Complete regression of HIV-associated multicentric Castleman disease treated with rituximab and thalidomide (2008)

Multicentric Castleman disease (MCD) is a potentially fatal, lymphoproliferative disease with increased incidence in HIV-infected persons. It is associated with human herpes virus-8 (HHV-8) and characterized by episodic clinical manifestations such as night sweats, fever, generalized lymphadenopathy and hepatosplenomegaly [1]. Due to the rareness of the disease, information on MCD from prospective trials is scarce and consequently no standardized treatment guidelines exist. We report the case of an HIV-infected patient with MCD successfully treated with rituximab and thalidomide. A 46-year old white HIV-positive male patient with a history of recurrent fever, night sweats and profound malaise was referred to our hospital. In the past year, he was treated episodically with various antibiotics for a presumed occult infectious disease. HIV infection had been known since January 2003 and the patient had been successfully treated with highly active anti-retroviral therapy (HAART) consisting of lamivudine, zidovudine and efavirenz for the last 2 years. HIV virus load was not detectable (<50 copies/ml) and (FACS) fluorescent activated cell sorting analysis revealed cells/μl equal to 395. No AIDS-defining events were reported. At admittance, a physical examination revealed fever of 39.5°C as well as cervical, axillary and inguinal lymphadenopathy. The laboratory results showed elevated C-reactive protein (16.13 mg/dl) levels and hypergammaglobulinemia with polyclonal immunoglobulin rearrangement. Computed tomography (CT) of the chest and abdomen disclosed a generalized lymphadenopathy and splenomegaly (Fig. 1a), whereas a positron emission tomography scan showed only borderline pathological mediastinal lymph nodes. Diffusion-weighted magnetic resonance imaging (DWI) revealed a restricted diffusion capacity in supraclavicular lymph nodes, which was indicative of malignancy (Fig. 1b). In malignancies, restricted diffusion capacities are caused by hypercellularity of rapidly growing tissues with high energy turnover, which is consistent with lymphoma. Thus DWI seems to be a powerful tool to reveal the course of lymphadenopathy.Fig. 1: Radiologic and histologic findings in multicentric Castlemans disease. (a) Coronal reconstruction of a multidetector-CT scan revealed extensive lymphadenopathy (indicated by arrowheads) and a splenomegaly (indicated by arrows) without any sign of ascites. (b) Coronal DWI with b-factor 800. The pathological axillary lymph nodes present with increased signal intensities reflecting a restricted diffusion capacity, indicating malignancy (indicated by arrows). (c) Immunohistological stainings of an axillary lymph node revealed reactivity against anti-CD138 and anti-CD20 antibodies. (d) The response of the MCD to the combination therapy of rituximab and thalidomide was demonstrated by CT as soon as after 3 months. Please note the decline of the lymphadenopathy (indicated by arrowheads) and the reduced splenomegaly (indicated by arrows). DWI, diffusion-weighted magnetic resonance imaging; MCD, multicentric Castleman disease.Histological examination of an axillary lymph node biopsy established the diagnosis of MCD of the plasmablastic variant with reactivity against anti-CD138 and anti-CD20 antibodies in immunohistochemistry (Fig. 1c). Presence of HHV-8 was detected by PCR, whereas anti-Epstein–Barr virus antigen stainings yielded negative results. Treatment options for MCD include steroids, chemotherapeutic agents and monoclonal antibodies neutralizing the interleukin-6 receptor [2,3]. In addition, HAART might have a favorable effect [4]. Other therapeutic strategies, such as anti-CD20 antibodies [2], virostatic agents [5], thalidomide [6] or even stem cell transplantation [7], can but must not be efficacious [8,9,2]. In view of the promising results of MCD monotherapy with thalidomide or rituximab, as well as the favorable effect of these compounds when used as combination treatment in other B-cell malignancies, we decided to administer both drugs employing an induction-maintenance strategy. Low-dose thalidomide (200 mg once daily) and aspirin 100 mg, to avoid venous thromboembolism were combined with rituximab 375 mg/m2 given four times at 3-week intervals. This initial regimen was followed by a maintenance dose of rituximab given every 3 months for 1 year. Constitutional symptoms subsided promptly and C-reactive protein decreased to normal levels (<1.0 mg/dl) within the first week. After 3 months, the CT of the chest and abdomen showed a significant regression of lymphadenopathy and splenomegaly (Fig. 1d). One year after the diagnosis, the patient was in complete remission as demonstrated by clinical and radiological means. The rituximab infusions were stopped and thalidomide was reduced to 100 mg once daily. During the period of cyclic rituximab administration, the patient was depleted of peripheral B-cells with stable serum immunoglobulin levels. No episodes of fever or lymphadenopathy and no adverse events occurred during 20 months. A CT of the chest and abdomen at the end of the follow-up period did not reveal any evidence of relapse and DWI showed a regular lymph node configuration. Several reports indicate a beneficial effect of rituximab and thalidomide in the treatment of MCD when used as single agents [2,6]. Both substances are effective against other B-cell and plasma cell malignancies such as multiple myeloma and Waldenström's macroglobulinemia. Although we cannot exclude the theoretical possibility that monotherapy with either rituximab or thalidomide would have also been effective in our patient, combination therapy might offer the benefit that smaller doses of the individual compounds can be used. A further rationale for combining these two agents is provided by data reporting an in-vitro upregulation of the CD20 antigen on myeloma cells upon thalidomide exposure [10]. To the best of our knowledge, this is the first report of MCD successfully treated with rituximab and thalidomide. This combination therapy was immediately effective, well tolerated and had a sustained effect on MCD.