Post on 12-May-2020
Advances in the frontline treatment of Waldenström macroglobulinemia
Jorge J. Castillo, MD Assistant Professor of Medicine
Harvard Medical School JorgeJ_Castillo@dfci.harvard.edu
Disclosures
Consulting • Janssen Pharmaceuticals • Merck Co. • Pharmacyclics Inc • Roche
Research Funding • Abbvie Inc • Gilead Sciences • Janssen Pharmaceuticals • Millennium
Pharmaceuticals • Pharmacyclics Inc
Diagnostic criteria
1. Lymphoplasmacytic lymphoma in the bone marrow
2. IgM monoclonal protein is serum protein electrophoresis
3. MYD88 L265P gene mutation
WHO Classification 2018
No relationship between serum IgM levels and BM involvement
Ser
um Ig
M (m
g/dL
)
Treon et al. Blood 2009 Bone marrow involvement
Manifestations of WM
≤20% at diagnosis; 50-60% at relapse.
↓HB>>> ↓PLT> ↓WBC
Hyperviscosity Syndrome: Epistaxis, Headaches
Impaired vision >6,000 mg/dL or >4.0 CP
Treon. Hematol Oncol 2013
Cold Agglutinemia (5%) Cryoglobulinemia (10%) IgM Neuropathy (22%) Amyloidosis (10-15%) Hepcidin
↓Fe Anemia
Bone Marrow
Bing Neel Syndrome
MYD88 L265P
MYD88
L265P
M232T
S219C
S243N
93-95% MYD88 L265P 2% Non-L265P MYD88
Treon et al, NEJM 2012; Treon et al, NEJM 2015; Jiménez et al, Leukemia 2013; Varettoni et al Blood 2013; Poulain et al, Blood 2013, Xu et al, Blood 2013.
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%
B
CXCR4 mutations in WM
Hunter, Blood 2013; Roccaro, Blood 2014; Poulain, Blood 2016; Cao, Leukemia 2014; Cao, BJH 2015
• 30-40% of WM patients • >30 Nonsense, Frameshift
Mutations • High serum IgM levels/
Hyperviscosity • Promote ibrutinib resistance
through enhanced AKT/ERK signaling.
FRONTLINE TREATMENT OPTIONS
Bendamustine and rituximab
Subset analysis RCT • Bendamustine-R (N=22)
vs. CHOP-R (N=19) • Good option for patients
with lymphadenopathy or enlarged liver/spleen
• ORR 80%; CR 20% • PFS 69 months
Rummel et al. Lancet 2013
Adverse events • Potential stem cell toxicity • Cytopenias • Infusion reactions • 0.5-1% risk of secondary leukemia
Bortezomib-based therapy Several phase II studies • Combined with rituximab
and/or dexamethasone • ORR 80-90% • CR 10-20% • Median TTR: 4-8 weeks • No risk of secondary
malignancies Adverse events • Peripheral neuropathy – less
with weekly or SQ • Thrombocytopenia • Steroids and zoster prophylaxis
Treon et al. J Clin Oncol 2009 Dimopoulos et al. Blood 2013
Castillo et al. Br J Haematol 2018
Log-rank p=0.10
0.00
0.25
0.50
0.75
1.00
PFS
prob
abilit
y
38 27 19 9 4 0CDR85 54 27 12 4 0BDR57 32 12 3 0 0Benda-R
Number at risk
0 2 4 6 8 10Years from treatment initiation
Benda-R BDR CDRA
Log-rank p=0.06
0.00
0.25
0.50
0.75
1.00
OS
prob
abilit
y
38 30 22 12 8 1CDR85 70 39 27 17 2BDR57 33 13 5 0 0Benda-R
Number at risk
0 2 4 6 8 10Years from treatment initiation
Benda-R BDR CDRARegimen HR (95% CI) P
CDR 1.00 (Ref) Benda-R 0.18 (0.07-0.43) <0.001
BDR 0.55 (0.30-0.99) 0.046
Regimen HR (95% CI) P CDR 1.00 (Ref)
Benda-R 0.24 (0.05-1.27) 0.09 BDR 0.14 (0.03-0.61) 0.009
PFS OS
Castillo et al. Br J Haematol 2018
Log-rank p<0.001
0.00
0.25
0.50
0.75
1.00
PFS
prob
abilit
y
116 89 50 23 8 0Maintenance64 24 8 1 0 0No maintenance
Number at risk
0 2 4 6 8 10Years from treatment initiation
No maintenance MaintenanceB
Log-rank p=0.03
0.00
0.25
0.50
0.75
1.00
OS
prob
abilit
y
116 93 55 34 19 1Maintenance64 40 19 10 6 2No maintenance
Number at risk
0 2 4 6 8 10Years from treatment initiation
No maintenance MaintenanceBRegimen HR (95% CI) P
Observation 1.00 (Ref)
Maintenance 0.54 (0.45-0.66) <0.001
Regimen HR (95% CI) P
Observation 1.00 (Ref)
Maintenance 0.72 (0.55-0.93) 0.01
All MYD88+ CXCR4-
MYD88+ CXCR4+ p
ORR 100% 100% 100% 1.00
Major 83% 94% 71% 0.16
VGPR 20% 31% 7% 0.18
TTR 1 0.9 1.7 0.07
TTMR 1.9 1.8 7.3 .01
18-month PFS: 92%
Treon et al. J Clin Oncol 2018
Dimopoulos et al. N Engl J Med 2018
30-month PFS: 82%
Is ibrutinib-rituximab better than ibrutinib alone?
Ibrutinib + rituximab
Ibrutinib relapsed
Ibrutinib INNOVATE
Ibrutinib frontline
N prev untreated 34 - - 30 N 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; Dimopoulos et al. Lancet Oncol 2017; Dimopoulos et al. N Engl J Med 2018; Treon et al. J Clin Oncol 2018
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
Ibrutinib Related Adverse Events in previously treated WM patients
• No impact on IGA and IGG immunoglobulins Treon et al. N Engl J Med 2015
Screening
Informed Consent and Registration
Venetoclax 200 mg PO QD
800 mg PO QD Progressive Disease or
Unacceptable Toxicity SD or Response à Continue for 2 years
Stop venetoclax Event Monitoring
www.clinicaltrials.gov: NCT02677324
Phase II Study of Venetoclax in Previously Treated WM
Phase II Study of Venetoclax in Previously Treated WM
No prior BTK inhibitor Prior BTK inhibitor
Bes
t ser
um Ig
M le
vel c
hang
e (%
)
Median follow-up 12 months Castillo et al. EHA 2018; IWWM10
Phase II Study of Venetoclax in Previously Treated WM
Response Number (%)
Overall (≥Minor) 26 (87%)
Major (≥Partial) 24 (74%)
Very good 5 (17%)
Partial 17 (57%)
Minor 4 (13%)
Stable 4 (13%)
Castillo et al. EHA 2018; IWWM 10
Ibrutinib and venetoclax for patients with previously untreated Waldenström macroglobulinemia
Conclusions
▪ Alkylators, proteasome inhibitors and BTK inhibitors with and without rituximab are standard frontline treatment options.
▪ The choice of therapy is largely personalized. ▪ Future studies should focus on deeper, longer
responses and finite treatments with lower toxicity rates.
Advances in the frontline treatment of Waldenström macroglobulinemia
Jorge J. Castillo, MD Assistant Professor of Medicine
Harvard Medical School JorgeJ_Castillo@dfci.harvard.edu