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Originally published as JCO Early Release 10.1200/JCO.2008.19.1841 on October 6 2008 © 2008 American Society of Clinical Oncology.
Can Rituximab Change the Usually Dismal Prognosis of Patients With Intravascular Large B-Cell Lymphoma?
Unit of Lymphoid Malignancies, Department of Oncology, San Raffaele Scientific Institute, Milan, Italy; International Extranodal Lymphoma Study Group, Bellinzona, Switzerland
Department of Hematology and Lymphoma, Evangelismos Hospital, Athens, Greece
University Hospital of Essen, Essen, Germany
Centre Hospitalier Universitaire Hôtel-Dieu, Clermont-Ferrand, France
Centre Hospitalier Universitaire Lille, Lille, France
The Ohio State University, Columbus, OH
Centre Henri Becquerel, Rouen, France
National Tuberculosis and Lung Diseases Research Institute, Warsaw, Poland
Clinica di Ematologia, Azienda Ospedali Riuniti di Ancona, Ancona, Italy
First Department of Medicine, University of Pecs, Pecs, Hungary
International Extranodal Lymphoma Study Group, Bellinzona, Switzerland; Division of Medical Oncology, Istituto Oncologico della Svizzera Italiana, Bellinzona, Switzerland
Unit of Lymphoid Malignancies and Pathology Unit, Department of Oncology, San Raffaele Scientific Institute, Milan, Italy; International Extranodal Lymphoma Study Group, Bellinzona, Switzerland To the Editor: We read with great interest the article by Shimada et al1 reporting encouraging results of the addition of rituximab to anthracycline-based chemotherapy in a retrospective series of Japanese patients with intravascular large B-cell lymphoma (IVL). Despite the short median follow-up (18 months), the positive impact on survival is in line with previous observations in other diffuse large B-cell lymphomas,2 and suggests that rituximab should be included as part of first-line treatment for this lymphoma, with otherwise dismal prognosis. IVL is a typically disseminated and aggressive malignancy that results in severe performance status impairment and multiorgan failure. A recent International Consensus Meeting recognized at least two different clinical forms of IVL: a classical form, with a more favorable cutaneous variant, and a hemophagocytosis-related form, which exhibits significant differences in prevalence between Japanese and Western patients.3-6 These IVL forms display interesting clinical, pathologic, and biologic differences,3,5 suggesting that the same treatment may be associated with potential outcome variability. For instance, the addition of rituximab can potentially show variable efficacy and tolerability between Eastern and Western patients with IVL. Although disappointing results with anthracycline-based chemotherapy are well documented,7 information regarding the efficacy and tolerability of rituximab in IVL patients diagnosed in Western countries is scant. These data are limited to a few single case reports, where rituximab use often has been associated with a favorable outcome. However, this benefit might be overestimated due to the usually short follow-up period and publication bias. To better investigate the role of rituximab as part of first-line treatment for IVL in Western countries, we contacted all of the authors of previous pertinent reports, and asked for updated follow-up of their published and unpublished cases of IVL treated with rituximab, as well as data for every additional case of IVL treated without this drug at their institutions, within the same time period. Complete information on presentation, staging, treatment, rituximab schedule, toxicity, response, relapses, and survival was assembled meticulously. We collected data on 41 patients with IVL diagnosed in 12 Western countries, with a follow-up updated to June 2008 in three fourths of cases. Seven patients were excluded from the analysis. The reasons for exclusion were death before treatment initiation (n = 2) and rituximab administration only after disease relapse/progression (n = 5). The remaining 34 patients treated with first-line rituximab, either alone (n = 3) or in combination with anthracycline-based chemotherapy (n = 31), constituted the study population (median age, 65 years; range, 20 to 86 years; 18 males). Clinical and laboratory findings of this series were not significantly different with respect to those previously reported for IVL patients diagnosed in Western countries.3,5,6 In particular, 32% of patients had Eastern Cooperative Oncology Group performance status 3 to 4, 86% had elevated lactate dehydrogenase serum levels, 70% had "B" symptoms, and 73% had stage IV disease, with bone marrow (35%), skin (32%), and CNS (26%; n = 9) being the most commonly involved organs. Rituximab (375 mg/m2) was administered concurrently with first course of chemotherapy (within the same day) in all patients except two (administered from the second course); this information was not available in two patients. No patient received rituximab maintenance. Chemotherapy regimens included cyclophosphamide, doxorubicin, vincristine, and prednisone administrated every 21 days (n = 29); cyclophosphamide, doxorubicin, vincristine, and prednisone administrated every 14 days (n = 1); and cyclophosphamide, epidoxorubicin, vincristine, and prednisone administrated every 21 days (n = 1). First-line treatment included high-dose methotrexate in one of the nine patients with CNS involvement; four of the 25 patients without CNS involvement at diagnosis received CNS prophylaxis (high-dose methotrexate in one patient; intrathecal chemotherapy in three patients). Twenty-six (84%) of the 31 patients treated with chemoimmunotherapy completed the planned program (six to eight courses); two patients died after two to four