Standard VCR Research Articles

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

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. 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. 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. 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.

Neurotoxicity Profile of Vincristine Sulfate Liposome Injection (VSLI, Marqibo®) Monotherapy in Adults with Relapsed Acute Lymphoblastic Leukemia and Universal Prior Standard Vincristine Exposure

AbstractAbstract 3568 Background:VinCRIStine sulfate LIPOSOME injection (VSLI, Marqibo®) is a nanoparticle formulation of vincristine sulfate (VCR) that encapsulates the drug in long-circulating sphingomyelin and cholesterol liposomes. The unique pharmacologic properties of VSLI impart superior nonclinical efficacy and pharmacokinetic properties versus standard VCR. Decades of clinical experience with standard VCR has established peripheral neuropathy as the most notable toxicity and one that underpins the common practice of individual dose capping which limits cumulative dosing. We recently conducted clinical trials to support VSLI accelerated approval for the treatment of adults with relapsed and refractory Philadelphia chromosome negative acute lymphoblastic leukemia (ALL). Here we present data on the neurotoxicity profile of weekly VSLI at the approved dose. Methods:Eighty-three subjects received weekly VSLI 2.25 mg/m2as a 1-hour infusion, with no dose cap, for treatment of advanced, relapsed and/or refractory ALL; Sixty-five patients were enrolled in a pivotal, Phase 2 study and 18 patients were enrolled in an expanded cohort in a Phase 1 study. Signs and symptoms of peripheral neuropathy were proactively assessed using a detailed 15-point evaluation. The pooled data from these studies are the primary safety population for VSLI. Neurotoxicity data are presented here in comparison to two published studies that prospectively evaluated standard VCR induced peripheral neuropathy in patients with Hodgkin disease, non-Hodgkin lymphoma or acute lymphoblastic leukemia (Haim et al, Cancer 1994; 73:2515–2519 and Verstappen et al Neurology 2005; 64:1076–1077. Results:The median individual VSLI dose per infusion was 4.1 mg (range 3.1–5.5) and the median cumulative dose was 18.4 mg (range 3.5–70.1). All patients had prior exposure to VCR containing regimens that resulted in 80% of patients entering the studies with Grade 1 or Grade 2 residual neuropathy. The most common neurological adverse events were constipation (56.6%) and peripheral neuropathy (37.3%). Serious adverse events (SAEs) were reported in 76% of patients and were consistent with advanced ALL. The most frequently reported neuropathy-associated SAEs in patients treated with VSLI were peripheral neuropathy (4.8%) and constipation (3.6%). Incidence of paraesthesia, the only neuropathy uniformly reported across VSLI and VCR studies, was greater in the VCR studies than following much higher dosages and dose density (based on BSA of 1.8) of VSLI.StudyDoseDose Density (mg/week)Paraesthesia Rate (%)Haim1.4 mg/m2/3 weeks0.8478Verstappen4 mg/3 weeks1.3360Verstappen2 mg/3 weeks0.6734VSLI2.25 mg/m2/week4.0423 Conclusions:Experience with VCR has established a clear relationship between dose intensity and symptoms of peripheral neuropathy. Administration of VSLI at a dose of 2.25 mg/m2with no dose cap did not result in any new or unexpected toxicity. Although neuropathy remains a significant toxicity associated with VSLI, the frequency and severity of neuropathic AEs was no greater than what would be expected from a standard VCR regimen. Despite administration of higher doses and dose density, incidence of peripheral neuropathy following exposure to VSLI was lower than previously reported with standard VCR. This is significant given that the individual and cumulative doses of VSLI were 2–3 fold greater than what is generally achieved with standard VCR. VSLI facilitates increasing the tolerable dose and dose density and may result in improved clinical response with similar or less toxicity than VCR.*On behalf of the RALLY trial investigators Disclosures:Deitcher:Talon Therapeutics: Employment, Equity Ownership. Silverman:Talon Therapeutics: Employment.

Vincristine Sulfate Liposome Injection (VSLI, Marqibo®) Facilitates Increased Delivery of Vincristine Sulfate to Target Cancer Tissues.

