Phase 2 studies of lenalidomide, subcutaneous bortezomib, and dexamethasone as induction therapy in patients with newly diagnosed multiple myeloma.

There are limited prospective data on lenalidomide, subcutaneous bortezomib, and dexamethasone (RsqVd) in transplant-eligible/transplant-ineligible patients with newly diagnosed multiple myeloma. Reliable biomarkers for efficacy and toxicity are required to better tailor therapy. Two parallel studies were conducted by Cancer Trials Ireland (CTI; NCT02219178) and the Dana-Farber Cancer Institute (DFCI; NCT02441686). Patients received four 21-day cycles of RsqVd and could then receive either another 4 cycles of RsqVd or undergo autologous stem cell transplant. Postinduction/posttransplant, patients received lenalidomide maintenance, with bortezomib included for high-risk patients. The primary endpoint was overall response rate (ORR) after 4 cycles of RsqVd. Eighty-eight patients were enrolled and 84 treated across the two studies; median age was 64.7 (CTI study) and 60.0 years (DFCI study), and 59% and 57% had stage II-III disease. Pooled ORR after 4 cycles in evaluable patients was 93.5%, including 48.1% complete or very good partial responses (CTI study: 91.9%, 59.5%; DFCI study: 95.0%, 37.5%), and in the all-treated population was 85.7% (44.0%). Patients received a median of 4 (CTI study) and 8 (DFCI study) RsqVd cycles; 60% and 31% of patients (CTI study) and 33% and 51% of patients (DFCI study) underwent transplant or received further RsqVd induction, respectively. The most common toxicity was peripheral neuropathy (pooled: 68%, 7% grade 3-4; CTI study: 57%, 7%; DFCI study: 79%, 7%). Proteomics analyses indicated elevated kallikrein-6 in good versus poor responders, decreased midkine in good responders, and elevated macrophage inflammatory protein 1-alpha in patients who stopped treatment from neurotoxicity, suggesting predictive biomarkers warranting further investigation.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) - a novel clinico-pathological entity with heterogeneous clinical presentations.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a novel entity that emerged in March 2021 following reports of unusual thrombosis after ChAdOx1 nCoV-19, (AstraZeneca) vaccination. Following the recognition of this syndrome, multiple consensus guidelines have been released to risk stratify patients presenting with possible symptoms after ChAdOx1 nCoV-19 vaccination. All guidelines rapidly identify VITT in patients with the complete triad of thrombocytopenia, thrombosis and elevated D-dimers after ChAdOx1 nCoV-19 vaccination. However, with earlier recognition of the associated symptoms, the clinical manifestations are likely to be more heterogeneous and represent an evolving spectrum of disease. In this setting, current guidelines may lack the sensitivity to detect early cases of VITT and risk missed or delayed diagnoses. The broad clinical phenotype and challenges associated with diagnosis of VITT are highlighted in our present case series of four patients with confirmed VITT. Dependent on the guidance used, each patient could have been classified as a low probability of VITT at presentation. The present study highlights the issues associated with the recognition of VITT, the limitations of current guidance and the need for heightened clinical vigilance as our understanding of the pathophysiology of this novel condition evolves.

Inherited thrombophilia testing in a large tertiary hospital in New Zealand: implementation of a Choosing Wisely protocol to reduce unnecessary testing and costs.

AIM: To evaluate the practice of inherited thrombophilia testing at Waikato Hospital Laboratory, benchmarked against the British Society of Haematology (BSH) guidelines with the plan to reduce unnecessary testing. METHODS: We retrospectively reviewed data on all inherited thrombophilia tests performed in the Waikato Hospital Laboratory during August 2015. We then established a local Choosing Wisely guideline for testing. A clinical and laboratory programme was developed to facilitate the implementation of this guideline. Ordering practices were re-evaluated six months after the implementation of the Choosing Wisely programme. RESULTS: Of the 94 requests received in August 2015, only one complied with BSH guidelines. Most abnormal results did not change the clinical management of patients. In the first six months following the implementation of our intervention, there was a significant reduction of tests performed with an estimated savings of $118,000. CONCLUSIONS: The majority of inherited thrombophilia tests performed in our laboratory did not comply with BSH guidelines. A multimodal inherited thrombophilia Choosing Wisely programme was successful in reducing unnecessary testing. A laboratory protocol that required screening of every inherited thrombophilia request by a haematologist was necessary for the success of this programme.

