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Prolonged hypogammaglobulinemia following rituximab treatment for post transplant Epstein–Barr virus-associated lymphoproliferative disease

Bone Marrow Transplantation volume 33, pages 129–130 (2004)Cite this article

Rituximab (a humanized anti-CD20 monoclonal antibody) is a useful treatment for Epstein–Barr virus-associated post transplant lymphoproliferative disease (EBV-PTLD). However, hypogammaglobulinemia is a complication associated with this treatment.1,2 Little is known about the duration and severity of rituximab-induced low serum immunoglobulin (Ig) status. Recently, Castagnola et al3 reported a patient with severe hypogammaglobulinemia that persisted for more than 2 years (27 months+) after rituximab infusion for pre-emptive therapy for EBV-PTLD. One of three patients reported by Verschuuren et al1 died of invasive aspergillosis due to hypogammaglobulinemia after 7 months of rituximab treatment.

Completion of the replacement therapy combined with continuous administration of cyclosporin A (CSA) for the control of limited chronic GVHD resulted in low serum Ig levels: IgG 431, IgA and IgM 7 mg/dl just before the rituximab treatment. After the first course of rituximab (Figure 1), serum Ig levels declined to their lowest levels: IgG 318, IgA 7 and IgM 3 mg/dl. In response to the replacement therapy (intravenous immunoglobulin, 10 g per 4 weeks) initiated soon after the second course of rituximab (Figure 1), serum IgG levels have remained at 550–650 mg/dl, however, IgA and IgM levels remained below 10 mg/dl. Serum levels of IgD (<1.0 mg/dl, normal <11.5) and IgE (3 mg/dl, normal <300) were also very low. Over the past 2 years, repeat analysis of peripheral blood mononuclear cells revealed that T(CD2+)-cell numbers ranged from 660 to 998/μl (normal 605–2564) and B(CD20+)-cell numbers ranged from 6 to 132/μl (normal 70–663). The CD4+ T-cell subset was in the range of 228–382/μl and the CD8+ T-cell subset ranged from 337 to 519/μl, with a CD4/CD8 ratio of 0.61–0.83. Although spontaneous recovery of Ig production has not yet occurred as of May 2003, slow immune reconstruction is expected due to the steady increase in B-cells that are doubling approximately every 9 months (Figure 1). Treatment with rituximab for EBV-PTLD (as opposed to treatment for autoimmune hemolytic anemia2) appears to cause more severe and prolonged B-cell deficiency and hypogammaglobulinemia.5,6,7 However, extremely long-lasting B-cell deficiency like our case may be rare.3 In the report of van Esser et al,6 B lymphopenia recovered between 6 and 9 months after a single infusion of rituximab as a pre-emptive therapy. In addition, in the control of PTLD, one to nine infusions were shown to be effective.5,7 Our case might be exceptional, because he needed two courses (a total of 16 infusions) because of very refractory multiple LPD masses in the adrenal glands, lungs, kidneys, liver and para-aortic lymph nodes as well as no availability of donor-derived EBV-specific CTLs at the time.4 It is possible that this intensive treatment might be responsible for such prolonged B-cell deficiency in our patient, but in the case of Castagnola et al,3 only a single dose was administered. A correlation between the duration of B lymphopenia and numbers (doses) of rituximab administered needs to be analyzed in future studies.

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  1. Kyoto City Institute of Health and Environmental Sciences, Kyoto, Japan

    S Imashuku & T Teramura

  2. Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan

    A Morimoto

  3. Division of Pediatrics, Kyoto City Hospital, Kyoto, Japan

    S Imashuku, M Naya & H Kuroda

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  1. S Imashuku
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Imashuku, S., Teramura, T., Morimoto, A. et al. Prolonged hypogammaglobulinemia following rituximab treatment for post transplant Epstein–Barr virus-associated lymphoproliferative disease. Bone Marrow Transplant 33, 129–130 (2004). https://doi.org/10.1038/sj.bmt.1704307

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