Current Approaches to Management ofWaldenström Macroglobulinemia

Jorge J. Castillo, MDAssociate Professor of Medicine, Harvard Medical Schooljorgej_castillo@dfci.harvard.edu

1. Lymphoplasmacytic lymphoma in the bone marrow

2. IgM monoclonal protein is serum protein electrophoresis

3. MYD88 L265P gene mutation

Diagnostic Criteria

Differential Diagnosis

Characteristic WM IgM MGUS MZL IgM myelomaBone marrow ++ - +/- +Lymph nodes + - ++ +/-Splenomegaly +/- - +++ (SMZL) +/-

Extramedullary +/- - +++ (MALT) +/-

CD20 expression +++ - +++ +/-Cyclin D1 or t(11;14) - - - ++MYD88 L265P 95% 50% 5% 0%

Manifestations of Waldenström Macroglobulinemia

Bing NeelSyndrome (1%)

Bone MarrowHB>>> PLT> WBC

Hepcidin Fe Anemia

Cold Agglutinemia (5%)Cryoglobulinemia (10%) IgM Neuropathy (20%)

Amyloidosis (5-10%)

Hyperviscosity Syndrome (15%)Epistaxis, Headaches

Impaired vision >6,000 mg/dL or >4.0 CP

≤20% at diagnosis;50-60% at relapse.

Why Not Treat Everybody at Diagnosis?

• WM is incurable• Treatment promotes resistance• Treatment comes with toxicity• No evidence that treating early prolongs survival• WM patients enjoy decades of life

Kyle et al. Semin Oncol 2003; Castillo et al. Br J Haematol 2016

• Hemoglobin ≤10 g/dL on basis of disease• Platelet

Bustoros et al. J Clin Oncol 2019

https://awmrisk.com

TREATMENT OPTIONS

Dimopoulos et al. Blood 2014; Treon et al. Blood 2015

ChemoimmunotherapyRegimen ORR VGPR/CR PFS (mo)

Rituximab/cyclophosphamide i.e. CHOP-R, CVP-R, CDR 70-80% 20-25% 30-36

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

70-90% 20-30% 36-62

Rituximab/bendamustine 80-90% 30-40% 69

Treon et al. J Clin Oncol 2009; Dimopoulos et al. Blood 2013;Treon et al. Blood 2014; Castillo et al. Clin Cancer Res 2018

Proteasome Inhibitors

Regimen N OverallresponseMajor

response PFS

BDR 23 88% 65% 66 monthsBDR weekly 59 85% 68% 42 months

CaRD 31 87% 68% 46 monthsIDR 26 96% 77% NR at 36 months

Castillo et al. Br J Haematol 2018

Treon et al. N Engl J Med 2012; Xu et al. Blood 2013

MYD88 Mutations

2% non-L265P MYD88 mutations

Study Method %Xu AS-PCR 93%Gachard PCR 70%Varettoni AS-PCR 100%Landgren Sanger 90%Jimenez AS-PCR 86%Poulain PCR 80%Argentou PCR-RFLP 92%Willenbacher Sanger 86%Mori AS-PCR 80%Ondrejka AS-PCR 100%Ansell WES/AS-PCR 97%Patkar AS-PCR 85%Cao AS-PCR 92%

Hunter et al. Blood 2014; Xu et al. Br J Haematol 2017

CXCR4 MutationsB Study Method %

Hunter WGS 27%Roccaro AS-PCR 28%Poulain NGS/Sanger 25%Schmidt Sanger 36%Xu AS-PCR/Sanger 40%Ballester Sanger 25%Cao Sanger 24%Shin Target capture 19%

Treon et al. Br J Haematol 2018; Castillo et al. Exp Rev Hematol 2019

MYD88 and CXCR4 Mutations are Determinants of Clinical Presentation

MYD88MUTCXCR4WT

(50-60%)

MYD88MUTCXCR4MUT

(30-40%)

MYD88WTCXCR4WT

(5-10%)

Bone marrow involvement ++ +++ +Lymphadenopathy + + +++Serum IgM levels ++ +++ ++Hyperviscosity ++ +++ ++Acquired VWD + +++ +Risk of DLBCL + + +++

Yang et al. Blood 2013

BTK is an important component of the activation pathway of MYD88 L265P

BTK Inhibitors

Regimen N OverallresponseMajor

response PFSIbrutinib

Relapsed 63 91% 73% NR at 5 yearsIbrutinib

R refractory 31 90% 71% 86% at 18 monthsIbrutinibPrimary therapy

30 100% 83% 92% at 18 months

Treon et al. N Engl J Med 2015; Dimopoulos et al. Lancet Oncology 2017; Treon et al. J Clin Oncol 2018

Treon et al. N Engl J Med 2015; Treon et al. ASH 2017

Responses to Ibrutinib are Impacted by Mutational Status

ALL MYD88MUT

CXCR4WTMYD88MUTCXCR4MUT

MYD88WTCXCR4WT

N= 63 36 21 5ORR 90% 100% 86% 60%Major (>PR) 78% 97% 67% 0%VGPR 27% 44% 10% 0%TTR (mos.) 1.0 1.0 1.0 1.0TTMR (mos.) 2.0 2.0 6.0 N/A

