How I treat Waldenstrรถm Macroglobulinemia in 2016
Jorge J. Castillo, MD Assistant Professor of Medicine Harvard Medical School Jorgej_castillo@dfci.harvard.edu
Disclosures Consulting • Otsuka Pharmaceuticals • Biogen IDEC • Alexion Pharmaceuticals
Research Funding • Millennium Pharmaceuticals • Gilead Sciences • Pharmacyclics Inc. • Abbvie Inc.
Waldenström’s Macroglobulinemia – first described by Jan Gosta Waldenström in 1944.
Lymphoplasmacytic Lymphoma • Cellular Morphology: lymphocytes, lymphoplasmacytic cells, plasma cells • BM Pattern: interstitial with diffuse or nodular infiltrates with excess mast cells associated with lymphoid aggregates. • LN/SP: diffuse pattern
BM
BM
LN
1.00
0.00
0.00
Overall survival probability 0.25 0.50 0.75
Overall survival probability 0.25 0.50 0.75
1.00
Improved survival in patients with Waldenstrom macroglobulinemia
0 0
5
10 Years from diagnosis 1981-1990 2001-2010
15 1991-2000
20
5
10 Years from diagnosis 20-49 years 60-69 years 80+ years
15 50-59 years 70-79 years
Age at diagnosis is the most important prognostic factor Castillo et al. Br J Haematol 2015
20
Manifestations of Waldenstrom macroglobulinemia ↓HCT, ↓PLT, ↓WBC
Hyperviscosity Syndrome: Nosebleeds, headache, Impaired vision >4.0 CP Adenopathy, splenomegaly ≤20% (at Dx) Treon, Hematol Oncol 2013
Hepcidin ↓Fe Anemia
IgM Neuropathy (22%) Cryoglobulinemia (10%) Cold Agglutinemia (5%)
Guidelines for Initiation of Therapy • • • • •
Hemoglobin ≤10 g/dL on basis of disease Platelet <100,000 mm3 on basis of disease Symptomatic hyperviscosity (>4.0 cp) Moderate/severe peripheral neuropathy Symptomatic extramedullary disease (e.g. lymphadenopathy, hepatosplenomegaly, renal involvement, pleural effusions, Bing-Neel syndrome, etc.) • Symptomatic cryoglobulins, cold agglutinins, autoimmune-related events, amyloidosis. Kyle, Semin Oncol 2003; Anderson, JNCCN 2016.
TREATMENT OPTIONS
Bendamustine and rituximab Subset analysis RCT • Bendamustine-R (N=22) vs. CHOP-R (N=19) • Good option for patients with lympadenopathy or enlarged liver/spleen • ORR 80%; CR 20% • PFS 69 months Rummel, Lancet 2013 Treon Clin Lymphoma Myeloma Leuk 2011
Adverse events Potential stem cell toxicity Cytopenias Infusion reactions 0.5-1% risk of secondary leukemia
Cyclophosphamide-based therapy Phase II studies • Combined with rituximab and dexamethasone (CDR) • Widely available • Well tolerated • ORR 83%; CR 7% • Median PFS 3 years when given upfront Dimopoulos, J Clin Oncol 2007 Buske, Leukemia 2009 Kastritis Blood 2015
Adverse events • Alopecia • Cytopenias • 1% risk of secondary leukemia
Bortezomib-based therapy Advantages • Combined with rituximab and dexamethasone (BDR) • ORR 80-90% • CR 10-20% • Median TTR: 4-8 weeks • No risk of secondary malignancies Treon, J Clin Oncol 2009 Ghobrial, Am J Hematol 2010 Dimopoulos, Blood 2013.
Disadvantages • Peripheral neuropathy – less with weekly or SQ • Thrombocytopenia • Steroids and zoster prophylaxis
Carfilzomib-based therapy Advantages • Combined with rituximab and dexamethasone (CARD) • ORR 87% • CR 3%; VGPR 35% • Less neuropathy (<5%)
Treon, Blood 2014
Disadvantages • Increases glucose and cholesterol • Hypogammaglobulinemia • Heart problems: HTN, CAD • Steroids and zoster prophylaxis
Nucleoside analogues Advantages • Randomized study showed fludarabine better than chlorambucil • ORR: 48% vs. 39% • Median PFS: 36 vs. 27 months • ORR 80% when rituximab added Dimopoulos, J Clin Oncol 2009 Leleu, J Clin Oncol 2009 Leblond J Clin Oncol 2013
Disadvantages • Risk of MDS/AML is 5-10% • Avoid in ASCT candidates • Lower doses for older patients
Rituximab single agent Advantages • Well tolerated • ORR: 30-40% • Median TTR 3-4 months • Most commonly used regimen for Waldenström in the US.
Treon Clin Cancer Res 2001 Castillo Br J Haematol 2016 Olszewski Oncologist 2016
Disadvantages • Delayed responses • Infusion reactions • Avoid if IgM >4,000 mg/dL or HV • IgM flare: 40% of patients • Rituximab Intolerance (7%) – Consider Ofatumumab.
To Maintain or Not to Maintain?