Unusual case of antiphospholipid syndrome presenting as adrenal insufficiency.

A 64-year-old man presented to the emergency department with generalised fatigue and dizzy spells. His background history includes a previous admission with right leg deep vein thrombosis, provoked by pneumonia. Laboratory results showed evidence of hyponatremia and hyperkalaemia. A synacthen test was performed that indicated hypoadrenalism. CT of his abdomen revealed enlarged adrenal glands bilaterally. Adrenal antibodies and positron emission tomography (PET) scan were performed to assess the cause of enlarged adrenals. PET scan showed no evidence of increased uptake. Adrenal antibodies were found to be negative. Tuberculous (TB) adrenalitis was the principle differential diagnosis. TB QuantiFERON was strongly positive. Following 9 months of TB treatment, surveillance CT scan indicated a significant reduction in adrenal gland size. However, subsequent events culminated in a retrospective review of CT scans questioning the initial clinical diagnosis and suggesting that the observed adrenal gland enlargement was secondary to bilateral adrenal infarction and haemorrhage. Equally, the subsequently observed marked reduction in adrenal gland size was not secondary to an assumed response to TB therapy, but rather the sequela of infracted atrophied adrenal glands, as a manifestation of the underlying antiphospholipid syndrome (APS). The case highlights the importance of recognising adrenal insufficiency in patients with a history of APS. It also illustrates the role of multidisciplinary meetings in the management of such complex cases.

Pneumocystis jiroveci prophylaxis in patients undergoing Bendamustine treatment: the need for a standardized protocol.

The decision for PJP prophylaxis depends on a physician's evaluation of multiple variables. The high rate of PJP infection described in this article combined with the known impaired T-cell function post Bendamustine treatment justifies considering all patients for PJP prophylaxis when they receive Bendamustine treatment.

D-dimer testing to select patients with a first unprovoked venous thromboembolism who can stop anticoagulant therapy: a cohort study.

BACKGROUND: Normal D-dimer levels after withdrawal of anticoagulant therapy are associated with a reduced risk for recurrence in patients with unprovoked venous thromboembolism (VTE) and may justify stopping treatment. OBJECTIVE: To determine whether patients with a first unprovoked VTE and negative D-dimer test result who stop anticoagulant therapy have a low risk for recurrence. DESIGN: Prospective management study with blinded outcome assessment. (ClinicalTrials.gov: NCT00720915). SETTING: 13 university-affiliated clinical centers. PATIENTS: 410 adults aged 75 years or younger with a first unprovoked proximal deep venous thrombosis or pulmonary embolism who had completed 3 to 7 months of anticoagulant therapy. INTERVENTION: Anticoagulant therapy was stopped if D-dimer test results were negative and was not restarted if results were still negative after 1 month. MEASUREMENTS: Recurrent VTE during an average follow-up of 2.2 years. RESULTS: In 319 patients (78%) who had 2 negative D-dimer results and did not restart anticoagulant therapy, rates of recurrent VTE were 6.7% (95% CI, 4.8% to 9.0%) per patient-year overall (42 of 319), 9.7% (CI, 6.7% to 13.7%) per patient-year in men (33 of 180), 5.4% (CI, 2.5% to 10.2%) per patient-year in women with VTE not associated with estrogen therapy (9 of 81), and 0.0% (CI, 0.0% to 3.0%) per patient-year in women with VTE associated with estrogen therapy (0 of 58) (P = 0.001 for the 3-group comparison). LIMITATIONS: Imprecision in female subgroups. Results may not be generalizable to different D-dimer assays from the one used in the study. CONCLUSION: The risk for recurrence in patients with a first unprovoked VTE who have negative D-dimer results is not low enough to justify stopping anticoagulant therapy in men but may be low enough to justify stopping therapy in women. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research.

