Effectiveness of brentuximab vedotin monotherapy in relapsed or refractory Hodgkin lymphoma:a systematic review and meta-analysis

This systematic review and meta-analysis aimed to determine the effectiveness of brentuximab vedotin (BV) in relapsed/refractory classical Hodgkin lymphoma (R/R cHL) in the clinical practice setting using most recent results. A total of 32 observational studies reporting on treatment patterns, overall response rate (ORR), complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and adverse events were found. After four cycles, a random-effect model yielded pooled ORR and CR rates of 62.6% (95% confidence interval (CI): 56.0-68.9; I-2 = 9.7%) and 32.9% (95% CI, 20.8-46.3, I-2 = 64.8%), respectively. Regarding survival, 1-year, 2-year, and 5-year PFS ranged from 52.1% to 63.2%, 45.2% to 56.2%, and 31.9% to 33.0%, respectively. OS rates were 68.2-82.7%, 58.0-81.9%, and 58.0-62.0%, respectively. Most common adverse events were hematological toxicities (neutropenia: 13.3-23%, anemia: 8.8-39.0%, and thrombocytopenia: 4-4.6%), and grade >= 3 peripheral neuropathy (3.3-7.3%). This study supports the effectiveness and safety of BV in R/R cHL patients in the real-world setting

Alcohol reversibly disrupts TNF-α/TACE interactions in the cell membrane

BACKGROUND: Alcohol abuse has long been known to adversely affect innate and adaptive immune responses and pre-dispose to infections. One cellular mechanism responsible for this effect is alcohol-induced suppression of TNF-α (TNF) by mononuclear phagocytes. We have previously shown that alcohol in part inhibits TNF-α processing by TNF converting enzyme (TACE) in human monocytes. We hypothesized that the chain length of the alcohol is critical for post-transcriptional suppression of TNF secretion. METHODS: Due to the complex transcriptional and post-transcriptional regulation of TNF in macrophages, to specifically study TNF processing at the cell membrane we performed transient transfections of A549 cells with the TNF cDNA driven by the heterologous CMV promoter. TNF/TACE interactions at the cell surface were assessed using fluorescent resonance energy transfer (FRET) microscopy. RESULTS: The single carbon alcohol, methanol suppressed neither TNF secretion nor FRET efficiency between TNF and TACE. However, 2, 3, and 4 carbon alcohols were potent suppressors of TNF processing and FRET efficiency. The effect of ethanol, a 2-carbon alcohol was reversible. CONCLUSION: These data show that inhibition of TNF-α processing by acute ethanol is a direct affect of ethanol on the cell membrane and is reversible upon cessation or metabolism

Follow-up of the GHSG HD16 trial of PET-guided treatment in early-stage favorable Hodgkin lymphoma.

The primary analysis of the GHSG HD16 trial indicated a significant loss of tumor control with PET-guided omission of radiotherapy (RT) in patients with early-stage favorable Hodgkin lymphoma (HL). This analysis reports long-term outcomes. Overall, 1150 patients aged 18-75 years with newly diagnosed early-stage favorable HL were randomized between standard combined-modality treatment (CMT) (2x ABVD followed by PET/CT [PET-2] and 20 Gy involved-field RT) and PET-2-guided treatment omitting RT in case of PET-2 negativity (Deauville score [DS] < 3). The study aimed at excluding inferiority of PET-2-guided treatment and assessing the prognostic impact of PET-2 in patients receiving CMT. At a median follow-up of 64 months, PET-2-negative patients had a 5-year progression-free survival (PFS) of 94.2% after CMT (n = 328) and 86.7% after ABVD alone (n = 300; HR = 2.05 [1.20-3.51]; p = 0.0072). 5-year OS was 98.3% and 98.8%, respectively (p = 0.14); 4/12 documented deaths were caused by second primary malignancies and only one by HL. Among patients assigned to CMT, 5-year PFS was better in PET-2-negative (n = 353; 94.0%) than in PET-2-positive patients (n = 340; 90.3%; p = 0.012). The difference was more pronounced when using DS4 as cut-off (DS 1-3: n = 571; 94.0% vs. DS ≥ 4: n = 122; 83.6%; p < 0.0001). Taken together, CMT should be considered standard treatment for early-stage favorable HL irrespective of the PET-2-result

