Steven R. Deitcher

Secondary prevention of venous thromboembolic events in patients with active cancer: enoxaparin alone versus initial enoxaparin followed by warfarin for a 180-day period.

This study evaluated enoxaparin alone versus initial enoxaparin followed by warfarin in secondary prevention of venous thromboembolic events in adults with active malignancy. Cancer patients (n = 122) with acute symptomatic venous thromboembolic events were randomly allocated to receive subcutaneous enoxaparin 1.0 mg/kg every 12 hours for 5 days, followed by 1.0 mg/kg daily (group 1a) or 1.5 mg/kg daily (group 1b) for 175 days, or subcutaneous enoxaparin 1.0 mg/kg every 12 hours for at least 5 days and until a stable international normalized ratio of 2 to 3 was achieved on oral warfarin begun on day 2 and continued to day 180 (group 2). There were no significant differences in major and minor bleeding rates between treatment groups. No bleeding events were intracranial or fatal. Enoxaparin treatment was feasible, generally well tolerated, and effective for a 180-day period in the secondary prevention of venous thromboembolic events in patients with active malignancy.

Use of a Constitutively Active Hypoxia-Inducible Factor-1α Transgene as a Therapeutic Strategy in No-Option Critical Limb Ischemia Patients Phase I Dose-Escalation Experience

Background— Critical limb ischemia, a manifestation of severe peripheral atherosclerosis and compromised lower-extremity blood flow, results in a high rate of limb loss. We hypothesized that adenoviral delivery of a constitutively active form of the transcription factor hypoxia-inducible factor-1&agr; (ie, Ad2/HIF-1&agr;/VP16 or HIF-1&agr;) into the lower extremity of patients with critical limb ischemia would be safe and might result in a durable clinical response. Methods and Results— This phase I dose-escalation program included 2 studies: a randomized, double-blind, placebo-controlled study and an open-label extension study. In total, 34 no-option patients with critical limb ischemia received HIF-1&agr; at doses of 1×108 to 2×1011 viral particles. No serious adverse events were attributable to study treatment. Five deaths occurred: 3 in HIF-1&agr; and 2 in placebo patients. In the first (randomized) study, 7 of 21 HIF-1&agr; patients met treatment failure criteria and had major amputations. Three of the 7 placebo patients rolled over to receive HIF-1&agr; in the extension study. No amputations occurred in the 2 highest-dose groups of Ad2/HIF-1&agr;/VP16 (1×1011 and 2×1011 viral particles). The most common adverse events included peripheral edema, disease progression, and peripheral ischemia. At 1 year, limb status observations in HIF-1&agr; patients included complete rest pain resolution in 14 of 32 patients and complete ulcer healing in 5 of 18 patients. Conclusions— HIF-1&agr; therapy in patients with critical limb ischemia was well tolerated, supporting further, larger, randomized efficacy trials.

Marqibo (vincristine sulfate liposome injection) improves the pharmacokinetics and pharmacodynamics of vincristine

Vincristine (VCR) is a mainstay of treatment of hematologic malignancies and solid tumors due to its well-defined mechanism of action, demonstrated anticancer activity and its ability to be combined with other agents. VCR is an M-phase cell cycle-specific anticancer drug with activity that is concentration and exposure duration dependent. The pharmacokinetic profile of standard VCR is described by a bi-exponential elimination pattern with a very fast initial distribution half-life followed by a longer elimination half-life. VCR also has a large volume of distribution, suggesting diffuse distribution and tissue binding. These properties may limit optimal drug exposure and delivery to target tissues as well as clinical utility as a single agent or as an effective component of multi-agent regimens. Vincristine sulfate liposome injection (VSLI), Marqibo®, is a sphingomyelin and cholesterol-based nanoparticle formulation of VCR that was designed to overcome the dosing and pharmacokinetic limitations of standard VCR. VSLI was developed to increase the circulation time, optimize delivery to target tissues and facilitate dose intensification without increasing toxicity. In xenograft studies in mice, VSLI had a higher maximum tolerated dose, superior antitumor activity and delivered higher amounts of active drug to target tissues compared to standard VCR. VSLI recently received accelerated FDA approval for use in adults with advanced, relapsed and refractory Philadelphia chromosome-negative ALL and is in development for untreated adult ALL, pediatric ALL and untreated aggressive NHL. Here, we summarize the nonclinical data for VSLI that support its continued clinical development and recent approval for use in adult ALL.

