Washington 000: 19 investigators, countries Washington 2000: 19 investigators, countries



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Washington 2000: 19 investigators, 4 countries

  • 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



Which disease entities come under the label of 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.





    • 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.



IgM > 30g/l

    • 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.



¼ of patients are diagnosed by chance

  • 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.



What are the triggers for starting 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 can be measured in some labs

  • 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


PATIENT FACTORS:

  • 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?



WM-RELATED FACTORS:

  • 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


Chlorambucil

  • 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



Works in WM because it is a B cell lymphoma and has CD20 on its surface

  • 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



May be given alone or in combination with chemotherapy

  • 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



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

  • 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



CHOP/CVP: comparable response rates to other treatments (e.g. Chlorambucil)

  • 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.



Stem cell transplantation

  • Stem cell transplantation

    • From self (autologous stem cell transplantation)
    • From donor (allogeneic stem cell transplantation)










Bortezomib

  • Bortezomib

  • Bendamustine

  • Thalidomide

  • New monoclonal antibodies

    • Ofatumumab
    • GA101


As a result of increased activity on the part of physicians and lay people alike, the outcome for WM patients is improving

  • 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




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