A multi-centre retrospective study of rituximab use in the treatment of relapsed or resistant warm autoimmune haemolytic anaemia.

This retrospective analysis assessed the response, safety and duration of response to standard dose rituximab 375 mg/m(2) weekly for four weeks as therapy for patients with primary or secondary warm autoimmune haemolytic anaemia (WAIHA), who had failed initial treatment. Thirty-four patients received rituximab for WAIHA in seven centres in the Republic of Ireland. The overall response rate was 70·6% (24/34) with 26·5% (9/34) achieving a complete response (CR). The time to response was 1 month post-initiation of rituximab in 87·5% (21/24) and 3 months in 12·5% (3/24) of patients. The median duration of follow-up was 36 months (range 6-90 months). Of the patients who responded, 50% (12/24) relapsed during follow up with a median time to next treatment of 16·5 months (range 6-60 months). Three patients were re-treated with rituximab 375 mg/m2 weekly for four weeks at relapse and responded. There was a single episode of neutropenic sepsis. Rituximab is an effective and safe treatment for WAIHA but a significant number of patients will relapse in the first two years post treatment. Re-treatment was effective in a small number of patients, suggesting that intermittent pulse treatment or maintenance treatment may improve long-term response.

An assessment of the utility of unselected coagulation screening in general hospital practice.

Coagulation screening using prothrombin time (PT) and activated partial thromboplastin time (APTT) is widely used. We performed an audit of coagulation screening in an Irish teaching hospital. We analysed PT and/or APTT results received during normal working hours during a 1-week period in our hospital. Abnormal results due to anticoagulants were excluded from further study. In samples with PT longer than 15.5 s and/or APTT longer than 42 s, we proceeded to 1: 1 mixing studies if the PT was prolonged and 1: 1 mixing studies, factor XII assay and lupus screen if the APTT was prolonged. We also obtained referral source for all samples and clinical details for abnormal samples. Six hundred and seventy-one coagulation requests were received during the study period. Three hundred and eighteen of 671 (47.4%) coagulation requests were for monitoring of anticoagulation. Three hundred and fifty-three of 671 (52.6%) requests were for coagulation screening rather than anticoagulant monitoring. In the coagulation screens received, PT was prolonged in 19 of 353 (5.4%). PT was longer than 20 s in four of 353 cases (1.1%). APTT was prolonged in 19 of 353 (5.4%). APTT was longer than 50 s in four of 353 (1.1%). No patients with abnormal PT or APTT had any bleeding sequelae during the study period. Unregulated coagulation screening has a low yield of abnormal results; the majority of these abnormal results show mild prolongation of PT or APTT with no evidence that they are associated with an increased bleeding risk.

The heparin binding properties of heparin cofactor II suggest an antithrombin-like activation mechanism.

The serpin heparin cofactor II (HCII) is a glycosaminoglycan-activated inhibitor of thrombin that circulates at a high concentration in the blood. The antithrombotic effect of heparin, however, is due primarily to the specific interaction of a fraction of heparin chains with the related serpin antithrombin (AT). What currently prevents selective therapeutic activation of HCII is the lack of knowledge of the determinants of glycosaminoglycan binding specificity. In this report we investigate the heparin binding properties of HCII and conclude that binding is nonspecific with a minimal heparin length of 13 monosaccharide units required and affinity critically dependent on ionic strength. Rapid kinetics of heparin binding indicate an induced fit mechanism that involves a conformational change in HCII. Thus, HCII binds to heparin in a manner analogous to the interaction of AT with low affinity heparin. A fully allosteric 2000-fold heparin activation of thrombin inhibition by HCII is demonstrated for heparin chains up to 26 monosaccharide units in length. We conclude that the heparin-binding mechanism of HCII is closely analogous to that of AT and that the induced fit mechanism suggests the potential design or discovery of specific HCII agonists.