Addition of the nuclear export inhibitor selinexor to standard intensive treatment for elderly patients with acute myeloid leukemia and high risk myelodysplastic syndrome.

Treatment results of AML in elderly patients are unsatisfactory. In an open label randomized phase II study, we investigated whether addition of the XPO1 inhibitor selinexor to intensive chemotherapy would improve outcome in this population. 102 AML patients > 65 years of age (median 69 (65-80)) were randomly assigned to standard chemotherapy (3 + 7) with or without oral selinexor 60 mg twice weekly (both arms n = 51), days 1-24. In the second cycle, cytarabine 1000 mg/m2 twice daily, days 1-6 with or without selinexor was given. CR/CRi rates were significantly higher in the control arm than in the investigational arm (80% (95% C.I. 69-91%) vs. 59% (45-72%; p = 0.018), respectively). At 18 months, event-free survival was 45% for the control arm versus 26% for the investigational arm (Cox-p = 0.012) and overall survival 58% vs. 33%, respectively (p = 0.009). AML and infectious complications accounted for an increased death rate in the investigational arm. Irrespective of treatment, MRD status after two cycles appeared to be correlated with survival. We conclude that the addition of selinexor to standard chemotherapy does negatively affect the therapeutic outcome of elderly AML patients. (Netherlands Trial Registry number NL5748 (NTR5902), www.trialregister.nl ).

Monoclonal gammopathy with significance: case series and literature review.

Monoclonal gammopathy of undetermined significance (MGUS) is considered an asymptomatic precursor of malignant lymphoid disorders. This case series and literature review shows that these monoclonal gammopathies can cause significant morbidity. We describe a patient with angioedema due to acquired C1-esterase inhibitor deficiency, a patient with cryoglobulinemia type II causing skin vasculitis and glomerulonephritis, and a patient with glomerulonephritis and nephrotic syndrome - all caused by a monoclonal gammopathy that can be classified as MGUS. Clinicians should be familiar with these consequences of monoclonal gammopathies. The term MGUS should only be used in patients without organ damage caused by monoclonal gammopathies.

Perioperative bridging of anticoagulation: towards a more reserved approach.

BACKGROUND: Most invasive procedures require the interruption of oral anticoagulation. In 2015, an international randomised trial demonstrated that perioperative bridging caused more harm than benefit in most anticoagulated patients with atrial fibrillation, leading to a more restrictive Dutch national guideline in April 2016. The objective of the present study was to analyse the integration of the 2016 Dutch guideline for perioperative antithrombotic management from after publication until update of hospital protocols. METHODS: This is a retrospective cohort study of patients on vitamin K antagonists undergoing a surgical procedure between April 2016 and June 2017. RESULTS: The proportion of high-risk patients with venous thromboembolism or atrial fibrillation receiving bridging therapy decreased from 91% and 77%, respectively at the start of the study to 33% in both groups in the last months. In high-risk patients with a mechanical heart valve, the bridging rate remained stable at 70-80% for 12 months and increased to 100% in the last 3 months. Protocol adherence for high-risk patients decreased from 80% to below 43%. The 30-day incidence of major bleeding was 4.1% (15.2% in bridged patients and 0.7% in non-bridged patients) and 10.3% for clinically relevant non-major bleeding (23.9% in bridged patients and 6.0% in non-bridged patients). The incidence of thrombo-embolism was 0.5%. CONCLUSION: New evidence from the Dutch national guideline on perioperative bridging was adopted by physicians before the local hospital protocol was updated. Low incidence of thromboembolism in non-bridged patients and high incidence of bleeding in bridged patients support a more restrictive bridging policy.

Effect of thalidomide with melphalan and prednisone on health-related quality of life (HRQoL) in elderly patients with newly diagnosed multiple myeloma: a prospective analysis in a randomized trial.

Thalidomide with melphalan/prednisone (MPT) was defined as standard treatment in elderly patients with multiple myeloma (MM) based on five randomized trials. In one of these trials, HOVON49, a prospective health-related quality-of-life (HRQoL) study was initiated in order to assess the impact of thalidomide on QoL. Patients aged >65 years with newly diagnosed MM were randomized to receive melphalan plus prednisone (MP) or MPT, followed by thalidomide maintenance in the MPT arm. Two hundred eighty-four patients were included in this side study (MP, n=149; MPT n=135). HRQoL was assessed with the EORTC Core QoL Questionnaire (QLQ-C30) and the myeloma-specific module (QLQ-MY24) at baseline and at predetermined intervals during treatment. The QLQ-C30 subscales physical function (P=0.044) and constipation (P<0.001) showed an improvement during induction in favour of the MP arm. During thalidomide maintenance, the scores for the QLQ-MY24 paraesthesia became significantly higher in the MPT arm (P<0.001). The QLQ-C30 subscales pain (P=0.12), insomnia (P=0.068), appetite loss (P=0.074) and the QLQ-MY24 item sick (P=0.086) scored marginally better during thalidomide maintenance. The overall QoL-scale QLQ-C30-HRQoL showed a significant time trend towards more favourable mean values during protocol treatment without differences between MP and MPT. For the QLQ-C30 subscales emotional function and future perspectives, difference in favour of the MPT arm from the start of treatment was observed (P=0.018 and P=0.045, respectively) with no significant 'time × arm' interaction, indicating a persistent better patient perspective with MPT treatment. This study shows that the higher frequency of toxicity associated with MPT does not translate into a negative effect on HRQoL and that MPT holds a better patient perspective.