High-dose vincristine sulfate liposome injection (Marqibo) Is not associated with clinically meaningful hematologic toxicity.

BACKGROUND: Vincristine sulfate liposome injection (VSLI) facilitates vincristine dose intensification and densification, is active in untreated and relapsed lymphoma, and has been approved in the United States for relapsed and refractory acute lymphoblastic leukemia. Cancer- and concomitant chemotherapy-related anemia, neutropenia, and thrombocytopenia in patients with hematologic malignancy have complicated the evaluation of hematologic toxicity related to new drugs. PATIENTS AND METHODS: We assessed the hematologic toxicity of VSLI 2.25 mg/m(2) administered every 14 (cohort 1) or 7 (cohort 2) days in 54 patients with metastatic uveal melanoma, a cancer not known to involve the bone marrow. RESULTS: Cohort 2 received a greater median number of VSLI doses (6 vs. 4) within a shorter median period (5.7 vs. 8.7 weeks), resulting in a larger median cumulative exposure (22.6 vs. 17.7 mg) and near doubling of the median dose density (2.2 vs. 4.0 mg/wk) compared with cohort 1. Despite greater VSLI exposure and dose density, cohort 2 had a lower median decrease from baseline in the neutrophil count and a greater increase from baseline in the platelet count compared with cohort 1. Hematologic adverse events (AEs) were uncommon and mostly grade 1 or 2 in severity. No grade 4 hematologic AEs developed. CONCLUSION: VSLI at its approved dose resulted in a low incidence of clinically meaningful hematologic toxicity. A near doubling of the median dose density did not have an identifiable effect on the reported incidence and severity of hematologic AEs. VSLI could be well suited for use combined with myelosuppresive drugs and for patients unable to tolerate peripheral blood cytopenia.

Phase II study of vincristine sulfate liposome injection (Marqibo) and rituximab for patients with relapsed and refractory diffuse large B-Cell lymphoma or mantle cell lymphoma in need of palliative therapy.

BACKGROUND: VSLI (Marqibo) is active in advanced non-Hodgkin lymphoma (NHL) and untreated aggressive NHL. Because of its favorable hematologic toxicity profile, VSLI might be useful in patients unable to tolerate myelosuppressive therapies. PATIENTS AND METHODS: Twenty-two patients with heavily pretreated, advanced CD20(+) DLBCL or MCL were treated with VSLI 2.0 mg/m(2), without a dose cap, every 2 weeks plus 4 weekly doses of rituximab 375 mg/m(2). ORR, complete response (CR), or partial response (PR), was the primary end point. Secondary end points included response duration, time to progression (TTP), and OS. Safety variables included adverse events and neurologic assessments. RESULTS: The ORR was 13 of 22 (59%); 6 patients achieved a CR (27%), and 7 patients achieved a PR (32%). Median response duration, TTP, and OS were 147 days, 121 days, and 322 days, respectively. The median number of VSLI doses was 5, the median individual VSLI dose was 3.5 mg, and the maximum cumulative VSLI dose was 43 mg. Grade 3 peripheral neuropathy, febrile neutropenia, and constipation were reported in 4, 2, and 1 patients, respectively. CONCLUSION: VSLI plus rituximab resulted in durable responses in patients with heavily pretreated advanced stage DLBCL and MCL. The toxicity profile was predictable and manageable with limited hematologic toxicity. Despite near-universal previous VCR exposure (96%) and doses of VSLI unachievable with standard VCR treatment, peripheral neuropathy and constipation were modest. This study supports further evaluation of VSLI as a component of DLBCL management.

Pharmacokinetics and pharmacodynamics of vincristine sulfate liposome injection (VSLI) in adults with acute lymphoblastic leukemia.

Vincristine sulfate liposome injection (VSLI,) is a sphingomyelin and cholesterol nanoparticle formulation of vincristine sulfate (VCR) that was designed to overcome the dosing and pharmacokinetic limitations of standard VCR. In contrast to the rapid CL and wide tissue distribution of non-liposomal VCR, VSLI circulates in plasma for a prolonged period of time, with a slow CL of 345 mL/h and relatively small Vd of 3,570 mL. This facilitates enhanced and prolonged tumor-tissue delivery of VCR. The maximum tolerated dose of VSLI, 2.25 mg/m(2) once per week without a dose cap, enables individual and cumulative VCR exposure unachievable with non-liposomal VCR at its labeled dose of 1.4 mg/m(2) . VSLI is associated with a dose-dependent peripheral neurotoxicity albeit at doses that are two to three times that of standard VCR. VCR dose intensification with VSLI correlated with an increased probability of overall response and a strong trend towards increased complete response in adults with relapsed and/or refractory acute lymphoblastic leukemia. Overall, VSLI improves the therapeutic index by facilitating increased dose intensification while maintaining a predictable and manageable safety profile.

