Jordi Martínez

GEMOX‐R regimen is a highly effective salvage regimen in patients with refractory/relapsing diffuse large‐cell lymphoma: a phase II study

Objectives:  The prognosis of old or immunocompromised patients with refractory or relapsing diffuse large‐cell lymphoma (DLCL) is very poor as the current standard of salvage therapy with autologous stem cell transplantation (ASCT) is not feasible for most of them. New active regimens with an acceptable toxicity profile are needed. We aim to report the results of a phase II trial of the GEMOX‐R regimen in DLCL.

Rituximab, gemcitabine and oxaliplatin: An effective regimen in patients with refractory and relapsing mantle cell lymphoma

Mantle cell lymphoma constitutes one of the lymphomas with poorest prognosis at relapse with limited effective salvage regimens due to advanced age. We present results of a new salvage regimen, rituximab, gemcitabine and oxaliplatin (GEMOX-R), in 14 patients with relapsing (n = 9) or refractory (n = 5) mantle cell lymphoma. The median number of cycles was 5.5 for a total of 72 cycles evaluated in the current study. The median age was 69.5 years with high-risk features. Patients received a mean number of prior treatment lines of 1.79. Sixty-four percent achieved CR (total response rate of 85%). With a median follow-up of 11 months, OS and PFS were 58% and 45% at 12 months. The major toxicity was thrombopenia grade III-IV (35%). Factors related with overall survival were ECOG performance status and a-IPI at GEMOX-R. We conclude that GEMOX-R displays an outstanding efficacy with an excellent toxicity profile in a pretreated elderly population.

Minerval induces apoptosis in Jurkat and other cancer cells.

Minerval is an oleic acid synthetic analogue that impairs lung cancer (A549) cell proliferation upon modulation of the plasma membrane lipid structure and subsequent regulation of protein kinase C localization and activity. However, this mechanism does not fully explain the regression of tumours induced by this drug in animal models of cancer. Here we show that Minerval also induced apoptosis in Jurkat T‐lymphoblastic leukaemia and other cancer cells. Minerval inhibited proliferation of Jurkat cells, concomitant with a decrease of cyclin D3 and cdk2 (cyclin‐dependent kinase2). In addition, the changes that induced on Jurkat cell membrane organization caused clustering (capping) of the death receptor Fas (CD95), caspase‐8 activation and initiation of the extrinsic apoptosis pathway, which finally resulted in programmed cell death. The present results suggest that the intrinsic pathway (associated with caspase‐9 function) was activated downstream by caspase‐8. In a xenograft model of human leukaemia, Minerval also inhibited tumour progression and induced tumour cell death. Studies carried out in a wide variety of cancer cell types demonstrated that apoptosis was the main molecular mechanism triggered by Minerval. This is the first report on the pro‐apoptotic activity of Minerval, and in part explains the effectiveness of this non‐toxic anticancer drug and its wide spectrum against different types of cancer.

Pathogenic study of anti-CD20 infusion-related severe refractory shock in diffuse large B-cell lymphoma

Although rituximab is an effective and safe therapy for B-cell lymphoid malignancies, a few cases of severe infusion-related reactions have been reported. Severe refractory distributive shock is an infrequent side-effect of treatment with rituximab and, to our knowledge, there are no reports describing its pathogenesis in a case of fatal outcome in detail. We present for the first time a case of fatal rituximab infusion-related refractory distributive shock in a patient with CD5+ diffuse large B-cell lymphoma (DLBCL) and analyse the pathogenic mechanisms involved. We have compared measurements obtained from the patient that experienced lethal refractory shock with the four subsequent DLBCL patients treated with rituximab, either at diagnosis or upon relapse, at our center. Serum cytokines [interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70] and complement components C3 and C4 were analysed, both pretreatment, and 3 h and 9 h after the onset of infusion. When compared with the control subjects, the potential risk factors for rituximab toxicity displayed by the patient that suffered refractory shock included C4 hypercomplementemia, IFN-γ and IL-10 hypercytokinemia, as well as a high tumor burden. The refractory shock was distributive with most cytokines (IFN-γ, TNF-α, IL-2, IL-4, IL-6 and IL-8) peaking 3 h after infusion and coinciding with the onset of the shock. Furthermore, the concentrations of IL-10 were persistently elevated. In conclusion, the cytokine pattern was similar to that observed in patients with rapid onset septic shock and serum cytokines reached levels markedly higher than previously described in other cases of severe rituximab infusion-related toxicity.