High-Dose Vincristine Sulfate Liposome Injection for Advanced, Relapsed, and Refractory Adult Philadelphia Chromosome–Negative Acute Lymphoblastic Leukemia

PURPOSE Relapsed adult acute lymphoblastic leukemia (ALL) is associated with high reinduction mortality, chemotherapy resistance, and rapid progression leading to death. Vincristine sulfate liposome injection (VSLI), sphingomyelin and cholesterol nanoparticle vincristine (VCR), facilitates VCR dose-intensification and densification plus enhances target tissue delivery. We evaluated high-dose VSLI monotherapy in adults with Philadelphia chromosome (Ph) -negative ALL that was multiply relapsed, relapsed and refractory to reinduction, and/or relapsed after hematopoietic cell transplantation (HCT). PATIENTS AND METHODS Sixty-five adults with Ph-negative ALL in second or greater relapse or whose disease had progressed following two or more leukemia therapies were treated in this pivotal phase II, multinational trial. Intravenous VSLI 2.25 mg/m(2), without dose capping, was administered once per week until response, progression, toxicity, or pursuit of HCT. The primary end point was achievement of complete response (CR) or CR with incomplete hematologic recovery (CRi). RESULTS The CR/CRi rate was 20% and overall response rate was 35%. VSLI monotherapy was effective as third-, fourth-, and fifth-line therapy and in patients refractory to other single- and multiagent reinduction therapies. Median CR/CRi duration was 23 weeks (range, 5 to 66 weeks); 12 patients bridged to a post-VSLI HCT, and five patients were long-term survivors. VSLI was generally well tolerated and associated with a low 30-day mortality rate (12%). CONCLUSION High-dose VSLI monotherapy resulted in meaningful clinical outcomes including durable responses and bridging to HCT in advanced ALL settings. The toxicity profile of VSLI was predictable, manageable, and comparable to standard VCR despite the delivery of large, normally unachievable, individual and cumulative doses of VCR.

Safety and Efficacy of Alteplase for Restoring Function in Occluded Central Venous Catheters: Results of the Cardiovascular Thrombolytic to Open Occluded Lines Trial

PURPOSE To evaluate the safety and efficacy of alteplase (TPA) for restoring function to occluded central venous catheters (CVCs). PATIENTS AND METHODS The study design was a phase III, open-label, single-arm multicenter trial. Subjects with occluded, nondialysis CVCs were enrolled. All subjects received a 2-mg dose of TPA within the dysfunctional catheter lumen that was allowed to dwell for 30 to 120 minutes. Functionality was tested at 30 and 120 minutes. If the CVC remained obstructed at 120 minutes, a second 2-mg TPA dose was allowed to dwell for 30 to 120 minutes. The primary safety end point was the rate of intracranial hemorrhage (ICH) within 5 days of treatment, and serious adverse events were recorded up to 30 days. RESULTS Nine hundred ninety-five patients received treatment (female, 562; male, 433; mean age, 50.7 years; range, 2 to 91 years). CVCs treated were as follows: single (26%), double (39%), or triple (6%) lumen catheters or ports (29%). The primary end point was 0% ICH within 5 days. There were no cases of death, major bleeding episodes, or embolic events attributable to treatment. Flow was successfully restored in 52% and 78% of CVCs at 30 and 120 minutes after one dose, and 84% and 87% at 30 and 120 minutes after a second dose, respectively. Restoration of flow was 86%, 93%, 90%, and 79%, for single, double, and triple lumen catheters and ports, respectively. Estimated 30-day catheter patency was 74%. CONCLUSION A regimen of up to two 2-mg doses of TPA is safe and effective for the restoration of flow to occluded central venous catheters.

Vincristine sulfate liposomes injection (Marqibo) in heavily pretreated patients with refractory aggressive non-Hodgkin lymphoma: Report of the pivotal phase 2 study

Marqibo, a sphingosomal/cholesterol encapsulation of vincristine sulfate has targeted, increased, and sustained delivery of vincristine to tumor tissues. A phase 2, open‐label, single‐arm, and multinational study evaluated the efficacy and tolerability of Marqibo as a single agent in patients with multiply relapsed or refractory aggressive non‐Hodgkin lymphoma (NHL).

Interpretation of the international normalised ratio in patients with liver disease

Wide acceptance of the international normalised ratio (INR) and thromboplastins with low international sensitivity indices (ISIs) has inadvertently led to the application of the INR to patients other than those on anticoagulation treatment. I examined the degree of factor deficiency for a given INR in patients with liver disease and controls receiving stable-dose warfarin. The degree of factor V and VII, but not prothrombin, deficiencies for a given INR were greater in liver patients than controls. The INR measured with a low-ISI thromboplastin can quantify the coagulation status of patients with liver disease, but should not be interpreted as having the same meaning as the INR in patients receiving warfarin.