Long term results of a phase 2 study of vincristine sulfate liposome injection (Marqibo(®) ) substituted for non-liposomal vincristine in cyclophosphamide, doxorubicin, vincristine, prednisone with or without rituximab for patients with untreated aggressive non-Hodgkin lymphomas.

Vincristine sulfate liposome injection (VSLI; Marqibo(®) ; M) is active in relapsed and refractory lymphomas, and approved in the United States for relapsed and refractory adult acute lymphocytic leukaemia. We evaluated VSLI (2·0 mg/m(2) without dose cap) substituted for non-liposomal vincristine (VCR) in a cyclophosphamide, doxorubicin, vincristine, prednisone ± ritiximab (CHOP±R) regimen, creating CHMP±R in 72 untreated, aggressive non-Hodgkin lymphoma patients, including 60 with diffuse large B-cell lymphoma (DLBCL). The overall response rate was 96% (69/72) including complete response (CR) in 65 (90%) and unconfirmed CR in 2 (3%). Median progression-free survival (PFS) and overall survival (OS) were not reached at median follow-up of 8 and 10·2 years, respectively. The 5- and 10-year PFS and OS were 75%, 63%, 87%, and 77%, respectively. Despite VSLI exposure of up to 35 mg, the safety profile of CHMP±R was comparable to that reported for CHOP±R. Grade 3 peripheral neuropathy was reported in 2 (3%) patients; there was no reported Grade 3/4 constipation. CHMP±R was highly active, generally well tolerated, and compared favourably to historical trials with R-CHOP in DLBCL. This enhanced activity probably reflects VCR dose intensification, pharmacokinetic optimization, and enhanced delivery afforded by VSLI. A Phase 3 trial of R-CHMP versus R-CHOP in elderly patients with untreated DLBCL is ongoing.

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.

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.

Phase 1 multicenter study of vincristine sulfate liposomes injection and dexamethasone in adults with relapsed or refractory acute lymphoblastic leukemia.

BACKGROUND: Dose intensification of chemotherapy has improved outcome for younger adults with de novo acute lymphoblastic leukemia (ALL). Novel formulations of standard chemotherapy agents may further reduce the incidence of disease recurrence after frontline chemotherapy. Vincristine (VCR) sulfate liposomes injection (VSLI) is a sphingomyelin/cholesterol nanoparticle encapsulated VCR formulation that improves the pharmacokinetic profile of VCR without augmenting neurotoxicity. METHODS: A phase 1 trial of weekly, intravenous VSLI at 1.5 mg/m(2), 1.825 mg/m(2), 2.0 mg/m(2), 2.25 mg/m(2), or 2.4 mg/m(2) was conducted to determine the maximum tolerated dose (MTD) using a standard, 3 + 3 dose-escalation design. Dexamethasone (40 mg) was given on Days 1 through 4 and on Days 11 through 14 of each 4-week cycle. RESULTS: Thirty-six adults with relapsed/refractory ALL, all previously treated with conventional VCR, received at least 1 dose of VSLI. The MTD of VSLI was 2.25 mg/m(2) based on dose-limiting toxicities of grade 3 motor neuropathy, grade 4 seizure, and grade 4 hepatotoxicity in 1 patient each at the 2.4 mg/m(2) dose level. The most common toxicities attributed to VSLI included peripheral neuropathy (55%) and constipation (53%). A complete response (CR) was achieved in 7 of 36 patients (19%) based on an intent-to-treat analysis; the CR rate was 29% for the 14 patients who underwent therapy as their first salvage attempt. Four of 7 patients who achieved a CR underwent subsequent allogeneic stem cell transplantation in remission. CONCLUSIONS: In this study, VSLI plus dexamethasone appeared to be an effective salvage therapy option for relapsed/refractory ALL. A phase 2, international, multicenter clinical trial assessing the efficacy of single-agent VSLI as second salvage therapy for patients with previously treated ALL is underway.