AbstractAbstract 2457 Background:Standard vincristine sulfate (VCR) plasma pharmacokinetics (PK) is described by a bi-exponential profile with a very short half-life followed by a longer elimination half-life; the volume of distribution is large, suggesting wide and diffuse distribution and perhaps tissue binding. These PK characteristics may limit optimal therapeutic activity of VCR by limiting Cmaxand drug exposure in target tissues involved with cancer. VinCRIStine sulfate LIPOSOME injection (VSLI, Marqibo) is a sphingomyelin- and cholesterol-based nanoparticle formulation of VCR that was designed to be different from and overcome the dosing and pharmacokinetic limitations of standard VCR. The objectives for development of VSLI were to: 1) increase the plasma circulation time; 2) increase tumor tissue delivery by preferential extravasation from fenestrated (“leaky”) vasculature; 3) accumulation in tumor tissues; and 4) slow release of VCR in tumor tissues instead of the systemic circulation. VSLI recently received accelerated FDA approval for use in adults with advanced, relapsed and refractory Philadelphia chromosome negative ALL and is in development for pediatric ALL and aggressive NHL. Methods:The PK and tissue distribution of VCR was evaluated in Sprague-Dawley rats following a single IV bolus dose (2.0 mg/m2) of VSLI or VCR, utilizing 3H-VCR as a marker. The tissue levels of total VCR were measured for up to 72 hours post-dose. PK analysis was performed using noncomparmental methods with the WinNonlin software package. Results:The PK profile and calculated parameters of VSLI in rats showed a substantially lower total vincristine clearance (CL) and volume of distribution (Vdz) and correspondingly greater area under the plasma concentration versus time curve (AUC) compared to standard VCR. VSLI has a long circulation time and remains in the plasma instead of being widely distributed in tissues. For most tissues from VSLI treated animals, tissue to plasma concentration ratios increased over time and peaked at 72 h after VSLI injection, indicating progressive accumulation of radiolabeled drug from plasma into the tissues. The rank order of tissues based on Cmax demonstrated that total VCR concentrations in MPS tissues (i.e., spleen, liver, lymph nodes and bone marrow) and in ovaries were substantially higher than in other organs or tissues. The lowest radioactivity levels were observed in brain, spinal cord, nerves and muscle. Higher exposures, as measured by AUCinf, of VCR were observed in plasma (83 fold), spleen (12 fold), lymph nodes (10 fold), liver (4 fold) and bone marrow (2 fold) following a radiolabeled dose of VSLI compared to VCR.AUCinf, ng eq*hr/gSpleenLiverLymph nodeBone marrowVSLI381,15428,20266,33340,936VCR30,7656,4966,42017,767 Conclusion:The long circulation time and small, 100 nm, mean nanoparticle size of VSLI facilitate extravasation from fenestrated vasculature and accumulation in tissues involved in hematologic malignancies such as lymph nodes, bone marrow and spleen. Slow release of VCR in target tissues following administration of VSLI results in higher and prolonged tissue drug levels providing superior drug delivery to tissues than the same doses of standard formulation of VCR. Disclosures:Silverman:Talon Therapeutics: Employment. Deitcher:Talon Therapeutics: Employment, Equity Ownership.

Neurological Toxicity Profile of Weekly Vincristine Sulfate Liposomes Injection (Marqibo®) 2.25 mg/m2 Compared to Historical Standard Vincristine Sulfate 1.4 mg/m2, 2 mg, and 4 mg Administered Less Frequently

