RE-MIND: Comparing Tafasitamab + Lenalidomide (L-MIND) with a Real-world Lenalidomide Monotherapy Cohort in Relapsed or Refractory Diffuse Large B-cell Lymphoma.

PURPOSE: Tafasitamab, an Fc-modified, humanized, anti-CD19 monoclonal antibody, in combination with lenalidomide, demonstrated efficacy in transplant-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), in the single-arm, phase II L-MIND study (NCT02399085). RE-MIND, a retrospective observational study, generated a historic control for L-MIND to delineate the contribution of tafasitamab to the efficacy of the combination. PATIENTS AND METHODS: Data were retrospectively collected from patients with R/R DLBCL treated with lenalidomide monotherapy for comparison with tafasitamab + lenalidomide-treated patients (L-MIND). Key eligibility criteria were aligned with L-MIND. Estimated propensity score-based Nearest Neighbor 1:1 Matching methodology balanced the cohorts for nine prespecified prognostic baseline covariates. The primary endpoint was investigator-assessed best overall response rate (ORR). Secondary endpoints included complete response (CR) rate, progression-free survival (PFS), and overall survival (OS). RESULTS: Data from 490 patients going through lenalidomide monotherapy were collected; 140 qualified for matching with the L-MIND cohort. The primary analysis included 76 patients from each cohort who received a lenalidomide starting dose of 25 mg/day. Cohort baseline covariates were comparable. A significantly better ORR of 67.1% (95% confidence interval, 55.4-77.5) was observed for the combination therapy versus 34.2% (23.7-46.0) for lenalidomide monotherapy [odds ratio, 3.89 (1.90-8.14); P < 0.0001]. Higher CR rates were achieved with combination therapy compared with lenalidomide monotherapy [39.5% (28.4-51.4) vs. 13.2% (6.5-22.9)]. Survival endpoints favored combination therapy. Lenalidomide monotherapy outcomes were similar to previously published data. CONCLUSIONS: RE-MIND enabled the estimation of the additional treatment effect achieved by combining tafasitamab with lenalidomide in patients with R/R DLBCL.

Lung deposition of a liposomal cyclosporine A inhalation solution in patients after lung transplantation.

BACKGROUND: Bronchiolitis obliterans is the most important long-term sequelae of lung transplantation limiting survival. Optimized immunosuppression, including inhalation of cyclosporine A (CsA), may be a promising approach to overcome this problem. METHODS: In this study a liposomal CsA solution was characterized in vitro, doses of 10 and 20 mg were inhaled with the PARI eFlow inhaler by 12 stable lung transplant recipients, and lung deposition was evaluated by gamma scintigraphy. RESULTS: Inhalation of CsA leads to lung deposition of 40 +/- 6% (10 mg) and 33 +/- 7% (20 mg), respectively. This deposition resulted in a peripheral lung dose of 2.0 +/- 0.4 mg (10 mg) and 3.4 +/- 0.8 mg (20 mg), respectively. Extrathoracic deposition was 16 +/- 6% (10 mg) and 14 +/- 4% (20 mg), respectively, and the total deposition was calculated with 56% (10 mg) and 46% (20 mg). Lung deposition and peripheral lung deposition increased significantly with treatment time. The maximum CsA blood concentration and the area under the time course of blood concentration correlated with peripheral lung deposition. There were no statistically significant differences between patients with single- and double-lung transplantation. Inhalation of the study medication was well tolerated, and led to only minor but statistically significant changes in lung function parameters (FEV(1): -0.07 L; FVC: -0.09 L; sRaw: +0.35 kPa s.). CONCLUSIONS: The new liposomal CsA PARI formulation can be deposited to the peripheral lung using the PARI eFlow nebulizer. The treatment was well tolerated, and no drug-related side effects were observed. Once or twice daily dosing of 10 mg CsA A PARI would result in a sufficient peripheral lung deposition of approximately 14 and 28 mg/week, respectively.

Comparative permeability and diffusion kinetics of cyclosporine A liposomes and propylene glycol solution from human lung tissue into human blood ex vivo.

Aerolized cyclosporine A (CsA) has been successfully used for prevention of organ rejection in lung transplant recipients. Various formulations of CsA are available and so far no direct comparison of their pharmacokinetics has been performed. Since clinical studies are elaborate, we sought a way to predict the kinetic behaviour of a propylene glycol solution of CsA (CsA-PG) and a liposomal formulation (L-CsA). The permeability across the human bronchial cell line Calu-3 revealed low permeability for CsA with the apparent permeability for CsA-PG being twice as high as for L-CsA. Employing a previously described dialysis model, the diffusion of CsA from human lung tissue into human blood was determined ex vivo. Consistent with the cell culture model results, we observed that the degree and rate of drug transfer into human blood was more pronounced for CsA-PG than for L-CsA with the area under the curve (AUC) of CsA-PG being about 1.6 times higher than for the L-CsA formulation. The diffusion rate was more than 50% higher from CsA-PG than from the liposomes. To conclude, both model systems consistently revealed that L-CsA displayed clearly a prolonged release effect and favourable longer tissue retention than CsA-PG.