Rituximab

Additional information

Rituximab can be used to treat several different conditions. It is used in autoimmune diseases such as vasculitis, idiopathic thrombocytopenia, rheumatoid arthritis, and off licensein multiple sclerosis. Rituximab is also used to treat different types of lymphomas and chronic lymphocytic leukemia.

Pharmacokinetics and dosing

A faster clearance of rituximab in men has been shown in pharmacokinetic studies of patients with rheumatoid arthritis, diffuse large B-cell lymphoma, follicular lymphoma and antibody associated vasculitis.

In a pharmacokinetic study in rheumatoid arthritis patients (22 men, 85 women), men had a 38.7% faster clearance of rituximab than women after adjusting for body surface area [1].  Similar findings were presented in a study in patients with diffuse large B-cell lymphoma (DLBCL) (9 men, 11 women) where men had a 55% faster clearance [2].  In the same study the elimination half-life (t1/2β) of rituximab was significantly shorter in men (24.7 days) compared to women (30.7 days) [2]. Also in elderly patients with DLBCL (325 men, 285 women), men had a 25% faster median rituximab clearance [3]. In patients with follicular lymphoma (8 men, 9 women), the median AUC total in men was 81% of the values observed in women [4]. Ctrough and AUC were generally higher in women than in men both in the induction phase and in the maintenance phase. In patients with antibody associated vasculitis (43 men, 46 women) the rituximab levels were approximately 20% lower in men compared with women [5].

Effects

Better outcome in women

Follicular lymphoma

Data from the population-based Swedish Lymphoma Registry (1307 men, 1332 women) indicate improved overall survival (OS) by each calendar period in both men and women although the improvement was greater in women. Male sex was a significant risk factor among those ≥60 years, but not in those <60 years [6]. An analysis restricted to the 195 patients ≥70 years who received first-line rituximab showed better OS in women, results that remained when extending the analysis to include patients ≥60 years [6]. Similar results were found in a prospective phase II trial investigated the treatment effect of rituximab patients with follicular lymphoma (15 men, 14 women). Complete remission was detected in 86 % of women as compared to 47 % in men (OR 6.8) [4]. Also an observational study from Helsinki and Lund in rituximab treated patients with follicular lymphoma (51 men, 59 women) found better results in women regarding progression free survival (PFS) [12].

Diffuse large B-cell lymphoma (DLCBL)

A meta-analysis of 20 prospective and retrospective randomized controlled studies of adult patients with DLBCL (2879 men, 2414 women) extracted data on overall survival (OS) [7]. The studies showed a heterogenous result regarding sex differences but reports a HR of 1.2 (95% CI 1.037–1.286; p<0.009) indicating worse outcome in men [7].

In the CORAL study of patients with relapsed or refractory DLBCL (76 men, 46 women), the event free survival was 63% in women as compared to 46% in men. This was evident only in premenopausal and not post-menopausal women [8]. In a cohort study from Italy and Brazil (943 men, 850 women), women treated with rituximab had a 5 year OS rate of 81% (95% CI 77-84) as compared to 72% in men (95% CI 69-75) [9].

The NCCN Oncology Outcomes Database for Non-Hodgkin’s Lymphoma was used to analyze the outcome of patients with DLBCL (749 men, 637 women) [10]. Men had worse outcomes with lower 3-year PFS (HR 1.3). Male sex was associated with worse clinical outcomes after adjusting for age and BMI or BSA. The higher risk of poor outcome in men was most pronounced in patients >60 years [10]. 

The Danish Lymphoma Registry (LYFO) was used to identify patients with DLBCL (1094 men, 896 women). A multivariate analysis indicates that sex was of prognostic significance for OS (HR 1.3; 95%CI 1.1–1.7), with poorer OS in men (≤70 years). However, this effect was not seen after correction of multiple testing [11]. In an observational study from Helsinki and Lund on patients with DLBCL (126 men, 91 women), women had a significantly better 4-yr PFS (75% in women vs. 60% in men) [12]. A multivariate analysis of a cohort of patients from Singapore with DLBCL (47 men, 49 women), indicates that female sex was associated with a better OS (HR 8.4) [13].

In the SEXIE-R-CHOP-14 study of elderly patients with DLBCL (66 men, 57 women) an increased dose of rituximab was administered to men (500 mg/m2). Women received a standard dose of 375 mg/m2. Although men received higher rituximab doses, there was no difference with respect to PFS and OS compared to women. The 2-year PFS for men was 79% (95%CI 72-86) as compared to 74% (95%CI 66-82) for women. The OS was 86% (95%CI 80-91) for men and 78% (95%CI 70-85) for women [14].

