RBC-transfusion dependence is common in persons with myeloproliferative neoplasm (MPN)-associated myelofibrosis. The objective of this study was to determine the rates of RBC-transfusion independence after therapy with pomalidomide vs placebo in persons with MPN-associated myelofibrosis and RBC-transfusion dependence. Two hundred and fifty-two subjects (intent-to-treat (ITT) population) including 229 subjects confirmed by central review (modified ITT population) were randomly assigned (2:1) to pomalidomide or placebo. Trialists and subjects were blinded to treatment allocation. Primary end point was proportion of subjects achieving RBC-transfusion independence within 6 months. One hundred and fifty-two subjects received pomalidomide and 77 placebo. Response rates were 16% (95% confidence interval (CI), 11, 23%) vs 16% (8, 26% P=0.87). Response in the pomalidomide cohort was associated with ⩽4 U RBC/28 days (odds ratio (OR)=3.1; 0.9, 11.1), age ⩽65 (OR=2.3; 0.9, 5.5) and type of MPN-associated myelofibrosis (OR=2.6; 0.7, 9.5). Responses in the placebo cohort were associated with ⩽4 U RBC/28 days (OR=8.6; 0.9, 82.3), white blood cell at randomization >25 × 109/l (OR=4.9; 0.8, 28.9) and interval from diagnosis to randomization >2 years (OR=4.9; 1.1, 21.9). Pomalidomide was associated with increased rates of oedema and neutropenia but these adverse effects were manageable. Pomalidomide and placebo had similar RBC-transfusion-independence response rates in persons with MPN-associated RBC-transfusion dependence.

Bortezomib, a proteasome inhibitor, is extremely effective for the treatment of multiple myeloma (MM). However, nearly all patients will eventually become refractory to bortezomib. Vorinostat is a potent inhibitor of histone deacetylase enzymes, and has been shown to affect growth of various cell lines, including MM, in a variety of in vitro non-clinical studies. Furthermore, the combination of bortezomib and vorinostat has demonstrated synergy in several in vitro and murine models. Subsequently, 2 multicenter, open-label, Phase I clinical trials have been conducted to investigate the combination of vorinostat with bortezomib in patients with MM. In the first trial, 34 patients with relapsed/refractory MM were enrolled. Patients received escalating doses of vorinostat (200 mg bid or 300–400 mg daily for 14 days) and bortezomib (0.7, 0.9, 1.1, or 1.3 mg/m2 on days 1, 4, 8, and 11); cycles were repeated every 21 days for ≤8 cycles or until progressive disease (PD) or intolerable toxicity. In the event of PD, oral dexamethasone (20 mg on days 1–4 and 17–20) could be added to the bortezomib plus vorinostat combination. The highest dose level of vorinostat was 400 mg daily for 14 days and bortezomib 1.3 mg/m2. The maximum tolerated dose (MTD) was not determined because ≥2 dose-limiting toxicities (DLTs) did not occur at any dose level. The most common drug-related adverse events were nausea (61.8%), diarrhea (58.8%), thrombocytopenia (50%), and vomiting (50%). Two patients experienced a DLT; grade 3 transient AST elevation was experienced by 1 patient receiving 400 mg vorinostat daily and 0.9 mg/m2 bortezomib, and grade 4 thrombocytopenia was experienced by 1 patient receiving 400 mg vorinostat daily and 1.3 mg/m2 bortezomib. Among 34 evaluable patients, the best response to vorinostat plus bortezomib was a partial response (PR) in 9 (26%) patients, minimal response (MR) in 7 (21%) patients, and stable disease (SD) in 18 (53%) patients. Mean duration of SD was 89 days, range 9–369 days. Of the 13 evaluable patients who had previously been treated with bortezomib, 5 achieved a PR, 1 had a MR, and 7 had SD. The effect of adding dexamethasone will also be analyzed and presented. The second trial enrolled 23 patients who received vorinostat (100–500 mg on days 4–11) and bortezomib (1–1.3 mg/m2 on days 1, 4, 8, and 11). Dexamethasone was added at cycle 2 for 6 patients who achieved less than a PR, and at cycle 4 for 5 patients with PD and at cycle 6 for 2 patients with PD. There was no upgrade in response for any patients who received additional dexamethasone. Two patients in the vorinostat 500 mg group experienced DLT (fatigue and prolonged QTc); MTD was identified as vorinostat 400 mg plus bortezomib 1.3 mg/m2. The main toxicities in this trial were hematologic (anemia, neutropenia, and thrombocytopenia). Twenty-one patients were evaluable for response (2 achieved very good PR, 7 PR, 10 SD, 2 progressive PD). Of the 9 patients who were refractory to bortezomib, 3 had PR, 4 had SD, 1 had PD, and 1 was non-evaluable. Co-administration of bortezomib did not alter the pharmacokinetics of vorinostat. In conclusion, these data suggest that the combination of vorinostat plus bortezomib is active for treatment of MM, even among some patients with prior exposure to bortezomib.

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Background: Over the past years, several emergency medical service providers have introduced mechanical chest compression devices (MCDs) in their protocols for cardiopulmonary resuscitation (CPR). Especially in helicopter emergency medical systems (HEMS), which have limitations regarding loading weight and space and typically operate in rural and remote areas, whether MCDs have benefits for patients is still unknown. The aim of this study was to evaluate the use of MCDs in a large Swiss HEMS system. Materials and methods: We conducted a retrospective observational study of all HEMS missions of Swiss Air rescue Rega between January 2014 and June 2016 with the use of an MCD (Autopulse®). Details of MCD use and patient outcome are reported from the medical operation journals and the hospitals' discharge letters. Results: MCDs were used in 626 HEMS missions, and 590 patients (94%) could be included. 478 (81%) were primary missions and 112 (19%) were interhospital transfers. Forty-nine of the patients in primary missions were loaded under ongoing CPR with MCDs. Of the patients loaded after return of spontaneous circulation (ROSC), 20 (7%) experienced a second CA during the flight. In interhospital transfers, 102 (91%) only needed standby use of the MCD. Five (5%) patients were loaded into the helicopter with ongoing CPR. Five (5%) patients went into CA during flight and the MCD had to be activated. A shockable cardiac arrhythmia was the only factor significantly associated with better survival in resuscitation missions using MCD (OR 0.176, 95% confidence interval 0.084 to 0.372, p < 0.001). Conclusion: We conclude that equipping HEMS with MCDs may be beneficial, with non-trauma patients potentially benefitting more than trauma patients.