courses as a result of infectious complications, one patient discontinued chemotherapy after the first course as a result of toxicity but proceeded with rituximab alone, one patient discontinued treatment as a result of progressive disease, and treatment is ongoing in one patient. The three patients treated with rituximab alone completed the eight planned weekly doses. Adverse effects attributed to rituximab were absent in 28 patients, mild (chills, fever, hypotension) in four patients (12%), and severe in two patients (6%; pulmonary failure and coma after the first course). Overall, rituximab was discontinued in four (12%) patients as a result of severe adverse effects (n = 2), progressive lymphoma, and chemotherapy-related toxicity. After rituximab treatment (n = 33), 29 patients (88%) achieved a complete remission, and one patient achieved a partial response (overall response rate, 91%). At a median follow-up of 2 years, six patients experienced relapse, with CNS involvement in five patients; only one of these patients had CNS disease at diagnosis. Twenty-eight patients are alive, with a 3-year overall survival of 81% ± 7% (mean ± standard deviation); two patients died as a result of toxicity, one died as a result of unrelated causes, and only three patients died as a result of lymphoma (all of them after CNS relapse). Even if publication bias can not be excluded in the present series, this study represents the widest cumulative experience with first-line rituximab in Western patients with IVL. This experience allowed us to draw the following preliminary conclusions. First, treatment with rituximab at diagnosis or relapse was feasible in 95% of IVL patients. Severe adverse effects attributable to rituximab were uncommon; only two (6%) patients required rituximab interruption due to toxicity. Unfortunately, we did not find predictors of toxicity because the two patients with severe complications had neither multiorgan involvement nor B symptoms. Thus, caution is recommended until greater experience can be accumulated, and rituximab administration delay of 3 to 4 days at the first course should be considered, at least in high-risk patients (large tumor burden). Second, in line with Shimada et al,1 our data suggest that rituximab could change the dismal natural history of IVL. A significant survival improvement can be observed when the present series is compared with the largest cumulative series of IVL diagnosed in Western countries and treated in the prerituximab era (Fig 1). High rituximab efficacy in IVL patients (and its acute adverse effects) may be explained by the presence of lymphomatous cells in the lumina of small vessels, where this drug shows high bioavailability and complement reaches elevated concentrations.
Third, CNS was the principal site of IVL failure, both in patients with and without CNS lesions at diagnosis. The failure of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone to control CNS disease could be explained by the presence, in some patients, of concomitant extravascular dissemination,3,8 with the resulting formation of perivascular cuffings8 like those currently observed in primary CNS lymphomas—another malignancy that is poorly responsive to anthracycline-based chemotherapy. Given that extravascular dissemination in the CNS is indistinguishable with current neuroimaging,8 the addition of drugs with a better CNS bioavailability in patients with IVL is strongly recommended.3 Rituximab efficacy is a major gain in the treatment of IVL, both in Eastern and Western patients. A better control of rituximab adverse effects and of CNS disease will further improve therapeutic efficacy. Worldwide prospective case collection, like those conducted by the International Extranodal Lymphoma Study Group (www.ielsg.org/trialsonfr.html), will allow us to better understand this lymphoma and to optimize its therapeutic management. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
NOTES published online ahead of print at www.jco.org on October 6, 2008 REFERENCES
1. Shimada K, Matsue K, Yamamoto K, et al: Retrospective analysis of intravascular large B-cell lymphoma treated with rituximab-containing chemotherapy as reported by the IVL study group in Japan. J Clin Oncol 26:3189-3195, 2008 2. Coiffier B, Lepage E, Briere J, et al: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235-242, 2002 3. Ponzoni M, Ferreri AJ, Campo E, et al: Definition, diagnosis, and management of intravascular large B-cell lymphoma: Proposals and perspectives from an international consensus meeting. J Clin Oncol 25:3168-3173, 2007 4. Murase T, Nakamura S: An Asian variant of intravascular lymphomatosis: An updated review of malignant histiocytosis-like B-cell lymphoma. Leuk Lymphoma 33:459-473, 1999[Medline] 5. Ferreri AJ, Dognini G, Campo E, et al: Variations in clinical presentation, frequency of hemophagocytosis and clinical behavior of intravascular lymphoma diagnosed in different geographical regions. Haematologica 92:486-492, 2007 6. Ferreri AJ, Campo E, Seymour JF, et al: Intravascular lymphoma: Clinical presentation, natural history, management and prognostic factors in a series of 38 cases, with special emphasis on the ‘cutaneous variant'. Br J Haematol 127:173-183, 2004[CrossRef][Medline] 7. Ferreri AJ, Campo E, Ambrosetti A, et al: Anthracycline-based chemotherapy as primary treatment for intravascular lymphoma. Ann Oncol 15:1215-1221, 2004 8. Imai H, Kajimoto K, Taniwaki M, et al: Intravascular large B-cell lymphoma presenting with mass lesions in the central nervous system: A report of five cases. Pathol Int 54:231-236, 2004[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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