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An Approach to the Treatment of Waldenström's Macroglobulinaemia

An Approach to the Treatment of Waldenström's Macroglobulinaemia. Dr Shirley D’Sa UCLH NHS Foundation Trust & Mount Vernon Cancer Centre. International WM workshops. Washington 2000: 19 investigators, 4 countries Athens 2002: 55 investigators, 9 countries

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An Approach to the Treatment of Waldenström's Macroglobulinaemia

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  1. An Approach to the Treatment of Waldenström's Macroglobulinaemia Dr Shirley D’Sa UCLH NHS Foundation Trust & Mount Vernon Cancer Centre

  2. 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

  3. 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.

  4. Bone marrow biopsy NORMAL LYMPHOMA

  5. 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. Increasing number of lymphoma cells MGUS Asymptomatic WM Symptomatic WM

  6. 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.

  7. 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.

  8. 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

  9. 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

  10. 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?

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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.

  17. What other treatments are available? • Stem cell transplantation • From self (autologous stem cell transplantation) • From donor (allogeneic stem cell transplantation)

  18. Age > 65 years, not for stem cell transplant 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 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 +/- R Max 6 courses Chlorambucil 8 mg/m2 /day for 7-10days every 4-6 weeks +/- Prednisolone 1 mg/kg/day for 7-10days every 4-6 weeks 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. Low blood counts, low M-protein (low enough to allow gradual reduction) Peripheral neuropathy Frailer patient, gradual disease, adequate marrow reserve Low blood counts, high M-protein DRC x 6 Or Rituximab R-CVP Or Fludarabine Chlorambucil

  19. 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 No Yes R-CHOP or DRC R-Cladribine Stem cell harvest W&W Stem cell transplant

  20. What other treatments are available? • Bortezomib • Bendamustine • Thalidomide • New monoclonal antibodies • Ofatumumab • GA101

  21. 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

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