Leonard Minuk

Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study

BACKGROUND Bortezomib with dexamethasone is a standard treatment option for relapsed or refractory multiple myeloma. Carfilzomib with dexamethasone has shown promising activity in patients in this disease setting. The aim of this study was to compare the combination of carfilzomib and dexamethasone with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma. METHODS In this randomised, phase 3, open-label, multicentre study, patients with relapsed or refractory multiple myeloma who had one to three previous treatments were randomly assigned (1:1) using a blocked randomisation scheme (block size of four) to receive carfilzomib with dexamethasone (carfilzomib group) or bortezomib with dexamethasone (bortezomib group). Randomisation was stratified by previous proteasome inhibitor therapy, previous lines of treatment, International Staging System stage, and planned route of bortezomib administration if randomly assigned to bortezomib with dexamethasone. Patients received treatment until progression with carfilzomib (20 mg/m(2) on days 1 and 2 of cycle 1; 56 mg/m(2) thereafter; 30 min intravenous infusion) and dexamethasone (20 mg oral or intravenous infusion) or bortezomib (1·3 mg/m(2); intravenous bolus or subcutaneous injection) and dexamethasone (20 mg oral or intravenous infusion). The primary endpoint was progression-free survival in the intention-to-treat population. All participants who received at least one dose of study drug were included in the safety analyses. The study is ongoing but not enrolling participants; results for the interim analysis of the primary endpoint are presented. The trial is registered at ClinicalTrials.gov, number NCT01568866. FINDINGS Between June 20, 2012, and June 30, 2014, 929 patients were randomly assigned (464 to the carfilzomib group; 465 to the bortezomib group). Median follow-up was 11·9 months (IQR 9·3-16·1) in the carfilzomib group and 11·1 months (8·2-14·3) in the bortezomib group. Median progression-free survival was 18·7 months (95% CI 15·6-not estimable) in the carfilzomib group versus 9·4 months (8·4-10·4) in the bortezomib group at a preplanned interim analysis (hazard ratio [HR] 0·53 [95% CI 0·44-0·65]; p<0·0001). On-study death due to adverse events occurred in 18 (4%) of 464 patients in the carfilzomib group and in 16 (3%) of 465 patients in the bortezomib group. Serious adverse events were reported in 224 (48%) of 463 patients in the carfilzomib group and in 162 (36%) of 456 patients in the bortezomib group. The most frequent grade 3 or higher adverse events were anaemia (67 [14%] of 463 patients in the carfilzomib group vs 45 [10%] of 456 patients in the bortezomib group), hypertension (41 [9%] vs 12 [3%]), thrombocytopenia (39 [8%] vs 43 [9%]), and pneumonia (32 [7%] vs 36 [8%]). INTERPRETATION For patients with relapsed or refractory multiple myeloma, carfilzomib with dexamethasone could be considered in cases in which bortezomib with dexamethasone is a potential treatment option. FUNDING Onyx Pharmaceuticals, Inc., an Amgen subsidiary.

Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial

BACKGROUND The phase 3 ENDEAVOR trial was a head-to-head comparison of two proteasome inhibitors in patients with relapsed or refractory multiple myeloma. Progression-free survival was previously reported to be significantly longer with carfilzomib administered in combination with dexamethasone than with bortezomib and dexamethasone in an interim analysis. The aim of this second interim analysis was to compare overall survival between the two treatment groups. METHODS ENDEAVOR was a phase 3, open-label, randomised controlled trial in patients with relapsed or refractory multiple myeloma. Patients were recruited from 198 hospitals and outpatient clinics in 27 countries in Europe, North America, South America, and the Asia-Pacific region. Patients were aged 18 years or older, had relapsed or refractory multiple myeloma, and had received between one and three previous lines of therapy. Patients were randomly assigned (1:1) to receive carfilzomib and dexamethasone (carfilzomib group) or bortezomib and dexamethasone (bortezomib group) through a blocked randomisation scheme (block size of four), stratified by International Staging System stage, previous lines of treatment, previous proteasome inhibitor therapy, and planned route of bortezomib delivery if assigned to the bortezomib group. Carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1; 56 mg/m2 thereafter) was given as a 30-min intravenous infusion on days 1, 2, 8, 9, 15, and 16 of 28-day cycles; bortezomib (1·3 mg/m2) was given as an intravenous bolus or subcutaneous injection on days 1, 4, 8, and 11 of 21-day cycles. Dexamethasone (20 mg oral or intravenous infusion) was given on days 1, 2, 8, 9, 15, 16, 22, and 23 in the carfilzomib group and on days 1, 2, 4, 5, 8, 9, 11, and 12 in the bortezomib group. The primary endpoint of ENDEAVOR, progression-free survival, has been previously reported. A stratified log-rank test was used to compare overall survival between treatment groups for this prospectively planned second interim analysis. Efficacy assessments were done in all randomly assigned patients (the intention-to-treat population) and the safety analysis included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01568866, and is no longer enrolling patients. FINDINGS Between June 20, 2012, and June 30, 2014, 1096 patients were assessed for eligibility, of whom 929 were randomly assigned (464 to the carfilzomib group and 465 to the bortezomib group). The cutoff date for this prespecified interim analysis was Jan 3, 2017. Median overall survival was 47·6 months (95% CI 42·5-not evaluable) in the carfilzomib group versus 40·0 months (32·6-42·3) in the bortezomib group (hazard ratio 0·791 [95% CI 0·648-0·964], one-sided p=0·010). Grade 3 or worse adverse events were reported in 377 (81%) of 463 patients in the carfilzomib group and 324 (71%) of 456 patients in the bortezomib group, and serious adverse events in 273 (59%) patients in the carfilzomib group and 182 (40%) in the bortezomib group. The most frequent grade 3 or worse adverse events were anaemia (76 [16%] of 463 patients in the carfilzomib group vs 46 [10%] of 456 patients in the bortezomib group), hypertension (67 [15%] vs 15 [3%]), pneumonia (42 [9%] vs 39 [9%]), thrombocytopenia (41 [9%] vs 43 [9%]), fatigue (31 [7%] vs 35 [8%]), dyspnoea (29 [6%] vs ten [2%]), decreased lymphocyte count (29 [6%] vs nine [2%]), diarrhoea (18 [4%] vs 39 [9%]), and peripheral neuropathy (six [1%] vs 28 [6%]). Treatment-related deaths occurred in five (1%) of 463 patients in the carfilzomib group (pneumonia [n=2], interstitial lung disease [n=1], septic shock [n=1], and unknown [n=1]) and two (<1%) of 456 patients in the bortezomib group (cardiac arrest [n=1] and pneumonia [n=1]). INTERPRETATION Carfilzomib provided a significant and clinically meaningful reduction in the risk of death compared with bortezomib. To our knowledge, carfilzomib is the first and only multiple myeloma treatment that extends overall survival in the relapsed setting over the current standard of care. This study is informative for deciding which proteasome inhibitor to use for treating this disease. FUNDING Onyx Pharmaceuticals Inc, an Amgen Inc subsidiary.

Health-related quality of life in patients with newly diagnosed multiple myeloma in the FIRST trial: lenalidomide plus low-dose dexamethasone versus melphalan, prednisone, thalidomide

