It's ALL in the Liposomes: Vincristine Gets a New Package

In 1963, the US Food and Drug Administration approved vincristine at a dose of 1.4 mg/m, and almost 50 years later on August 9, 2012, the same agency approved vincristine sulfate liposome injection (VSLI) for weekly dosing at 2.25 mg/m for the treatment of Philadelphia chromosome (Ph) –negative acute lymphoblastic leukemia (ALL). The manuscript by O’Brien et al that accompanies this editorial served as the basis for this accelerated approval. The approval covers adult patients whose disease is in second or greater relapse or whose disease has progressed following two or more lines of antileukemia therapy. As is the usual case for new chemotherapeutic agents, the approval does not include pediatric patients. In the 50 years since its approval, vincristine has found use in multiple tumors such as non-Hodgkin lymphoma, Hodgkin lymphoma, myeloma, Wilms tumor, neuroblastoma, breast cancer, soft tissue sarcomas, and others. It has continued to be used in all phases of ALL therapy including induction, consolidation, and maintenance. Thus, it is an important component of the chemotherapy for a large number of adults and children with malignant disease. Vincristine binds to tubulin causing cell cycle arrest in metaphase, and it was apparent from the time of its early development that it had a narrow therapeutic index, due primarily to neurotoxicity. The approved dose in adults is 1.4 mg/m, but most regimens cap the dose at 2 mg so as to avoid severe neurotoxicity. Despite capping, many recent reports of unusual types of vincristine-induced neurotoxicity continue to appear. Neuropathic symptoms may appear after only a few doses even with capping. Since the efficacy, dosing, and neurotoxicity related to vincristine are all linked, in any patient over 1.43 m, almost all adults and some children, the capped dose is no doubt suboptimal. Dose-limiting toxicity, dose capping, and rapid plasma clearance of vincristine have thus made it difficult to achieve optimal delivery to cancer cells. VSLI was designed to deliver a larger dose of vincristine directly to tumor cells via encapsulation within an aqueous core of nanoparticles comprised of sphingomyelin and cholesterol liposomes, thereby avoiding undue toxicity. Preclinical studies showed that dose intensity, dose density, and enhanced target tissue delivery could be achieved, especially for tissues with a disrupted vasculature or those associated with the phagocytic system. Phase I studies had established safe dosing for monotherapy efficacy studies. Relapsed or refractory adult Ph-negative ALL represented an ideal disease in which to test VSLI as monotherapy. While it is a rare malignancy (an estimated 1,400 new cases per year in the United States), and while 80% to 90% of adults will have an initial response on standard multiagent chemotherapy induction regimens, only approximately 20% to 30% will stay in remission, depending on patient and disease-related factors. For the vast majority of patients who relapse, even those who achieve a second remission, survival is measured only in months, and allogeneic stem-cell transplantation offers the sole means to achieve long-term disease-free survival. For those who cannot proceed to transplantation due to comorbidities, suboptimal disease control, or lack of a suitable donor, available treatment options offer little chance of a complete remission (CR) or of survival prolongation. In fact, there is no standard of care for these patients, and many are offered a supportive care approach without additional chemotherapy. Where chemotherapy has been tried, there is a high mortality rate and often disease resistance and rapid progression. Any advance in the treatment of relapsed ALL would be welcome, as median survival is only about 3 months in these patients and only approximately 20% respond to available therapies, which can include high-dose cytarabine, clofarabine, nelarabine for T-cell ALL, and multiple other single agent and combination regimens. The report by O’Brien et al describes a pivotal phase II, singlearm, open-label trial of VSLI administered at 2.25 mg/m weekly in heavily pretreated adults with advanced, relapsed or refractory B-or T-lineage Ph-negative ALL. All enrollees were required to have demonstrated a previous response to therapy at initial diagnosis. Sixty-five adult patients with a median age of 31 years (range, 19 to 83 years) were treated based on actual body-surface area with no dose capping until response, progression, toxicity, or transition to a stem-cell transplantation occurred. Provision was made for dose reduction or delay based on toxicities. The CR/CRi (complete absence of blasts with lack of recovery of either neutrophils or platelets) was 20%, and overall response was 35%. The median CR/CRi duration was 23 weeks, and 12 patients bridged to a stem-cell transplant. In those who responded, median survival was 7.7 months. There were five long-term ( 1 year) survivors, and the 30-day mortality rate was low at 12% with most treatment being given in an outpatient setting. The study results are impressive on several fronts. Responses were seen in both Tand B-cell lineage ALL. Some responders had undergone prior stem-cell transplantation, and this was a population with heavily pretreated and advanced disease, with median blast percentage at study entry of 82%. More than half of the patients had three or more lines of prior therapy, and responses were seen in those who had up to five prior therapies. Eight out of 12 CR/CRis tested had JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 6 FEBRUARY 2