Set - Out - English

oimbra

496

ssoc

ras

2014; 60(5):490-499

WM due to the lower concentration of monoclonal IgM

(< 3 g/dL) and absence of bone marrow infiltration (<10%).

The risk of progression from asymptomatic to sympto-

matic WM is 6%/year, and only 55% of these patients will

show progression within 5 years

rognosis

symptomatic

The International Prognostic Staging System for Wal-

denström Macroglobulinemia adopts five variables that

correlate with poor survival of patients under treatment:

age> 65 years,

2-microglobulin concentration >3 mg/L,

platelets count ≤100x10

/L, monoclonal IgM concentra-

tion > 7000 mg/dL, and hemoglobin concentration ≤11.5g/

dL.

The absence or presence of one or more prognostic

factors categorizes the patient into 3 risk levels: low (0 -1

risk factor, excluding age), intermediate (2 risk factors

and age

65 years) or high (more than 3 risk factors).

Based on the degree of risk, it is possible to estimate

the average/overall survival. In patients at low risk, the

average survival time is 12 years, and treatment should

involve low toxicity, preserving quality of life. The use of

this system in symptomatic patients that are candidates

for treatment enables tailoring treatment to the patient,

taking into account the estimated average survival.

In a recent study, high concentrations of

lactate dehydro-

genase

(> 250 IU/L) were also seen as a poor prognosis fac-

tor, especially in high risk patients.

reatment

Clinical decision to prescribe therapy takes into account

different factors such as patient age, clinical manifesta-

tions, prognostic factors, quality of life and patient sur-

vival potential, the risk/benefit and cost/benefit of treat-

ment, effectiveness and side effects.

The treatment of asymptomatic patients does not im-

prove their quality of life and survival;

biannual clinical

observation is the recommended option in these cases if

hematologic function is preserved.

There is a study that

suggests bimonthly/quarterly follow-ups during the first

year after diagnosis and, if remaining stable, monitoring

should be quarterly/half-yearly in the following years.

Patients with WM are candidates for treatment if they

have clinical evidence of aggressive disease progression

or if they have had clinical and laboratory manifestations

associated with WM, such as lymphadenopathy or sple-

nomegaly, symptoms of hyperviscosity, severe peripheral

neuropathy, AL amyloidosis (resulting in tissue deposi-

tion of light immunoglobulin chains), cryoglobulinemia,

autoimmune hemolytic anemia, hemoglobin concentra-

tion <10 g/dL and/or platelet count <100x10

/L.

In fact, the choice of treatment is a critical option and

should not be taken so as to limit future options, since

all patients will inevitably present relapses after initial

treatment, requiring treatment.

Age, the presence of cy-

topenia, the need to control the disease and the possibi-

lity of autologous stem cell transplantation should be

considered in the approach to treatment.

First-line therapy includes alkylating agents, purine

analogs and monoclonal anti-CD20 antibodies.

Treat-

ment with alkylating agents may cause cytopenias and

myelosuppression, and should be avoided in patients that

are candidates for autologous transplantation.

63,64

Puri-

ne analogs may be responsible for the development of

myelodysplasia and acute myeloid leukemia.

63.65

The Mayo Clinic has developed a therapeutic approach

adapted to the clinical characteristics of the patient.

Most

symptomatic patients are treated with Rituximab as mo-

notherapy or combined with chemotherapy. Monothe-

rapy is recommended in symptomatic patients with mo-

derate hematological impairment, in patients with

neuropathy associated with the IgM autoantibody, and

in cases of hemolytic anemia resistant to corticosteroids.

Rituximab is an IgG1 anti-CD20 monoclonal anti-

body. The connection to the CD20 receptor on B-lym-

phocytes activates the complement cascade, leading to

the formation of the membrane attack complex that in-

duces cell lysis.

This antibody also activates natural kil-

ler cells by binding to receptors for the Fc fragment of

IgG (Fc

R), leading to cell lysis. The fragments of com-

plement component C3, together with rituximab, are re-

cognized by the membrane of macrophages, binding to

receptors for complement component C3 and Fc

R re-

ceptors, respectively, and activating phagocytosis.

66,67

The

genetic polymorphism of Fc

R receptors may condition

the treatment response,

and a correlation has been ob-

served between polymorphisms at position 158 of the

RIIIa (CD16) receptor and the response to rituximab.

At the start of rituximab treatment, some patients

have a paradoxical and often transient increase in serum

concentrations of IgM (IgM flare), which can persist for

up to 4 months and is not indicative of treatment failu-

re.

69,70

The underlying mechanism remains unclear, but

two hypotheses have been proposed - release of intracel-

lular IgM resulting from rituximab-mediated cell death

and cell signaling mediated by binding to CD20.

In patients requiring urgent control of the disease, plas-

mapheresis is indicated if they have clinical manifestations

of moderate to severe hyperviscosity, cryoglobulinemia and

cytopenias caused by the action of the monoclonal IgM

autoantibody.

62,3

Usually 2 to 3 plasmapheresis sessions