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 4235

A 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.