PKCα and PKCδ Regulate ADAM17-Mediated Ectodomain Shedding of Heparin Binding-EGF through Separate Pathways

Epidermal growth factor receptor (EGFR) signalling is initiated by the release of EGFR-ligands from membrane-anchored precursors, a process termed ectodomain shedding. This proteolytic event, mainly executed by A Disintegrin And Metalloproteases (ADAMs), is regulated by a number of signal transduction pathways, most notably those involving protein kinase C (PKC). However, the molecular mechanisms of PKC-dependent ectodomain shedding of EGFR-ligands, including the involvement of specific PKC isoforms and possible functional redundancy, are poorly understood. To address this issue, we employed a cell-based system of PMA-induced PKC activation coupled with shedding of heparin binding (HB)-EGF. In agreement with previous studies, we demonstrated that PMA triggers a rapid ADAM17-mediated release of HB-EGF. However, PMA-treatment also results in a protease-independent loss of cell surface HB-EGF. We identified PKCα as the key participant in the activation of ADAM17 and suggest that it acts in parallel with a pathway linking PKCδ and ERK activity. While PKCα specifically regulated PMA-induced shedding, PKCδ and ERK influenced both constitutive and inducible shedding by apparently affecting the level of HB-EGF on the cell surface. Together, these findings indicate the existence of multiple modes of regulation controlling EGFR-ligand availability and subsequent EGFR signal transduction

Relapsed or refractory classical Hodgkin's lymphoma. Novel therapeutic approaches

Classical Hodgkin's lymphoma is highly curable with risk-adapted first-line therapy. Despite a reduction of potential therapy-associated short-term and long-term toxicities, treatment of patients with relapsed or primary refractory disease (r/r HL) remains a clinical challenge. This review summarizes the currently available data regarding safety and efficacy of different therapeutic approaches in r/r HL and provides recommendations for specific clinical situations. Up to 50% of patients eligible for intensified therapies achieve long-term remission after high-dose chemotherapy and autologous stem cell transplantation (ASCT); however, multiple relapsed, refractory, elderly or frail patients until recently had an unfavorable prognosis with mostly palliative therapy. The anti-CD30 antibody-drug conjugate brentuximab vedotin (BV) constitutes a highly effective and tolerable therapeutic option with some durable complete remissions. Accordingly, BV has been approved for r/r HL after ASCT or two prior therapies. More recently, two checkpoint inhibitors, i.aEuroe., the anti-PD1 antibodies nivolumab and pembrolizumab were also investigated in heavily pretreated r/r HL patients. Both drugs were very well tolerated and resulted in high response rates with long-lasting remission. Nivolumab and pembrolizumab were recently approved for r/r HL after prior treatment with BV. In addition, other targeted drugs, such as AFM13, everolimus, panobinostat, mocetinostat as well as agents, such as lenalidomide or bendamustine showed activity in intensively pretreated r/r HL patients

Novel therapeutic approaches in relapsed or refractory Hodgkin lymphoma

Background While classical Hodgkin lymphoma (HL) is curable in most cases with risk-adapted first-line therapy, the treatment of patients with relapsed or primary refractory (r/r) HL in particular remains a challenge. Methods This review article discusses the currently available data on the safety and efficacy of newer therapeutic approaches for r/r HL from a practice-oriented perspective. Results In patients suitable for intensified therapy, durable remission can be achieved in approximately 50% of cases with polychemotherapy-based salvage followed by high-dose chemotherapy with autologous stem cell transplantation (ASCT). With the approval of targeted agents, even multiply relapsed, refractory, elderly, or multimorbid patients now have multiple treatment options. In addition to the anti-CD30 antibody-drug conjugate brentuximab vedotin (BV), the two anti-PD1 antibodies nivolumab and pembrolizumab are increasingly being used here as immune checkpoint inhibitors. The anti-PD1 antibodies are also used in earlier lines of therapy, e.g., significantly longer progression-free survival (PFS), was achieved with pembrolizumab in an international phase III trial compared to BV with comparable response rates. The therapeutic landscape of r/r HL is rapidly changing and additional promising targeted agents such as the antibody-drug conjugate camidanlumab tesirine, different checkpoint inhibitors, and anti-CD30 CAR T cells are currently being tested in trials. Conclusions Rational use of available therapeutic approaches is expected to improve the prognosis of patients with multiple r/r HL