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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?

Expert Opinions

“Promising, although still preliminary results of a study of a combination of venetoclax with the classical FLAG-IDA regimen. Impressive 97% CRc rate is reported in the newly diagnosed AML group. This suggests that venetoclax may be effective not only in combination with hypomethylating agents, but also with intensive chemotherapy.”

“This study shows the feasibility and promising clinical activity of an intensive chemotherapeutic regimen plus venetoclax. Paved the way for ongoing upfront Phase III randomized studies.”

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.

Expert Opinions

“Outcomes of adults with relapsed AML remain poor and whilst allogeneic stem cell transplantation can deliver long term survival in a proportion of patients who achieve a second CR, current salvage strategies are unsatisfactory. In this important Phase II study, Lachowiez et al demonstrate that it is possible to combine FLAG-IDA with venetoclax (VEN) as a salvage therapy and define a tolerable dosing schedule…In further studies they also report that the FLAG-IDA VEN combination is tolerable in newly diagnosed high-risk AML and also associated with an encouraging CR rate. These promising data justify further examination of the tolerability and clinical activity of FLAG-IDA VEN in a randomized clinical trial.”

“These data demonstrate FLAG-IDA+VEN represents a highly active therapy in both ND AML and relapsed/refractory AML and is a potent, effective regimen for bridging patients to curative allogeneic stem cell transplantation.”

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.

Expert Opinion

This updated report of the trial comparing CPX-351 (dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar drug ratio) vs 7+3 in older adults with newly diagnosed high-risk/secondary AML reinforces this novel therapy as a valid option in this setting. After a median follow-up of 60 months, estimated survival rates were higher for CPX-351 vs 7+3 at 3 years (21% vs 9%) and 5 years (18% vs 8%). CR or CRi was achieved by 73 (48%) and 52 (33%) patients in the CPX-351 and 7+3 arms, respectively. Allogeneic transplantation (HCT) was more frequently performed in the CPX-351 arm than in the 7+3 arms. Among patients who underwent HCT, the Kaplan-Meier–estimated survival rate landmarked from the date of HCT was higher for CPX-351 vs 7+3 at 3 years (56% vs 23%). CPX-351 received FDA and EMA approval as front-line treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes and it is extended to patients below sixty years. Currently, the role of this agent in patients with primary AML outside the mentioned high-risk categories, as well in combination with other novel agents, is being investigated.”

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.

Expert Opinions

This five-year follow-up data demonstrating a continued overall survival benefit for CPX-351 vs 7+3 was impressive, in particular, the landmark analysis from time of transplant which showed the potential of CPX-351 followed by allogeneic transplant to cure > 50% of these high-risk AML patients.”

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.

Expert Opinion

The authors analyzed a cohort of 298 patients with AML treated with ‘7+3’ induction who achieved marrow blast clearance below 5% on Day 15, of whom 150 were randomized to receive a second induction cycle (arm D) and 148 to no second induction cycle (arm S). CR/CRi rates at the end of induction were 86% in arm S and 85% in arm D. Relapse-free survival was slightly but not significantly lower after single induction with a 3-year relapse-free survival of 53% vs 64% (HR, 1.4; p = 0.125), whereas no differences were seen in 3-year OS in arms D vs S. The study suggests that there is no benefit in indicating a second induction course for patients in complete morphological remission on Day 15 after 7+3 induction.”

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.

Expert Opinion

“Despite the fact the classical ‘7+3’ regimen combining cytarabine with an anthracycline has been standardly used in AML induction for more than 50 years, questions still remain regarding how to optimally use this regimen. For example, in many centers, patients are given a second course of induction at Day 14 or 15. In this German Study Group trial, patients ages 18–64 years who achieved a marrow response of < 5% blasts after initial induction with 7+3 were randomized to receive, or not receive, a second induction course of the same regimen. The data suggest that, for patients achieving < 5% blasts after the first induction, a second induction course does not result in improved outcomes, this means these ‘good responders’ can be spared the additional toxicity risked in a second induction.”

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?

Expert Opinion

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.

Expert Opinion

“This abstract by Wang and colleagues may be easily overlooked among the many abstracts reporting on new AML drugs and drug combinations. However, I believe this well-done randomized controlled trial showing that outcomes with 7+3 are the same regardless of whether cytarabine is given as continuous infusion over 7 days or as subcutaneous shots twice daily for 7 days is important, as it provides the basis for a simplified (and less costly) administration of 7+3 in this hospital. It would even enable convenient administration of 7+3 in the outpatient clinic – as an important step toward moving AML care to the ambulatory setting.”

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.

  1. Tamamyan G, Kadia T, Ravandi F, et al. Frontline treatment of acute myeloid leukemia in adults. Crit Rev Oncol Hematol. 2017;110:20-34. DOI: 10.1016/j.critrevonc.2016.12.004
  2. Wang H, Liu L, Zhou J, et al. Comparison of subcutaneous injection versus intravenous infusion of cytarabine for induction therapy in young adult acute myeloid leukemia: results of a prospective, multicenter, noninferiority, randomized trial. Oral abstract #459. 62nd ASH Annual Meeting and Exposition; Dec 6, 2020; Virtual.
  3. Ossenkoppele G, Löwenberg B. How I treat the older patient with acute myeloid leukemia. Blood. 2015;125(5):767–774. DOI: https://doi.org/10.1182/blood-2014-08-551499
  4. Lachowiez C, Konopleva M, Kadia TM, et al. Interim analysis of the phase 1b/2 study of the BCL-2 inhibitor venetoclax in combination with standard intensive AML induction/consolidation therapy with FLAG-IDA in patients with newly diagnosed or relapsed/refractory AML. Oral abstract #332. 62nd ASH Annual Meeting and Exposition; Dec 6, 2020; Virtual.
  5. Lancet J, Uy G, Newell L, et al. Five-year final results of a phase 3 study of CPX-351 versus 7+3 in older adults with newly diagnosed high-risk/secondary acute myeloid leukemia (AML): Outcomes by age subgroup and among responders. Oral abstract #635. 62nd ASH Annual Meeting and Exposition; Dec 7, 2020; Virtual.
  6. Röllig C, Steffen B, Alakel N, et al. Remission and survival after single versus double induction with 7+3 for newly diagnosed acute myeloid leukemia: results from the planned interim analysis of randomized controlled SAL-Daunodouble trial. Oral abstract #458. 62nd ASH Annual Meeting and Exposition; Dec 6, 2020; Virtual.

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