Factor product utilization and health outcomes in patients with haemophilia A and B on extended half-life concentrates: A Canadian observational study of real-world outcomes.

INTRODUCTION: Recombinant factors VIII and IX Fc (rFVIIIFc/rFIXFc) became available in Canada in 2016 and were the only extended half-life (EHL) factor concentrates available in Canada until 2018. OBJECTIVES: We aim to describe the change in product utilization in Canadians who switched to rFVIIIFc/rFIXFc. METHODS: This prospective and retrospective cohort study enrolled males aged ≥6 years with moderate or severe haemophilia who switched to rFVIIIFc/rFIXFc and those who remained on standard half-life (SHL) between 2016 and 2018. Factor utilization and annualized bleeding rates (ABR) were collected at baseline, 1-year and 2-years. Due to low prospective enrolment (n = 25 switchers), prospective and retrospective data were pooled. RESULTS: 125 switchers (93 rFVIIIFc, 32 rFIXFc) and 33 non-switchers were included. The median age was 17 (rFVIIIFc) and 38 years (rFIXFc). Prior to switch, over 80% were on prophylaxis. There was a statistically significant reduction in the prescribed weekly prophylactic dose after the switch to rFVIIIFc/rFIXFc for all age groups, with a corresponding reduction (15-16%) in actual annualized FIX utilization in switchers (combined adults and children) to rFIXFc, and a smaller non-significant reduction in actual annualized FVIIII utilization (7%) in children who switched to rFVIIIFc. A significant reduction in the median ABR was only observed in children who switched to rFVIIIFc, but not in adults who switched to rFVIIIFc or rFIXFc. CONCLUSION: Switching from SHL to EHL products led to a small reduction in factor utilization, while preserving a low ABR in children and adults with haemophilia. Further patient-reported outcomes data will further elucidate the role of EHL in the haemophilia landscape.

An overview of inherited factor VII deficiency.

Factor VII (FVII) deficiency is the most common of the Rare Inherited Coagulation Disorders. The inheritance is autosomal recessive but there is variable penetrance. Overall there is poor correlation between the FVII level and the bleeding phenotype. Heterozygotes may have significant bleeding and severe homozygotes, or compound heterozygotes can be asymptomatic. Typically, homozygotes have FVII levels <10% and heterozygotes have levels above that. In most cases bleeding is uncommon with FVII levels>10-20%. A personal and family history is essential to determine the bleeding risk and to plan for surgical and obstetrical prophylaxis. Severe bleeding complications including central nervous system bleeding, gastrointestinal system bleeding and bleeding into the joints occurs in 10-15% of FVII deficient patients. Mucocutaneous bleeding is a common symptom but 30% of patients are asymptomatic. Fifty to 69% of women have heavy menstrual bleeding. Due to the limited number of publications regarding this rare disorder there are no consensus guidelines. There is registry data which has led to the best recommendations for treatment of bleeding episodes, initiation of long-term prophylaxis in addition to surgical plus ante and peripartum prophylaxis. Recombinant FVII concentrate is the best replacement therapy and a review of treatment and prophylaxis dosing is discussed.

The impact of extended half-life factor concentrates on patient reported health outcome measures in persons with hemophilia A and hemophilia B.

BACKGROUND: Recombinant factors VIII and IX Fc (rFVIIIFc/rFIXFc) were the only available extended half-life (EHL) products in Canada during 2016 to 2018. OBJECTIVES: To evaluate if patient-reported outcome measures (PROMs) improved in Canadian persons with hemophilia who switched from standard half-life (SHL) to EHL products (rFVIIIFc/rFIXFc). PATIENTS/METHODS: This prospective cohort study enrolled persons with moderate or severe hemophilia aged ≥6 years who switched to rFVIIIFc/rFIXFc (2016-2018) and those who remained on SHL. Health-related quality of life (HRQoL) was assessed using the Haemophilia-specific Quality of Life (Haem-A-QoL) and 36-item Short-Form Survey (SF-36) at baseline, 3-months, 12 months, and 24 months. Other PROMs included the Work Productivity and Impairment Questionnaire, chronic pain scale, partner/parent ratings of mood, International Physical Activity Questionnaire, and Treatment Satisfaction Questionnaire for Medication. We identified meaningful changes using minimally important difference for SF-36 and responder definition for Haem-A-QoL. RESULTS: We enrolled 25 switchers (16 rFVIIIFc, 9 rFIXFc) and 33 nonswitchers. Those switched to rFVIIIFc/rFIXFc had improved overall HRQoL, and improved subscale physical activity, mental health, and social functioning at 3 months. The rFIXFc switchers had improved chronic pain and ability to engage in normal activities while the rFVIIIFc switchers had improved treatment satisfaction. There was no change in work impairment after the switch. Observed improvement disappeared by 24 months in most domains. CONCLUSION: Switching from SHL to rFVIIIFc/rFIXFc resulted in short-term meaningful improvement in overall HRQoL and other PROMs in a small proportion. Longitudinal changes on PROMs are affected by ceiling effects and response shift, warranting further studies in instrument optimization in the era of EHL and nonfactor products.