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

BACKGROUND: 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). METHODS: Eligible patients had relapsed or refractory de novo or transformed aggressive NHL and prior treatment with at least 2 multiagent chemotherapy regimens. Marqibo was administered at 2 mg/m2, every 2 weeks, for a maximum of 12 cycles or until toxicity or disease progression. RESULTS: One hundred and nineteen patients were enrolled and treated on trial. Ninety-six had histological confirmed de novo (N=89) or transformed (N=7) aggressive NHL. Median number of cycles was 4 (median dose/cycle 4 mg). Overall response (CR and complete response unconfirmed and PR) was 25% (95% confidence interval [CI], 17, 35), CR and complete response unconfirmed confirmed by external reviewers was 5%. Median overall survival was 6.6 months (Kaplan-Meier estimate, 95% CI, 4.7, 9.8). Grade 3 of 4 neurotoxicity occurred in 32% of patients. All patients had prior neurotoxic agents, and 85% had baseline residual neuropathy symptoms (grades 1-2) from prior treatment. CONCLUSIONS: Marqibo is an active agent in patients with heavily pretreated aggressive NHL, and tolerated at approximately twice the dose intensity of standard vincristine. Its activity supports further investigation as a substitution for vincristine in combination treatment of lymphoid disorders.

A pilot study with vincristine sulfate liposome infusion in patients with metastatic melanoma.

Vincristine sulfate liposome infusion (VSLI) is a sphingomyelin/cholesterol liposome encapsulated formulation of vincristine that results in an extended drug circulation time and the potential for enhanced malignancy targeting, exposure, and anticancer activity. We assessed the safety and activity of VSLI in patients with metastatic melanoma. VSLI, to provide VCR 2.0 mg/m without dose capping, was infused over 1 h every 2 weeks (one cycle). Safety, tumor response, and survival were determined. Twenty-seven patients with metastatic melanoma of cutaneous (n=19), uveal (n=4), mucosal (n=1), and unknown (n=3) primary were treated. Twenty-five (93%) patients had received one or more prior lines of chemotherapy and/or immunotherapy; 14 (48%) had received a vinblastine-containing regimen. Hematologic adverse events (AEs) primarily manifested as grade 1/2 neutropenia. Nonhematologic AEs primarily consisted of gastrointestinal and constitutional symptoms of grade 1/2 severity. Grade 3 AEs included one case of paresthesia and four cases of constipation. The disease control rate in 26 evaluable patients was 31%. One complete (uveal melanoma metastatic to lung) and two partial responses (previously untreated cutaneous melanoma metastatic to the bone, brain, spleen and lung, and another with melanoma of unknown primary involving the lung, liver, and lymph node) were found. Five patients had stable disease. The median time to progression was 1.9 months. The median survival was 9.6 months with 30% of the patients alive at 1 year. VSLI was generally well tolerated and showed promising antitumor activity against metastatic melanoma and uveal melanoma in particular. A phase 2 trial to further elucidate the efficacy and safety of VSLI in metastatic uveal melanoma is ongoing.

To clot or not to clot: are there predictors of clinically significant thrombus formation in patients with gastroparesis and prolonged IV access?

Some patients with gastroparesis (GP) require sustained central intravenous access for hydration, medication and/or nutrition, leaving them at risk for venous thrombosis. We studied a group of 53 patients with gastroparesis for identifiable risk factors of clinically significant thrombosis. Patients requiring prolonged central IV access fell into two groups: those who had clinical incidence of IV catheter-related thrombosis confirmed radiologically (CLOT, n = 14), and those who did not form IV catheter thrombosis (NOCLOT, n = 39). We analyzed and compared clinical symptoms, serum/plasma coagulation studies, and autoimmune antibodies in the CLOT and NOCLOT groups. Patients in the CLOT group had statistically more Scl 70 antibodies than did the NOCLOT group, and another autoantibody, Ku 66, was found in higher titers in the NOCLOT group than the CLOT group. Other autoimmune and coagulation factors were not statistically different between the two groups, although a subgroup of CLOT patients had lower plasma Protein S levels. We conclude that the presence of Scl 70 autoantibodies is associated with increased clotting risk in this group of GP patients, and that the Ku 66 antibody may be associated with decreased risk of thrombosis in patients with GP. These findings, coupled with lower Protein S levels in some CLOT patients, suggests that autoimmune factors may be associated with GP patients who thrombose IV access versus patients who do not.

Recombinant nematode anticoagulant protein c2 in patients with non-ST-segment elevation acute coronary syndrome: the ANTHEM-TIMI-32 trial.

