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E. Lucchini et al.
serious adverse reactions are exceptional, especially if prednisone is included in premedication.
Serum sickness is a much rarer adverse reaction, charac- terized by fever, rash, polyarthralgia or arthritis, protein- uria, hematuria, elevated inflammatory markers and decreased complement, which usually arises 10-14 days after treatment.92 It is the result of immune activation against the chimeric mouse-human drug, with the forma- tion and deposition of immune complexes, and conse- quent activation of the complement cascade.93 This type III delayed hypersensitivity reaction to rituximab has been reported more commonly in autoimmune disorders than in hematologic malignancies, but overall it remains a very rare occurrence in adults, with less than 50 cases having been reported.92
Hypogammaglobulinemia
Since rituximab does not affect pre-existing long-lived plasma cells, there are not significant changes in the IgG or IgM levels in patients treated with one “standard dose” course.38,46–48 However, patients treated with multiple courses are more likely to develop hypogammaglobuline- mia, which usually recovers spontaneously in a few months.94 Since dexamethasone also affects plasma cells, 10-20% of patients treated with the combination may experience a marked hypogammaglobulinemia, which usually recovers within 1 year.50,54,70
Some reports suggest that a pre-existing hypogamma- globulinemia can be aggravated by rituximab, which can in some cases trigger or accelerate the development of a real common variable immunodeficiency (CVID).95,96 It is worthwhile remembering that ITP may be the initial man- ifestation of CVID and can precede its diagnosis by years.97 It is therefore important, in ITP patients treated with rituximab, to monitor immunoglobulin levels before and after therapy. In addition to monitoring and possibly even temporarily giving intravenous immunoglobulin replacement, prior assessment of genetic markers and vac- cine responses98,99 may be useful.
The efficacy and safety of standard-dose rituximab in patients with CVID-associated ITP or autoimmune hemolytic anemia was assessed in a multicenter, retro- spective, French study. The ORR was 85%, with a 74% CR rate and a sustained response rate of 60% at a median follow up of 39 months; severe infections occurred in 24% of patients, four of whom were not on immunoglobulin replacement therapy. The authors concluded that ritux- imab is highly effective and relatively safe in the manage- ment of CVID-associated immune cytopenias, and that immunoglobulin replacement is strongly recommended in this cohort of patients.100
Infections
An increased risk of infections after rituximab therapy is generally uncommon and more frequently observed in severely immunocompromised patients.101 Chugh et al., in a meta-analysis including five trials and 463 ITP patients treated with rituximab, did not find an increased risk of infection.102 Khellaf et al. concluded that the risk of infec- tions was acceptable (cumulative incidence of 2.3 infec- tions per 100 patient-years at a median follow up of 24 months), with the most severe infections occurring in adults older than 70 years of age, who suffered from severe comorbidities.41
Rituximab therapy reduces the genesis of new long-
lived plasma cells, thus impairing the immune response to vaccines. Vaccines against encapsulated bacteria (Streptococcus pneumoniae, meningococci and Haemophilus influenzae) should be administered before rituximab, con- sidering that patients, especially non-responding ones, may require a subsequent splenectomy.103
Reactivation of hepatitis B virus (HBV) is a well-recog- nized complication of immunosuppressive therapy. Patients who are HBcAb positive (likely occult carriers) should receive antiviral prophylaxis with lamivudine, while patients with HBsAg or HBV-DNA positivity (active carriers and inactive carriers) should be referred to a hepa- tologist and treated with entecavir or tenofovir.104
A rare but life-threatening infection that has been linked to rituximab is progressive multifocal leukoencephalopa- thy (PML), caused by the activation of Jakob-Creutzfeld virus and its spread to the central nervous system.105 This complication, although rare, has been almost only report- ed in patients with lymphoproliferative disorders, and only a very few cases have been observed in patients with autoimmune diseases, especially in systemic lupus erythe- matosus.106,107 Furthermore, patients who develop PML are usually profoundly immunocompromised from combina- tion chemotherapy, and rituximab is often just one of the many drugs received.108,109 There is only one well-studied case of PML in ITP and the course was unusual with the PML occurring more than 3 years after exposure to ritux- imab.
The occurrence of late-onset (>4 weeks after treatment) neutropenia has been described in patients treated with rituximab for both malignant110 and non-malignant condi- tions,111,112 including a few ITP patients.40 Most cases appear to be self-limiting and resolve without issue,113 and according to some authors retreatment with rituximab is safe.86
Malignancies
Immunosuppression secondary to rituximab could increase the risk of second primary malignancies. In large follow-up studies, rituximab has not been shown to increase the risk of cancer in patients with rheumatoid arthritis,114 among non-Hodgkin lymphoma patients115 and in patients with ANCA-associated vasculitis.116
No malignancies were reported in ITP by Arnold et al. in a meta-analysis including more than 300 patients,42 or in other studies,40,41,58 including combination studies with dexamethasone.54,69,70 In other reports nearly 3-4% of patients developed a second primary malignancy after having received rituximab for ITP, but the low percentage and the heterogeneity of the neoplasia led the authors to conclude that a causative relationship with rituximab could not be assessed.39,44,56
Use of rituximab in children
Following the development of rituximab for adults with ITP, studies soon migrated to pediatric patients (Table 4).
The first large series was reported in 2005 and included 24 chronic ITP patients who were refractory to or relapsed after previous treatments. The ORR to “standard-dose” rituximab was 78%, with a 63% CR rate and an overall sustained response rate of 37%.117
The first prospective phase I/II study of rituximab in children and adolescents with chronic ITP included 36
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