Sequential response-adapted induction and consolidation regimens idarubicin/cytarabine and mitoxantrone/etoposide in adult acute myelogenous leukemia: 10 year follow-up of a study by the Canadian Leukemia Studies Group.

PURPOSE: The Canadian Leukemia Studies Group (CLSG) sought to test the safety and efficacy of response-adapted, non-cross resistant chemotherapy in de novo acute myeloid leukemia (AML). The combinations of idarubicin 12 mg/m(2)/d on days 1 - 3 and Ara-C (200 mg/m(2)/d) on days 1 - 7 (IDAC) followed by mitoxantrone 10 mg/m(2)/day, and etoposide 100 mg/m(2)/day, on days 1 - 5 (NOVE) were used according to patient response to induction and consolidation. PATIENTS AND METHODS: In this multi-centre open-label phase II study, 140 patients up to age 80 were given induction with IDAC. Patients were entered between March 1993 and August 1995. If patients had persistent blasts at day 14 or on recovery, they were given NOVE. As consolidation, patients achieving complete remission (CR) with IDAC were given 1 further cycle of IDAC and 1 cycle of NOVE. Patients achieving CR after NOVE were given 2 further cycles of NOVE. RESULTS: 76% of all patients achieved remission after IDAC +/- NOVE, 81% in patients aged < or =60 years and 67% in patients aged >60. Overall, induction mortality was 11% and toxicity was similar to other cooperative group studies. Median follow-up was 104.0 months with 95% CI: (100.0, 105.2). Median overall survival (OS) in responding patients < or =60 was not reached: of the 79 responders < or =60, 35 died. The median disease free survival (DFS) in these responding patients was 22.7 (14.9, na) months. Median OS and DFS in responding patients >60 was 10.0 (7.3, 15.2) months and 7.5 (6.2, 15.2) months, respectively. CONCLUSION: The results of this trial are very encouraging and suggest that there may be long-term benefit to this method. On the basis of these results, a randomized phase III trial has been performed.

Randomized Phase III Trial Comparing ABVD Plus Radiotherapy With the Stanford V Regimen in Patients With Stages I or II Locally Extensive, Bulky Mediastinal Hodgkin Lymphoma: A Subset Analysis of the North American Intergroup E2496 Trial.

PURPOSE: The phase III North American Intergroup E2496 Trial (Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With Hodgkin's Lymphoma) compared doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with mechlorethamine, doxorubicin, vincristine, bleomycin, vinblastine, etoposide, and prednisone (Stanford V). We report results of a planned subgroup analysis in patients with stage I or II bulky mediastinal Hodgkin lymphoma (HL). PATIENTS AND METHODS: Patients were randomly assigned to six to eight cycles of ABVD every 28 days or Stanford V once per week for 12 weeks. Two to 3 weeks after completion of chemotherapy, all patients received 36 Gy of modified involved field radiotherapy (IFRT) to the mediastinum, hila, and supraclavicular regions. Patients on the Stanford V arm received IFRT to additional sites ≥ 5 cm at diagnosis. Primary end points were failure-free survival (FFS) and overall survival (OS). RESULTS: Of 794 eligible patients, 264 had stage I or II bulky disease, 135 received ABVD, and 129 received Stanford V. Patient characteristics were matched. The overall response rate was 83% with ABVD and 88% with Stanford V. At a median follow-up of 6.5 years, the study excluded a difference of more than 21% in 5-year FFS and more than 16% in 5-year OS between ABVD and Stanford V (5-year FFS: 85% v 79%; HR, 0.68; 95% CI, 0.37 to 1.25; P = .22; 5-year OS: 96% v 92%; HR, 0.49; 95% CI, 0.16 to 1.47; P = .19). In-field relapses occurred in < 10% of the patients in each arm. CONCLUSION: For patients with stage I or II bulky mediastinal HL, no substantial statistically significant differences were detected between the two regimens, although power was limited. To the best of our knowledge, this is the first prospective trial reporting outcomes specific to this subgroup, and it sets a benchmark for comparison of ongoing and future studies.

