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E. Lucchini et al.
study in 248 adult patients, Khellaf et al. found that after a median follow-up of 24 months, 39% of patients were still responding.41 In other studies a long-term response, at approximately 2 years after initial treatment, was observed in about 40% of patients.39,56,68 However, the only study with a 3-5 year follow up showed that the response was maintained after 5 years in only 21% of adults and 26% of children treated with rituximab.40
Given that a long-term response greater than 20-30% would be desirable, several strategies have been imple- mented in order to augment response rates and sustained remissions.
Anticipated use of rituximab in patients with immune thrombocytopenia
Although not supported by randomized, controlled tri- als, some studies pointed out that better outcomes can be achieved if rituximab is administered in an early stage of the disease.46,58 Following this observation, two studies69,70 compared the combination of “standard dose” rituximab and dexamethasone (40 mg/day for 4 days) to dexametha- sone alone as first-line therapy in adult patients with ITP. In both studies the combination led to higher sustained response rates (63%69 vs. 36% and 58%70 vs. 37%), com- pared to those achived with dexamethasone alone.
Combination treatment to improve long-term outcome with rituximab
Since rituximab affects almost exclusively B cells, with- out directly affecting the activity of other cells of the immune system (in particular T cells and plasma cells), the combination with other drugs with different modes of action looked appealing. The addition of 28 mg/m2 dex- amethasone (as an anti-plasma cell treatment), given for three 4-day cycles at 2-week intervals, to “standard-dose” rituximab was explored in a cohort of 67 patients (41 adults and 26 children) with ITP, of whom only five were treatment-naïve. This combination led to a 75% initial response rate and an almost 50% estimated long-term cure rate at 5 years.54 However, the good long-term responses were seen almost exclusively in women of child-bearing age within 1 year of diagnosis.
The combination of high-dose dexamethasone, low- dose rituximab and cyclosporine (TT4) administered over 1 month was tested in 20 ITP patients (including 7 with newly diagnosed ITP and 5 with secondary ITP), with the aim of targeting, in addition to B cells, also plasma cells and T cells. The response rate at 6 months was 60% and among responders, the relapse-free survival rate was 92% at 12 months and 76% at 24 months. The treatment was well tolerated.71
Two Chinese studies explored the combination of low- dose rituximab with recombinant human thrombopoietin. The first study enrolled 14 patients with refractory ITP, who had an ORR of 93%.72 The second was a random- ized, open-label study in which the combination was compared with rituximab 100 mg weekly for 4 weeks in patients with relapsed or refractory ITP. The group treated with the combination had a substantially shorter time to response (7 vs. 28 days).73 The long-term response rate (79.2% vs. 71.1%) was not significantly different between the two groups.
Gómez-Almaguer et al. recently published the results of a single-center, pilot study conducted to assess the safety and efficacy of the combination of eltrombopag, low-dose
rituximab and dexamethasone in 13 newly diagnosed ITP patients. The ORR was 100%, with 92% CR rate and a relapse-free survival rate of almost 80% at 12 months.74
The results of the most relevant studies of the use of rit- uximab in combination with dexamethasone and other drugs in ITP are summarized in Table 3a and 3b, respec- tively.
Efficacy of rituximab retreatment
Limited data are available concerning retreatment with rituximab. In a retrospective study, Hasan et al. explored the response to retreatment with standard-dose rituximab in patients with chronic ITP: 80% of the retreated patients responded again to standard-dose rituximab.75
Zaja et al. showed that even low-dose rituximab can be effective in patients who previously responded to the standard dose of the drug, although only three patients received a second course of rituximab.50 Khellaf et al. reported that most of 11 patients retreated with rituximab responded again.41 In other studies, very small numbers of patients were retreated with rituximab, in most of cases with good responses.38,56,68,76–78
Rai et al., in 17 patients with autoimmune cytopenias (including 11 cases of ITP) who previously responded, but then relapsed after a standard course of rituximab, explored the use of rituximab maintenance: a single 375 mg/m2 infusion every 4 months for a total of 2 years: 88% of patients achieved a CR, with a mean duration of response of 48 months.79
B-cell recovery after rituximab
The depletion of circulating B cells after rituximab administration is rapid (within 1 week) and deep, with B- cell counts remaining low in the peripheral blood for at least 6-12 months.8 The repopulating pool is dominated by immature B cells, while memory B cells recover after 2 years.80 A similar depth of peripheral B-cell depletion has also been observed with low-dose rituximab.50 In the vast majority of patients who achieve a complete remission, the recovery of B cells is not associated with disease relapse,46 while in non-responders or in patients who relapse, B cells tend to reappear sooner in the peripheral blood and increase to higher levels.40,46 Rituximab also induces nearly complete depletion of splenic B cells, and in patients who do not respond the recovery of B cells in the spleen is faster.81
Effects of rituximab on T cells
In rituximab responders, all the immune-system abnor- malities seen in patients with active disease tend to revert towards normal: in the peripheral blood, there is restora- tion of the Th1/Th2 and Tc1/Tc2 ratios, a decreased expression of Fas ligand and Bcl-2 mRNA, an increased expression of Bax mRNA and an increased number of reg- ulatory T cells82,83. The numbers of interleukin-10-produc- ing B cells (regulatory B cells) and interleukin-6-producing B cells are also normalized after treatment.84
In contrast, these abnormalities are still detectable in the spleens of non-responders: reduced regulatory T cells, an increased Th1/T-regulatory cell ratio,81 and persistence of the Tc1 polarization with CD8+ cytotoxic T cells display- ing the phenotype of effector memory T cells with a restricted T-cell receptor repertoire.85 These findings sug- gest that the action of rituximab is not limited to B cells and humoral immunity, but that rituximab also affects cel-
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haematologica | 2019; 104(6)