First-line daratumumab shows high efficacy and tolerability even in advanced AL amyloidosis: the real-world experience.

BACKGROUND: Daratumumab was the first monoclonal CD38 antibody with single-agent activity approved for the treatment of multiple myeloma. Moreover, daratumumab demonstrated high response rates in relapsed immunoglobulin light-chain (AL) amyloidosis. PATIENTS AND METHODS: In our single-center retrospective real-life case series, we analyzed the efficacy and safety of daratumumab as first-line treatment. Daratumumab was administered with low-dose dexamethasone alone or in combination with other multiple myeloma therapeutics RESULTS: Fourteen patients were eligible, including nine patients with cardiac stage IIIa or IIIb. Overall hematologic response rate was 100%, with 64.3% achieving complete response after a median of 16 cycles of treatment. Median time to hematologic response was 1.4 months. Organ response rates were 45.5% after a median of 4.0 months and 66.7% after a median of 10.0 months, for heart and kidney involvement, respectively. After a median follow-up of 20.5 months, two patients underwent successful autologous stem cell transplantation (ASCT), while another three patients were in preparation for ASCT. Three patients remained on daratumumab at the last follow-up. There were no unexpected toxicities and no grade III or IV adverse events, although more than half of our patients were in stage IIIa or IIIb. CONCLUSION: Daratumumab proved to be highly effective in newly diagnosed AL amyloidosis with excellent hematologic and organ response rates, a remarkable safety profile, and good tolerability even in patients with advanced stage of disease.

Post-transplantation diabetes mellitus: evaluation of treatment strategies.

BACKGROUND: Post-transplantation diabetes mellitus (PTDM) is a serious complication after kidney transplantation, but evidence regarding long-term outcomes of treatment regimens remains scarce. AIM AND METHODS: The aim of this retrospective cohort analysis was to assess the long-term efficiency and safety of antidiabetic treatments in kidney transplant recipients (KTRs), who were diagnosed with PTDM by an oral glucose tolerance test (OGTT). RESULTS: Of 561 KTRs that were screened for PTDM at our outpatient clinic, 71 (13%) had a diabetic OGTT and were included in this study. Mean follow-up was 34.2 ± 16.1 months. Thirty-six PTDM patients (51%) received antidiabetic treatment after diagnosis with either a dipeptidyl peptidase-4 (DPP-4) inhibitor, a sulfonylurea, pioglitazone, or insulin. These patients had significantly higher fasting glucose and two-h plasma glucose (2HPG) values at baseline than those who remained without therapy. In contrast to lifestyle modification alone or sulfonylureas, DPP-4 inhibitors improved glycemic control significantly. Adverse events were generally mild and occurred at similar rates in all groups. CONCLUSION: While sulfonylureas failed to improve glycemic control, DPP-4 inhibitors appeared effective and safe for the therapy of PTDM after kidney transplantation.

Efficacy and safety of vildagliptin in new-onset diabetes after kidney transplantation--a randomized, double-blind, placebo-controlled trial.

New-onset diabetes after transplantation (NODAT) is a serious complication after kidney transplantation, but therapeutic strategies remain underexplored. Dipeptidyl peptidase-4 (DPP-4) inhibitors selectively foster insulin secretion without inducing hypoglycemia, which might be advantageous in kidney transplant recipients (KTRs) with NODAT. We conducted a randomized, double-blind, placebo-controlled, phase II trial to assess safety and efficacy of the DPP-4 inhibitor vildagliptin. Intraindividual differences in oral glucose tolerance test (OGTT)-derived 2-h plasma glucose (2HPG) from baseline to 3 months after treatment served as primary endpoint. Among secondary outcomes, we evaluated HbA1c, metabolic and safety parameters, as well as OGTTs at 1 month after drug discontinuation. Of 509 stable KTRs who were screened in our outpatient clinic, 63 (12.4%) had 2HPG ≥ 200 mg/dL, 33 of them were randomized and 32 completed the study. In the vildagliptin group 2HPG and HbA1c were profoundly reduced in comparison to placebo (vildagliptin: 2HPG = 182.7 mg/dL, HbA1c = 6.1%; placebo: 2HPG = 231.2 mg/dL, HbA1c = 6.5%; both p ≤ 0.05), and statistical significance was achieved for the primary endpoint (vildagliptin: 2HPG-difference -73.7 ± 51.3 mg/dL; placebo: -5.7 ± 41.4 mg/dL; p < 0.01). Adverse events were generally mild and occurred at similar rates in both groups. In conclusion, DPP-4 inhibition in KTRs with overt NODAT was safe and efficient, providing a novel treatment alternative for this specific form of diabetes.

CMV late phase-induced mTOR activation is essential for efficient virus replication in polarized human macrophages.

Human cytomegalovirus (CMV) remains one of the most important pathogens following solid-organ transplantation. Mounting evidence indicates that mammalian target of rapamycin (mTOR) inhibitors may decrease the incidence of CMV infection in solid-organ recipients. Here we aimed at elucidating the molecular mechanisms of this effect by employing a human CMV (HCMV) infection model in human macrophages, since myeloid cells are the principal in vivo targets of HCMV. We demonstrate a highly divergent host cell permissiveness for HCMV with optimal infection susceptibility in M2 but not M1 polarized macrophages. Employing an ultrahigh purified HCMV stock we observed rapamycin-independent viral entry and induction of IFN-ß transcripts, but no proinflammatory cytokines or mitogen-activated protein kinases and mTOR activation early after infection. However, in the late infection phase, sustained mTOR activation was observed in HCMV-infected cells and was required for efficient viral protein synthesis including the viral late phase proteins pUL-44 and pp65. Accordingly, rapamycin strongly suppressed CMV replication 3 and 5 days postinfection in macrophages. In conclusion, these data indicate that mTOR is essential for virus replication during late phases of the viral cycle in myeloid cells and might explain the potent anti-CMV effects of mTOR inhibitors after organ transplantation.