We compared the health-related quality-of-life of patients with newly diagnosed multiple myeloma aged over 65 years or transplant-ineligible in the pivotal, phase III FIRST trial. Patients received: i) continuous lenalidomide and low-dose dexamethasone until disease progression; ii) fixed cycles of lenalidomide and low-dose dexamethasone for 18 months; or iii) fixed cycles of melphalan, prednisone, thalidomide for 18 months. Data were collected using the validated questionnaires (QLQ-MY20, QLQ-C30, and EQ-5D). The analysis focused on the EQ-5D utility value and six domains pre-selected for their perceived clinical relevance. Lenalidomide and low-dose dexamethasone, and melphalan, prednisone, thalidomide improved patients’ health-related quality-of-life from baseline over the duration of the study across all pre-selected domains of the QLQ-C30 and EQ-5D. In the QLQ-MY20, lenalidomide and low-dose dexamethasone demonstrated a significantly greater reduction in the Disease Symptoms domain compared with melphalan, prednisone, thalidomide at Month 3, and significantly lower scores for QLQ-MY20 Side Effects of Treatment at all post-baseline assessments except Month 18. Linear mixed-model repeated-measures analyses confirmed the results observed in the cross-sectional analysis. Continuous lenalidomide and low-dose dexamethasone delays disease progression versus melphalan, prednisone, thalidomide and has been associated with a clinically meaningful improvement in health-related quality-of-life. These results further establish continuous lenalidomide and low-dose dexamethasone as a new standard of care for initial therapy of myeloma by demonstrating superior health-related quality-of-life during treatment, compared with melphalan, prednisone, thalidomide.

Treatment of Hodgkin lymphoma with adriamycin, bleomycin, vinblastine and dacarbazine without routine granulocyte-colony stimulating factor support does not increase the risk of febrile neutropenia: a prospective cohort study

Abstract Although patients with Hodgkin lymphoma treated with adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy frequently develop neutropenia, febrile neutropenia is uncommon. Three retrospective trials reported that ABVD could be safely administered without dose delays or granulocyte-colony stimulating factor (G-CSF) support. We retrospectively reviewed the charts of 89 patients treated with ABVD and found that the incidence of febrile neutropenia was 0.5% (five of 927 treatments). This prompted a change to our institutional policy so that patients receiving ABVD no longer receive routine G-CSF for uncomplicated neutropenia. We then prospectively assessed the safety of this policy change. Thirty-three patients received a total of 327 ABVD treatments, 185 (57%) of which were administered with a neutrophil count <1.5 × 109/L. Febrile neutropenia occurred in 2/33 patients (6%), complicating 0.6% of chemotherapy treatments (2/327). Eliminating routine G-CSF saved

Cardiovascular disease (CVD) in Canadians with haemophilia: Age‐Related CVD in Haemophilia Epidemiological Research (ARCHER study)

10 241 per patient. Omission of G-CSF for uncomplicated neutropenic patients receiving ABVD for Hodgkin lymphoma is cost-saving and safe.

Desmopressin responsiveness at a capped dose of 15 μg in type 1 von Willebrand disease and mild hemophilia A.

Improvements in haemophilia care have increased life expectancy in persons with haemophilia (PWH). This ageing population presents clinicians with management challenges as they develop age‐related comorbidities such as cardiovascular disease (CVD).

The pandemic H1N1 influenza vaccine results in low rates of seroconversion for patients with hematological malignancies

Desmopressin (DDAVP) is commonly used in the treatment of patients with type 1 von Willebrand disease (VWD) and mild hemophilia A. A patients responsiveness to DDAVP based on a 0.3 &mgr;g/kg dose determines future therapeutic efficacy of the drug. The aim of the study was to determine whether a capped dose of 15 &mgr;g subcutaneous DDAVP is able to achieve the same level of DDAVP responsiveness as previously reported. This is a retrospective chart review of patients from 1995 to 2013 in adults and children with type 1 VWD and hemophilia A weighing more than 50 kg. Levels of factor VIII, ristocetin cofactor, and von Willebrand factor antigen were measured before and after 1 h of administration of 15 &mgr;g of DDAVP. In patients with type 1 VWD, the complete response rate was 82.5% with a partial response rate of 12.5% and 5% nonresponders. In patients with mild hemophilia A, the complete response rate was 53.8% with a partial response rate of 38.5% and 7.7% nonresponders. These results using a capped 15-&mgr;g dose of DDAVP are similar to previously published reports using the 0.3-&mgr;g/kg dose.

