High-dose vincristine sulfate liposome injection for advanced, relapsed, and refractory adult Philadelphia chromosome-negative acute lymphoblastic leukemia

Abstract

Purpose: Relapsed 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).

Results: The 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.

Trial registration: ClinicalTrials.gov NCT00495079.

Fig 1.

Overall survival and hematopoietic cell transplantation after vincristine sulfate liposome injection (post-VSLI HCT) among the 65 patients treated with VSLI monotherapy. The median overall survival in the 65 patients treated with VSLI monotherapy was 4.6 months, with 34% of patients living longer than 6 months. There were five long-term survivors (ie, survival for longer than 1 year) and two patients who remain alive and potentially represent cures. The median overall survival in responders (patients experiencing complete response, complete response with incomplete hematologic recovery, partial remission, and bone marrow blast response [CR + CRi + PR + BMB]) was 7.7 months, with 70% of patients alive for longer than 6 months. Nonresponders had a median overall survival of 3.0 months, with 14% alive for longer than 6 months. The median overall survival in the 12 patients who underwent post-VSLI HCT was 9.3 months, with 83% alive for longer than 6 months.

Fig 2.

Relationship between cumulative vincristine sulfate liposome injection (VSLI) exposure, worst grade of related peripheral neuropathy adverse events, and response. Each grade of VSLI-related peripheral neuropathy has two columns of data. The blue rectangles in the left-hand columns of data represent nonresponders. The blue diamonds in the right-hand columns of data represent patients who achieved a partial remission or bone marrow blast response. The gold diamonds represent patients who achieved complete response or complete response with incomplete hematologic recovery. Responses, including complete response or complete response with incomplete hematologic recovery, were achieved at each grade of related peripheral neuropathy. Application of the dose reduction algorithm was intended to manage grade 3 toxicity and continue dosing to achieve response.