A Cumulative Series from 14 Western Countries Suggests That Rituximab Significantly Changed the Dismal Natural History of Intravascular Large B-Cell Lymphoma (IVL) .
Authors: Ferreri Andres JM , Govi Silvia , Dognini Giuseppina Patrizia , Bouzani Maria , Bollinguer Claudia Ruth , D’Incan Michel , Delaporte Emmanuel , Hamadani Mehdi , Jardin Fabrice , Martusewicz-Boros Magdalena , Montanari Mauro , Szomor Arpad , Crocchiolo Roberto , Zucca Emanuele , Cavalli Franco , Ponzoni Maurilio 
Published: April 2020

Abstract
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we contacted all the authors of previous pertinent reports, asking for updated follow-up of their published and unpublished cases of IVL, treated with or without rituximab at their Institutions, from August 2002 to June 2008.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 1st course of chemotherapy (within the same day) in all pts except 2 (administered from the 2nd 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 1st 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.