Current Approaches to Management of Waldenström Macroglobulinemia · 2020. 8. 29. · Waldenström...
Transcript of Current Approaches to Management of Waldenström Macroglobulinemia · 2020. 8. 29. · Waldenström...
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Current Approaches to Management ofWaldenström Macroglobulinemia
Jorge J. Castillo, MDAssociate Professor of Medicine, Harvard Medical [email protected]
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1. Lymphoplasmacytic lymphoma in the bone marrow
2. IgM monoclonal protein is serum protein electrophoresis
3. MYD88 L265P gene mutation
Diagnostic Criteria
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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%
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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.
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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
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Kyle et al. Semin Oncol 2003; Castillo et al. Br J Haematol 2016
• Hemoglobin ≤10 g/dL on basis of disease• Platelet
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Bustoros et al. J Clin Oncol 2019
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https://awmrisk.com
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TREATMENT OPTIONS
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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
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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
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Castillo et al. Br J Haematol 2018
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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%
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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%
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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 + + +++
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Yang et al. Blood 2013
BTK is an important component of the activation pathway of MYD88 L265P
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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
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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
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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
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Dimopoulos et al. N Engl J Med 2018
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Dimopoulos et al. N Engl J Med 2018
82%
28%
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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%
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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
★
★
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The Dana-Farber approach
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Owen et al. Lancet Haematol 2020
Grade 3/4 Adverse eventsNeutropenia 6%/10%Thrombocytopenia 2%/2%LFT increased 7%/1%Pneumonia 15%Anemia 5%
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ONGOING CLINICAL TRIALS
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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
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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
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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
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Other Clinical TrialsBTK inhibitors
TirabrutinibVecabrutinib (BTK C481S)LOXO-305 (BTK C481S)
Anti-CXCR4 agentsUlocuplumabMavorixafor
PI3K inhibitorsUmbralisib
HCK inhibitorsDasatinib (BTK C481S)
Anti-CD38 antibodiesDaratumumab
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Current Approaches to Management ofWaldenström Macroglobulinemia
Jorge J. Castillo, MDAssociate Professor of Medicine, Harvard Medical [email protected]
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