Background: Progressive multifocal leukoencephalopathy is a demyelinating CNS disorder. Reactivation of John Cunningham virus leads to oligodendrocyte infection with lysis and consequent axonal loss due to demyelination. Patients usually present with confusion and seizures. Late diagnosis and lack of adequate therapy options persistently result in permanent impairment of brain functions. Due to profound T cell depletion, impairment of T-cell function and potent immunosuppressive factors, allogeneic hematopoietic cell transplantation recipients are at high risk for JCV reactivation. To date, PML is almost universally fatal when occurring after allo-HCT. Methods:To optimize therapy specificity, we enriched JCV specific T-cells out of the donor T-cell repertoire from the HLA-identical, anti-JCV-antibody positive family stem cell donor by unstimulated peripheral apheresis [1]. For this, we selected T cells responsive to five JCV peptide libraries via the Cytokine Capture System technology. It enables the enrichment of JCV specific T cells via identification of stimulus-induced interferon gamma secretion. Results:Despite low frequencies of responsive T cells, we succeeded in generating a product containing 20 000 JCV reactive T cells ready for patient infusion. The adoptive cell transfer was performed without complication. Consequently, the clinical course stabilized and the patient slowly went into remission of PML with JCV negative CSF and containment of PML lesion expansion. Conclusion:We report for the first time feasibility of generating T cells with possible anti-JCV activity from a seropositive family donor, a variation of virus specific T-cell therapies suitable for the post allo transplant setting. We also present the unusual case for successful treatment of PML after allo-HCT via virus specific T-cell therapy.

Background The objective of this study was to assess the durability of response of dolutegravir (DTG) as an antiretroviral core agent by comparing its efficacy and safety with other recommended or commonly used core agents up to 96-weeks (W96). Methods A previously published systematic review was updated to identify phase 3/4 randomised controlled trials (RCTs) of core agents in treatment-naïve HIV-1 patients. Efficacy [virologic suppression (VS), CD4+ cell change from baseline] and safety [adverse events [AEs], discontinuations, drug-related AEs [DRAEs]] were analysed at W96 using Bayesian network meta-analysis (NMA) adjusting for nucleoside/nucleotide reverse transcriptase inhibitors' (NRTIs') backbone. Subgroups of patients with VL > 100,000 copies/mL or CD4+ ≤ 200 cells/μL at baseline were analysed separately. Results The NMA included 20 studies reporting data at W96. A higher proportion of patients receiving DTG achieved VS compared to those on protease inhibitors [PI:Range:8.7%(CrI:3.1,16.0)-19.9%(10.8,30.5)], efavirenz [EFV:6.9%(1.3,10.8)] and cobicistat-boosted elvitegravir [EVG/c:8.2%(0.2,17.4)], and similar but numerically higher compared to rilpivirine [RPV:5.0%(− 2.8,12.5)], raltegravir [RAL:2.9%(− 1.6,7.7)] and bictegravir [BIC:2.7%(− 2.7,10.6)]. The probability that more patients on DTG would achieve VS at W96 compared to any other core agent was greater than 80%. A higher proportion of patients on DTG achieved VS compared to PI/rs [Range:33.1%(13.6,50.4)-45.3%(24.1,61.6)] and RAL [16.7%(3.3,31.2)] in patients with VL > 100,000 copies/mL at baseline, and similar VS was achieved in patients with CD4+ ≤ 200 cells/μL at baseline. DTG also achieved greater increase in CD4+ cells from baseline compared to EFV [32.6(10.7,54.7)], ritonavir-boosted darunavir [DRV/r:25.7(3.6,48.1)] and BIC [24.7(1.5,47.7)]. Patients receiving DTG had lower odds of discontinuing therapy by W96 compared to PI/rs, EFV, RAL and EVG/c. Patients on DTG had lower odds of experiencing an adverse event (AE) compared to patients on EFV [odds ratio:0.6(0.3,0.9)], ATV/r [0.4(0.3,0.6)] and LPV/r [0.3(0.2,0.5)]. For patients on DTG, the odds of experiencing a drug-related AE were lower than the odds for patients on EFV [0.3(0.2,0.4)], comparable to patients on RAL [1.1(0.8,1.4)] and higher than those on BIC [1.5(1.1,2.0)]. Conclusion Un-boosted integrase inhibitors had better efficacy and similar safety compared to PI/rs at W96 in treatment-naïve patients with HIV-1, with DTG being among the most efficacious core agent, particularly in patients with baseline VL > 100,000 copies/mL or ≤ 200 CD4+ cells/μL, who can be difficult to treat.

<b><i>Background:</i></b> Multiple myeloma is the second most common hematologic malignancy, which to date remains incurable despite advances in treatment strategies including the use of novel substances such as proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. <b><i>Summary:</i></b> The bone marrow-based disease is preceded by the 2 sequential premalignant conditions: monoclonal gammo­pathy of undetermined significance and smoldering myeloma. Plasma cell leukemia and extramedullary disease occur, when malignant clones lose their dependency on the bone marrow. Key genetic features of these plasma cell dyscrasias include chromosomal aberrations such as translocations and hyperdiploidy, which occur during error-prone physiologic processes in B-cell development. Next-generation sequencing studies have identified mutations in major oncogenic pathways and tumor suppressors, which contribute to the pathogenesis of multiple myeloma and have revealed insights into the clonal evolution of the disease, particularly along different lines of therapy. More recently, the importance of epigenetic alterations and the role of the bone marrow microenvironment, including immune and osteogenic cells, have become evident. <b><i>Key Messages:</i></b> We herein review the current knowledge of the pathogenesis of multiple myeloma, which is crucial for the development of novel targeted therapeutic strategies. These can contribute to the endeavor to make multiple myeloma a curable disease.

Purpose To assess, from a United States (US) perspective, the cost-effectiveness of chemotherapy-induced nausea and vomiting (CINV) prophylaxis using a single dose of netupitant and palonosetron in a fixed combination (NEPA) versus aprepitant plus granisetron (APR + GRAN), each in combination with dexamethasone, in chemotherapy-naïve patients receiving highly emetogenic chemotherapy (HEC). Methods We analyzed patient-level outcomes over a 5-day post-HEC period from a randomized, double-blind, phase 3 clinical trial of NEPA (n = 412) versus APR + GRAN (n = 416). Costs and CINV-related utilities were assigned to each subject using published sources. Parameter uncertainty was addressed via multivariate probabilistic sensitivity analyses (PSA). Results Compared to APR + GRAN, NEPA resulted in a gain of 0.09 quality-adjusted life-days (QALDs) (4.04 vs 3.95; 95% CI −0.06 to 0.25