traditional therapies in WM

Traditional Therapies for
Waldenstrom’s
Macroglobulinemia
Christine Chen
Princess Margaret Cancer Centre
Toronto, Canada
May 2014
Jeff Atlin (1953-2014)
Standard treatment options
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Single drug therapies
Chlorambucil (alkylating agents)
Fludarabine and cladribine (nucleoside analogues)
Rituximab (monoclonal antibodies)
Bendamustine
Bortezomib (proteasome inhibitors)
Combination therapies
Alkylator-rituximab
Fludarabine/cladribine-based
Bendamustine-based
Bortezomib-based
Transplantation
Chlorambucil
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Alkylating agent (cyclophosphamide, melphalan)
Oral drug used for decades
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Many different regimens:
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– Continuous daily dose
– Intermittent dosing 7-10days every month
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Major responses:
– First-line 60-70%, response duration 30 mos
– Slow onset (can take up to a year!)
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Side effects:
– Short term – nausea, hair loss, low blood counts
– Long term – secondary cancers, myelodysplasia (MDS)
Chlorambucil
PROS:
- Oral drug
- Convenient and cheap
- Well-tolerated
- Lots of experience
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CONS:
- Slow onset
- Requires prolonged therapy
- Risk of cancers or MDS
Still used commonly worldwide but usually
reserved for elderly or debilitated
Fludarabine and cladribine
fludarabine
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Nucleoside (NA) analogues
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Regimen:
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Major Responses:
– Intravenous (oral is available in
some countries)
– Fludarabine daily x 5 days every
month for 4-8 cycles
– 30-100% (CR <10%)
– Rapid onset (<2 mos)
– Response durations up to 5 years
Nucleoside analogue side-effects
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Short term:
– Low blood counts
– Immune suppression
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unusual pneumonias
(pneumocystis) and viral
infections
Long term:
– Risk of second cancers
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1.6% MDS/AML and 6.2%
transformed lymphoma
(Leleu et al J Clin Oncol 2009;27:250-55)
– Stem cell toxic
– Immune suppression  late
infections even years after
therapy
Fludarabine and cladribine
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PROS:
– Rapid onset
– High response rates
– Long response duration
(>2 yrs)
– Shorter treatment
periods
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CONS:
– Intravenous
– Side effects
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Infections
Secondary MDS
– Stem cell toxic
– CR still uncommon
Rituximab
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Monoclonal antibody to CD20
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3 different mechanisms for
killing cancer cells
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Used extensively to treat
various lymphomas and
immune disorders
Taylor et al. Nature Clin Practice Rheum (2007) 3, 86-95
Rituximab
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Regimens:
– Weekly infusions x 4 when used alone
– Also given in combination and as maintenance after chemo
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Major responses:
– 20-35% responses with short response duration
– Up to 58% with extended regimen (Dimopoulos; Treon)
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Side effects:
– Mostly related to infusion (shortness of breath, flushing, low BP)
 typically long infusions (2-6 hrs)
– Risk of hepatitis B flare  must check before starting
– IgM flare (54-90%)
Gertz et al Leuk Lymphoma 2004;45:2047-55
Dimopoulos et al J Clin Oncol 2002;20:2327-33
Treon et al Ann Oncol 2005;16:132-8
IgM flare with Rituximab
Treon, S. P. et al. Ann Oncol 2004 15:1481-1483
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50-60% with rituximab monotherapy
Higher risk if baseline IgM 6000mg/dL or M-spike >4000mg/dL
Typically occurs at 1 month, resolving by 4 months
Rituximab
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PROS:
– Generally well-tolerated
– Does not cause bone
marrow suppression
– Particularly useful for
hemolysis (failed
steroids) or neuropathy
– No known risk of MDS
