Perioperative oral eltrombopag versus intravenous immunoglobulin in patients with immune thrombocytopenia:a non-inferiority, multicentre, randomised trial

Background: Patients with immune thrombocytopenia are at risk of bleeding during surgery, and intravenous immunoglobulin is commonly used to increase the platelet count. We aimed to establish whether perioperative eltrombopag was non-inferior to intravenous immunoglobulin. Methods: We did a randomised, open-label trial in eight academic hospitals in Canada. Patients were aged at least 18 years, with primary or secondary immune thrombocytopenia and platelet counts less than 100 × 109 cells per L before major surgery or less than 50 × 109 cells per L before minor surgery. Previous intravenous immunoglobulin within 2 weeks or thrombopoietin receptor agonists within 4 weeks before randomisation were not permitted. Patients were randomly assigned to receive oral daily eltrombopag 50 mg from 21 days preoperatively to postoperative day 7 or intravenous immunoglobulin 1 g/kg or 2 g/kg 7 days before surgery. Eltrombopag dose adjustments were allowed weekly based on platelet counts. The randomisation sequence was generated by a computerised random number generator, concealed and stratified by centre and surgery type (major or minor). The central study statistician was masked to treatment allocation. The primary outcome was achievement of perioperative platelet count targets (90 × 109 cells per L before major surgery or 45 × 109 cells per L before minor surgery) without rescue treatment. We did intention-to-treat and per-protocol analyses using an absolute non-inferiority margin of –10%. This trial is registered with ClinicalTrials.gov, NCT01621204. Findings: Between June 5, 2013, and March 7, 2019, 92 patients with immune thrombocytopenia were screened, of whom 74 (80%) were randomly assigned: 38 to eltrombopag and 36 to intravenous immunoglobulin. Median follow-up was 50 days (IQR 49–55). By intention-to-treat analysis, perioperative platelet targets were achieved for 30 (79%) of 38 patients assigned to eltrombopag and 22 (61%) of 36 patients assigned to intravenous immunoglobulin (absolute risk difference 17·8%, one-sided lower limit of the 95% CI 0·4%; pnon-inferiority=0·005). In the per-protocol analysis, perioperative platelet targets were achieved for 29 (78%) of 37 patients in the eltrombopag group and 20 (63%) of 32 in the intravenous immunoglobulin group (absolute risk difference 15·9%, one-sided lower limit of the 95% CI –2·1%; pnon-inferiority=0·009). Two serious adverse events occurred in the eltrombopag group: one treatment-related pulmonary embolism and one vertigo. Five serious adverse events occurred in the intravenous immunoglobulin group (atrial fibrillation, pancreatitis, vulvar pain, chest tube malfunction and conversion to open splenectomy); all were related to complications of surgery. No treatment-related deaths occurred. Interpretation: Eltrombopag is an effective alternative to intravenous immunoglobulin for perioperative treatment of immune thrombocytopenia. However, treatment with eltrombopag might increase risk of thrombosis. The decision to choose one treatment over the other will depend on patient preference, resource limitations, cost, and individual risk profiles. Funding: GlaxoSmithKline and Novartis

Establishing a Target Exposure for Once-Daily Intravenous Busulfan Given with Fludarabine and Thymoglobulin before Allogeneic Transplantation

AbstractA combination of fludarabine (Flu) and daily i.v. busulfan (Bu) is well tolerated and effective in patients undergoing allogeneic hematopoietic stem cell transplantation. Although there is some evidence that Bu exposures exceeding 6000 μM/min may lead to excessive toxicity, there is little information on the effect of exposures below this level on outcomes. We studied Bu exposure, as measured by area under the concentration-time curve (AUC), in 158 patients with various hematologic malignancies in an attempt to identify an optimal range for targeted therapy. The preparative chemotherapy regimen comprised Flu 50 mg/m2 on days -6 to -2 and i.v. Bu 3.2 mg/kg on days -5 to -2 inclusive. Graft-versus-host disease (GVHD) prophylaxis included methotrexate, cyclosporin A, and antithymocyte globulin. Patients with Bu exposures below the median AUC of 4439 μM/min were at increased risk for acute GVHD grade II-IV (hazard ratio [HR], 2.30; 95% confidence interval [CI], 1.19 to 4.49; P = .014). Those in the highest and lowest Bu exposure quartiles (daily AUC <3814 μM/min and >4993 μM/min) had an increased risk of nonrelapse mortality (subdistribution HR, 3.32; 95% CI, 1.46 to 7.54; P = .004), as well as worse disease-free survival (HR, 1.81; 95% CI, 1.09 to 2.99; P = .021) and overall survival (HR, 1.94; 95% CI, 1.12 to 3.37; P = .018). Bu exposures between 4440 and 4993 μM/min were accompanied by the lowest risk of both nonrelapse mortality and acute GVHD

Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia

Background: chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma. Methods: we randomly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary end point was progression-free survival as assessed by an independent review committee. Results: the median age of the patients was 73 years. During a median follow-up period of 18.4 months, ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; P<0.001). Ibrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P=0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, P<0.001). The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib. Adverse events of any grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea; adverse events occurring in at least 20% of those receiving chlorambucil included nausea, fatigue, neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the patients in the ibrutinib group are continuing to take ibrutinib. Conclusions: ibrutinib was superior to chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma, as assessed by progression-free survival, overall survival, response rate, and improvement in hematologic variables. (Funded by Pharmacyclics and others; RESONATE-2 ClinicalTrials.gov number, NCT01722487.)

Case Series of 3 Patients Diagnosed With Atypical Hemolytic Uremic Syndrome Successfully Treated With Steroids, Plasmapheresis, and Rituximab

Rationale: Atypical hemolytic uremic syndrome, which has a high probability of chronic kidney disease, morbidity, and mortality, needs to be promptly recognized when patients present with microangiopathic hemolysis. Presenting Concerns of the Patient: Three patients present with laboratory parameters consistent with a thrombotic microangiopathy. With a suspected diagnosis of thrombotic thrombocytopenic purpura, steroids with plasmapheresis were initiated. Diagnoses: With ADAMTS13 levels reported normal, the suspected diagnoses were reevaluated. Given ongoing renal impairment, atypical hemolytic uremic syndrome was strongly considered. Interventions: When local funding issues precluded the prompt use of eculizumab, 4 doses of weekly rituximab were trialed. Outcome: Over 2 years later, all 3 patients have sustained durable remissions defined by the absence of kidney impairment or laboratory investigations concerning for microangiopathic hemolytic relapse. Lessons Learned: In cases of a suspected autoimmune mechanism leading to atypical hemolytic uremic syndrome, long-term use of eculizumab may not be required

The development of an aquatic ecosystem in Trojan Tailings Pond, Highland Valley Copper

Trojan Tailings Pond at Highland Valley Copper developed in only 15 years from a biologically inactive water body into a productive lake with a well established aquatic ecosystem and fishery. After a further 8 years, the Trojan system remains sustainable with small annual nitrogen additions. There were two compatible goals in this work; improving tailings water cover quality by biochemically modifying the sediment-water interface, and making the pond productive for wildlife and fish. This transformation was achieved using a few simple and inexpensive procedures including fertilization and introduction of essential organisms. The success at the Trojan Pond has encouraged the use of similar techniques in other water bodies on the mine site.Non UBCUnreviewedOthe

Developing tailings ponds and pit lakes as bioreactors and habitat cost-effective successes at Highland Valley Copper

Forty-five years of mining in the Highland Valley has created several completed tailings ponds and pit lakes. Efforts to enhance the development of these evolving water bodies have been underway since the mid-1990s. Extensive yet inexpensive techniques have been successful in establishing biochemically active and ecologically valuable aquatic resources. The results obtained and the techniques used, including nutrient growth factor additions, artificial upwelling, biorafts and microfloral introductions, will be described. The initial fertilization of a pit lake in the Highland Valley invariably results in an extensive phytoplankton bloom that is impossible to replicate in the second or subsequent years. This inability to sustain vigorous biologic production has implications to the development of productive ecosystems and imposes limitations on the metal removal potential of the phytoplankton. Recent work has led to an increased understanding of the role played by vitamins in these water bodies, and this work and some possible solutions will be presented.Non UBCUnreviewedOthe

Using multispectral remote sensing to monitor aquatic vegetation in ponds at a reclaimed mine site

Multispectral remote sensing is being investigated to monitor mine-site reclamation at Highland Valley Copper, a large copper-molybdenum mine in southern British Columbia. Two examples of the application of aerial mapping to the aquatic portions of the mine are presented here: Trojan Pond, a deep tailings pond that supports a small fishery, and Highmont Tailings Pond, a shallow tailings pond and wetland. Trojan Pond has a narrow band (1 to 3 m), of benthic aquatic vegetation around its shore, because it has a rapidly shoaling littoral zone, with very little shallow area – quite typical for a shallow, small lake in this region. By contrast, Highmont Pond is shallow and supports extensive benthic vegetation that was impossible to properly sample from the ground because a very soft bottom limits access. This vegetation was well mapped by the multispectral imagery in 2001 and 2002, and was only sampled from the ground after the pond was drained in 2003 – at which time the abundant vegetation in the centre of the pond came as a surprise to ground biologists.Non UBCUnreviewedOthe