Comparison of a nomogram and physician-adjusted dosage of warfarin for prophylaxis against deep-vein thrombosis after arthroplasty.

BACKGROUND: Warfarin is an effective agent for prophylaxis against deep-vein thrombosis following total hip or knee arthroplasty. However, management with warfarin in the postoperative setting is problematic because of the need for anticoagulant monitoring. We developed a nomogram for the dosing of warfarin that was specific for joint arthroplasty. The objective of this study was to compare the performance of this nomogram with that of physician-adjusted dosing of warfarin for patients undergoing total hip or knee arthroplasty. METHODS: The study involved two cohort trials. The historical control group consisted of 1024 patients who underwent total hip or knee arthroplasty during the course of a clinical trial (the Post-Arthroplasty Screening Study [PASS]) in which all warfarin dose adjustments were made by two hematologists. The first dose of warfarin was given on the evening of the surgery, and the warfarin dose was adjusted daily on the basis of the international normalized ratio and was discontinued at the time of discharge from the hospital. In the PASS study, the dosage of warfarin was designed to prolong the international normalized ratio to 1.7 by postoperative day 4 and to maintain it between 1.8 and 2.5 until discharge from the hospital. Subsequently, a warfarin nomogram was developed on the basis of the dose adjustments used in the PASS study, and it was used prospectively to manage a cohort of 729 patients undergoing total hip or knee arthroplasty. In the nomogram cohort, the initial dose of warfarin was given on the evening of the surgery. Both cohorts were followed for twelve weeks after the surgery to determine if any venous thromboembolic complications had developed. RESULTS: The nomogram cohort and the control cohort had similar daily doses of warfarin (mean, 3.2 versus 3.3 mg) and levels of international normalized ratio on postoperative day 4 (mean, 1.9 versus 1.9) (p > 0.2). The average number of days to achieve an international normalized ratio of >1.7 was 4.0 for the nomogram cohort compared with 4.3 for the control cohort (p = 0.01). The percentage of days that the international normalized ratio was between 1.8 and 2.5 was 61% for the nomogram cohort and 58% for the control cohort (p < 0.01), and the percentage of days that the international normalized ratio was >3.0 was only 6.5% for the nomogram cohort and 6.0% for the control cohort (p > 0.2). Eighty-two percent of the patients managed with the nomogram achieved an international normalized ratio of >1.7 by the time of discharge from the hospital compared with 92% in the control cohort (p = 0.01). In the three-month follow-up period, a deep-vein thrombosis or a nonfatal pulmonary embolism developed in nineteen patients (2.6%; 95% confidence interval, 1.6% to 4.0%) in the nomogram cohort compared with fourteen patients (1.4%; 95% confidence interval, 0.7% to 2.3%) in the control cohort. No major bleeding event or fatal pulmonary embolism was observed in the patients managed with use of the nomogram. CONCLUSION: This study demonstrated that the administration of warfarin during hospitalization with use of a nomogram designed for the prevention of deep-vein thrombosis following total hip or knee arthroplasty provided effective and safe prophylaxis that was comparable with that provided by physician-adjusted dosing of warfarin.

Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a Multicenter Study.

