Aspacytarabine a potential first-line option for chemotherapy-ineligible patients with AML
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The novel antimetabolite aspacytarabine appeared safe and efficacious as first-line therapy for patients with acute myeloid leukemia unfit for intensive chemotherapy, according to a study presented during the virtual ASCO Annual Meeting.
Aspacytarabine (BST-236, BioSight), a time-limited, single-agent treatment, could serve as a new, tolerable AML chemotherapy backbone, results of the phase 2b, open-label, single-arm study showed.
“Over the last handful of years, new approvals for the treatment for AML in adults have changed the landscape of treatment for our patients,” Jessica K. Altman, MD, professor of medicine (hematology and oncology) at Robert H. Lurie Comprehensive Cancer Center of Northwestern University, said during a presentation.
“Both in newly diagnosed and relapsed and refractory disease, we have a number of new treatments that have had a significant favorable impact on our patients,” Altman added. “Unfortunately, the majority of patients with AML still suffer from relapse and eventually die of their disease. Despite these advances, there is a need for more effective and less toxic chemotherapy approaches. ... [Aspacytarabine] has the potential to be a treatment strategy for this challenging patient population.”
Aspacytarabine is inactive in its intact, prodrug form until it metabolizes to cytarabine. It gradually releases cytarabine over approximately 8 hours, which allows for a shorter infusion of 1 hour and decreases systemic exposure to peak toxic cytarabine levels, resulting in reduced systemic toxicity and relative sparing of normal tissues. This enables therapy with high cytarabine doses for patients otherwise unfit to receive it, according to researchers.
As of data cutoff on April 19, researchers enrolled 60 patients with newly diagnosed AML who were ineligible for standard chemotherapy; results presented at ASCO included 46 patients (median age, 75 years; range, 60-88; secondary AML, 37%) deemed evaluable for safety and efficacy. The majority of these patients had an ECOG performance status of 0 to 1 (59%) vs. 2 (41%). About half (48%) had bone marrow blasts greater than 50; most had either an intermediate (26%) or adverse (39%) European LeukemiaNet risk score. Six patients previously received hypomethylating agents.
Researchers administered aspacytarabine at a dose of 4.5 g/m2 (containing 3 g/m2 cytarabine) in six daily, 1-hour infusions of one to two induction cycles and, for responding patients, one to three consolidation cycles.
The median number of cycles to achieve complete remission was one, Altman said. Complete remission rate served as the primary endpoint. Researchers also evaluated OS, duration of response and safety.
Results showed 39% of patients achieved complete remission as of the data cutoff date. When limiting analysis to patients who had not received a prior hypomethylating agent with or without venetoclax (Venclexta; AbbVie, Genentech), the complete remission rate increased to 45%.
All responders achieved complete hematological recovery within 28 days.
Most complete remissions (63%) were minimal residual disease negative, and researchers observed correlations of minimal residual disease negativity with improved OS and other superior clinical outcomes.
Median OS was 10 months (95%CI, 6-not reached) overall, 6.8 months (95% CI, 2.7-not reached) among patients with secondary AML, not reached among patients with complete remission and 5.1 months (95% CI, 1.5-not reached) among patients without complete remission.
Median duration of response had not yet been reached at 12 months, Altman said.
“(Aspacytarabine treatment) was safe and well-tolerated in this population with mainly expected adverse events and, in particular, no cerebellar toxicity or mucositis reported,” Altman said.
Treatment-related adverse events that occurred in at least 20% of patients included febrile neutropenia (57.4%), hypokalemia (44.7%) and peripheral edema (42.6%); notable grade 3 or higher treatment-adverse events included febrile neutropenia (48.9%) and thrombocytopenia (38.2%). Altman noted all were typical events among older adults with AML.
“Based on this work, additional trials are being initiated, including a single-agent study being conducted in Europe and the United States with aspacytarabine for the treatment of relapsed and refractory myelodysplastic syndromes and AML,” Altman said. “In addition, another front-line AML study is being initiated for those adults deemed unfit for intensive therapy, combining aspacytarabine with venetoclax and induction, and patients will receive aspacytarabine alone and in consolidation.”
Perspective
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Shyam A. Patel, MD, PhD
Improvements in outcomes for patients with AML over the past 4 years have been largely attributable to the introduction of more selective therapies with reduced toxicity. This year’s ASCO Annual Meeting continues to paint bright horizons for AML therapeutics with improved safety profiles. As we enter the genomic era of precision medicine in AML, much remains to be said about traditional cytotoxic chemotherapeutics.
Although we have numerous targeted therapeutics based on mutation-specific vulnerabilities, it may be better in some cases to optimize an existing drug and extend therapy to more patients. Altman and colleagues present seminal data on BST-236 (aspacytarabine), a prodrug of the traditional cytotoxic chemotherapy agent, cytarabine, in newly diagnosed AML.
The benefits of aspacytarabine are the dosing schedule (ease of dosing) and more favorable toxicity profile, as compared with 7 days of standard-dose cytarabine and 3 days of an anthracycline antibiotic (7 + 3 regimen). The regimen of six daily, 1-hour infusions of aspacytarabine is quite convenient vs. standard induction protocols. Aspacytarabine was well-tolerated and carried an overall low 30-day mortality of 11%, making it a better option for elderly and/or unfit patients who might not tolerate standard 7 + 3 induction.
Limitations to aspacytarabine include a slightly lower complete response rate (45%) than has been reported for hypomethylating agents (HMAs) plus venetoclax (73%).
A few salient research questions remain:
- How effective is aspacytarabine in the relapsed setting? Aspacytarabine did not appear to be effective against many relapsed cases, and it remains to be seen how it might compare to liposomal daunorubicin and cytarabine (Vyxeos, Jazz Pharmaceuticals) or combinations of HMAs with novel therapies.
- Which biological subgroups of unfit patients would benefit from aspacytarabine compared with HMAs plus venetoclax? Multiple cooperative group studies over the years have shown the benefit for traditional cytotoxic chemotherapeutics, especially in patients with AML with disruption of the core binding factor complex or AML without adverse cytogenetics. Cytarabine-based regimens also may confer improved outcomes (compared with HMA-based therapy) for patients with mutant TP53 variant allele frequency of 40% or less.
- How effective will single-agent aspacytarabine be in the absence of an anthracycline? Synergy between anthracyclines and cytarabine has been the cornerstone for AML therapy for nearly 4 decades.
- How likely will aspacytarabine yield measurable residual disease (MRD) negativity? The use of cytotoxic chemotherapy facilitates marrow ablation, but such agents often fail to eliminate the stem cell fraction of AML, especially if these cells harbor functional defects in TP53 or equivalent genes. MRD considerations are essential for allogeneic stem cell transplant, as curative-intent therapy is often the ultimate goal for most patients.
In summary, the data on aspacytarabine appear promising and may have great potential to benefit select groups of unfit patients. We look forward to longer-term data with more patients.
References:
DiNardo CD, et al. Lancet Oncol. 2018;doi:10.1016/S1470-2045(18)30010-X.
DiNardo CD, et al. Blood. 2019;doi:10.1182/blood-2018-08-868752.
Lachowiez CA, et al. Blood Adv. 2020;doi:10.1182/bloodadvances.2019001267.
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Altman JK, et al. Abstract: 7007. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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