Hormonal factors and risk of recurrent venous thrombosis: the Prevention of Recurrent Venous Thromboembolism trial

Summary.  Background: In some but not all studies, men with venous thrombosis had a higher risk of recurrence than women. Information on women with initial hormone‐related thrombosis is scant. Objective: We assessed the incidence of recurrent thrombosis by gender, and among women using exogenous hormones or pregnant/postpartum at the time of index thrombosis. Patients/methods: A total of 508 men and women with one or more previous venous thrombosis episodes were observed while participating in a randomized trial of low‐intensity warfarin or placebo for 2.1 years. Index thrombosis events during treatment with postmenopausal hormones, oral contraceptives, or during pregnancy, or the puerperium were considered to be hormone‐related events. Results: Among 268 men the 3‐year probability of recurrent thrombosis was 18.4% (95% confidence intervals; CI 12.3–24.4). Among 109 women without hormone‐related thrombosis, the rate was 15.0% (95% CI 6.3–23.8). Among 129 women with hormone‐related thrombosis, the rate was 5.0% (95% CI 1.1–8.9). Adjusting for other risk factors and treatment assignment, women had a 39% lower thrombosis recurrence risk than men: hazard ratio (HR) 0.61 (95% CI 0.34–1.08). Women with hormone‐related thrombosis had a 58% lower risk than men: HR 0.42 (95% CI 0.19–0.97); and a 46% lower recurrence risk than other women; HR 0.54 (95% CI 0.19–1.54). Women without hormone‐related index events had a recurrence rate similar to men; HR 0.83 (95% CI 0.42–1.66). Conclusions: In this trial population, women had a lower risk of recurrent venous thrombosis than men. This difference was explained by a low risk of recurrence among women with hormone‐related index thrombosis.

Treatment of occluded central venous catheters with alteplase: results in 1,064 patients.

PURPOSE Thrombosis of central venous access devices (CVADs) is a relatively frequent complication. Alteplase (tissue plasminogen activator) has been used to salvage dysfunctional devices. The purpose of this study was to analyze the safety and efficacy of alteplase after administration of a maximum of two 2-mg/2-mL doses to thrombosed CVADs. MATERIALS AND METHODS A combined analysis was performed of two pivotal prospective phase-III clinical trials (Cardiovascular thrombolytic to Open Occluded Lines [COOL] Trials) involving 80 centers enrolling patients from November 1999 through December 2000. Patients 2 years of age or older (with body weights >10 kg) with dysfunctional nondialysis CVADs were eligible, including those with peripherally inserted central catheters, apheresis catheters, and ports. Alteplase (2 mg/2 mL) was instilled into the lumen of the central venous catheter and allowed to dwell for as long as 120 minutes. For patients with body weights of 10-30 kg, 110% of the internal lumen volume of alteplase (2 mg/2 mL) was administered. If the device was still occluded after a maximum of 120 minutes, a second alteplase dose was given and allowed to dwell for as long as 120 minutes. The primary efficacy endpoint was designated as restored function after a maximum of two doses. The primary safety endpoint was intracranial hemorrhage (ICH) within 5 days. RESULTS A total of 1,064 patients (465 men, 599 women; mean age, 50.7 y; range, 2-91 y) with dysfunctional catheters were treated. After alteplase administration, function was restored in 798 patients (75.0%; 95% CI: 72.3%, 77.6%) after one dose and 905 (85.1%; 95% CI: 82.8%, 87.2%) after two doses. Efficacy rates were similar among catheter types (single-, double-, and triple-lumen catheters, and ports). Serious adverse events monitored within 30 days of treatment included ICH (0.0%), embolic events (0.0%), gastrointestinal bleeding (0.3%), thrombosis (0.3%), and sepsis (0.4%). One event (fever) was attributed to the study drug. Efficacy was independent of age, sex, body weight, and catheter type. CONCLUSION A regimen of as many as two 2-mg doses of alteplase is safe and effective for restoring flow to occluded central venous access devices.

Detection of a novel point mutation of the prothrombin gene at position 20209.

Detection of the prothrombin G20210A mutation was performed on the LightCycler Instrument (Roche Molecular Biochemicals, Mannheim, Germany) using commercially available primers and hybridization probes. Herein we report four cases from unrelated African American individuals where LightCycler analysis showed atypical melting curves. Sequence analysis of the four samples showed heterozygosity for a C to T mutation 1 bp upstream from the known 20210 mutation at position 20209. The clinical significance of this mutation is not known, but three patients in whom it was detected had a history of venous thrombosis or stroke. The fourth patient had severe liver disease, which may have masked thrombotic predisposition. Since most assays used to detect the G20210A mutation use a PCR/restriction digestion assay, which would not detect the C20209T mutation, this new mutation may be underrecognized when prothrombin gene mutation testing is performed by PCR/restriction digestion assay.