BACKGROUND: Bendamustine hydrochloride is a novel alkylating agent. In this multicenter study, the authors evaluated the efficacy and toxicity of single-agent bendamustine in patients with rituximab-refractory, indolent B-cell lymphoma. METHODS: Eligible patients (N = 100, ages 31-84 years) received bendamustine at a dose of 120 mg/m(2) by intravenous infusion on Days 1 and 2 every 21 days for 6 to 8 cycles. Histologies included follicular (62%), small lymphocytic (21%), and marginal zone (16%) lymphomas. Patients had received a median of 2 previous regimens (range, 0-6 previous regimens), and 36%were refractory to their most recent chemotherapy regimen. Primary endpoints included overall response rate (ORR) and duration of response (DOR). Secondary endpoints were safety and progression-free survival (PFS). RESULTS: An ORR of 75% (a 14% complete response rate, a 3% unconfirmed complete response rate, and a 58% partial response rate) was observed. The median DOR was 9.2 months, and median PFS was 9.3 months. Six deaths were considered to be possibly treatment related. Grade 3 or 4 (determined using National Cancer Institute Common Toxicity Criteria [version 3.0.19]. reversible hematologic toxicities included neutropenia (61%), thrombocytopenia (25%), and anemia (10%). The most frequent nonhematologic adverse events (any grade) included nausea (77%), infection (69%), fatigue (64%), diarrhea (42%), vomiting (40%), pyrexia (36%), constipation (31%), and anorexia (24%). CONCLUSIONS: Single-agent bendamustine produced a high rate of objective responses with acceptable toxicity in patients with recurrent, rituximab-refractory indolent B-cell lymphoma.

Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin's lymphoma.

PURPOSE: Bendamustine HCl is a bifunctional mechlorethamine derivative with clinical activity in the treatment of non-Hodgkin's lymphoma. This study evaluated bendamustine plus rituximab in 67 adults with relapsed, indolent B-cell or mantle cell lymphoma without documented resistance to prior rituximab. PATIENTS AND METHODS: Patients received rituximab 375 mg/m(2) intravenously on day 1 and bendamustine 90 mg/m(2) intravenously on days 2 and 3 of each 28-day cycle for four to six cycles. An additional dose of rituximab was administered 1 week before the first cycle and 4 weeks after the last cycle. Sixty-six patients (median age, 60 years) received at least one dose of both drugs. RESULTS: Overall response rate was 92% (41% complete response, 14% unconfirmed complete response, and 38% partial response). Median duration of response was 21 months (95% CI, 18 to 24 months). Median progression-free survival time was 23 months (95% CI, 20 to 26 months). Outcomes were similar for patients with indolent or mantle cell histologies. The combination was generally well tolerated; the primary toxicity was myelosuppression (grade 3 or 4 neutropenia, 36%; grade 3 or 4 thrombocytopenia, 9%). CONCLUSION: Bendamustine plus rituximab is an active combination in patients with relapsed indolent and mantle cell lymphoma.

Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin's lymphoma: results from a phase II multicenter, single-agent study.

PURPOSE: Bendamustine hydrochloride is an alkylating agent with novel mechanisms of action. This phase II multicenter study evaluated the efficacy and toxicity of bendamustine in patients with B-cell non-Hodgkin's lymphoma (NHL) refractory to rituximab. PATIENTS AND METHODS: Patients received bendamustine 120 mg/m(2) intravenously on days 1 and 2 of each 21-day cycle. Outcomes included response, duration of response, progression-free survival, and safety. RESULTS: Seventy-six patients, ages 38 to 84 years, with predominantly stage III/IV indolent (80%) or transformed (20%) disease were treated; 74 were assessable for response. Twenty-four (32%) were refractory to chemotherapy. Patients received a median of two prior unique regimens. An overall response rate of 77% (15% complete response, 19% unconfirmed complete response, and 43% partial) was observed. The median duration of response was 6.7 months (95% CI, 5.1 to 9.9 months), 9.0 months (95% CI, 5.8 to 16.7) for patients with indolent disease, and 2.3 months (95% CI, 1.7 to 5.1) for those with transformed disease. Thirty-six percent of these responses exceeded 1 year. The most frequent nonhematologic adverse events included nausea and vomiting, fatigue, constipation, anorexia, fever, cough, and diarrhea. Grade 3 or 4 reversible hematologic toxicities included neutropenia (54%), thrombocytopenia (25%), and anemia (12%). CONCLUSION: Single-agent bendamustine produced durable objective responses with acceptable toxicity in heavily pretreated patients with rituximab-refractory, indolent NHL. These findings are promising and will serve as a benchmark for future clinical trials in this novel patient population.