PURPOSERelapsed 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).ResultsThe 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.
"It was designed to deliver a larger dose of VCR directly to tumor cells via encapsulation within an aqueous core of nanoparticles comprising sphingomyelin and cholesterol liposomes, thereby avoiding undue neurotoxicity. A recent landmark study of VSLI monotherapy in adults with multiply relapsed or refractory Ph− ALL demonstrated an overall response rate of 35% and a composite CR rate of 20%.33 In August 2012, the US Food and Drug Administration approved VSLI for the treatment of Ph− ALL in adult patients with progressive disease or second or greater relapse. "
[Show abstract][Hide abstract] ABSTRACT: Vincristine (VCR) is one of the most extensively used cytotoxic compounds in hemato-oncology. VCR is particularly important for the treatment of acute lymphoblastic leukemia (ALL), a disease that accounts for approximately one-third of all childhood cancer diagnoses. VCR's full therapeutic potential has been limited by dose-limiting neurotoxicity, classically resulting in autonomic and peripheral sensory-motor neuropathy. In the last decade, however, the discovery that liposomal encapsulation of chemotherapeutics can modulate the pharmacokinetic characteristics of a compound has stimulated much interest in liposomal VCR (vincristine sulfate liposomal injection [VSLI]) formulations for the treatment of ALL and other hematological malignancies. Promising data from recent clinical trials investigating VSLI in adults with ALL resulted in US Food and Drug Administration approval for use in patients with Philadelphia chromosome (t[9;22]/BCR-ABL1) (Ph)-negative (Ph-) disease. Additional clinical trials of VSLI in adults and children with both Ph-positive (Ph+) and Ph- ALL are ongoing. Here we review the preclinical and clinical experience to date with VSLI for ALL.
International Journal of Nanomedicine 11/2013; 8:4361-4369. DOI:10.2147/IJN.S54657 · 4.38 Impact Factor
"Based on the encouraging activity in the Phase I trial, and the clear unmet need of patients with relapsed or refractory ALL, for whom no accepted standard therapy exists, a multinational, pivotal, single-arm, open-label, Phase II trial of weekly VSLI monotherapy was conducted in patients with relapsed and refractory B-cell or T-cell lineage Philadelphia chromosome-negative ALL. The results of this trial have recently been reported,81 and have served as the basis for accelerated approval of VSLI in the US by the FDA on August 9, 2012. Sixty-five adult patients, of median age 31 (range 19–83) years, with clinically advanced and heavily pretreated relapsed or refractory ALL, received intravenous VSLI 2.25 mg/m2 weekly on days 1, 8, 11, and 22 of each 28-day cycle until disease progression, toxicity, or a decision to pursue other treatment, such as allogeneic HSCT, was made. "
[Show abstract][Hide abstract] ABSTRACT: Acute lymphoblastic leukemia (ALL) remains a disease with poor outcomes in adults. While induction chemotherapy achieves a complete remission in almost 90% of patients, the majority will relapse and die of their disease. Relapsed ALL is associated with a high reinduction mortality and chemotherapy resistance, with allogeneic hematopoietic stem cell transplantation offering the only therapy with curative potential. However, there is no efficacious and well tolerated standard regimen accepted as a "bridge" to allogeneic stem cell transplantation or as definitive treatment for patients who are not transplant candidates. Vincristine is an active drug in patients with ALL, but its dose intensity is limited by neurotoxicity, and its full potential as an anticancer drug is thus not realized. Encapsulation of vincristine into sphingomyelin and cholesterol nanoparticle liposomes facilitates dose-intensification and densification to enhanced target tissues with reduced potential for toxicity. Vincristine sulfate liposome injection (VSLI) is associated with significant responses in clinically advanced ALL, and has recently been approved by the US Food and Drug Administration for treatment of relapsed and clinically advanced Philadelphia chromosome-negative ALL. This review provides an overview of the preclinical and clinical studies leading to the approval of VSLI for the treatment of relapsed and refractory ALL, and suggests potential areas of future clinical development.
International Journal of Nanomedicine 09/2013; 8:3479-3488. DOI:10.2147/IJN.S47037 · 4.38 Impact Factor
"Based on the clear unmet medical need, the superiority of VSLI over standard VCR in nonclinical studies and encouraging activity in Phase 1 trials, a multi-national pivotal, Phase 2, single-arm, open-label trial (NCT00495079) of high dose (2.25 mg/m2), weekly VSLI monotherapy was conducted in heavily pre-treated adults with advanced, relapsed and refractory B or T cell lineage Philadelphia chromosome-negative (Ph-) ALL. VSLI monotherapy resulted in meaningful clinical outcomes; the CR/CRi rate and overall response rates were 20 % and 35 %, respectively . VSLI monotherapy was effective as third-, fourth-, and fifth-line therapy and in patients refractory to other single- and multi-agent therapies. "
[Show abstract][Hide abstract] ABSTRACT: 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.
Cancer Chemotherapy and Pharmacology 12/2012; 71(3). DOI:10.1007/s00280-012-2042-4 · 2.77 Impact Factor
Alessandra Lucchese, Giovanni Matarese, Gaetano Isola, Giorgio Gastaldi, Maurizio Manuelli, Enrico Gherlone
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