Cerebrospinal fluid diffusion of Zevalin® after high-activity treatment and stem cell support in a patient affected by diffuse large B-cell non-Hodgkin's lymphoma with central nervous system involvement

Current treatment of central nervous system non-Hodgkin's lymphomas (CNS NHLs) is restricted to limited therapeutic options, which include radiotherapy, systemic chemotherapy and intrathecal injections of cytotoxic drugs. We present a clinical case of a heavily pretreated patient affected by cerebral and systemic lymphoma enrolled in a phase I–II study of high-dose Zevalin with autologous stem cell support.

Zevalin is an anti-CD20 monoclonal antibody of murine origin labelled with an yttrium 90 (90Y) particle. At a standard activity level of 0.4 mCi/kg, Zevalin has been shown to be safe and effective in the treatment of low- and high-grade NHLs. Conversely, the use of Zevalin at high activity levels with haematological support in the treatment of diffuse large B-cell (DLBC) NHL and its ability to diffuse into liquoral spaces at active dosages, have not yet been investigated.

Monoclonal antibodies have recently been introduced in the clinical management of lymphomas and represent a valid option, either alone [1Go] or in combination with chemotherapy [2Go]. Their radiolabelled counterparts may represent a further advance since penetrating radiation may obviate the problem of limited access to bulky or poorly vascularized tumours (cross-fire effect) [3Go].

The patient's clinical history began late in 2002, when he was aged 27 years, with a diagnosis of a DLBC NHL with a bulky mediastinal, pancreatic and gastric presentation. He was included in an experimental protocol for high-risk disease, which included up-front sequential high-dose chemotherapy and autologous transplantation. In July 2003, the patient presented with an early relapse, with CNS and mediastinal involvement, and started a new alternating hybrid chemotherapy regimen (COP/COPADEM/CYM). He subsequently underwent whole-brain (36 Gy) and mediastinal (36.8 Gy) radiotherapy, but unfortunately developed disease progression at new sites (lungs, thoracic wall, liver and kidneys) and was treated with a high-dose Ara-C-containing regimen (ESHAP) and later with non-cross-resistant drugs such as the IGEV protocol associated with concomitant immunotherapy (rituximab). Unfortunately, lymphoma progressed once again in the CNS as lymphomatous meningitis showing 15 lymphomatous cells/µl in the liquor and at the previously mentioned parenchymatous sites.

In the absence of adequate therapeutic options and in the presence of important symptoms (headache, nausea and vomiting, and amnesia), the patient was enrolled in June 2004 in a pivotal monocentric experimental trial of radio-immunotherapy using high-dose Zevalin and haematological support. After dosimetric evaluation, data showed that in the case of therapy with the planned Zevalin dose (2.1 GBq), the adsorbed dose would have been less than the maximum deliverable absorbed dose established by the protocol (3.0 Gy to red marrow and 20 Gy to normal organs).

Zevalin treatment was performed with 57 mCi, and 16 h later the liquor was evaluated, revealing a concentration of 0.01351 ± 0.0027 µCi/ml, corresponding to 0.5 ± 0.1 kBq/ml. In the mean time the patient experienced a gradual disappearance of all symptoms. A rachicentesis, performed on day 13, showed neither radioactivity nor pathological cells in the liquor. On day 21, the patient was reinfused with previously harvested autologous peripheral stem cells showing a full recovery from all haematological and non-haematological toxicity.

A complete disease re-evaluation via a total body CT scan was performed on day 45 and revealed significant disease regression at all previous disease sites, but mainly in CNS localizations. In fact the liquor become cytologically negative for the presence of lymphomatous cells with respect to diagnosis, and encephalic CT scans showed two-dimensional reduction of lesions. Aother total body CT scan was performed on day 90, confirming satisfactory disease control in the CNS localizations, still with negative liquor, but showing progression at the other parenchymatous sites.

Published data suggest the existence of a direct dose–response curve using monoclonal antibodies conjugated to different radioactive isotopes, and the possibility of overcoming the haemato-encephalic barrier could depend on higher dosages. On the other hand, there is no evidence of their liquoral diffusion at standard dose administration, even though after intravenous administration in patients with CNS lymphoma, rituximab is reproducibly detected in the CSF at concentrations that are at most 0.1% that of matched serum [4Go].

Rubenstein et al. [4Go] reported phase I results on safety and pharmacokinetics analysis of a direct intrathecal administration of rituximab in cynomolgus monkeys, showing its capacity to target the leptomeningeal compartment, and similar experimental treatments are ongoing on humans [4Go]. Moreover rituximab can be safely administered intraventricularly [5Go].

In conclusion, our data appear to support the possibility that Zevalin, when administered at high activity levels, is able to overcome the haemato-encephalic barrier without causing acute toxicity. The detection of Zevalin in the cerebrospinal fluid and at least the transient improvement of neuropathy signs in our patient appear to support this hypothesis. This finding needs to be confirmed by additional experience; however, it could offer a new strategy for treating CNS lymphomas with radio-immunotherapeutic compounds.

P. F. Ferrucci1,*, A. Vanazzi1, G. Tesoriere2, M. Ferrari2, M. Bartolomei2, P. Rocca2, M. Cremonesi2, G. Paganelli2 and G. Martinelli1

1 Hematoncology Division, 2 Nuclear Medicine Division and 3 Pathology and Laboratory Medicine Division at the European Institute of Oncology, Milan, Italy

* E-mail: pier.ferrucci{at}ieo.it

References

1. McLaughlin P, Grillo-Lopez AJ, Link BK et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998; 16: 2825–2833.[Abstract/Free Full Text]

2. Coiffier B, Lepage E, Brière J, Herbrecht R et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002; 346: 235–242.[Abstract/Free Full Text]

3. Witzig TE, Gordon LI, Cabanillas F et al. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol 2002; 20: 2453–2463.[Abstract/Free Full Text]

4. Rubenstein JL, Combs D, Rosenberg J et al. Rituximab therapy for CNS lymphomas: targeting the leptomeningeal compartment. Blood 2003; 101: 466–468.[Abstract/Free Full Text]

5. Schulz H, Pels H, Schmidt-Wolf I et al. Intraventricular treatment of relapsed central nervous system lymphoma with the anti-CD20 antibody rituximab. Haematologica. 2004; 89: 753–4.[ISI][Medline]





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