Abstract 4247 The accumulated clinical experience with standard vincristine sulfate (VCR) describes a safety profile most notable for the occurrence of a dose-related, symmetrical, sensorimotor and autonomic polyneuropathy. The various manifestations of neuropathy are the usual dose-limiting toxicities associated with standard VCR that limit the extent to which patients can derive clinical benefit from this therapy. Vincristine sulfate liposomes injection (VSLI, Marqibo®) is a sphingomyelin-based, liposomal formulation of VCR designed to intensify dose, prolong encapsulated drug circulation time, and target drug to sites of active cancer. We report here the neurological toxicity profile (Graded using CTCAE criteria v3.0) of weekly, single-agent IV VSLI 2.25 mg/m2 in 83 adult subjects with heavily pre-treated, relapsed and/or refractory acute lymphoblastic leukemia (ALL) and 100% past standard VCR exposure. Neuropathy signs and symptoms were rigorously evaluated at baseline and weekly during VSLI treatment in order to maximize adverse event detection. Findings were compared to baseline (post-standard VCR and before VSLI) neuropathy in the same VSLI treated population and to the best available published neurotoxicity data regarding standard VCR administration. In the study by Haim et al ([1] Cancer 1994; 73:2515–9), 104 VCR-naïve patients with lymphoma received multi-agent therapy including standard VCR 1.4 mg/m2 weekly to once every 28 days. In the study by Verstappen et al ([2] Neurology 2005; 64:1076–7), 114 VCR-naïve patients with lymphoma received multi-agent therapy including fixed dose standard VCR 2 mg or 4 mg every 3 weeks. Results are provided in the table below. NR = not reported. The baseline frequency of residual neuropathy in adults with ALL treated with weekly VSLI 2.25 mg/m2 was not unexpected considering that all patients received prior standard VCR. The on-study, incremental neuropathy burden was relatively modest. On-study neuropathy rates during and immediately following weekly VSLI 2.25 mg/m2 were comparable to or less than those reported in lymphoma patients receiving standard VCR at 1.4 mg/m2 every 1 to 3 weeks or at a fixed dose of 2 mg or 4 mg every 3 weeks, despite the dose intensification afforded by VSLI. Constipation, the most commonly reported neurological toxicity associated with standard VCR and VSLI, resulted in standard VCR dose reduction in 22% of patients reported by Haim et al compared to weekly VSLI dose reduction in only 5% of patients due to constipation. Frequent neurological assessments combined with a dose adjustment algorithm facilitated continued VSLI dosing in order to induce remission and minimization of Grade 3 or greater neurotoxicity. One VSLI patient developed peripheral motor neuropathy requiring drug discontinuation after 11 weekly doses. In the VSLI study, neurological toxicity was considered predictable and manageable. Disclosures: Schiller: Talon Therapeutics: Research Funding. Deitcher:Talon Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Vincristine Sulfate Liposomes Injection (Marqibo®) Facilitates Durable Remissions and Potentially Curative Hematopoietic Stem Cell Transplantation in Adults with Advanced, Relapsed and/or Refractory Acute Lymphoblastic Leukemia

Abstract 4235A durable response in advanced, relapsed and/or refractory adult acute lymphoblastic leukemia (ALL) may be defined as remission that results in a meaningful prolongation of life or response that facilitates “bridging” to a subsequent, potentially curative, hematopoietic stem cell transplantation (HSCT). Vincristine sulfate liposomes injection (VSLI, Marqibo®) is a sphingomyelin/cholesterol (SM/Chol) nanoparticle formulation of standard vincristine sulfate (VCR) designed to facilitate dose intensification, prolonged drug delivery and enhanced lymphoid malignancy penetration and concentration without increased toxicity. Recently, VSLI was evaluated in a multi-institutional, Phase 1/2 (VSLI-06; NCT00144963) clinical trial and a multi-national, Phase 2 (HBS407; NCT00495079) clinical trial in a combined 101 adults (median age 31 years [range 18 to 83 years]) with advanced, relapsed and/or refractory ALL. All but 1 patient had Philadelphia chromosome negative disease. Thirteen patients (13%) had extramedullary disease, 37 (37%) had undergone a prior HSCT, and 100% had received at least one prior line of therapy including standard VCR. Study VSLI-06 (N = 36) was a dose-ascending trial of weekly VSLI (1.5 to 2.4 mg/m2) combined with pulse dexamethasone. Study HBS407 was a single-arm trial of weekly single-agent VSLI at the maximum tolerated dose established in VSLI-06 of 2.25 mg/m2. Overall, 19 (19%) patients received VSLI as a first salvage therapy, 57 (56%) patients received VSLI as a second salvage therapy, and 25 (25%) patients received VSLI as a third or greater salvage therapy. All patients had to be deemed ineligible for immediate HSCT in order to enroll in VSLI-06 or HBS407. In the combined study population, the overall response rate (complete remission [CR], CR with incomplete hematologic recovery [CRi], partial remission [PR], and bone marrow blast response [BMB]) was 31% (95% CI: 22–41) with a 20% (95% CI: 13–29) rate of CR+CRi. Despite delivering intensified individual (2.8–5.5 mg) and cumulative (up to 70.1 mg) doses of VCR, VSLI had a similar safety profile to that reported for the approved dose of standard VCR. VSLI enabled bridging to a post-VSLI HSCT in 12 of 65 (18%) patients in HBS407 and 5 of 36 (14%) patients in VSLI06 for a total of 17 of 101 (17%). All 17 post-VSLI HSCT patients were under the age of 60 years. Three of 12 post-VSLI HSCT patients from HBS407 remain alive at greater than 28, 33, and 35 months following VSLI, respectively. All 12 patients lived for greater than 100 days after post-VSLI HSCT. Long-term survival (greater than 12 months) was achieved in 27% of those able to receive post-VSLI HSCT. These outcomes, that are important to patients, may reflect the effectiveness of the VCR dose intensification facilitated by VSLI. The neuropathy associated with the dose intensified VCR administered as VSLI was predictable, manageable, and comparable to that published for standard VCR. The lack of early, pre-day 100, mortality following post-VSLI HSCT suggests that the sphingomyelin-based liposomal formulation did not adversely affect subsequent transplantation procedures. In conclusion, VSLI produced both clinically important endpoints of prolonged survival and achievement of response allowing for a bridge to HSCT for advanced, relapsed and/or refractory ALL. Disclosures:Schiller:Talon Therapeutics: Research Funding. Silverman:Talon Therapeutics: Employment, Equity Ownership. Deitcher:Talon Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Vincristine sulfate liposomes injection (VSLI) “bridging” to potentially curative hematopoietic stem cell transplantation (HSCT) in adults with Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL).