Observation vs. maintenance rituximab therapy OS
100
100
75
75
50 Rituximab Maintenance
Alive (%)
Alive or without progression (%)
PFS
25
50
Rituximab Maintenance N=246
No Rituximab Maintenance N = 248
25 No Rituximab Maintenance
0
0 0
20
40
60
80
100
Time from treatment initiation (months)
Treon Br J Haematol 2011
120
0
20
40
60
80
100
Time from treatment initiation (months)
Disadvantages Infusion reactions Increased risk of infections Hypogammaglobulinemia
120
New Directions in WM
MYD88 L265P Somatic Mutation C to G at position 38186241 at 3p22.2
• 91% of WM pts • 10% IGM MGUS • No difference sporadic vs. familial pts Treon, New Engl J Med 2012
Acquired UPD at 3p22.
MYD88 L265P in WM/IGM MGUS METHOD
TISSUE
WM
IGM MGUS
Treon
WGS/Sanger
BM CD19+
91%
10%
Xu
AS-PCR
BM CD19+
93%
54%
Gachard
PCR
BM
70%
Varettoni
AS-PCR
BM
100%
Landgren
Sanger
BM
Jiminez
AS-PCR
BM
86%
Poulain
PCR
BM CD19+
80%
Argentou
PCR-RFLP
BM
92%
Willenbacher
Sanger
BM
86%
Mori
AS-PCR/BSiE1
BM
80%
Ondrejka
AS-PCR
BM
100%
Ansell
WES/AS-PCR
BM
97%
Patkar
AS-PCR
BM
85%
47% 54% 87% 1/1 MGUS
TLR
IL1R
L265P
BTK
MYD88
P
P
L265P
MYD88
PI3K
P
P
P
TAK1
MYD88 L265P Signal Pathway
P
TRAF6 P P
NEMO IKKα IKKβ
P P
IκBα
P
p50 P
p65
NFkB
Yang et al, Blood 2013 SURVIVAL
WHIM-like CXCR4 C-tail mutations in WM Warts, Hypogammaglobulinemia, Infection, and Myelokathexis.
B
Hunter Blood 2014
Most common: CXCR4C1013G (S338X )
Somatic WHIM-CXCR4 Mutations were detected in 21/63 patients (34%) on ibrutinib study.
MYD88 and CXCR4 mutations Genomic abnormalities
CXCR4
Treon Blood 2014
MYD88 Mutant
Wild-type
Mutant
30%
------------
Wild-type
60%
10%
Treon N Engl J Med 2015
Ibrutinib in previously treated WM Median
Range
63
44-86
Male/Female
48/15
N/A
Prior therapies
2
1-8
Hemoglobin (mg/dL)
10.5
8.2-13.8
Serum IgM (mg/dL)
3,610
735-8,390
B2M (mg/dL)
3.9
1.3-14.2
BM Involvement (%)
70
3-95
Adenopathy >1.5 cm
37 (58.7%)
N/A
Splenomegaly >15 cm
7 (11.1%)
N/A
Age (yrs)
Treon N Engl J Med 2015
Serial Serum IgM Levels Following Ibrutinib Best IgM Response: 3,610 to 915 mg/dL; p<0.0001 9000
Serum IgM (mg/dL)
8000
Median time to MR=4 weeks
7000 6000 5000 4000 3000 2000 1000 0 Baseline Cycle 2 Cycle 3 Cycle 6 Cycle 9 Cycle 12 Cycle 15 Cycle 18 Cycle 21
Serial Hemoglobin Levels Following Ibrutinib Best Hemoglobin Response: 10.5 to 13.5; p<0.0001 16
Hemoglobin (g/dL)
15 14 13 12 11 10 9 8
Response and survival outcomes
Treon NEJM 2015
FDA News Release FDA expands approved use of Imbruvica for rare form of non-Hodgkin lymphoma First drug approved to treat WaldenstrĂśmâ&#x20AC;&#x2122;s macroglobulinemia For Immediate Release January 29, 2015
Ibrutinib Related Adverse Events Early • Anemia • Neutropenia • Thrombocytopenia • Rash • Nausea • Diarrhea • Arthralgias
Delayed • Increased risk of bleeding • Atrial fibrillation • Hypertension
Novel pathways, novel targets, novel agents • Oral proteasome inhibitors – Ixazomib – Oprozomib – Marizomib
• Anti-CD38 antibodies – Daratumumab
• Anti-CXCR4 therapy – Ulocuplumab
• BTK inhibitors – Acalabrutinib – BGB-3111
• BCL2 antagonists – Venetoclax
• IRAK1/4 inhibitors • MYD88 assembly inhibitors
Summary § Waldenström macroglobulinemia is rare and incurable but patients enjoy prolonged survival. § Most treatment options are highly effective but with toxicity. § MYD88 L265P is present >90% of WM patients and triggers activation of BTK in WM cells. § The oral BTK inhibitor ibrutinib is safe, effective and approved to treat patients with symptomatic WM. § PI3K inhibitors, CXCR4 inhibitors, MYD88 blockers, BCL2 antagonists to enter clinical trials.
How I treat Waldenstrรถm Macroglobulinemia in 2016
Jorge J. Castillo, MD Assistant Professor of Medicine Harvard Medical School jorgej_castillo@dfci.harvard.edu