OBJECTIVES: We sought to evaluate the safety and efficacy of recombinant nematode anticoagulant protein c2 (rNAPc2) in patients with non-ST-segment elevation acute coronary syndrome (nSTE-ACS). BACKGROUND: Recombinant NAPc2 is a potent inhibitor of the tissue factor/factor VIIa complex that has the potential to reduce ischemic complications mediated by thrombin generation. METHODS: A total of 203 patients were randomized 4:1 to double-blinded intravenous rNAPc2 or placebo every 48 h for a total of 1 to 3 doses in 8 ascending panels (1.5 to 10 microg/kg). All patients received aspirin, unfractionated heparin (UFH), or enoxaparin and early catheterization; clopidogrel and glycoprotein IIb/IIIa blockers were encouraged. Two subsequent open-label panels evaluated 10 mug/kg rNAPc2 with half-dose UFH (n = 26) and no UFH (n = 26). The primary end point was the rate of major plus minor bleeding. Pharmacokinetics, pharmacodynamics, continuous electrocardiography, and clinical events were assessed. RESULTS: Recombinant NAPc2 did not significantly increase major plus minor bleeding (3.7% vs. 2.5%; p = NS) despite increasing the international normalized ratio in a dose-related fashion (trend p < or = 0.0001). Higher-dose rNAPc2 (> or =7.5 microg/kg) suppressed prothrombin fragment F1.2 generation compared with placebo and reduced ischemia by >50% compared to placebo and lower-dose rNAPc2. Thrombotic bailout requiring open-label anticoagulant occurred in 5 of 26 patients treated without UFH, but none in the half-dose UFH group (19% vs. 0%; p = 0.051). CONCLUSIONS: In patients with nSTE-ACS managed with standard antithrombotics and an early invasive approach, additional proximal inhibition of the coagulation cascade with rNAPc2 was well tolerated. rNAPc2 doses > or =7.5 microg/kg suppressed F1.2 and reduced ischemia, though some heparin may be necessary to avoid procedure-related thrombus formation. (Anticoagulation With rNAPc2 to Eliminate MACE/TIMI 32; http://www.clinicaltrial.gov/ct/show/NCT00116012?order=1; NCT00116012).

Plasminogen activator inhibitor type-1 (PAI-1) polymorphism 4G/5G is associated with prostate cancer among men with a positive family history.

BACKGROUND: Variation in the expression of plasminogen activator inhibitor type-1 (PAI-1) is associated with many human diseases, including several types of cancer. In particular, tumor cell overexpression of PAI-1 has been found to inhibit prostate cancer tumor growth, angiogenesis, and metastasis in mouse models. Normal host cell expression of PAI-1 is influenced by the 4G/5G insertion/deletion polymorphism in the promoter region of the PAI-1 gene. To evaluate the effect of PAI-1 expression on cancer development, we examined the association of the 4G/5G polymorphism in a sibling-based case-control study of prostate cancer. METHODS: One thousand one hundred thirty seven subjects, 655 cases, and 482 sibling controls from 526 families, were recruited from the major medical institutions in the greater Cleveland, OH area and from the Henry Ford Health System, Detroit, MI. A Cox age-of-onset model with robust variance estimation was used to evaluate the association between the PAI-1 4G/5G polymorphism and prostate cancer. RESULTS: No association was observed between the PAI-1 4G/5G polymorphism and prostate cancer in the entire sample. We did, however, identify a statistically significant association between the PAI-1 4G/5G polymorphism and prostate cancer in subjects with a family history of this disease (OR = 1.28, 95% CI 1.02-1.61, P-value = 0.036). The PAI-1 5G/5G genotype, associated with lower PAI-1 expression, appears to drive this result as it was associated with an increased risk of prostate cancer and an earlier mean age of onset compared to those with the 4G/4G genotype (OR = 1.83, 95% CI 1.12-2.99) while the 4G/5G genotype group did not show a significant difference in prostate cancer risk compared to the 4G/4G genotype group (OR = 0.98, 95% CI 0.75-1.28). CONCLUSIONS: These observations suggest that the 4G/5G polymorphism in PAI-1 may explain some of the increased risk and earlier mean age of onset of prostate cancer due to a positive family history.

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.

Phase II trial of alfimeprase, a novel-acting fibrin degradation agent, for occluded central venous access devices.