6527 Background: In a phase II, multi-national study (RALLY Trial; NCT00495079), 65 adults (median age 32 yrs, range 19 to 83) with Ph-ALL in second or greater relapse or who had progressed after two or more prior lines of treatment received single-agent, VSLI (Marqibo) 2.25 mg/m2 (without dose cap) IV weekly. All subjects were ineligible for immediate HSCT due to refractoriness to prior HSCT or the most recent salvage attempt, poor performance status, and/or insufficient anticipated lifespan. Methods: “Bridging” to HSCT was assessed as a pre-defined study secondary endpoint. Results: Overall response rate was 35% (95% CI: 24-48) with a 20% (95% CI: 11-32) complete response (CR) plus CR with incomplete hematologic recovery (CRi) rate. VSLI, despite delivering individual (2.8-5.5 mg) and cumulative (up to 70.1 mg) dose-intense VCR, had a similar safety profile to that reported for standard VCR. VSLI enabled bridging to HSCT in 11 of 65 (17%) subjects. Seven of the 11 (64%) subjects had undergone at least one pre-VSLI HSCT. Five of the 11 subjects were in CR/CRi at the time of post-VSLI HSCT. Three of 11 subjects remain alive at greater than 28, 33, and 35 mos, respectively, after post-VSLI HSCT. Five of 11 subjects relapsed and died following post-VSLI HSCT. Three of 11 subjects died of HSCT-related complications. All 11 subjects lived for greater than 100 days after post-VSLI HSCT. Conclusions: VSLI produced rapid CR/CRi or disease stabilization and a meaningful “bridge” to HSCT in 11 of 65 (17%) heavily pre-treated near end-stage adults with ALL. Long-term survival (greater than 12 mos) was achieved in 27% of those able to receive post-VSLI HSCT. These unexpected outcomes that are important to patients may reflect the effectiveness of the dose intensification facilitated by VSLI compared to that provided by standard VCR. Post-VSLI HSCT subject characteristic CR/CRi, N = 5 median (range) Non-CR/CRi, N = 6 median (range) Interval from 1st VSLI to HSCT, mos 2.7 (1.5-3.2) 5.0 (2.2-9.0) Cumulative VSLI exposure, mg 30.3 (15.8-41.4) 26.8 (4.0-49.0) OS following 1st VSLI, mos 8.6 (5.3-27.7+) 9.0 (6.3-34.9+)

Marqibo® (vincristine sulfate liposomes injection; VSLI) Optimizes the Dosing, Delivery, and Pharmacokinetic (PK) Profile of Vincristine Sulfate (VCR) In Adults with Relapsed and Refractory Acute Lymphoblastic Leukemia (ALL)

