an approach to the treatment of waldenström's macroglobulinaemia dr shirley d’sa uclh nhs...
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An Approach to the Treatment of Waldenström's Macroglobulinaemia
Dr Shirley D’SaUCLH NHS Foundation Trust & Mount Vernon Cancer Centre
International WM workshops
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?
Which disease entities come under the label of WM/LPL?– 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
Other kinds of lymphoma also produce an IgM paraprotein– 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
– 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.
MGUS Asymptomatic WM Symptomatic WM
Increasing number of lymphoma cells
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
>> 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?
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?
What are the triggers for starting treatment?– 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 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
Plasma viscosity can be measured in some labs– Normal plasma 1.4-1.8 x water– Normal blood ~3 x water
Hyperviscosity Syndrome: – 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: – 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?– 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’: 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%
Patients with more adverse features may need more intensive treatment to overcome this disadvantage
– Higher chemotherapy doses– Combinations of different agents– Inevitably more toxic effects
What treatments are available?
Chlorambucil– Tablet taken as outpatient, may cause low blood
counts, v few side effects, well tolerated, effective Purine analogues: Fludarabine, Cladribine
– 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
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
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
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?
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
DRC: Dexamethasone 20 mg iv on day 1, Rituximab 375 mg/m2 on day 1 and Cyclophosphamide 100 mg/m2 bd orally on days 1-5 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?
Stem cell transplantation– From self (autologous stem cell transplantation)– From donor (allogeneic stem cell transplantation)
Age > 65 years, not for stem cell transplant
Frailer patient, slowly progressive disease, adequate marrow reserve
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 a level that is low enough to allow
gradual reduction) Peripheral neuropathy
Chlorambucil 8 mg/m2 /day for
7-10days every 4-6 weeks
+/-Prednisolone
1 mg/kg/day for 7-10days every 4-6 weeks
R-CVP every 3-4 weeks up to 6 cycles(Consider R from cycle 2 if M-protein>40g/l)
Or
Fludarabine 40 mg/m2/day po for 3-5 d every 28d
+/- RMax 6 courses
DRC x 6
Or
Single-agent Rituximab (375mg/m2 weekly for 4 weeks) +/-
repeat after 3 months
>PR or adequate symptom control
YES NO
Watchful waiting until relapse 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 years, not for stem cell transplant
Frailer patient, gradual disease,
adequate marrow reserve
Low blood counts, high M-protein
Low blood counts, low M-protein
(low enough to allow gradual reduction)
Peripheral neuropathy
Chlorambucil
R-CVPOr
Fludarabine
DRC x 6
Or
Rituximab
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
And/or need to reduce burden of lymphoma quickly
R-CHOP or DRC
Stem cell harvest
Stem cell transplant
R-Cladribine
W&W
Yes No
What other treatments are available?
Bortezomib Bendamustine Thalidomide
New monoclonal antibodies– Ofatumumab– GA101
Conclusions
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