Treon et al. ASH 2017

Long-Term Follow-up of Previously Treated Patients Who Received Ibrutinib for Symptomatic Waldenström Macroglobulinemia: Update of Pivotal Clinical Trial

0.2

5.5

.75

1Pr

ogre

ssio

n-fre

e su

rviv

al p

roba

bilit

y

0 12 24 36 48 60Time from treatment initiation

63 51 41 38 24 1 Number at risk

95% CI Survivor function

0.00

0.25

0.50

0.75

1.00

Prog

ress

ion-

free

surv

ival

pro

babi

lity

5 2 1 1 0 0MYD88 WT/CXCR4 WT21 15 12 10 6 0MYD88 MUT/CXCR4 MUT36 34 28 27 18 1MYD88 MUT/CXCR4 WT

Number at risk

0 12 24 36 48 60Months from treatment initiation

MYD88 MUT/CXCR4 WT MYD88 MUT/CXCR4 MUT

MYD88 WT/CXCR4 WT

Dimopoulos et al. N Engl J Med 2018

Dimopoulos et al. N Engl J Med 2018

82%

28%

Treon et al. N Engl J Med 2015; Dimopoulos et al. Lancet Oncol 2017;Dimopoulos et al. N Engl J Med 2018; Treon et al. J Clin Oncol 2018

Is Ibrutinib-rituximab Better Than Ibrutinib Alone?

  Ibrutinib +rituximabIbrutinibrelapsed

IbrutinibINNOVATE

Ibrutinibfrontline

N prev untreated 34 - - 30N prev treated 41 63 31 -ORR 92% 91% 90% 100%MRR 72% 73% 71% 83%VGPR 23% 27% 13% 20%PFS 30-mo: 82% 60-mo: 60% 18-mo: 86% 18-mo: 92%

Treon et al. N Engl J Med 2015; Gustine et al. Am J Hematol 2016

Ibrutinib Related Adverse Events In Previously Treated WM Patients

0 5 10 15 20

Mucositis Hypertension Pre/Syncope Dehydration

Epistaxis Post-procedure bleed

Diarrhea Skin Infection

Lung Infection Arrythmia

Thrombocytopenia Anemia

Neutropenia

Grade 2 Grade 3 Grade 4

# of patients with toxicity10% incidence with larger experienceHigher risk: men, >75 years, h/o CAD, CHF or arrhythmias

★

★

The Dana-Farber approach

Owen et al. Lancet Haematol 2020

Grade 3/4 Adverse eventsNeutropenia 6%/10%Thrombocytopenia 2%/2%LFT increased 7%/1%Pneumonia 15%Anemia 5%

ONGOING CLINICAL TRIALS

A Study Comparing Zanubrutinib and Ibrutinib in Subjects With Waldenström Macroglobulinemia

MYD88 L265Pnegative

Therapy continues until unacceptable toxicity or disease

progression

www.clinicaltrials.gov: NCT03053440 Screening

Arm AZanubrutinib

160 mg PO BID

Arm BIbrutinib

420 mg PO QD

Arm CZanubrutinib

160 mg PO BID

Castillo et al. IMW 2019

Multicenter Prospective Phase II Study of Venetoclax in Patients With Previously Treated Waldenström Macroglobulinemia

No CXCR4 mutation CXCR4 mutation

www.clinicaltrials.gov:

NCT02677324

Ibrutinib and Venetoclax for Patients with Previously Untreated Waldenström Macroglobulinemia

Sample size50 patients

Primary outcomeVGPR ≥40%

Secondary outcomes• Impact of genomic

profiling• Overall response rate• Safety profile• Ability to stop therapy

www.clinicaltrials.gov:

NCT04273139

Other Clinical TrialsBTK inhibitors

TirabrutinibVecabrutinib (BTK C481S)LOXO-305 (BTK C481S)

Anti-CXCR4 agentsUlocuplumabMavorixafor

PI3K inhibitorsUmbralisib

HCK inhibitorsDasatinib (BTK C481S)

Anti-CD38 antibodiesDaratumumab

Current Approaches to Management ofWaldenström Macroglobulinemia

Jorge J. Castillo, MDAssociate Professor of Medicine, Harvard Medical Schooljorgej_castillo@dfci.harvard.edu

Slide 1Slide 2Diagnostic CriteriaDifferential DiagnosisManifestations of Waldenström MacroglobulinemiaWhy Not Treat Everybody at Diagnosis?Guidelines for Initiation of TherapySlide 8Slide 9Slide 10ChemoimmunotherapyProteasome InhibitorsSlide 13Slide 14Slide 15Slide 16Slide 17BTK InhibitorsResponses to Ibrutinib are Impacted by Mutational StatusSlide 20Slide 21Slide 22Slide 23Slide 24Slide 25Slide 26Slide 27Slide 28Slide 29Slide 30Slide 31Slide 32Slide 33Slide 34