Can rituximab-treatment of a pregnant woman be toxic to the fetus?/nBackground: A 36-year-old woman

Fråga: Can rituximab-treatment of a pregnant woman be toxic to the fetus?

Background: A 36-year-old woman with low-grade non-Hodgkin lymphoma was treated with Mabthera (rituximab) 10 months ago. Recently (9 weeks ago), Rituximab therapy was re-initiated with four courses in four weeks. The outcome of treatment is unknown to the Questioner - a gynaecologist who met the patient when it became evident that the woman is pregnant, now in week 8. It is also not clear to the Questioner if further treatment is planned. There is no other medication and the patient is in good condition.

Sammanfattning: There is no knowledge about the effects of rituximab on the fetus and the fetal immune development. If possible, rituximab treatment should be avoided, especially in later stages of pregnancy where passage of rituximab to the fetus is more pronounced. Monitoring of B-cell count and immunoglobulin levels seems highly motivated in the mother as well as in the newborn.

Svar: Rituximab is the first monoclonal antibody to be registered in Sweden for the use against malignant disease. The specific indication is treatment of patients with relapsed or chemo-resistant follicular B-cell non-Hodgkin lymphoma (1, 2).

This monoclonal antibody is a chimeric IgG molecule with a human constant region and variable regions from mice. The antibody is highly specific for binding to CD20, a specific cell-surface marker of the B-cell lineage (1-4), except plasma cells (4). More than 95 per cent of all non-Hodgkin lymphoma cells express CD20 (2). Binding of the antibody to CD20 has been shown to cause apoptosis or complement-dependent lysis of normal and malignant B-cells in vitro (2, 5).

The mechanism of rituximab action in vivo is less clear, which is in part explained by the lack of appropriate animal models with corresponding antigen/antibody cross-reactivity. However, data from monkey models indicate that 70-80 per cent of CD20-positive cells disappear from bone marrow and lymph nodes at doses of rituximab similar to human doses. No effects on other cells were found (2).

In different clinical trials, a response rate of around 40-50 per cent has been reported, with a median time for response of 50 days. CD20 is not expressed on lymphoid stem cells and complete recovery of B-cell numbers was seen after 9-12 months (2, 6). It is not clear if serum levels of immunoglobulins fall in treated patients, but hypogammaglobulinemia is not listed among adverse reactions in the official product review (1, 2). This is somewhat surprising considering the significant reduction of B-cells but might relate to the fact that immunoglobulin-secreting plasma cells do not express CD20. However, an interesting case report describing a 64-year-old man who developed hypogammaglobulinemia (IgG 2.7 g/l, reference value 6-15 g/l) and sepsis was found in the Swedish register of adverse drug reactions, where causality of rituximab was considered probable (7).

There is no documentation on rituximab treatment of pregnant women and according to the manufacturer the present case might represent the first worldwide (6). IgG molecules are the only immunoglobulins to cross the placenta, and this should also be true for rituximab. The passage of IgG to the fetus increases over time during pregnancy and IgG of maternal origin is the dominant immunoglobulin in the newborn and early infancy (3, 8). Fetal B-cells may be identified at week 8-9 of pregnancy but B-cell function is still immature until 2-4 months post-partum, when a more significant production of endogenous immunoglobulins becomes evident (3, 9, 10).

The above facts are all of potential importance when trying to estimate the risk of adverse effects of rituximab on the fetus. Firstly, is the mother at risk of hypogammaglobulinemia and how would that affect the fetus? Secondly, how is the fetal development of B-cell function affected by retuximab? Thirdly, are there other risks to be considered?

The mother should be at some risk of developing at least transient hypogammaglobulinemia. This should be possible to monitor by plasma analysis. Pregnant women with idiopathic hypogammaglobulinemia are usually subject to replacement therapy with exogenous gammaglobulins at 100 mg/kg/week, but only in severe cases where endogenous IgG-levels are below 3 g/l to avoid increased susceptibility to infections (11).

The fetal B-cell development might well be impaired by rituximab crossing the placenta. The fetal level of rituximab antibody is not only dependent on the length of pregnancy in relation to the latest course of rituximab, but also the clearance of monoclonal antibody. It is reasonable that rituximab given later in pregnancy will have more pronounced effects on the fetus. Given the overall uncertainty in the present case, it was proposed that blood should be drawn from the umbilical vein at birth to investigate B-cell numbers, immunoglobulin levels and also rituximab levels in the newborn (12). Furthermore, the development of lymphoid tissue might be possible to follow in the infant by, for instance, ultrasound examination (12).

Taken together, it is highly difficult to predict the different effects rituximab might have on the fetus. Rituximab should therefore be avoided in pregnancy (2, 11). On the other hand, treatment of the pregnant patient is also essential and to some extent it is possible to monitor the effects on the fetus

ewborn (12). Risk of teratogenic effects on the embryo seems low, given the specific CD20-binding properties of the substance (2). 1 http://www.mpa.se/mono/mabthera.html, as of 2000-10-16 2 http://www.eudra.org/humandocs/human/EPAR/Mabthera/Mabthera.htm, as of 2000-10-16 3 Roitt IM, Brostoff J, Male DK, Immunology. 3rd ed. Mosby, St Louis. p. 11.9-11.16 4 Feuring-Buske M, Buske C, Unterhalt M, Hiddemann W: Recent advances in antigen-targeted therapy in non-Hodgkin´s lymphoma. Ann Hematol 2000; 79: 167-74 5 Davis TA, Grillo-Lopez AJ, White CA, McLaughlin P, Czuczman MS, Link BK, Maloney DG, Weaver RL, Rosenberg J, Levy R: Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin´s lymphoma: safety and efficacy of re-treatment. J Clin Oncol 2000; 18: 3135-3143 6 Harjunpää A, Junnikkala S, Meri S: Rituximab (anti-CD20) therapy of B-cell lymphomas: direct complement killing is superior to cellular effector mechanisms. Scand J Immunol 2000; 51: 634-641 7 Swedis, the Swedish Drug Information System 8 Nicole Jones, International Medical Manager, Roche, Basel, personal communication 9 Silver RM, BranchDW: The immunology of pregnancy, In Maternal-Fetal Medicine, 4th ed. Saunders Company: 1999; p. 72-89 10 Magnus Westgren, Consultant in Obstetrics, Huddinge University Hospital, personal communication 11 Lennart Hammarström, Professor in Clinical Immunology, Karolinska Institute, personal communication 12 Edvard Smith, Professor in Clinical Immunology, Karolinska Institutet, personal communication