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This retrospective study aimed to describe the Hellenic experience on the use of brentuximab vedotin (BV) in relapsed/refractory (R/R) Hodgkin lymphoma (HL) given within its indication. From June 2011 to April 2015, ninety‐five patients with R/R HL, who received BV in 20 centers from Greece, were analyzed. Their median age was 33 years, and 62% were males. Sixty‐seven patients received BV after autologous stem cell transplantation failure, whereas 28 patients were treated with BV without a prior autologous stem cell transplantation, due to advanced age/comorbidities or chemorefractory disease. The median number of prior treatments was 4 and 44% of the patients were refractory to their most recent therapy. The median number of BV cycles was 8 (range, 2‐16), and the median time to best response was the fourth cycle. Fifty‐seven patients achieved an objective response: twenty‐two (23%), a complete response (CR), and 35 patients (37%), a partial, for an overall response rate of 60%. Twelve patients (13%) had stable disease, and the remaining twenty‐six (27%) had progressive disease as their best response. At a median follow‐up of 11.5 months, median progression‐free survival and overall survival were 8 and 26.5 months, respectively. Multivariate analysis showed that chemosensitivity to treatment administered before BV was associated with a significantly increased probability of achieving response to BV (P = .005). Bulky disease (P = .01) and response to BV (P <.001) were significant for progression‐free survival, while refractoriness to most recent treatment (P = .04), bulky disease (P = .005), and B‐symptoms (P = .001) were unfavorable factors for overall survival. Among the 22 CRs, 5 remain in CR with no further treatment after BV at a median follow‐up of 13 months. In conclusion, our data indicate that BV is an effective treatment for R/R HL patients even outside clinical trials. Whether BV can cure a fraction of patients remains to be seen.

In our study, we evaluated the safety and efficacy of Brentuximab vedotin (BV) with or without the addition of donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation (allo-SCT) in 16 patients with advanced Hodgkin lymphoma (HL). Thirteen patients with relapsed HL after allo-SCT received BV as treatment for active disease. Three patients without progression of HL after allo-SCT received BV as consolidation. Twelve patients had been previously exposed to BV for treatment of relapse after autologous-SCT. Ten out of 16 patients received BV in combination with DLI. Among the 13 patients treated for active disease, CR and PR was observed in 7 and 2 patients, respectively. With a median follow-up of 13 months, 13 out of 16 patients are alive, while 3 died because of disease progression. The median PFS was 6 months. DLI-associated GVHD occurred in seven patients. Five patients with GVHD required immunosuppression, and in all cases, GVHD resolved after a short course of low dose steroids, implying that an anti-GVHD modulating effect could be induced by the concurrent administration of BV. No serious adverse event was observed in any of the patients.

e Janus kinases (JAK) are intracellular tyrosine kinases that transduce cytokine-mediated signals to the nucleus, promoting gene expression. Cytokines play a major role in microbial sepsis, which is often associated with uncontrolled inflammation leading to death. JAK inhibitors have been used for the treatment of several autoimmune diseases by modulating immune response, but they have never been tested against microbial sepsis. Ruxolitinib is a small-molecule inhibitor of JAK1/2 proteins, which are involved in the downstream signaling pathway of the vast majority of proinflammatory and anti-inflammatory cytokines. We therefore studied the effect of ruxolitinib in a mouse model of sepsis due to Candida albicans. When ruxolitinib therapy (50 mg/kg [of body weight]/day) was started 1 day before infection, the median survival time was reduced by 3 days, the fungal loads in all organs were higher, the inflammation was significantly less, and serum tumor necrosis factor alpha (TNF-␣) and interleukin 10 (IL-10) levels and IL-10/TNF-␣ ratios were higher than in controls. When ruxolitinib therapy (50 to 1.5 mg/kg/day) was started 1 day after infection, an inverted-U relationship was found, with 6.25 mg/kg/day prolonging median survival time by 6 days, resulting in similar fungal loads, less inflammation, and similar cytokine levels but higher IL-10/TNF-␣ ratios than the controls. The optimal dose of ruxolitinib controlled infection and prolonged survival with less inflammation than in control animals. Administration of JAK inhibitors may be a promising therapeutic adjunct that needs further investigation.