AbstractAbstract 2142 Background:VCR is an important component of the treatment of ALL, non-Hodgkin lymphoma, Hodgkin's disease, multiple myeloma, and other adult and childhood cancers. In part, because of the cell cycle specific activity of VCR, its anti-cancer activity is believed to be very exposure time and concentration dependent. Standard dosing of conventional VCR (1.4 mg/m2 with a 2 mg cap) is limited because of early onset peripheral neuropathy and fails to achieve sustained VCR delivery. VSLI (Marqibo) is a nano-particle encapsulated formulation of VCR designed to facilitate dose intensification, prolonged drug delivery and enhanced cancer penetration and concentration. Methods:In a pivotal, Phase 2, multi-national study (RALLY Trial), 65 adults with Philadelphia chromosome negative ALL who were either in second or greater relapse or who had progressed after two or more prior lines of treatment received single-agent intravenous VSLI 2.25 mg/m2 (without any dose cap) weekly over 1 hour as salvage therapy. First-dose PK was investigated in a representative subset of 13 study subjects. Blood for analysis was collected at 8 time points ranging from 5 minutes to 48 hours following infusion. Total VCR plasma levels were determined by HPLC-MS/MS. PK parameters were calculated with Phoenix WinNonlin. Results:The PK subject subset had a median body surface area (BSA) of 1.92 m2 (range 1.47 to 2.45 m2) and received a median VSLI dose (VCR component) of 4.32 mg (range 3.3 to 5.51 mg). Based on BSA and the 2 mg dose cap, all subjects in this study group would have been dosed with 2.0 mg of conventional VCR. The median cumulative induction dose of VSLI (VCR component) that was administered in this study was 18.8 mg (range 3.5 to 70.1 mg). Total VCR plasma concentration decreased rapidly from Cmax after the VSLI infusion in 5 subjects (38%); 8 subjects (62%) exhibited a delay of 4 to 10 hours before the total VCR plasma concentration began to decrease. The calculated Tmax was 1.3 ± 0.4 hours (range 1.1 to 2.0 hours). The Cmax was 1214 ± 233 ng/mL (range 919 to 1720 ng/mL). The apparent mean half-life was 7.1 ± 3.2 hours. The mean AUCinf was 13,993 ± 6,588 ng hr/mL with a range from 7,167 to 27,233 ng hr/mL. The mean clearance (CL) was 6.4 ± 2.6 mL/min. The mean volume of distribution (Vd) was 0.051 ± 0.018 L/Kg. There were no significant differences in the PK parameters between the male and female subjects participating in this study. The table below presents VSLI PK parameters in addition to historical PK parameters for conventional VCR dosed at 2 mg. Conclusions:VSLI clearly provides dose intensification and prolonged VCR delivery compared to conventional, non-encapsulated VCR. VSLI, as dosed in this adult ALL clinical trial, delivered individual and cumulative amounts of VCR that exceed those achievable with standard and approved dosing of conventional VCR. This translated into a median dose intensification of 116% (range 65 to 176 percent) calculated as the percent change in VSLI dose from a standard VCR dose. This dose intensification is believed to have contributed to the 35% overall response rate including 20% complete responses (with or without full blood count recovery) reported in this heavily pre-treated, multiply-relapsed/refractory population without apparent enhanced toxicity [J Clin Oncol 28:15s, 2010 (suppl; abst 6507)]. VSLI has a distinctly different PK profile than conventional VCR. The larger VSLI Cmax and AUCinf reflect the dose intensification afforded by a larger mg/m2 dose and lack of dose capping. Even in the absence of dose capping, the 2.25 mg/m2 VSLI dose represents a 61% dose escalation above conventional VCR. While Cmax and AUCinf are dose-dependent PK parameters, the observed differences between VSLI and VCR control cannot be explained by dose alone. The larger AUCinf also reflects prolonged circulation afforded by the sphingomyelin:cholesterol liposome encapsulation. The modest VSLI mean CL and small Vd reflect the retention of encapsulated VCR within the plasma compartment for an extended period of time so that VCR can better penetrate and accumulate in sites of cancer through fenestrated vasculature. The enhanced delivery of encapsulated VCR contributes to maintenance of VCR concentrations above the effective concentration. Disclosures:Silverman: Hana Biosciences: Employment. Deitcher: Hana Biosciences: Employment.

