Intensive Chemotherapy Prior to Allo-HCT in Rel/Ref AML?

Intensive chemotherapy, in advance of allogeneic hematopoietic cell transplantation (allo-HCT), did not lead to improved outcomes or survival benefits compared with watchful waiting, sequential conditioning, and allo-HCT alone in patients with relapsed or refractory acute myeloid leukemia (rel/ref AML), according to the randomized controlled phase 3 ASAP trial, presented at the 2022 annual meeting of the American Society of Hematology. The ETAL-3 (evaluation of allogeneic HCT in acute leukemia) ASAP (as soon as possible) trial is the first of its kind, supporting the use of sequential conditioning and allo-HCT without prior chemotherapy. Physician’s Weekly interviewed Dr. Matthias Stelljes (University of Muenster, Germany) to comment on the study outcomes and its implications for the management of rel/ref AML.¹

Achieving a complete remission (CR) in advance of allo-HCT is an advantageous factor for patients with AML. However, it has not yet been thoroughly investigated whether intensive chemotherapy, with the goal to induce remission, prior to allo-HCT results in better outcomes than sequential conditioning and allo-HCT in patients with rel/ref AML. To assess this matter, the ETAL-3 ASAP trial randomized 281 patients with rel/ref AML who were eligible for intensive chemotherapy and allo-HCT in a 1:1 ratio to either high-dose cytarabine and mitoxantrone followed by allo-HCT, or a disease control regimen consisting of recommended watchful waiting but permission of low-dose cytarabine (LDAC) and single doses of mitoxantrone, followed by sequential conditioning and allo-HCT. The primary outcome was the complete remission rate at day 56 after allo-HCT.

In total, 76% of the patients in the disease control arm did not need disease-control measures and were carefully watched until the start of sequential conditioning. The primary endpoint did not reveal a significant difference between the disease control arm and the chemotherapy arm, with 84.1% and 81.3% of patients achieving a complete remission at day 56 after allo-HCT, respectively (non-inferiority P=0.047). Moreover, the 1-year leukemia-free survival rates following complete remission at day 56 were 71.5% in the disease control arm and 69.9% in the chemotherapy arm (P=0.8). The 3-year overall survival rates were comparable, with 51.0% in the disease control arm and 54.2% in the chemotherapy arm (log-rank P=0.47).

Physician’s Weekly discussed the study with Dr. Stelljes and asked him to lay out his perspective on the outcomes.

PW: What is the unmet need in patients that this study works toward fulfilling?

Dr. Stelljes: Currently, most centers worldwide do not proceed to allogeneic HCT when patients are not in remission. Patients suffering from a relapsed or refractory AML are usually treated with intensive salvage therapies or receive less toxic and/or target treatments, which can provide some chance to achieve a subsequent remission. Broadly speaking, the enormous need is that we need improve our treatment strategies to allow more patients to receive a transplant.

PW: Should we use intensive chemotherapy prior to allo-HCT in relapsed and refractory AML?

Dr. Stelljes: Given the potential risk of toxicity, we should probably only do so in selected patients with high proliferative disease when a transplant in time is not possible. Our data also show that in some patients, subsequent remission with an intensive salvage therapy is possible and allows an allogeneic HCT in subsequent remission. The main message to the international audience is that allo-HCT can be quite effective in patients with active disease. Until now, allo-HCT for patients with active/refractory disease was not considered a standard treatment option.

We are now showing with the ETAL3-ASAP results that even patients with active disease have a quite fair chance to reach remission after allogeneic HCT and, importantly, stay in remission for a reasonable amount of time. That is one very important message from this study.

The other message that stands out is that in patients with induction failure, or probably also with patients with relapse, it is not necessary to perform a salvage therapy. Salvage therapy can be quite effective; we can achieve a CR rate with high-dose chemotherapy of around 50%. But this did not transform into a better overall survival for the whole study population.

PW: What were some limitations to the study that you would like to see resolved in future studies?

Dr. Stelljes: Our study only used a classical salvage therapy. Some centers may choose an alternative salvage regimen in selected patients, which may be less toxic. However, with available data, we can only speculate whether alternative salvage therapies will allow better outcome results or if the setting “transplant as soon as possible” will result in similar outcomes. In addition, the main limitation to our study is that when we try to adapt our study results to the broader patient population, we first have to optimize the logistics, like donor availability in time, timely approval from healthcare professionals where needed, and an optimal communication with the transplant centers, ideally starting at the time of initial diagnosis. In other words, the donor has to be already available when the diagnosis of relapsed or refractory AML is made. In Germany, when we have a patient with a newly diagnosed leukemia, the donor search begins at the time of primary diagnosis; this is a standard workup for most leukemia patients, and this allows us to perform transplant as soon as possible—in the first CR or, as shown in our study, for patients with relapsed or refractory disease.

Unfortunately, this is not the same in other countries. That might be a limitation when centers stick to the practical guidelines to only perform a donor search when the patient has relapsing or refractory disease, which is too late.

PW: What’s on the horizon as follow-up for this study? 

Dr. Stelljes: We would like to the impact of novel salvage regimens (eg, venetoclax-based or new targeted therapies). These therapies should be tested in randomized trials comparing a direct transplant versus the new approach. Given the situation that usually all patients fit for therapy are, in principle, eligible for transplant after the salvage therapy, investigators will need to show in the future that their novel approaches are better than a direct transplant approach, at least for those patients for whom an allogeneic HCT “as soon as possible” can be performed.