Abstract:The immune response of the host against invading pathogens is clinically manifested as sepsis.Sepsis is a complicated process characterized by distinct phases that usually occur in a sequential manner. The initial hyper-inflammation helps in elimination of the pathogen, but potentially may lead to excessive tissue injury. Hypo-inflammation helps in restoring immune homeostasis, but may lead to significant immune suppression and death from secondary infections if not appropriately controlled. Immune-modulating intervention in sepsis should be based on a balanced control of both the hyper and the hypo-inflammatory phase. repeated cycles of hyper and hypo-inflammatory phases further complicating the septic process. Additional evidence for the sepsis-associated immunosuppression is the high incidence of herpes virus reactivation that occurs in patients with prolonged septic episodes (5). These clinical observations are supported from in vitro data showing impaired cytotoxicity and increased apoptosis of immune effectors from septic patients (6). Trials targeting the hyper-inflammatory phase of sepsisInterleukin-1 receptor antagonist (IL-1Ra) is a plasma protein that inhibits both IL-1a and IL-1b after binding to the type 1 IL-1 receptor (7). Anakinra is a recombinant human IL-1Ra. The efficacy of Anakinra as an immunemodulator in patients with sepsis was compared with placebo in a double blind phase III trial. In this trial anakinra failed to prolong 28-day survival, but in a subgroup analysis survival was improved in patients with septic shock or MOD in the arm of anakinra (8). Based on these data a phase III trial testing the efficacy of anakinra in patients with septic shock and/or severe sepsis was conducted, and again failed to show any survival benefit (9). However, in a subgroup analysis IL-1 inhibition improved survival in patients with severe sepsis and features of macrophage activation syndrome (MAS) (10). The beneficial efficacy of anakinra in this group of patients should be clarified in a prospective randomized trial.Most of the clinical trials conducted in the past were based on the notion that sepsis mortality was mainly due to an uncontrolled inflammatory response, and therefore were focused on testing the effect of blocking the hyperinflammatory phase by using various agents including corticosteroids, and anti-endotoxin or anti-cytokine antibodies. These studies failed to show therapeutic benefit, and moreover in many cases excessive anti-inflammatory inhibition had a negative impact on the outcome of septic patients (11-13). Reasons for failure of agents targeting the hyper-inflammatory phaseFailure of pro-inflammatory cytokine inhibition to improve the outcome of septic patients might be attributed to several reasons:(I) Inhibition of the hyper-inflammatory phase needs to occur at the right time. Anti-inflammatory blockade should occur at the very beginning of the septic process and not at later stages where patients are already in a state of immune-suppression. Previous trials included p...

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The outcome of patients with relapsed/refractory classical Hodgkin lymphoma (R/R cHL) after autologous stem cell transplantation (auto-SCT) is poor. Recently, the anti-CD30 monoclonal antibody-drug conjugate, brentuximab vedotin (BV), has shown remarkable activity in the setting of R/R cHL. In the pivotal phase II study, BV produced an overall response rate of 75% and a median progression-free survival of 6.7 months. Although these results have been reproduced by large registry studies, the impact of BV on the overall survival (OS) of patients with R/R cHL has not been addressed so far. The aim of this study was to examine the impact of BV on OS in the setting of post auto-SCT R/R cHL. Analysis was performed in a group of patients with R/R cHL after a previous auto-SCT reported in the Greek registry during the last 2 decades. By using a multivariate model and censoring patients at the time of subsequent allo-SCT or treatment with immune checkpoint inhibitors, we showed that treatment with BV in the posttransplant relapse setting has a positive impact on the outcome and results in significant improvement of OS. To our knowledge, this the first published study, addressing the impact of BV on the OS in the setting of posttransplant relapse.

Donor lymphocyte infusion (DLI) is an effective immunotherapeutic approach with significant activity in the treatment and prevention of relapse after allogeneic stem cell transplantation. DLI is associated with significant toxicity mainly due to graft-versus-host disease. Moreover, DLI does not produce durable responses in aggressive malignancies like acute leukemia. Improvement in DLI efficacy requires dissociation of graft-versus-leukemia effect from graft-versus-host disease. Minor histocompatibility antigens with tissue restriction and leukemia or tumor-associated antigens represent ideal antigenic targets. A brief overview of the existing methods of DLI administration is the topic of this article. T cells transduced with genes encoding for T-cell receptors with reactivity against minor histocompatibility antigens or leukemia-associated antigens is a promising option.