Treatment Advances in Waldenstromâ€™s Macroglobulinemia

12/16/2010

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Advances in the Biology of Waldenstrom’s Macroglobulinemia

Treatment Advances in Waldenstrom’s Macroglobulinemia

Steve Treon MD, MA, PhD

Director, Bing Center for WM

Associate Professor

Dana Farber Cancer Institute

Harvard Medical School


6th International Workshop on Waldenström’s Macroglobulinemia

Venice, Italy • October 6-10, 2010www.wmworkshop.org

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Case PresentationThis 63 year old went for a routine physical examand was found to have an elevated total protein.An IgM monoclonal spike was discovered, andhis total serum IgM level was 4,010 mg/dL.Hematocrit was 37.9%. A bone marrow biopsyshowed 30% involvement with LPC. He wass owed 30% vo ve e t w t C. e wasdiagnosed with WM and placed on watch andwait.


Case PresentationOne year later his IgM is 4,820 mg/dL, hematocrit is35 1% H h f ti bl d d i h i35.1%. He has more fatigue, nosebleeds, and is hearing“tree frogs”. He also is experiencing numbness andtingling in his feet. Exam shows “plump retinal vessels”.Neurological exam shows diminished sensation to touchover his soles. Fat pad biopsy with congo red staining isnegative. Anti-MAG IgM antibody screen is positive withtiter >102,400. He undergoes plasmapheresis andreports improvement in his neuropathy, and also stateshis “thinking” has improved.

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Case PresentationWhat is the most appropriate course of action for this patient?pp p p

1. Continue watch and wait2. Gabapentin or Pre-Gabapentin for symptomatic relief3. Continue with periodic plasmapheresis4. Treat with rituximab alone5. Treat with cyclophosphamide based rituximab therapy (CPR or RCD)6. Treat with fludarabine or cladribine based rituximab therapy7. Treat with bortezomib based rituximab therapy (BDR or VR)8 Treat with bendamustine plus rituximab8. Treat with bendamustine plus rituximab


Clinicopathological Manifestations of WM

HCT PLT WBC

Adenopathy, l l

HCT, PLT, WBCHyperviscositySyndrome:Epistaxis, HA,Impaired vision

>4.0 CP

splenomegaly ≤15% IgM Neuropathy (~20%)

Cryoglobulinemia (<5%)Cold Agglutinemia (<10%)Fatigue, Constitutional Sxs

Cytokinemia?

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

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Anemia in Waldenstrom’s macroglobulinemia

Bone marrow replacementBone marrow replacement

Hemodilution (high IgM levels)

Hemolysis (cold agglutinin; warm antibody)

Therapeutic injury (nucleoside analogue mediated hemolysis; MDS)hemolysis; MDS)

Iron deficiency (Hepcidin)


Actions of Hepcidin

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1. 2.

Hepcidin vs. BM involvement and Anemia in WM

Ciccarelli et al, ASH 2009.


Ferrlicit improves Hematocrit in Oral Iron Refractory WM patients who display high hepcidin levels.

p=0.032

Ciccarelli et al, ASH 2009

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Consensus Panel Recommendations for Initiation of Therapy in WM Hb ≤ 10 g/dL on basis of diseaseHb ≤ 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, y p y g , gg ,amyloidosis, or symptomatic autoimmune related events on the basis of disease

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


First published report of response to rituximab in WM

Semin Oncol. 1999; 26:97-106.

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Serum IgM Levels Following Rituximabin Patients With WM

14,000

WM 1P12,000

eru

m Ig

M (

mg

/dL

)

10,000

8000

6000

4000

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

P

P

P

PP

P

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

P denotes patient-required plasmapheresis for hyperviscosity.

00 2 4 6 8 10

Wks

S

4000

2000

12 14

WM 11P


IL-6 blockade leads to inhibition of IgM release in Co-Culture Studies with WM cells and Rituximab StimulatedMonocytes.

2200

2400

2600

ml) Monocytes

FcγRIIA

RituximabIVIg

1200

1400

1600

1800

2000

IgM

(n

g/m IL-6

WM-LPC

IL-6R

IgM

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Primary Therapy of WM with Rituximab Based Options

Regimen ORR CR

Rituximab x 4 25 30% 0%Rituximab x 4 25-30% 0%

Rituximab x 8 40-45% 0%

Rituximab/cyclophosphamidei.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/bortezomibi.e. BDR, VR

70-90% 10-25%

Rituximab/bendamustine 90% 30%


Dexamethasone, Rituximab, Cyclophosphamidein WM

N=72

Dexamethasone 40 mg IV D1; Rituximab 375 mg/m2 D1;

Cyclophosphamide 100 mg/m2 PO BID D1-5.