PURPOSE: Alfimeprase is a recombinantly produced, genetically modified variant of the metalloproteinase, fibrolase. Alfimeprase proteolytically cleaves fibrin, independent of plasminogen activation to plasmin, and directly dissolves thrombi. Based on the direct fibrin degradation effect of alfimeprase, rapid activity in patients with occluded central venous access devices (CVADs) was hypothesized. PATIENTS AND METHODS: We performed a phase II, randomized, double-blind, active-control, multicenter, dose-ranging study to compare the safety and efficacy of one or two instillations of three intraluminal doses of alfimeprase (0.3, 1.0, and 3.0 mg) and alteplase 2.0 mg in re-establishing patency to occluded CVADs in 55 adult patients. RESULTS: All three alfimeprase doses were more successful than alteplase during the first 15 and 30 minutes of treatment. The alfimeprase 3.0-mg dose resulted in 40%, 50%, and 60% patency restoration rates at 5, 15, and 30 minutes, respectively, compared with 0%, 0%, and 23% for alteplase. The difference at 15 minutes was highly significant (P = .0075). Alfimeprase 3.0 mg produced the highest patency rate at 120 minutes after the first (60%) and second (80%) doses. No major hemorrhagic or embolic events were reported. CONCLUSION: A single 1- or 3-mg dose of alfimeprase has the potential to restore function to occluded CVADs rapidly and safely, and to facilitate on-time infusion of vital therapies.

Alfimeprase: a novel recombinant direct-acting fibrinolytic.

Alfimeprase is a recombinant, direct-acting fibrinolytic zinc metalloprotease. Alfimeprase has direct proteolytic activity primarily against the fibrin(ogen) Aalpha chain. Alfimeprase is covalently bound and neutralised by serum alpha(2)-macroglobulin, a prevalent mammalian protease inhibitor. Preclinical pharmacology studies have shown that fibrinolysis with alfimeprase is up to sixfold more rapid than with select plasminogen activators, such as tissue-type plasminogen activator and urokinase. Alfimeprase directly delivered to a site of thrombosis has the potential to be a fast and effective fibrinolytic, which does not generate the systemic lytic state seen with plasminogen activators that is associated with major bleeding, including intracerebral haemorrhage. Phase I and II studies in individuals with arterial or venous thrombotic events indicate that alfimeprase is active and generally well tolerated.

Incidence and risk factors of venous thromboembolism (VTD) in patients with amyloidosis.

BACKGROUND: Coagulation problems in amyloidosis are historically associated with bleeding tendencies (mostly Factor X abnormalities). Increased clotting was observed in isolated cases diagnosed with low-grade disseminated intravascular coagulation (DIC). Problem of venous thromboembolic disaease (VTD) in amyloidosis was not systematically investigated. METHODS: We evaluated frequency of VTD and risk factors for VTD in 56 consecutive amyloidosis patients with a documented disease evaluated and followed up at our Center from 1991-2001. Data was collected in 5 categories: (a) demographics, (b) disease and treatment, (c) thrombosis case information, (d) major risk factors for thrombosis and (e) baseline laboratory data. Univariable correlates of VTD were assessed using Kaplan-Meier analysis and Cox proportional hazards analysis. RESULTS: Mean age of the patients was 67 (years range 21-83). Male/female percentage ratio was 70/30. 29% of the patients had high creatinine level (> 1.4 mg/dl). Personal or family history of VTD was recorded in 2 and 0% of patients, respectively. Known hypercoagulable state was present in 1 patient (2%). 8% of patients were smokers. Of 56 patients, 6 developed VTD (11%). Median time from diagnosis of amyloidosis to VTD was 12.5 month (range 1-107). Treatment was given within a median of 1 month (range 0-4) from the development of thrombosis. Only sites of VTD were lower extremities. No cases were associated with I.V. line. 1 case (17%) was identified postoperatively. We identified several univariable correlates of VTD in amyloid patients, including greater age at diagnosis (HR-2.99, P = .041), personal history of DVT (HR-47.7, P = .006) and immobility (HR-11.78, P = .006). Presence of circulating serum M-protein had protective role in our analysis (HR-.08, P = .031). There was no correlation with the type of treatment patients were receiving. CONCLUSION: Risk for thromboembolic diseases in patients with amyloidosis is similar to one previously described for multiple myeloma. Additional studies with higher number of thromboembolic events could help to further elucidate risk factors for VTD in this population of patients.

A phase I trial of alfimeprase for peripheral arterial thrombolysis.

