What has ASH 2020 taught us about advancing frontline chemotherapy in AML?

Increased understanding of the driving genetic and epigenetic factors of acute myeloid leukemia (AML) in recent years has helped to refine novel chemotherapy combinations in the frontline setting.  Advances in the frontline treatment of AML, including both the optimization of chemotherapeutic approaches and emergence of targeted therapies, have led to better outcomes in specific genetic subsets of AML. Furthermore, risk stratification of patients with AML has allowed for personalized treatment decisions and improved outcomes.¹

The ‘7+3’ regimen (7 days of cytarabine + 3 days of an anthracycline) is the predominant induction chemotherapy for young patients with newly diagnosed (ND) AML,² but treatment options for elderly patients are more limited.³ Among the efforts being made to optimize frontline therapy are dose/schedule modifications of existing regimens. The aim here is to improve patient experience and limit the frequency of toxicities, all while maintaining efficacy. Changes to established regimens also require validation through clinical trials.

Despite advances in the frontline treatment options for patients with AML, challenges with treatment safety and efficacy persist. The AML Hub will be focusing on advances in frontline chemotherapy as an educational theme. In this introductory article, the AML Hub outlines the abstracts from the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition considered by our Steering Committee to be practice changing in this setting. These abstracts are summarized below, accompanied by expert commentary from leaders in the AML community.

Novel chemotherapy combinations

Venetoclax + FLAG-IDA as induction or consolidation therapy for patients with AML (#332)⁴

It has been suggested that the Bcl-2 inhibitor, venetoclax, might enhance the anti-leukemic activity of the combination regimen FLAG-IDA: fludarabine, cytarabine, granulocyte-colony stimulating factor, and idarubicin. At ASH 2020, Curtis Lachowiez presented the interim results of a phase Ib/II study of venetoclax in combination with FLAG-IDA for the treatment of patients with ND or relapsed/refractory AML.

In patients with ND AML, an overall response rate of 97% was observed, and the highest composite complete remission (CRc) rates were achieved in patients with ND AML (90%). MRD negativity was attained in 96% of patients when venetoclax + FLAG-IDA was employed in the frontline setting. Read the AML Hub summary for the full study design and safety and efficacy data.

Below you’ll find the thoughts of some of our Steering Committee members, as well as a video interview with Curtis Lachowiez in which we asked, What patients benefit most from the addition of venetoclax to FLAG-IDA?

The significance of this study is not limited to the frontline setting, as described by Charles Craddock and Courtney DiNardo, who highlighted the promising results from the relapsed/refractory patient population.

CPX-351 vs 7+3 in older adults with ND high-risk/secondary AML – Final five-year results and subgroup analysis (#635)5 

CPX-351 is a dual-drug liposomal encapsulation of daunorubicin and cytarabine (1:5 molar drug ratio) that has been approved by the FDA and EMA for the treatment of patients with ND therapy-related AML or AML with myelodysplasia-related changes. Results from the phase III study (NCT01696084) comparing CPX-351 to 7+3 induction in patients aged 60–75 with ND high-risk/secondary AML supported these approvals, and data from the 5-year follow-up were presented at the 2020 ASH Meeting.

At ASH, Jeffrey Lancet highlighted the sustained improvement in overall survival (OS) with CPX-351 over conventional 7+3 chemotherapy, which was not influenced by patient age, hematopoietic stem cell transplantation, or achievement of CR/CRi (CR with incomplete hematologic recovery). Rates of 5-year survival were 18% and 8% with CPX-351 and 7+3, respectively, and CPX-351 demonstrated favorable safety in difficult-to-treat age groups. Steering Committee member Jorge Sierra provided an overview of the key results and what they mean moving forward.

The AML Hub was pleased to speak with Jeffrey Lancet during ASH, who answered the question, Does CPX-351 induce deeper responses compared to 7+3? You can watch the video below.

Optimizing conventional chemotherapeutic regimens

Single vs double induction with 7+3 for patients with ND AML (#458)⁶

The SAL-Daunodouble trial is evaluating the benefit of single vs double induction with 7+3 in patients aged 18–65 years with ND AML, and data from an interim analysis were presented by Christoph Röllig at ASH 2020. The data suggest that, in patients who achieve a good response (blast count < 5%) to initial therapy, CR rates are highly comparable after single vs double induction. The findings of this study indicate that a second induction could be avoided in good responders, which is encouraging, as a second round of therapy can be a risk to the patient.

Eduardo Rego outlines some of the major findings from the study.

AML Hub Chair, Gail Roboz, highlighted the significance of these findings for clinical practice and how these data will positively influence patient quality of life.

The AML Hub thanks Christoph Röllig for taking the time to discuss the question, Can we omit a second induction cycle in patients with good early response?

Cytarabine via subcutaneous injection vs intravenous infusion for induction in AML (#459)²

Subcutaneous injection of cytarabine appears to yield higher Ara-CTP (anti-leukemia active metabolite) concentrations vs intravenous (IV) infusion over 5 hours. Subcutaneous administration is more convenient for patients and does not require prolonged hospital administration. To date, there is no prospective, multicenter, clinical data determining the efficacy and safety of subcutaneous injection vs IV infusion of cytarabine.

A study by Huafeng Wang and colleagues investigated whether, in the standard 7+3 regimen, subcutaneous administration of cytarabine is noninferior to IV infusion in young patients with de novo AML. At the 62nd ASH Meeting, Wang presented the data from the open-label, prospective, multicenter, randomized clinical trial evaluating subcutaneous vs IV administration of cytarabine in this setting. The study was carried out in ten locations across China and the follow-up took place in June 2020.²

Among 240 patients randomized 1:1 to receive to idarubicin (3 days) and cytarabine by subcutaneous injection vs IV infusion (7 days):

• CR after the first cycle of induction therapy: 71.7% vs 70.8% (p value for noninferiority = 0.003)
• CR after the first two cycles of induction therapy: 77.5% vs 75.8% (p value for noninferiority = 0.001)
• 3-year OS: 60% vs 58%
• 3-year event-free survival: 49% vs 44%
• Levels of hematologic toxicity, non-hematologic toxicity, and early death rate were comparable

As demonstrated by the data, this multicenter study shows that subcutaneous cytarabine was non-inferior to, and posed no greater toxicity over, IV infusion in young adults with de novo AML.

Roland Walter provided a statement outlining what impact he believes this data will have on clinical practice and patients with ND AML.

Conclusion

Although the number of novel targeted agents for AML is increasing, frontline chemotherapy remains central to the treatment paradigm of patients with AML. Therefore, research to improve the safety and efficacy of chemotherapeutic agents to enhance patient quality of life is of the utmost importance. The AML Hub will be looking into the progress being made in the frontline chemotherapy setting over the coming months – stay tuned for more articles.