Observed Toxicities: fatigue, diarrhea, nausea, myalgia, headache, and pneumonia. No apparent hepatic or renal toxicities. No evidence of cumulative hematologic toxicity.

PCI 327625 in Relapsed/Refractory WMScreening

Registration

560 mg po qD PCI-32765

Progressive Disease (PD) or Unacceptable Toxicity

Stable Disease or ResponseContinue x 24 four week cycles

(maximum)

Stop PCI-32765

Event Monitoring

Event Monitoring

WHOLE GENOME SEQUENCING IN WM

only 70 years

WM ===========*====

Paired Sequencingfrom same individuals

30 patients with WMIncluding familial and

sporadic patients

NORMAL ================

WHOLE GENOME SEQUENCING IN WM

Treon et al, ASH 2011; Xu et al; ASH 2011 (Accepted).

BCWM.1 BCWM.1 + control

agent

BCWM.1 + WM Inhibitory agent

Specific drug targeting of WM mutant protein

Summary (I)Summary (I)

• WM has histological, immunophenotypic, clinical and molecular features which can distinguish it from MM.

• Familial predisposition is more common in WM, and impacts therapy.

• Bendamustine, bortezomib, cyclophosphamide, and thalidomide–based rituximab therapies are active, and can be used for symptomatic WM.

Summary (II)Summary (II)•Use of nucleoside analogues should be carefully weighed against other options. Lenalidomide avoided. Bortezomib used with caution for neuropathy.

•Maintenance is an reasonable option for patients responding to a rituximab containing regimen.

•Genomic investigation has revealed novel targets for therapy of WM.

Waldenström’s macroglobulinemia:Similar but Different to Myeloma.