Waldenstroms Macroglobulinaemia
Key recommendations § Monoclonal IgM paraprotein and evidence of a lymphoplamacytoid lymphoma § IgM+, IgD+, CD19+, CD20+ but usually CD5-, CD10-, CD23- and CD138- § Therapy should be reserved for patients who are symptomatic or in whom there is haematological suppression or clear evidence of disease progression § Aim of treatment should be to improve quality and duration of life with minimal side-effects § Not clear that achievement of CR confers clinical benefit and it is possible that prolonging therapy to maximal response may increase toxicity without extra benefit § Main treatments are alkylating agents, purine analogues and rituximab § Plasma exchange is indicated for the acute management of severe problems from circulating paraprotein § Patients who are resistant to alkylating agents may be candidates for combination therapy with purine analogues and antibody therapy. § Fludaribine has a higher response rate than CAP (cyclophosphamide, doxorubicin and prednisolone).
Epidemiology § 2% of all haematological malignancy § Incidence 6.1 per million in males and 2.5 per million in females in US Caucasians (seems to be lower in other non-Caucasians). § Median age at presentation 71 § Median overall survival 60 months
Aetiology § Unknown possible role of viral agents (HepC / HHV8) and genetic factors (12 families with 31 cases identified). § Cells likely to be derived from post germinal centre memory B cells (have somatic hypermutation without intraclonal diversity).
Clinical features 1. Incidental finding 2. Tissue infiltration (anaemia, organomegaly) 3. Paraprotein related symptoms (hyperviscosity syndrome, cryoglobulinaemia, autoimmune phenomena eg. peripheral neuropathy, cold agglutinin disease 4. Primary amyloidosis (rarely)
Diagnositic criteria 1. IgM paraprotein of any concentration 2. Bone marrow infiltration with small lymphocytes showing plasmacytoid / plasma cell differentiation 3. Intertrabecular pattern of bone marrow infiltration 4. Immunophenotype IgM+, IgD+, CD19+, CD20+, CD22+, CD25+, CD27+, CD79+, FMC7+, BCL2+, PAX5+ but usually CD5-, CD10-, CD23-, CD75-, CD103-, CD138- and BCL6- Variations in immunophenotype can occur and need to be careful to exclude other lymphoproliferative conditions especially when CD5+
Investigations § Paraprotein (NB has no prognostic significance and does not reflect bulk of disease) § Plasma viscosity § Urine free light chain analysis § Bone marrow (need trephine) § Not essential in asymptomatic patients but may be useful to differentiate occult Waldenstroms from IgM MGUS. § Some patients have disease detectable by flow cytometry but not morphologically – invariably asymptomatic and best classified as MGUS. § Cytogenetics not routinely helpful (50% have deletions of 6q but prognostic significance unclear. Occasionally FISH for t(14:18) and t(11:14) useful in diagnostically difficult cases. § DAT and if positive cold agglutinin titre § Cryoglobulins § B2 microglobulin § CT at baseline prior to chemotherapy § Nerve conduction studies § MAG serology (anti-myelin-associated glycoprotein serology) useful prior to treatment if trigger is peripheral neuropathy
Prognostic factors § Highly variable - significant minority never require systemic therapy § Main prognostic factors: 1. Age 2. Hb 3. Albumin 4. B2M Eg Age<60, Hb>10, Albumin >35 - survival 178 months Age>60, Hb<10, Albumin <35 - survival 33 months
Treatment Indications for treatment: § Effects of paraprotein (hyperviscosity, peripheral neuropathy, amuloidosis, symptomatic cryoglobulinaemia) § Haematological suppression (Hb <10, Plt <100)
1. Plasma Exchange Hyperviscosity syndrome § Spontaneous bleeding § Neurological symptoms § Retinopathy § Cardiac failure (due to expanded plasma volume) § No simple linear relationship between plasma viscosity and IgM concentration (viscosity tends to increase more with an increase from 40 to 50 than 20 to 30) § Plasma exchange 1-2 procedures exchanging 1-1.5 calculated plasma volumes (NB plasma volume may be greater than that calculated).
Neuropathy § Usually sensory with the EMG showing demyelination § Evidence weak for plasma exchange as treatment in peripheral neuropathy
Cryoglobulins § Immunoglobulins that precipitate at temperatures <37 and redissolve on warming § Type I consist of monoclonal immunoglobulin § Type II cryoglobulins consist of a complex of polyclonal IgG and monoclonal IgM with rheumatoid factor activity (typically associated with Hep C infection). § General consensus that plasma exchange is useful in acute severe disease
2. Alkylating agents § Cyclophosphamide +/- prednisolone § 60% response rate – slow and toxicity minimal § Median survival 60 months § Optimal duration of treatment is unknown § No evidence on high dose cyclophosphamide in Waldenstrom
3. Combination chemotherapy § Several phase II studies using combination chemotherapy but no evidence it is superior to alkylating agents (there are no head to head trials)
4. Purine analogues (fludaribine and cladribine) § Fludaribine response rates range from 38-100% § Cladribine 55-100% (smaller studies) § Some evidence that fludaribine can be effective in cladribine resistant patients but not vice-versa § Toxicity primarily neutropenia (grade 3 in 60%) § Both F and C are effective in patients who are primarily resistant or relapse with alkylating agents (response rates 14-78%) § Fludaribine is more effective than CAP in patients with primary refractory disease or relapse (n=92 30 v 11% response rate / 30 v 3 month duration of response – Leblond et al., 2001)
5. Anti CD20 antibodies § 20-50% response rate to rituximab § Risk of flare of IgM levels causing hyperviscosity and then plasmapheresis (with loss of monoclonal Ab) (caution if IgM>40g/L or symptoms of hyperviscosity). § Also case reports of response to campath
6. Thalidomide § 25% response rate in some studies
7. Transplantation § Small studies of autografts as well as a few allografts but most patients too old
On going trials § Fludaribine v chlorambucil – hoping to recruit 400 patients § Velcade
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