Patterns of tertiary prophylaxis in Canadian adults with severe and moderately severe haemophilia B

Patients with hematological malignancies are at increased risk of influenza and its complications, but evidence for the efficacy of influenza vaccination in this population is limited. We sought to determine whether patients being treated for hematological malignancies were able to mount protective antibodies to the H1N1 influenza vaccine. Pre- and post-vaccination plasma samples were collected from patients with hematological malignancies during the 2009–2010 influenza season. Seroconversion was defined as a four-fold increase in antibody titer, as measured by the hemagglutinin inhibition test. Sixty-two patients received the H1N1 vaccine and 41 patients were unvaccinated controls. The rate of seroconversion among vaccinated patients was 21%, which was significantly higher than that in unvaccinated patients (0%), but significantly lower than that previously reported for healthy adults. Physicians should be aware that influenza vaccination may not generate an immune response in patients with hematological malignancies. Larger studies are required to confirm these results.

Normal levels of protein C and protein S tested in the acute phase of a venous thromboembolic event are not falsely elevated

From a young age patients with severe and moderately severe FIX deficiency (haemophilia B) can experience spontaneous or traumatic bleeding and joint destruction may result. The use of coagulation factor IX concentrate to prevent anticipated bleeding, as primary or secondary prophylaxis, has become a common and recommended practice in children. The current practice of using tertiary prophylaxis, in the presence of established joint arthropathy, in adults with haemophilia B is not well characterized. This observational study was conducted to gain a better understanding of the recent Canadian experience with tertiary prophylaxis in adults with severe and moderately severe haemophilia B. Data were collected from all eligible adult (≥ 18 years of age) males with baseline FIX:C ≤ 2% from seven Canadian Hemophilia Treatment centres over a 2‐year observation period from 2009 to 2011. Thirty‐four per cent of the 67 subjects with moderately severe haemophilia B were exposed to prophylaxis with the majority as continuous prophylaxis (≥45 weeks year‐1). The severe subgroup (FIX:C < 1%) demonstrated a 52% exposure rate. None had primary prophylaxis exposure in childhood. Eighty‐one per cent used once or twice weekly infusion regimens and reported a median annual bleeding rate of five bleeds per year versus four bleeds per year for those using on‐demand treatment. Annual median factor utilization for all subjects using prophylaxis was 196 283 U year‐1 compared to 46 361 U year‐1 for on demand. Approximately 50% of adults with severe haemophilia B are using continuous tertiary prophylaxis in Canada, a practice likely to increase which warrants further study.

Cardiovascular disease prevalence and relevance in haemophilia: a scoping review.

BackgroundProtein C (PC) and protein S (PS) determination is part of the thrombophilia investigation in patients with idiopathic venous thromboembolism (VTE). Based on scarce evidence it is a common notion that PC and PS levels decrease during the acute phase of VTE, necessitating delay of testing and temporary transition from warfarin to low molecular weight heparin. We have previously demonstrated that an abnormal PC or PS result determined within 24 hours of VTE diagnosis and before the initiation of warfarin needs to be repeated for confirmation ≥3 months after starting treatment and ≥14 days after stopping anticoagulation therapy. In the current study, we sought to show that normal PC and PS values determined during the acute phase of VTE are not false negatives.Methods99 patients with acute idiopathic VTE who had normal PC and PS determination within the first 24 hours of presentation and who subsequently had their oral anticoagulation discontinued after six months of therapy. PC and PS determinations were repeated ≥6 months after starting treatment and ≥ 14 days after stopping warfarin. Proportions of patients who tested abnormal on the second test were calculated and 95% confidence intervals obtained using the Wilsons score method. Data from a previously published study on patients with abnormal initial tests was included for comparison.ResultsNone of the 99 patients who had normal PC and PS initially had an abnormal result on repeated testing (0%; 95% CI 0 - 3.7%). Data from the previous study showed that, among patients who initially had abnormal results, 40% (95%CI 35.4-84.8%) were confirmed to have low PC and 63.6% (95%CI 16.8-68.7%) low PS on repeated testing. The difference between proportions was statistically significant (χ2 p-value < 0.001).ConclusionOur results suggest that PC and PS can be determined during the acute phase of VTE and whereas abnormal results need to be confirmed with repeat testing at a later date, a normal result effectively rules out deficiency with only one test.