Aspacytarabine, a cytarabine prodrug, was reported to be safe and effective as first-line therapy for patients with acute myeloid leukemia (AML) who were unfit for intensive induction chemotherapy, according to the results of a phase II study presented during the 2021 ASCO Annual Meeting.¹ The complete remission rate was 39% with single-agent aspacytarabine, and safety was as expected.

“Aspacytarabine has the potential to be a treatment strategy as a new chemotherapy backbone for this challenging patient population,” said lead author Jessica Altman, MD, of Lurie Comprehensive Cancer Center at Northwestern University, Chicago. In August 2020, aspacytarabine was granted Fast Track designation for first-line treatment of patients with AML unfit for standard chemotherapy.

Aspacytarabine could expand the reach of intensive chemotherapy to a broader range of patients with AML.

— Jessica Altman, MD

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Background

There have been several advances in the treatment of AML over the past few years, most notably with therapies targeted to mutations and less intensive schedules of standard drugs. Once remission is attained during induction therapy, many patients will relapse and eventually die of AML.

Intensive induction chemotherapy is the standard of care for first-line treatment of AML. Cytarabine is part of the standard approach, but many older adults and those with significant comorbidities have difficulty tolerating it. Thus, there is a need for newer, less toxic chemotherapy approaches.

This is where aspacytarabine enters the picture. It is a prodrug of cytarabine, and as such, it is inactive and not toxic until it becomes metabolized to cytarabine once it is administered. Aspacytarabine is given in a 1-hour infusion; over the course of the next 8 hours, it gradually releases cytarabine. By contrast, high-dose cytarabine is given in a 3-hour infusion, Dr. Altman told listeners.

“The gradual release of cytarabine over 8 hours reduces peak levels and limits the damage to normal tissues,” she explained.

Study Details

The open-label, single-arm, multicenter phase II study enrolled 60 patients with newly diagnosed AML who were not eligible for standard induction therapy. Of these patients, 46 were evaluable for analysis of efficacy and safety. Patients were treated with one to four courses of aspacytarabine at 4.5 g/m²/d (each consisting of six daily 1-hour infusions); each dose contained 3 g/m² of cytarabine.

Eligibility criteria included a broad spectrum of patients such as those with secondary AML, prior hypomethylating agent therapy, and treatment-related AML. The median age was 75 years; 29 patients (63%) had de novo AML; 17 patients (37%) had secondary AML; and 6 patients (13%) had previously received hypomethylating agents.

Key Findings

For the primary endpoint, 39% of patients attained a complete response; the complete response rate was 45% in patients who had not previously received hypomethylating agents. The median number of cycles to achieve a complete response was one. At 12 months, the median duration of response was not reached.

Rapid complete hematologic recovery was observed in all patients who achieved a complete response, with a median time of 28 days (range, 17–39 days) for complete neutrophil recovery following induction and 15 days (range, 11–31 days) following consolidation. The median time for complete platelet ­recovery was 26 days (range = 20–37 days) and 23 days (range = 22–31 days) following induction and consolidation, respectively. Almost two‑thirds of complete responders (63%) achieved undetectable measurable residual disease.

The 30-day mortality rate was 10.6%. Median overall survival for the total population was 10 months. Median overall survival was not reached for those with newly diagnosed de novo AML and for patients in complete response; it was 6.8 months for those with secondary AML. Among those who did not attain a complete response, median overall survival was 5.1 months, compared with not reached for those with a complete response.

The safety profile of aspacytarabine was as expected. Grade 3 or higher adverse events occurring in at least 20% of patients included hematologic events and infections. No new safety signals were observed, and no cerebellar toxicity or mucositis was reported.

Follow-up of the study is ongoing. The median duration of response was not reached at the end of patient follow-up at 12 months.

“The complete remission rate is 39% in a patient population with challenging baseline characteristics, including patients with secondary AML, prior treatment with hypomethylating agents, older age, and adverse European LeukemiaNet risk scores. These encouraging efficacy data as a monotherapy, combined with a favorable safety profile in patients with AML unfit for intensive chemotherapy, with all responders achieving complete hematologic recovery, underscores my belief that aspacytarabine could expand the reach of intensive chemotherapy to a broader range of patients with AML,” Dr. Altman stated.

Accrual to the phase IIB trial of aspacytarabine has been completed. Based on these results, the next group of studies will focus on single-agent aspacytarabine in relapsed or refractory AML and myelodysplastic syndromes. In addition, a study of aspacytarabine in combination with venetoclax in AML will be initiated. 

DISCLOSURE: The study was funded by BioSight. Dr. Altman has served as a consultant or advisor to AbbVie, Agios, Astellas Pharma, BioSight, GlycoMimetics, Kura Oncology, Syros Pharmaceuticals, and Theradex; has received institutional research funding from AbbVie, Agios, Ambit BioSciences, Amgen, Amphivena, Aprea AB, ARIAD Pharmaceuticals, Astellas Pharma, Astex, BiolineRx, BioSight, Bristol Myers Squibb, Celgene, Cyclacel, Fujifilm, Kartos, Kura Oncology, MethylGene, Pfizer, and Spectrum Pharmaceuticals; and has been reimbursed for travel, accommodations, or other expenses by Astellas Pharma, BioSight, and Daiichi Sankyo.

REFERENCE

1. Altman JK, Koprivnikar J, McCloskey JK, et al: Efficacy and safety of aspacytarabine (BST-236) as a single-agent, first-line therapy for patients with acute myeloid leukemia unfit for standard chemotherapy. 2021 ASCO Annual Meeting. Abstract 7007. Presented June 4, 2021.