A Chinese report also indicates a better response in women with DLBCL, but exact information on the number of women and men treated with rituximab are lacking [15].

Indolent B cell lymphoma

A retrospective univariate analysis (Cleveland, Ohio, US) on patients with indolent B cell lymphoma (152 men, 151 women) [16] indicates a trend towards better event-free survival for women (HR 0.73; P=0.061). In patients without follicular lymphoma (non-FL), male sex was significantly associated with worse EFS outcome.

Mantle cell lymphoma

A multivariate analysis of data from the Swedish and Danish Lymphoma Registries on patients with mantle cell lymphoma (966 men, 393 women) indicates a better OS in women (HR 1.36) [17].  

Primary idiopathic thrombocytopenia (ITP)

A cohort from Italy of patients with primary ITP) treated with rituximab (42 men, 61 women) indicates a better long term (48 and 72 months) response in women [18]. A cohort from New York of adult patients with ITP (22 men, 27 women) indicates that women were more than twice as likely to have a continuing response to rituximab (44.1%) compared to men (19.6%). Women with an ITP duration of <12 months at the time of rituximab treatment had a continuing unmaintained long-term response of 78.6% (median duration of response 44 months), compared to all three other groups (men of short and long duration ITP and women with ITP>12 months) which had estimated unmaintained long-term responses of 21.2, 15.9, and 0% [19].

A systematic review of idiopathic thrombotic thrombocytopenic purpura (TTP) included 15 case series and 16 case reports (31 men, 69 women). Treatment with rituximab was associated with a complete remission rate of 98%. There was no significant difference between men and women in terms of the response to rituximab therapy [20]. A study of consecutive cases of established ITP (69 men, 156 women) from Strasbourg did not indicate any statistically significant difference regarding outcome or treatment response in relation to patient’s sex [21].

Chronic lymphocytic leukemia

Data extracted from British Columbia on patients with CLL (435 men, 259 women) indicates a worse OS for men, HR 1.4 (95%CI 1.18-1.66) and age ≥70 years HR 2.63 (95%CI 2.22-3.12) [22].

No differences in effect reported between men and women

Antibody associated vasculitis

In patients with antibody associated vasculitis (43 men, 46 women) treated with four weekly infusion of rituximab (375 mg/m2), rituximab-levels were approximately 20% lower in men compared with women, but no difference in outcome between men and women were detected [5].

Rheumatoid arthritis

In patients with rheumatoid arthritis (388 men, 1321 women) included in the French Autoimmunity and Rituximab (AIR) Registry, disease activity assessed by the 28-joint DAS (DAS28) was recorded at baseline and at follow-up (6, 12, 18 and 24 months) [23]. Response criteria [European League Against Rheumatism (EULAR) remission defined as a DAS28<2.6 and EULAR response] were compared in both sexes. Approximately 78.6% of the patients were positive for rheumatoid factor (RF) and 75.8% for anti-CCP. Women had a longer disease duration, less frequently anti-CCP and lower CRP levels at baseline. Six months after rituximab, 11% were in remission and 62% had a good to moderate EULAR response, irrespective of sex (P=0.81 and P=0.38, respectively). No differences were observed in terms of remission or EULAR response during the follow-up except at 12 months, when men achieved remission more frequently (18% vs 12%). In the cases of anti-TNF failure, remission rates with rituximab were higher in men than in women at 6, 12 and 18 months [23].

Adverse effects

A cohort study from Korea analyzed risk factors for neutropenia in patients with DLBCL (111 men, 70 women) treated with rituximab. Multivariate analysis indicates that female sex was a risk factor for the occurrence of neutropenia (OR 2.0). Female sex was also a risk factor of febrile neutropenia (OR 2.4) [24]. In contrast, an Australian cohort study of patients with Non-Hodgkin Lymphoma (163 men, 131 women) who received 376 courses and 1,571 cycles of rituximab infusion assessed risk factors for adverse events. Patient’s sex was not found to be significantly associated with the occurrence of the adverse events [25].

According to a Swedish registry analysis on patients with rheumatoid arthritis (861 men, 2725 women), rituximab did not increase the risk for malignancies in neither men nor women [26].

Reproductive health issues

Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).