Transcript Rituximab

An Approach to the Treatment of
Waldenström's Macroglobulinaemia
Dr Shirley D’Sa
UCLH NHS Foundation
Trust & Mount Vernon
Cancer Centre
International WM workshops
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Washington 2000: 19 investigators, 4 countries
Athens 2002: 55 investigators, 9 countries
Paris 2004: 57 investigators, 13 countries
Kos 2007: 150 persons (part of the Myeloma Workshop)
Stockholm 2008
Venice 2010: 200 people, 17 sessions with 80 technical
presentations from over 90 speakers, including 14 young
investigators, 5 guest presentations, 5 debates, and 2
consensus panel discussions
http://www.wmsupportgroup.org.uk
Is it really WM/LPL?
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Which disease entities come under the label of WM/LPL?
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Other kinds of lymphoma also produce an IgM paraprotein
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LPL plus IgM
LPL plus IgA or IgG
Cut-off for amount of paraprotein or lymphoma cells in the BM
BM vs. lymph node involvement
B-CLL, Marginal Zone Lymphoma, Monocytoid B cell lymphoma
Expert review by a ‘Haematopathologist’ is essential
Owen RG, Treon SP, Al-Katib A, et al. Clinicopathological definition of Waldenstrom’s macroglobulinemia: consensus panel recommendations from
the Second International Workshop on Waldenström’s Macroglobulinemia. Semin Oncol. 2003;30(2):110-115.
Bone marrow biopsy
NORMAL
LYMPHOMA
Making the diagnosis
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IgM MGUS: PP <30g/l; BM lymphocytes< 10%; no
symptoms; no discernible lymphoma
Only 25% of IgM MGUS will develop a symptomatic
lymphoproliferative disorder within 15 years
Cumulative probability of progression is 1.5% per year
>> Follow up every 6-12 months
Kyle RA, Rajkumar SV, Therneau TM, Larson DR, Plevak MF, Melton LJ III. Prognostic factors and predictors of outcome of immunoglobulin M
monoclonal gammopathy of undetermined significance. Clin Lymphoma. 2005;5(4):257-260.
Increasing number of lymphoma cells
MGUS
Asymptomatic WM
Symptomatic WM
Asymptomatic WM
IgM > 30g/l
– Bone marrow lymphoma cells > 10%
– No symptoms
– No anaemia
– No viscosity problems
– No enlarged lymph nodes or spleen
The risk of progression to symptomatic WM is 6% per year
Only 55% of patients with smouldering WM will progress within 5 years
No evidence to date that the treatment of smouldering/asymptomatic WM
provides a survival benefit compared to starting treatment once symptoms
occur
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>> Follow up every 4-6 months
Kyle RA, Benson J, Larson D, et al. IgM monoclonal gammopathy of undetermined significance and smoldering Waldenström’s macroglobulinemia.Clin Lymphoma Myeloma.
2009;9(1):17-18.
Alexanian R, Weber D, Delasalle K, Cabanillas F, DimopoulosM. Asymptomatic Waldenström’s macroglobulinemia. Semin Oncol.2003;30(2):206-210.
Is treatment required?
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¼ of patients are diagnosed by chance
½ of patients who do not have symptoms or do not
need treatment at diagnosis will not require
treatment for 3 years
1 in 10 patients will not need treatment for 10 years
Garcia-Sanz R, Montoto S, Torrequebrada A, et al. Waldenström macroglobulinaemia: presenting features and outcome in a series
with 217 cases. Br J Haematol. 2001;115(3):575-582.
Ghobrial IM, Fonseca R, Gertz MA, et al. Prognostic model for disease-specific and overall mortality in newly diagnosed symptomatic
patients with Waldenström macroglobulinaemia. Br J Haematol. 2006;133(2):158-164.
When to start treatment?
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What are the triggers for starting treatment?
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Symptoms- fever, night sweats, weight loss, fatigue due to
anaemia
Increasing size of lymph nodes or spleen
Low blood counts (typically Hb < 10g/dl, platelets < 100)
due to the presence of the lymphoma in the marrow
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But should be tailored to the patient’s situation, rate of change
High blood viscosity
Worsening peripheral neuropathy symptoms
Rare complications such as amyloidosis, cryoglobulinaemia
Plasma Viscosity
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Plasma viscosity can be measured in some labs
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Hyperviscosity Syndrome:
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Normal plasma 1.4-1.8 x water
Normal blood ~3 x water
Affects 10-40% of WM patients with IgM > 50g/l
Headache, lethargy, confusion, irrational behaviour,
visual disturbance, seizures, strokes or angina
Bleeding manifestations include gum and nosebleeds
Plasma exchange:
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Indicated for symptomatic patients at any level
May be required prior to blood transfusion
Certain centres only
Treatment Considerations
PATIENT FACTORS:
 Is there a possibility of a stem cell transplant now or
in the future?
>> important to AVOID treatments that will damage
stem cells or affect the ability to harvest
 What other health-related factors need to be taken
into account?
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Frail or fit
Other medical problems such as high BP, diabetes,
heart disease, kidney disease
Any current problems such as neuropathy which
could be made worse by certain treatments?
Treatment Considerations
WM-RELATED FACTORS:
What is the IPSSWM?
5 ‘adverse features’:
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Age > 65, Hb < 11.5, Plats < 100, β2microglobulin > 3mg/l, IgM > 70 g/l
– 3 risk groups with 5 year survival rates of 87%, 68%, 36%
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Patients with more adverse features may need more
intensive treatment to overcome this disadvantage
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Higher chemotherapy doses
Combinations of different agents
Inevitably more toxic effects
What treatments are available?
