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