or second cancers
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CONS:
– “Moderately effective”
when used alone
– Infusion toxicities
– Expensive ($5000 per
dose)
Bortezomib (Velcade)
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proteasome
PostGlutamyl
Site
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Regimen:
– Traditionally given IV twice
weekly  once weekly
subcutaneous dosing now used
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Major responses:
– 78-85% as a single agent
– Rapid onset (often within 6 wks)
– Does not damage stem cells
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Side effects:
– neuropathy (74%), low platelets,
risk of shingles (herpes zoster)
Tryptic
Site
Bortezomib
Chymotryptic
Site
proteasome cross-section
Proteasome inhibitor
Bortezomib
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PROS:
– Generally welltolerated
– Rapid responses
– No known risk of MDS
or second cancers
– Not stem cell toxic
– No IgM flare
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CONS:
– Injection
– Inconvenient dosing
– Toxicities:
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Neuropathy
Herpes zoster
– Expensive ($7500 per
cycle)
• Not routinely available for WM in many countries
Bendamustine
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Structurally similar to
alkylators and nucleoside
analogues
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Regimen:
– Typically given IV for 2
days at the beginning of
each 4 week cycle
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Major responses:
– 80% first-line
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Side effects:
– low blood counts, rash,
infusion reactions
– not known to cause late
cancers
Bendamustine
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PROS:
– Generally welltolerated – does not
cause hair loss
– Can be used in
patients with kidney
dysfunction
– No IgM flare
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CONS:
– Intravenous
– Inconvenient dosing
– Toxicities:
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Rash
Low blood counts
Long-term effects?
– Expensive ($4000 per
cycle)
Combination therapies
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Alkylating agents with rituximab
– CVP-R/CPR, CHOP-R, CDR, Benda-R
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Nucleoside analogue combinations
– FC, FR, FCR
– CR, CCR
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Bortezomib combinations
– BR, BDR
Alkylator-Rituximab
Combinations
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CVP-R:
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Cyclophosphamide (IV)
Vincristine (IV)
Prednisone (oral)
Rituximab (IV)
every 3-4 weeks for 6-8 cycles
Side effects:
– Vincristine – neuropathy
– Prednisone – insomnia, diabetes, stomach upset
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Efficacy in indolent lymphoma:
– Overall responses 80%
– Time to progression 30 mos
Doubled over CVP
Marcus et al Blood 2005;105:1417
Should we step up CVP-R to
CHOP-R?
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CHOP-R  addition of doxorubicin (H) can cause
hair loss, low counts, nausea, skin irritation
CP-R  vincristine can cause/worsen neuropathy
Response
CHOP-R (23 pts) CVP-R (16 pts) CP-R (19 pts)
Overall responses
22 (96%)
14 (68%)
18 (95%)
Complete responses
4 (17%)
2 (12%)
0
Time to progression
18 mos
>35 mos
>20 mos
Ioakimidis et al. Clin Lymph Myeloma 2009;9:62
CDR
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Regimen:
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Cyclophosphamide orally twice daily (days 1-5)
Dexamethasone IV
Day 1 only
Rituximab IV
Given every 3 weeks for 6 months
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Major responses: 83% but takes 4 mos to response
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Side effects:
– Well-tolerated
– Minimal drops in blood counts
– 1/3 developed IgM flare
Dimopoulos J Clin Oncol 2007;25:3344
Nucleoside Analogue Combinations
Ref Regimen
Major
Resp
%
CR
%
Median
Response
Duration
1
FR (Fludarabine + Rituximab)
86
4.6
TTP 51.2 mos
2
CR (Cladribine + Rituximab)
89
28
TTTF 60.3 mos
3
CCR (Cladribine,
cyclophosphamide + rituximab)
94
17
Duration of
response 58.6 mos
4
FCR
79
11.6
EFS >77 mos
5
FCM (FC + mitoxantrone)
91
72
TTF >50 mos
Durable responses!
But toxicities are significant – low counts (prolonged), infections
1.
2.
3.
4.
5.