PURPOSE: To evaluate the safety profile, pharmacokinetics, and thrombolytic activity of alfimeprase, a novel direct-acting thrombolytic agent, in patients with chronic peripheral arterial occlusion (PAO). MATERIALS AND METHODS: In this multicenter, open-label, single-dose, dose-escalation study, 20 patients with worsening symptoms of lower extremity ischemia within 6 months of enrollment were treated with alfimeprase in five escalating dose cohorts (0.025 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.3 mg/kg, and 0.5 mg/kg) by means of intraarterial and sometimes intrathrombic pulsed infusion. The primary endpoint was safety assessed by adverse event rates. Additional safety assessments included vital sign monitoring, serum chemistry testing, hematologic testing, and coagulation testing for 28 days after the procedure, as well as alpha2-macroglobulin and antialfimeprase antibody testing for as long as 3 months after treatment. Pharmacokinetic parameters were evaluated with use of an assay that measures free and alpha2-macroglobulin-bound (ie, total) alfimeprase. RESULTS: No patient experienced a hemorrhagic adverse event. Mean plasminogen and fibrinogen concentrations were not substantially altered by treatment. Three transient treatment-related adverse events were reported in the same patient: one incidence each of increased blood fibrinogen level, skin rash, and headache. All three adverse events were graded as mild. The pharmacokinetic profile of alfimeprase suggested that the half-life for total alfimeprase ranges from 11 to 54 minutes (median, 25 min) in patients with PAO. The serum alpha2-macroglobulin concentrations decreased transiently in a dose response-like manner between 12 and 24 hours and returned to within normal limits approximately 14 days after alfimeprase exposure. CONCLUSIONS: Alfimeprase in doses as high as 0.5 mg/kg was generally well-tolerated in patients with chronic PAO. No bleeding complications were noted. The stable fibrinogen concentrations suggest that the activity of alfimeprase may be limited to the target thrombus. Alfimeprase holds the potential to achieve dissolution of thrombus with a diminished risk of hemorrhage.

Risk of anaphylaxis after reexposure to intravenous lepirudin in patients with current or past heparin-induced thrombocytopenia.

OBJECTIVE: To retrospectively assess the signs and symptoms indicative of adverse reactions to repeated exposures to lepirudin in patients with heparin-induced thrombocytopenia who received at least 2 courses of lepirudin therapy. PATIENTS AND METHODS: Medical records were retrospectively assessed from adult patients who received at least 2 courses of lepirudin therapy separated by at least 1 week between January 1999 and June 2002 at The Cleveland Clinic, Cleveland, Ohio. We evaluated the list of 289 low-level terms for possible signs and symptoms of anaphylactic reactions In the medical dictionary for regulatory activities as well as patient vital signs to detect manifestations of immediate hypersensitivity reactions. Vital signs from the day before initiation of lepirudin therapy were compared with those from days 1 and 2 after exposure. RESULTS: No cases of anaphylaxis or allergic reaction related to lepirudin administration were identified among 43 adult patients. On day 1 of lepirudin, 10 patients had lower systolic blood pressures (by > or =20 mm Hg) than pre-lepirudin values, and 4 patients had systolic blood pressures of less than 100 mm Hg. CONCLUSIONS: Isolated asymptomatic decreases in blood pressure after patient reexposure to lepirudin most likely do not reflect anaphylaxis due to lepirudin. We believe that isolated and uncommon cases of anaphylaxis temporally related to lepirudin exposure should not preclude its use in patients with heparin-induced thrombocytopenia and past lepirudin exposure.

Non-clinical and clinical characterization of a novel acting thrombolytic: alfimeprase.

Alfimeprase (ALF) is a recombinant, truncated form of fibrolase, a directly fibrinolytic zinc metalloproteinase that was first isolated from the venom of the Southern copperhead snake (Agkistrodon contortrix contortrix). ALF has direct proteolytic activity against the fibrin(ogen) Aalpha chain. ALF can be covalently bound and neutralized by serum alpha2-macroglobulin, a prevalent mammalian protease inhibitor. Preclinical pharmacology studies have shown that thrombolysis with ALF is up to 6-times more rapid than with select plasminogen activators. Additional studies suggest that intra-thrombus ALF has the potential to be a fast and effective thrombolytic without generation of a systemic lytic state. Investigations of phases 1 and 2 indicate that ALF is active and generally well tolerated. This paper reviews the biochemical characteristics of ALF and a review of the preliminary clinical experience in subjects with acute peripheral arterial occlusion and in those with central venous access device occlusion.

Clinically evident venous thromboembolic events in children with brain tumors.

We evaluated the incidence and significance of central venous access device dysfunction and symptomatic major thrombosis in 253 pediatric patients with brain tumors. Central venous access device dysfunction was a common complication (28.4%) and was associated with major thrombosis development and a reduced overall survival rate. Major thrombosis was relatively uncommon (2.8%).