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Chlorambucil
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Purine analogues: Fludarabine, Cladribine
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Tablet taken as outpatient, may cause low blood
counts, v few side effects, well tolerated, effective
Oral or intravenous, outpatient or day case,
suppresses the immune system profoundly for
many months (need preventive medication), low
blood counts, can affect stem cell collections
Adding other drugs generally improves the response
rate but may also increase the side effects
Rituximab- anti-CD20 monoclonal Ab
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Works in WM because it is a B cell lymphoma and has CD20 on its
surface
Produces major responses in 27-35% of previously treated and
untreated patients
Better blood counts and reduction of bulky disease
Standard dose 375 mg/m2 weekly for 4 weeks
Time to response following Rituximab alone > 3 months on
average
Patients with IgM of <60 g/l are more likely to respond
Improves the response to treatment when added to chemotherapy
Rituximab
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May be given alone or in combination with chemotherapy
Given intravenously as a day case
First infusion lasts 6 hours
Main side effects occur at the time of the infusion due to the body’s
reaction to the drug (a protein)
Subsequent infusions may be as short as 90 minutes as reactions are
much less likely to occur at this point
If the initial IgM level is >40g/l, Rituximab may cause a further temporary
rise in the level with a risk of viscosity problems
Long term side effects are few: lowered immunity, increased risk of
infections, possibility of low white cell count, v rarely inflammation and
stiffening of the lungs
Rituximab
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Both response rates and response duration may be improved by
an extended Rituximab schedule (two 4-weekly courses of 375
mg/m2 given 3 months apart)- but more studies needed before
this is a standard approach
Maintenance Rituximab (Rituximab given as a single agent
every 2-3 months for 2 years after completion of initial
treatment) has been shown to prolong remissions in some forms
of lymphoma but this has not been validated in WM
In many parts of the UK, specific permission to prescribe
Rituximab in WM patients has to be sought
What other treatments are available?
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CHOP/CVP: comparable response rates to other treatments (e.g.
Chlorambucil)
More rapid, but greater toxicity.
Does not compromise subsequent stem cell harvesting
R-CHOP is superior to CHOP alone in WM patients (94% vs. 69%)
Buske C, Dreyling MH, Eimermacher H, Boeck H-P, Pfreundschuh M, Metzner B, et al. Combined Immuno-Chemotherapy (R-CHOP) Results in
Significantly Superior Response Rates and Time to Treatment Failure in First Line Treatment of Patients with Lymphomplasmocytoid/ic
Immunocytoma (LP-IC) - Results of a Prospective Randomized Trial of the German Low Grade Lymphoma Study Group (GLSG). ASH Annual
Meeting Abstracts 2004;104(11):162
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DRC: Dexamethasone 20 mg iv on day 1, Rituximab 375 mg/m2
on day 1 and Cyclophosphamide 100 mg/m2 bd orally on days 15 given on a 21 day cycle for 6 courses
Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC, Zervas K, Tsatalas C, Kokkinis G, et al. Primary treatment of Waldenstrom macroglobulinemia with
dexamethasone, rituximab, and cyclophosphamide. J Clin Oncol 2007;25(22):3344-9.
What other treatments are available?
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Stem cell transplantation
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From self (autologous stem cell transplantation)
From donor (allogeneic stem cell transplantation)
Age > >
65 years,
not for stemnot
cell
Age
65 years,
transplant
for stem cell
transplant
Frailer patient, slowly progressive
disease, adequate marrow reserve
Frailer patient,
gradual disease,
adequate marrow
reserve
Chlorambucil
8 mg/m2 /day for
7-10days
every 4-6 weeks
+/Prednisolone
1 mg/kg/day for
7-10days every 4-6 weeks
Cytopenias, high M-protein (clinical
decision dictates the level of M-protein
that is regarded as high, taking account
of co-morbidities)
Cytopenias, low M-protein
(at Low
a level that
is low enough
to allow
blood
counts,
gradual reduction) Peripheral neuropathy
low M-protein
(low enough to allow
gradual reduction)
Peripheral
neuropathy
DRC x 6
Low blood counts,
high M-protein
R-CVP every 3-4 weeks up to 6 cycles
(Consider R from cycle 2 if M-protein>40g/l)
Or
Or
Fludarabine 40 mg/m2/day po
for 3-5 d every 28d
+/- R
Max 6 courses
Single-agent Rituximab (375mg/m2
weekly for 4 weeks) +/- repeat after
3 months
DRC x 6
R-CVP
Or
Chlorambucil
YES
Watchful waiting until relapse
Or
>PR or adequate symptom control
Fludarabine
Rituximab
NO
Depends on first line agent used, duration and quality of response,
tolerance of initial treatment, real-time age and performance
status:
>12 months response: retreat with initial drug
If <12months response: consider initial agent plus additional drug
or alternative class of drug.
If no prior Rituximab, consider it now.
Age < 65 y
At least 2 of the following poor
prognostic factors:
Hb < 11.5 g/dl, platelets <100 x 109/l,
2 microglobulin > 3, M-protein>70g/l
Yes
No
And/or need to reduce burden of
lymphoma quickly
R-CHOP or DRC
R-Cladribine
Stem cell harvest
Stem cell
transplant
W&W
What other treatments are available?
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Bortezomib
Bendamustine
Thalidomide
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New monoclonal antibodies
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Ofatumumab
GA101
Conclusions
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As a result of increased activity on the part of
physicians and lay people alike, the outcome for WM
patients is improving
Improved understanding of the origins and behaviour
of WM is leading to more effective therapy
Newer agents are being developed to tackle the
disease >> a brighter outlook for WM patients