Page 2030 - Williams Hematology ( PDFDrive )

2004 Part XII: Hemostasis and Thrombosis Chapter 117: Thrombocytopenia 2005

complement neutralization, and dendritic cell priming. 178,200,201 The rec- The optimal dosing regimen and duration of therapy have not been
ommended total dose of IVIG is 2 g/kg administered either as 0.4 g/kg determined for patients with ITP. Usual rituximab doses are in the range
2
per day on 5 consecutive days or as 1 g/kg per day on 2 consecutive of 100 to 375 mg/m . Most studies have used weekly infusion for 4 con-
2
days. If the need to increase the platelet count is urgent, the preferred secutive weeks at, the dose used to treat B-cell lymphoma (375 mg/m ).
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dosing is 1 g/kg per day for 2 days combined with glucocorticoids. Studies with low-dose rituximab (100 mg weekly for 4 weeks) showed
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For maintenance therapy, 0.5 to 1.0 g/kg as a single dose may be used, similar activity to the standard dose. Published studies with rituximab,
administered every 3 to 4 weeks, or as needed. Although the annual however, have generally not been controlled and are extremely hetero-
total world consumption of IVIG exceeds 100 tons, the cost of IVIG geneous in terms of rituximab dosing and response criteria. Approx-
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is still high, and this also limits the use of IVIG in adults. Adverse imately 40 to 60 percent of the ITP patients demonstrate a response
effects of IVIG therapy include headache, backache, nausea, fever, asep- to rituximab at 1 year, and 20 to 25 percent of those have a long-term
tic meningitis, alloimmune hemolysis, hepatitis, renal failure, pulmo- response (at 5 years). 215,219 Splenectomy does not affect response rates to
nary insufficiency, and thrombosis. Anaphylactic reactions may occur rituximab therapy. 135,216 In ITP patients who have relapsed more than
in patients with congenital IgA deficiency. The patient may become 1 year after rituximab therapy, retreatment with the drug will induce
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203
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refractory to the effect with repeated infusions of IVIG. IVIG is used similar responses in 75 percent of patients who responded initially.
as a first-line therapy in childhood ITP, because the thrombocytope- In spite of the apparent benefit of rituximab, its use is still considered
nia is usually transient. In adult ITP, however, IVIG is usually reserved “off-label” for ITP.
for patients with life-threatening bleeding, when a prompt increase in Different patterns of response have been reported in ITP patients
platelet count is needed, 147,148 or as first-line therapy when glucocorti- treated with rituximab. Although the majority of patients responded
coids are contraindicated. 148 within 4 to 6 weeks (early responders), response was delayed for sev-
eral months in some patients (late responders). In ITP patients who
Anti-(Rh)D Anti-(Rh)D is a polyclonal γ-globulin containing high responded to rituximab, the increase in platelet count was associated with
titers of antibodies against the Rh (D) antigen of erythrocytes. It is reduction in the quantity of platelet-associated autoantibodies. Rituxi-
o
administered intravenously for treatment of ITP. Anti-(Rh)D binds mab also indirectly affects T cells, as depletion of autoreactive B cells pre-
Rh-positive erythrocytes and leads to their destruction in the spleen. vents T-cell activation. Interestingly, despite the depletion of peripheral B
Because splenic Fc receptors are blocked, more antibody-coated cells, platelet-associated autoantibodies were still found in the plasma of
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platelets survive in the circulation. 204,205 Anti-(Rh)D also can also ITP patients who do not respond to rituximab. A study analyzing the
modulate Fcγ receptor expression and regulate the production of var- spleens of ITP patients who did not respond to rituximab therapy demon-
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ious cytokines, including IL-6, IL-10, and tumor necrosis factor-α. strated the presence in the spleen of long-lived plasma cells that produced
A positive direct antiglobulin test, a decrease in serum haptoglobin antiplatelet antibodies for as long as 6 months after rituximab therapy
levels, and mild and transient hemolysis occur in all Rh-positive ended. However, this class of cells was not found in the spleens of patients
patients after anti-(Rh)D infusion, generally without requiring a who had not received rituximab. The authors of this study suggested that
