Waldenstrom’s: The Future
Barts Cancer Institute
Rebecca Auer
r.l.auer@qmul.ac.uk
www.cancer.qmul.ac.uk
WM treatment
•
•
•
•
•
WM1 recently closed
No other UK trials
No standard treatment
Difficult to achieve CR
New agents
Development pathway
Novel strategies
• Combinations including rituximab and/or
bortezomib
• Novel anti-CD20 Abs / proteasome inhibitors
• Bendamustine
• Novel signal inhibitors
Everolimus
Perifosine
• Epigenetic modifiers
Panobinostat
• Immunomodulators
IMiDs
• Stem cell transplantation
The BCR study
Waldenstrom’s macroglobulinemia is somewhat similar to two other types of cancer,
multiple myeloma (plasma cell cancer) and
non-Hodgkin's lymphoma (a group of cancers of lymphocytes).
Bortezomib
Rituximab
plasma cells
B cells
Bortezomib in WM
• Predominantly in phase II trials in the
relapsed or refractory setting
• Alone or in combination
• Rapid responses
• As a salvage treatment option - Fourth
International Workshop on WM treatment
recommendations
Rituximab
• Minimal myelosuppression
• Single agent RR 40-50%
• Combination
– chemotherapy
– IMiDs
Bortezomib & Rituximab in WM
• Barts study in relapsed lymphoma
– 9 of 10 patients with WM responded
• 2 studies in USA in untreated WM
– BDR twice a week
– BR once a week
83% responded
65% responded
Complete response/near-complete response =
22%
A phase II trial of bortezomib, rituximab and cyclophosphamide in
patients with symptomatic, untreated Waldenstrom macroglobulinemia
• To determine the efficacy and safety of bortezomib, rituximab and
cyclophosphamide
• Symptomatic untreated WM
• IV Bortezomib 1.6 mg/m2 on days 1, 8, 15
• Oral Cyclophosphamide 250 mg/m2 on days 1, 8, 15
• IV Rituximab 375 mg/m2 d1, 8, 15, 22 of cycles 2 and 4
– this will be repeated every 28 days for 6 cycles in responding patients.
• 1° endpoint: Response rate
• 2° endpoint: Toxicity, complete response rate, duration of response,
speed of response, time to next treatment, progression free survival
Study design
•
•
•
•
Run in phase 6 patients
Multicentre phase 33 patients
Recruit over 2 years
6 centres
– Barts, Leeds, Mid-Yorkshire, Heartlands,
King’s, UCH, Plymouth
• Plan to follow on with a phase III
– BCR versus FCR
Randomised phase II
FCR
BCR v
or
DCR
Possibility of s/c bortezomib
Side effects
• Bortezomib
neurological
• Rituximab
allergic / infections
• Cyclophosphamide
low blood counts
Assessments
• Blood tests every cycle
• Bone marrow and CT scans at start, midway, at completion
• Blood and BM assays to look for better markers of
response
• Research samples to look at some of the genetic & protein
changes in WM
Timelines
•
•
•
•
•
Application to CRUK
Decision by CRUK
Expectation open
Duration recruitment
Duration follow up
Aug 2010
Nov 2010
May 2011
2 years
5 years
April 2011
July 2011
Jan 2012
2 years
5 years
New proteasome inhibitors
• s/c Bortezomib
– less neurotoxicity but as active
• Carfilzomib
– phase I data
– no grade 3/4 neuropathy
– activity
• Marizomib
– phase I studies recruiting
Main mechanisms of action of rituximab and ways to increase its clinical efficacy
Cartron, G. et al. Blood 2004;104:2635-2642
Copyright ©2004 American Society of Hematology. Copyright restrictions may apply.
Novel anti-CD20 Abs
• GA101
• Ofatumumab
And other Abs to other proteins eg. Belimumab
Bendamustine
StiL Group - Rummel
• BR versus R-CHOP first line
n=549
– WM n=42
– ORR similar BUT CR, PFS, TTNT all
significantly better with BR
– Progressive disease in 2/23 BR versus 7/17
R-CHOP
– Less grade 3/4 neutropenia with BR
StiL Group - Rummel
• BR versus FR
relapse
– BR higher ORR 83.5% v 52.5%
CR 38.5% v 16.2%
– grade 3/4 neutropenia similar
n=219
PI3K/Akt/mTOR cell signalling pathway
Overactive in WM cells
Perifosine
Everolimus
Everolimus
• Oral
• ORR – 70%
– PR 42%
MR 28%
• Median PFS and duration response not reached
• Toxicities
– Grade 3 or higher in 56%
– Lung toxicity in 10%
Perifosine
• Oral
• ORR - 35%
• Median PFS 12.6 months
• Toxicities
– cytopenias
– GI
– Arthritis flare
IMiDs
IMiDs
• Thalidomide + rituximab
– dose reductions required in all patients
– neuropathy
• Lenalidomide + rituximab
– study discontinued due to unexpected
clinically significant anaemia
• Pomolidomide
HDACI
Eg. Panobinostat
Open studies
Ofatumumab
anti-CD20 monoclonal Ab
Panobinostat
epigenetic - HDACI
Everolimus + BR mTOR inhibitor
Belimumab
monoclonal Ab
Pomolidomide ImiD
Waldenstrom’s: The Future
Chemotherapy
Monoclonal Ab
Biologic agent