A phase II study of the tolerability and activity of weekly vincristine sulfate liposomes injection (VSLI) in adults with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) in second relapse or progressing following two antileukemia treatment lines

7046 Background: VSLI (Marqibo) is a nanoparticle formulation of vincristine sulfate (VCR) encapsulated in sphingomyelin/cholesterol liposomes called Optisomes. The optisomal formulation lends itself to an improved pharmacokinetic profile and enhanced tumor penetration and concentration. Preclinical studies of VSLI showed enhanced efficacy versus standard VCR in a variety of solid and hematologic malignancies. VSLI has a maximum tolerated dose of 2.25 mg/m2 with no dose cap, while conventional VCR is dosed at 1.4 mg/m2 with a 2 mg dose cap. A previous study in relapsed ALL showed a complete response rate of 19%, warranting further study. Methods: Eligible adult subjects received single agent intravenous VSLI at a dose of 2.25 mg/m2 weekly with no dose cap. This international, multicenter, single-arm study will enroll approximately 56 subjects. Major endpoints include response rate and overall survival (OS). An interim analysis was planned following enrollment of 29 evaluable subjects. Results: 29 heavily pretreated subjects received ≥ 1 dose of VSLI. To date, at least 9 of 29 subjects had clearing of leukemic blasts and achievement of an M1 bone marrow. Based on preliminary data, the median OS is estimated to be 7.5 months (95% CI: 4.7–10.5) using the Kaplan-Meier method. The most frequent related adverse event (AE) was peripheral neuropathy (PN) (48%), half of which was grade 3. No grade 4 PN was reported. Six subjects had 8 treatment-associated grade 4 AEs of neutropenia (4), thrombocytopenia (2), anemia (1), and inappropriate antidiuretic hormone secretion (1). Conclusions: These results are encouraging, as VSLI was given as a single agent to a heavily pretreated patient population who nearly universally received prior VCR. This population typically has a very low response rate to anti-leukemia therapies. Early OS data compares favorably to an historical median OS of ∼ 2 months (8.7 weeks) in a second salvage population (data on file, M. D. Anderson). VSLI was well tolerated in these patients in the context of universal prior vincristine treatment. [Table: see text]

A Randomised Phase II Study of Pegylated Liposomal Doxorubicine in Elderly Patients with Acute Lymphoblastic Leukemia (ALL): The GRAALL-SA1 Study.

The GRAALL-SA1 study aimed to randomly compare the efficacy and toxicity of liposomal pegylated doxorubicin (Peg-Dox) vs continuous infusion doxorubicin (CI-Dox) in elderly patients with Philadelphia chromosome-negative ALL. Induction chemotherapy, supported by G-CSF, comprised either CI-Dox 12 mg/m2/d and CI-VCR 0.4 mg/d on d1-4 or Peg-Dox 40 mg/m2 IV and standard VCR 2 on d1, in combination with dexamethasone. A second cycle, reinforced by cyclophosphamide 1 g/m2, was started at d28. Consolidation included two additional cycles using reduced doses of CI-Dox (12mg/m2/d d1-3) or Peg- Dox (30 mg/m2 d1) with VCR in both treatment arms (5 minutes infusion on d1,8,15) alternating with two cyclophosphamide (650 mg/m2 d1) /thioguanine (60 mg/m2 d2- d15) /cytarabine (75 mg/m2/d4-7 and d11-14) cycles. Maintenance included 6-MP and methotrexate for 2 years. CNS prophylaxis was based on 6 triple ITs and cranial irradiation. From March 2002 to October 2006, 60 patients aged 55 years or more from 26 centers were enrolled in this multicenter study. The median age was 66 years (range 55–80), 17% had initial WBC 3 30 x109/l, 2 patients had CNS leukemia and 6.6% had mediastinal involvement. Immunophenotyping showed 85% B-lineage ALL, 12% T-ALL, and 3% aberrant expression of myeloid antigens. Patient characteristics were comparable in the two randomization groups except for a small unbalance with more T-ALL and more steroids resistant leukemia in the Peg-Dox group (6/29 vs 1/31, P = .05 and 5/29 vs 1/31, P = .1, respectively). Tolerance was improved in the Peg-Dox arm with less Grade 3–4 infectious events during induction (27% vs 48%; P = .04), less Gram negative bacteriemia during induction (1 vs 9, P = .02) and consolidation courses (2 vs 7, P = .07) and less cardiac toxicities (1/29 vs 6 /31, P = .12). Duration of neutropenia was reduced from 7 days in the CI-Dox arm to 6 days in the Peg-Dox arm (P= .06). RBC units transfused were reduced from 7.2 to 4.5 during induction (P= .02) and from 2.9 to 1.1 during consolidation course (P= .003). Days with platelets < 50.109/L were reduced from 13.4 to 6.4 (P=0.03). After the 2 induction cycles, CR rate was 82%, with 10% failures and 8% induction deaths. With a median follow-up of 40 months, median OS for the entire population was 10 months and 19% of the patients were alive in CR at 3 years (95% CI, 9–30). Despite the better tolerance, there was a trend for a worse 2-year OS in the Peg-Dox arm (11 vs 27% ; P=0.07), due to higher induction failure (17 vs 3%) as well as relapse incidence rates (62 vs 39%). Younger age, B-lineage, and steroid sensitivity were the three factors identified for a higher CR rate in multivariate analysis. The decreased toxicity of Peg-Dox over CI-Dox was thus offset by a decreased efficacy. Further studies should evaluated higher doses of pegylated versus conventional formulations of anthracycline in patients with ALL.