ORR: 83% CR: 7%.

Median PFS: 35 months; TTNT: 51 months.

Short-term toxicities included:

Myelosuppression (9% G>3 Neutropenia); PNA (1 death).

Long-term hematological toxicities: DLBCL (1).

Dimopoulos et al, ASH 2008; Abstract 2887

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Fludarabine and Rituximab in WM

Median PFS (All): 51.2 mo.Median PFS (>VGPR): >88 moMedian PFS (>VGPR): >88 mo.Median PFS (<VGPR): 36.9 mo.

Median Follow-up: 50.6 months

Treon et al, Blood 2008; Updated IWWM6, 2010


N=43 (63% untreated).

Fludarabine and Rituximab in WM

N 43 (63% untreated).

6 cycles (25 mg/m2 per day for 5 days) of fludarabine and 8 infusions (375 mg/m2 per week) of rituximab.

ORR: 95.3%; CR/VGPR: 37%


Myelosuppression (G>3 neutropenia 62%).

PNA (6). Including 2 deaths due to non-PCP PNA.

Long-term toxicities: DLBCL (3); MDS/AML (3).

Blood 2008; 113:3673.

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Disease transformation following nucleoside analogues in WMStudy Population N= Median

F/U (mo)Outcome

( )

Leleu et al, JCO 2009

Prev treated with NA vs. non-NA or untreated

439 60 Histological Transformation (5%)MDS/AML (2%)

Tamburini et al, Leukemia 2005

Firstline with Fludara/Cyclo

49 41 Histological Transformation (10%)

Leblond JCO Previously treated 71 34 Histological Transformation (10%)Leblond, JCO 1998

Previously treated with Fludara

71 34 Histological Transformation (10%)

Rakkhit et al, ASH 2008

Untreated; 2CDA based therapy

111 NA Histological Transformation (9%)


N=25

Thalidomide and Rituximab in WM

Thalidomide at 200 mg, increase to 400 mg and 8 infusions (375 mg/m2 per week) of rituximab.

ORR: 72%; CR/VGPR: 4%


Sensory neuropathy (11); resolved grade 1 or less: 10.

Confusion (3), tremors (2), bradycardia (2).

Dose reduction in all pts. 50-100 mg/day tolerated.

Blood 2008; 112:4452

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Thalidomide and Rituximab in WM

Median PFS: 41.9 months

Median Follow-up: 40.4 months


Lenalidomide (Revlimid)-Induced Anemia in WM

D d H t b d i 38Pretherapy Posttherapy

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

28

30

32

34

36

38

emat

ocr

it (

%)

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

Treon SP, et al. Clin Cancer Res 2008

20

22

24

26

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

He

Patient

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Bortezomib combination therapy in WM

Primary

Bortezomib (1.3 mg/m2/biwkly)/Dexamethasone/Rituximab( g y)

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

Bortezomib (1.6 mg/m2/wk)/Rituximab

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

Salvage

Bortezomib (1.6 mg/m2/wk)/Rituximab

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

Bortezomib (randomized wkly vs. biwkly)/Rituximab

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

Treon et al, JCO 2009; Ghobrial et al, AJH 2010; Ghobrial et al, JCO 2010; Agathocleous et al, ASH 2007


Bortezomib, Dexamethasone and Rituximab

in WM

Median PFS: >56.1 months

Median Follow-up: 43.3 monthsTreon et al, JCO 2009

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PFS: BendaPFS: Benda--R vs CHOPR vs CHOP--R in frontline WMR in frontline WM

0 9

1.0

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Pro

bab

ility

Bendamustine-R

0 12 24 36 48 60 72

0.0

0.1

0.2

months

CHOP-R

Presented on the Vth International Workshop on Waldenstrom´s Macroglobulinemia, Stockholm, Oct 15-19, 2008

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CR >90 mos.

CR

VGPR

PR

MR

Progression Free Survival

VGPR >75 mos.

PR 42.8 mos.

MR 30.8 mos.

MR

NR

CR/VGPR

Survival (n=159) p<0.0001Response Estimated

PFS (mo.)

CR >90

VGPR >75

P<0.0001

NR 10.1 mos.