Treon et al. Blood 2009;113:3673
Laszlo et al. JCO 2010;28:2233
Thomas et al. Haematologica 2007;92:PO-1227
Tedeschi et al. Cancer 2012;118:434
Federico et al. JCO 2013;31:1506
Bendamustine + rituximab
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Responses >90%
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Less toxic than CHOP-R
– Fewer low blood counts,
infections, neuropathy,
and hair loss
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Many now prefer BendaR as first line therapy
Progression-free survival in WM subgroup
Rummel et al. Lancet 2013;381:1203
Rituximab maintenance significantly
reduces the risk of progression by 50%
Progression-free rate
1.0
82%
Rituximab maintenance
N=505
0.8
0.6
Observation
N=513
66%
0.4
stratified HR=0.50
95% CI 0.39; 0.64
p<.0001
0.2
0
0
6
12
18
24
30
36
103
82
18
15
Time (months)
Patients at risk
505
472
443
513
469
411
336
289
230
195
Salles et al PRIMA study ASCO 2010
Maintenance Rituximab Schedules
2
End of
chemo
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4
6
8
10
12
2 years
3
6
9
12
3
6
9
12 months
Best dosing schedule and duration of maintenance unclear
Salles ASCO 2010 abstract
Van Oers Blood 2006;108:3295
Hainsworth JCO 2005;23:1088
Ghielmini Blood 2004;103:4416
Fortspointner Blood 2006;108:4003
Bortezomib combinations
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BR
(Ghobrial JCO 2010;28:1422; Ghobrial Am J Hematol June 2010 Epub)
– Weekly bortezomib
– Responses: first-line 65%, relapse 51%
– Only 5% severe neuropathy
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BDR (Treon JCO 2009;27:3830)
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Bortezomib twice weekly
Responses: firstline 83%
Time to response (1.1 mos)
Severe neuropathy 30%
Advantages to bortezomib combinations:
– Rapid onset of action
– No IgM flare
– Non-myelosuppressive, non-stem cell toxic
Autologous stem cell transplant
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Used at some institutions for
young patients in relapse
Must avoid stem-cell
damaging chemo prior
(fludarabine)
EBMT review of 158 WM pts:
– Half relapse at 5 years
– Best results if still sensitive to
chemotherapy and ≤3 prior
lines of therapy
(Kyriakou J Clin Oncol 2010;28:2227)
Salvage chemo
The “patient’s stem cells”
are collected with growth
factors ± chemotherapy
High-dose chemotherapy ±
radiation to kill cancer cells
in the bone marrow
Stem cell infusion to regrow
the normal bone marrow
Plasmapheresis (PLEX)
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Mechanical removal of proteins from blood
One pheresis removes up to 50% IgM and reduces
viscosity by 60%
Temporizing measure
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Indications
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– Hyperviscosity
– Peripheral neuropathy
– Bleeding related to the IgM protein
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Longterm PLEX may be useful (Buskard et al. CMAJ 1977)
How to choose?
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Patient considerations:
– Age
– Comorbidities (diabetes, pre-existing neuropathy, heart
disease, etc)
– Fitness or functional level
– Patient location, access to hospital/clinic
– Patient preference
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Disease considerations:
– Low blood counts
– Need for rapid disease control (hyperviscosity, severe
cytopenias, cryoglobulinememia)
– WM complications (neuropathy, hemolysis, etc)
General First-line Approach
Older, debilitated
Younger and fit
Chlorambucil
(Rituximab alone)
Alkylator-rituximab combinations
(Benda-R, CP-R, CDR) followed
by maintenance rituximab
Special considerations:
- Low blood counts  Rituximab alone
- Need rapid response (i.e. hyperviscosity)
 fludarabine (FR) or bortezomib (BDR) combos
 avoid rituximab alone
General relapse approach
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Additional considerations:
– Choice of first-line therapy (duration of response,
tolerance)
– Whether stem cell transplant candidate
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Guidelines:
– Consider repeat of same chemo if response >2 years
– If <2 years, alternate regimen
– Consider stem cell collection in advance of
fludarabine
– Clinical trials
Summary – Traditional
Therapies for WM
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Many options available  must take an
individualized approach
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Supportive care important
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How do new agents like ibrutinib change
the use of traditional therapies in WM?
Myeloma and WM Group at
Princess Margaret Cancer Centre
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Donna Reece (head)
Christine Chen
Suzanne Trudel
Rodger Tiedemann
Vishal Kukreti
Anca Prica