blood transfusion. The rate of serious hemolytic reactions has been depletion of peripheral B cells by rituximab promotes the differentiation
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estimated as one in 1115 patients; any reaction occurs within 4 hours of long-lived plasma cells in the spleen of ITP patients, which might be
of administration in almost all cases. Anti-(Rh)D therapy is not responsible for the persistence of antiplatelet antibodies. 222
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effective in patients who have undergone splenectomy or in Rh-neg- In a meta-analysis of 306 ITP patients treated with rituximab,
ative patients, and is not recommended in patients with a positive adverse reactions were reported as mild-to-moderate in 66 patients (21.6
direct antiglobulin test. 148 percent) and life-threatening in 10 patients (3.7 percent); nine patients
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It is recommended that anti-(Rh)D be given as a single dose of (2.9 percent) died. Although some of these deaths were attributed to
50 to 100 mcg/kg by intravenous infusion over 3 to 5 minutes. 204,208,209 ITP-related complications and not to rituximab itself, this mortality
Adverse effects of anti-(Rh)D therapy resemble those observed with rate is higher than expected. Infusion-related reactions in rituximab
both γ-globulin infusion and autoimmune hemolytic anemia; symp- therapy can be severe, and rarely fatal. Premedication with methylpred-
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toms include headache, asthenia, chills, fever, abdominal pain, diarrhea, nisolone is recommend to avoid these reactions. The risk of infection
vomiting, dizziness, and myalgia. Patients can experience immediate can increase as a result of depletion of B cells, decreased antibody pro-
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anaphylactic reactions and both type I (IgE-mediated) and type III duction, and, rarely, neutropenia. Treatment can also reactivate latent
(immune complex–mediated) hypersensitivity reactions. 204,205,208,210,211 viruses, especially hepatitis B. Alteration of T- and B-cell populations,
Although anti-(Rh)D reportedly increases platelet counts within 1 and decreased antibody titers against HBV may stimulate HBV repli-
week in more than 70 percent of patients who are Rh-positive and have cation, and rarely cause fatal fulminant hepatitis. All patients should
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their spleen, and may obviate the need for splenectomy, a random- be screened for HBV before rituximab therapy. Although preventive
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ized, controlled trial comparing anti-(Rh)D with conventional therapy lamivudine or entecavir can be used in HBV-positive ITP patients, it
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showed no differences in the rates of spontaneous remission or the need is instead recommended that alternative therapies be used. Other
for splenectomy. Anti-(Rh)D is listed in current ASH ITP guidelines viral reactivation syndromes are less common; progressive multifocal
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as a first-line agent when glucocorticoids are contraindicated. Anti- leukoencephalopathy (caused by reactivation of polyomavirus JC) is
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(Rh)D is currently not available in Europe. extremely rare.
Rituximab B lymphocytes play many roles in the pathophysiology of Thrombopoietin Receptor Agonists The observation that platelet
ITP, including producing antibodies, presenting antigens, and regu- production in patients with ITP is impaired, the massive megakaryo-
lating the functions of T cells and dendritic cells. B cells are targeted poiesis seen in the marrow of mice and humans treated with recom-
therapeutically with rituximab, a chimeric monoclonal antibody against binant TPO (far greater than seen in patients with ITP), and the
CD20, which binds B cells and causes Fc-mediated lysis, thereby deplet- unexpectedly normal or only modestly elevated TPO levels in patients
ing these cells from blood, lymph nodes, and marrow. Rituximab rap- with ITP suggested the potential benefit of megakaryocyte-stimulation
idly depletes B cells in patients with autoimmune diseases, with the therapy in patients with refractory ITP. Early use of an altered form of a
effect usually lasting 6 to 12 months. 114,213–217 recombinant TPO molecule to stimulate platelet production in normal

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