Automatic Target Handing Over System .

The image seen by the airborne seeker and the image (of the same scene) seen by the operator through the high resolution sensor (thermal sight) are different in spatial resolution. In order to establish the correlation between these two images, the thermal sight image needs to be resampled and made similar to the seeker image by applying a preprocessing technique. The preprocessing is carried out by a handling over system (HOS) that resamples the thermal sight image making it compatible with seeker image and hands over the resampled image to the seeker. This paper discusses the implementation of the suitable handling over algorithm. (Boland, J.S. et al. automatic target hand using correlation techniques. Technical report, Auburn University, Alabama, 31 January, 1977, pp.57-63). Emphasis is laid on developing suitable hardware and software and tests to match the two images obtained by two different sensors of the same scene. The hardware and software have been evaluated with sets of images. The H/W is designed around iAPX 86 family of processor and software is developed in PL/M. Hardware also includes the recording facility on a standard VCR, to record the performance of handling over electronics (HOE) during testing/flight trials. Evaluation of the system by realistically simulating the field scenario in the laboratory has shown that the HOS is functioning satisfactorily.

The Third International Women's Literary Conference

DUBROVNIK, Yugoslavia, 15-21 April 1990 The Third International Women's Literary Conference in Dubrovnik this April brought together writers, scholars, performers, and artists from 15 countries. As usual, the announced schedule deconstructed almost immediately, the Americans behaved badly, the rains were biblical and incessant, and everyone had a fabulous time. Moreover, the conference couldn't have been produced at a more propitious historical moment. The inherent theatrics of the rapid dissolution of Eastern European Marxism, coupled with the current plague of nationalism that is bringing Yugoslavia to the boil, made what happened in hotel lobbies and city streets at least as dramatic and infuriating as what went on at the conference every day for a week. The conference's announced title, BEYOND IMAGES: Women, Culture and the Arts, and its announced languages, French and English, promised intensive forays into the complex relationships between theory and practice in woman-made art. In fact, the Frenchand English-speaking sessions were scheduled concurrently so that in order to hear, say, Florence Howe's extremely interesting biography of The Feminist Press, I might have to miss the Quebecoise artist Mireille Perron's enormously interesting video presentation. In fact, the usual practice was for the Frenchand English-speaking sections to pick up each other's lost stitches at dinner where most conversations began elegiacally (What a shame you missed .), continued bilingually, and ended, oddly, by taking the place of performances or presentations, as what was missed was recounted, enacted, criticized. Dinners were very animated. The three conference organizers (Graces under pressure), Myriam DiazDiocaretz (Chilean poet and translator of Adrienne Rich), Nada PopovichPerisic (Yugoslavian aesthetician and theatre scholar who had recently refused the position of Minister of Culture), and Svetlana Slapsak (classical scholar from Ljubljana), worked ceaselessly-mediating, rescheduling, changing everything but the weather to insure that this rather bumpy ride on the road to cross-cultural understanding stayed on its lively legs. The rest of us smoked, drank, revised our papers and performances (in my case completely-the long-promised American standard VCR didn't arrive in time and, along with the East German theatre director Gingka Tscholakowa-Henle, I had to relinquish hope of showing videos of my productions), and waited for friends and enemies to speak. The rhetoric did get a little thick at times (I'd never heard the term dogmatic residue so appropriately applied before and I'd never heard the word syncatagorematic at all). Some of the performance papers suffered the fatality of self-consciousness and almost all the theatre people continued to insist that almost all the scholars needed acting lessons. Nonetheless, everything that was going to get done got done, and everything that could be said was