High-Dose Vincristine Sulfate Liposome Injection for Advanced, Relapsed, and Refractory Adult Philadelphia Chromosome–Negative Acute Lymphoblastic Leukemia

Abstract

A B S T R A C T 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 highdose 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 MethodsSixty-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%). ConclusionHigh-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.

Acute Lymphoblastic Leukemia, Version 2.2015

“…120 Approximately 50% of patients had received 3 or more prior lines of therapy. In addition 48% of patients had undergone prior HCT, and all patients had previously been treated with a regimen containing standard vincristine.…”

“…The median duration of CR was 23 weeks (range, 5-66 weeks) and median OS for all patients was 20 weeks (range, 2-94 weeks); median OS for patients achieving a CR was 7.7 months. 120 The incidence of early induction death (30-day mortality rate) was 12%. 120 These outcomes appeared favorable compared with published historical data in patients with Ph-negative ALL treated with other agents at second relapse (n = 56; CR rate, 4%; median OS, 7.5 weeks; early induction death, 30%).…”

“…120 The incidence of early induction death (30-day mortality rate) was 12%. 120 These outcomes appeared favorable compared with published historical data in patients with Ph-negative ALL treated with other agents at second relapse (n = 56; CR rate, 4%; median OS, 7.5 weeks; early induction death, 30%). 120,121 The most common grade 3 or greater treatment-related toxicities with VSLI included neuropathy (23%), neutropenia (15%), thrombocytopenia (6%), anemia (5%; no grade 4), and tumor lysis syndrome (5%).…”

“…Febrile neutropenia occurred in 3% of patients (no grade 4). 120 Based on data from the RALLY study, VSLI was approved (in September 2012) by the FDA for the treatment of adult patients with Ph-negative ALL in second or greater relapse or whose disease progressed after 2 or more therapies. 122 In December 2014, the FDA approved blinatumomab for the treatment of relapsed or refractory Ph-negative precursor B-cell ALL.…”

“…96 This average remission rate of 88% 96 is significantly improved compared with the average remission rate for patients receiving standard-of-care chemotherapy after relapse (approximately 30%). 56,120,132 Furthermore, 7 of 16 patients were able to receive an allogeneic HCT, suggesting that CAR T cells may provide a bridge to allogeneic HCT. 96 No relapse has been seen in patients that had allogeneic HCT (followup, 2-24 months); however 2 deaths occurred from transplant complications.…”