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

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