Rituximab in space: intrapleural and other novel routes of administration for lymphomas and lymphoid leukemias

Rituximab was initially used as a single therapeutic agent in the treatment of lymphomas, but over the past decade, in an era of targeted anti-cancer treatment, it has become an essential component of the standard chemo-immunotherapeutic regimens used successfully for the treatment of CD20(+) B cell lymphoproliferative disorders, particularly non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) [1,2]. Rituximab has significantly contributed to improved responses and increased survival obtained in these patients. More recently it has also been introduced as a maintenance regimen for some of the subtypes of lymphoma, thereby prolonging progression-free survival for patients with these disorders even more [3,4]. In routine use, rituximab is usually administered intravenously as a single agent or as part of combination chemommunotherapy, but other novel routes of administration have also been attempted. These include intrathecal [5,6], intraventricular [7] and even intravitreal [8] use for targeting tumor infiltration in the leptomeningeal compartment, relapsed central nervous system (CNS) lymphoma and intra-ocular lymphomas, respectively, as well as intralesional and intradermal administration mostly for primary cutaneous lymphomas [9,10].

However, regarding CNS and leptomeningeal involvement by lymphoma and lymphoid leukemias, it is generally well recognized that intravenous rituximab has limited efficacy, considering that the concentration of the antibody within the cerebrospinal fluid (CSF) does not reach sufficiently adequate levels to be effective [5,11]. Nevertheless, the blood–brain barrier may indeed be disrupted in areas of contrast-enhancing tumor, and anecdotal examples where rituximab was efficacious in relapsed CNS lymphoma have been reported [12]. According to Swinnen [12], systemic use of the antibody with combination chemotherapy for CNS lymphoma should still be considered, particularly when attempting to achieve maximal blood levels early during therapy [12]. Because of this, the feasibility and safety of both intrathecal (IT) and intraventricular administration of rituximab have been evaluated in individual case studies [6,13] and in phase I trials [7]. IT use has been shown to be effective in some cases [5,6], particularly when used as salvage therapy together with high-dose combination chemotherapy, but durability of response and long-term safety have still to be proved consistently. Toxicity is dose-related, and the maximum tolerated dose is 25 mg, which achieves levels that are comparable to the serum levels obtained after standard intravenous administration for systemic disease [7,14]. Higher doses cause grade 3 infusion-related hypertension, but more studies are needed in this respect. Intraventricular use may well be superior to IT from a pharmacological point of view; however, the implantation of Omaya reservoirs for antibody therapy alone raises sensitive ethical issues, and intraventricular antibody administration may be easier to justify if the reservoir is already in place as part of a therapy protocol for primary CNS lymphoma [15]. After intrathecal administration of rituximab there appears to be rapid clearance from the CSF, and because of this higher concentrations are necessary for it to be effective, as evident from studies in monkeys. Nevertheless, prolonged remission status with impressive clinical benefit attributed to the antibody has been observed without excessive toxicity in individual patients after IT and intraventricular use [5,7]. Although some case studies suggest that intraventricular use may have a role in the treatment of CNS lymphomas, dosages and dose intensification issues, antibody pharmacokinetics and its use in combination with other agents still need to be studied more intensively. It seems from the studies by Rubenstein et al. [7] that 10–25 mg of rituximab is feasible and effective and distributes rapidly within the craniospinal axis. However, it does appear that the strategy of combining rituximab with chemotherapy to target brain, intraocular and leptomeningeal compartments in patients with relapsed/recurrent CNS lymphoma (comparable in concept to the significant addition of the antibody to CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone] regimens for systemic lymphomas) may indeed prove to have additive and synergistic effects. This approach seems worth following in future clinical studies of recurrent and relapsed CNS lymphoma.

Rituximab has also been used in much lower doses intraocularly, and in early studies small doses of 1 mg have been shown not to cause intraocular or optic nerve toxicity [8] in rabbits and humans. The half-life of the antibody in the vitreous cavity was estimated to be 4.7 days, implying that the antibody could be given about every 2 weeks, but further studies are still necessary to assess its efficacy and consistent safety as local therapy for intraocular lymphoma. The issues related to loss of the injected agent due to efflux from the injection site, which may be as high as 40%, still need to be taken into consideration. In this respect it seems that this will not be a very efficient way of delivering the antibody to this site [16].

In this issue of Leukemia and Lymphoma, Law et al. [17] describe two cases of NHL treated with intrapleural administration of rituximab for persistent and recurrent re-accumulated effusions despite systemic therapy and repeated tapping. One case was a patient with advanced mantle cell lymphoma with bone marrow and pleural involvement and a massive pleural effusion who had failed repeated pleural tapping and systemic therapy. A chest drain was inserted and intrapleural (IP) rituximab (R) (100 mg in 50 mL saline) was given as a bolus and the chest tube clamped for 2 h. This, together with the drainage procedure, resulted in clearance of the effusion without local recurrence despite systemic progression of the disease. In this case it was indeed possible that some of the effect was due to drainage and a late effect of the chemotherapy, and not to rituximab, but it is still impressive, and may well have been due just as well to the antibody effect. The second case was a patient with marginal zone lymphoma with recurrent specific pleural effusion who still had massive pleural effusion after receiving initial R-CHOP chemotherapy and drainage, who responded to instillation of rituximab (initially 50 mg was used followed by two 3-weekly doses of 100 mg) and subsequent systemic therapy. Here too, it is also possible that the late effect of the systemic therapy was significant and contributed just as much as the R instillation, but the findings are of great interest, although one could claim that there was too little information on the timing of the IP R relative to other therapies given, making the true effect of the R uncertain. All in all these are interesting data, and it is quite feasible to accept that the IP administration of R played a significant role in clearing these persistent effusions.

Intrapleural and intraperitoneal instillation of rituximab for the treatment of recurrent malignant pleural effusions or abdominal ascites unresponsive to systemic therapy and other local measures have been reported in individual cases [17–20]. This has been shown to be effective in controlling massive collections of fluid in these confined spaces. In addition, in individual cases there was also regional clearing of nodes, as well as a suggestion of a systemic effect, with a decrease in the number of circulating tumor cells and lasting improvement in anemia after only local application of the antibody [20]. It is indeed possible that specific involvement of the serosal lining and integrity of the lining enhances resorption of the antibody systemically, making it available to distant sites. One has to ask whether the concentration of antibody in the pleural space was sufficient for cell kill, given the way in which it was administered. The effect may be due to local lysis of tumor cells in the cavity and pleura itself or also due to lymphoma cell clearance from the pleural lymphatic vessels draining the area [18].

In summary, the intracavity administration of rituximab seems well tolerated, with no significant side effects reported. Obviously, clinical trials are required to assess the true efficacy of this mode of administration, the optimal dosage scheduling, and when best to use it together with systemic administration. These clinical preliminary data will need to be consolidated with pharmacokinetics studies regarding the local and systemic absorption of installed amounts given. In an era in which we are still learning to appreciate the varying biology of each compartment in a single disease, compartment-tailoring therapy or space-tailoring therapy may indeed have a role.

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