MR/PR

p=0.04

VGPR >75

PR 42.6

MR 30.8

NR/SD 10.6

Proc ASCO 2010; 28: 15s; Updated IWWM6, 2010

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

Treon et al, Clin Lymph Myeloma 2010

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80%

90%

FcγRIIIA158-VV or VF

FcγRIIIA-158 polymorphisms predict response in WM

p-values vs. VGPR/CR

20%

30%

40%

50%

60%

70%

80%

p=0.03 p=0.02

p=0.04

0%

10%

Non-Responders Minor Responders Partial Responders VGPR/CR Responders

Proc ASCO 2010; 28: 15s


PGx Healthwww.clda.com

“Your polymorphism results are back”

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GA101 --- a Novel Third Generation HumanizedType II CD20 Monoclonal Antibody

Ofatumumab (Arzerra®) a second generation fully

humanized antibody

approved by FDA for CLL

therapy in 2009

Rituximab Glycoengineered Fc domain-Enhanced ADCC effect

modified elbow hinge- Apoptosis induction

GA101

Rituximab Ofatumumab

GA101

CD20


In vitro ADCC efficacy for GA101 vs. Rituximab withprimary BM WM patient cells using autologous NK cells.

GA101

icit

y

70

80

90

V/V

120

WM patient

FcγRIIIA-158 V/V

Rituximab

Log Ab concentration (ug/ml)

% T

ota

l C

yto

tox

i

0

10

20

30

40

50

60

0.00001 0.00010 0.00100 0.01000 0.10000 1.00000

V/V

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 F/FF/F

Yang et al, ASCO 2010

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To Maintain or Not to Maintain?


PFS in rituximab naïve WM patients who underwent

observation or maintenance rituximab therapy.

Treon et al, ASH 2009

N=248

Untreated, Observation

Untreated, Maintenance

With Maintenance

No Maintenance

Prev Treated, Observation

Prev Treated, Maintenance

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N = 50 (DFCI and Mayo)

10 mg QD

RAD001 in Relapsed/Refractory WM

– 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.

Ghobrial et al, JCO 2010


RAD001 for Primary Therapy of WM

N = 60N 60

Eligibility: symptomatic, untreated WM

Dose: 10 mg QD

– Reduction to 7.5, 5.0 mg for AE

D ti 4 t i Duration: 4 yrs to progression

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

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IgM changes following RAD001 in untreated WM patients.


IgM Related Neuropathies in WM

Observed in about 20% of WM patients

IgM can often be found to react with specific neural antigens; these autoantibodies define very specific clinical syndromes.

– Myelin Associated Glycoprotein (MAG)

– Ganglioside M1 (GM1)

– Sulfatide

Courtesy Todd Levine, MD

MAG antibody staining

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Clinical characteristics of paraproteinrelated PN in WM.

900 consecutive WM Pts; Pts with treatment and non-900 consecutive WM Pts; Pts with treatment and nondisease related PN excluded.

199 (22.1%) had disease related PN.

Treon et al, 12th International Symposium on Amyloid, 2010.


Symptomatic Improvement following Therapy: Subset Analysis

p<0 0001

p=0.04

p<0.0001

p=0.06 p=0.07

Treon et al, ASCO 2010.

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Treatment Outcome of WM related PN.Treatment N= Overall

RRMajorRR

ImprovedPN

Oral alkylator 21 33.3% 19.0% 19.0%

Nucleoside analogue 11 45.5% 36.4% 45.5%

Rituximab 57 59.6% 35.1% 42.1%

Rituximab/nucleosideanalogue

26 50.0% 46.0% 54.0%

Rituximab/cyclophosphamide 18 83 3% 50 0% 55 6%Rituximab/cyclophosphamide 18 83.3% 50.0% 55.6%

Rituximab/thalidomide 7 71.4% 71.4% 71.4%

Rituximab/bortezomib 8 75% 50.0% 75.0%

Treon et al, ASCO, 2010.


Treatment Score Card

Is the patient a candidate for ASCT?

Is an immediate response needed?

Does the treatment meet the goals of therapy?

Is the patient able to tolerate myelosuppressive therapy?

Are potential side effects prohibitive for the patient?

Are long term treatment risks reasonable?

Is treatment covered by insurance?

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Summary

Watch and wait is appropriate for asymptomatic patients.

Bendamustine Bortezomib Cyclophosphamide and Bendamustine, Bortezomib Cyclophosphamide, andThalidomide based rituximab therapies are active and canbe considered in the upfront treatment of WM.

Use of nucleoside analogues should be carefullyconsidered due to potential long-term consequences.

Better categorical responses are associated with improvedPFS in rituximab naïve WM patients receiving rituximabbased therapy, and may reflect underlying FcγRIIIA-158polymorphisms.

Patients with IgM related PN benefit with earlier treatmentwith rituximab combination therapy.

Documents

Treatment Advances in Waldenstromâ€™s Macroglobulinemia