A Cumulative Series from 14 Western Countries Suggests That Rituximab Significantly Changed the Dismal Natural History of Intravascular Large B-Cell Lymphoma (IVL) .

Background: IVL is a typically disseminated and aggressive malignancy that results in severe multi-organ failure and poor survival. There are two well-recognized clinical forms of IVL (“classical” and “hemophagocytosis-related”) that exhibit significant clinical, biological and prognostic differences, with substantial variability between Japanese and Western patients (pts). Treatment with anthracycline-based chemotherapy is associated with disappointing results in both groups of pts (3-yr OS ~35%), but encouraging results of the addition of rituximab in a retrospective Japanese series were recently reported. Conversely, nothing is known on the efficacy and tolerability of rituximab in IVL pts diagnosed in Western countries since available information is limited to a few single case reports and a small retrospective series.

Methods: To investigate the role of rituximab as upfront treatment for IVL in Western countries, we contacted all the authors of previous pertinent reports, asking for updated follow-up of their published and unpublished cases of IVL, treated with or without rituximab at their Institutions, from August 2002 to June 2008. Three-fourth of investigators replied, providing complete information and updated follow-up of 41 pts. Seven pts were excluded due to death before treatment initiation (n=2) and rituximab administration only after relapse/progression (n=5). The remaining 34 pts treated with rituximab, either alone (n=3) or in combination with anthracycline-based chemotherapy (n=31), constituted the study population.

Results: Median age of the 34 pts was 65 yrs (range 20–86; 18 males), with ECOG-PS 3–4 in 32% of pts, elevated LDH levels in 86%, B-symptoms in 70%, and stage-IV disease in 73%, 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 the 1^st course of chemotherapy (within the same day) in all pts except 2 (administered from the 2^nd course); this information was not available in 2 cases. None of the patients received rituximab maintenance. Chemotherapy regimens included CHOP21 (n=29), CEOP21 (n=1) and CHOP14 (n=1). Upfront treatment included high-dose methotrexate in 1 of the 9 pts with CNS involvement; 4 of the 25 pts without CNS involvement at diagnosis received CNS prophylaxis (HD-MTX in 1; intrathecal chemo in 3). Twenty-nine pts (85%) completed the planned program; 2 pts died of infectious complications, 1 pt experienced disease progression, 1 pt interrupted chemotherapy for toxicity and proceeded with rituximab alone, 1 pt is still receiving treatment. Rituximab was generally well tolerated, with mild side effects in 4 pts (12%); it was discontinued due to severe toxicity only in 2 (6%) pts (pulmonary failure and coma after the first course). After treatment (n=33), 29 (88%) pts achieved a complete remission, with an ORR of 91%. At a median follow-up of 2 years, 6 pts experienced relapse, with CNS involvement in 5; only 1 of these pts had CNS disease at diagnosis. Twenty-eight pts are alive, with a 3-yr OS of 81%; 2 pts died of toxicity, 1 died of unrelated causes and only 3 pts died of lymphoma, all of them after CNS relapse.

Conclusions: This is the largest cumulative experience with upfront rituximab in IVL pts diagnosed in Western countries. The addition of rituximab was safe in 94% of cases and significantly improved the dismal prognosis of IVL. CNS was the principal failure site after R-CHOP therapy. To reduce rituximab side effects, perhaps by administration delay of 3–4 days at the 1^st course in pts with high tumour burden, and to improve CNS disease control by using drugs with a better CNS bioavailability are two advisable strategies to further improve therapeutic efficacy in pts with IVL.