Intensive remission induction chemotherapy versus less intensive pre-transplant approach for relapsed/refractory AML (2023)

By Alice Goodman
25 January 2023

Intensive rescue therapy aiming to achieve complete remission before allogeneic hematopoietic cell transplantation (aloHCT) may not be necessary in some patients with relapsed or refractory acute myeloid leukemia (AML), according to the results of the phase III ASAP study, which is based on presented at the Society's 2022 American Hematology (ASH) Annual Meeting and Exposition.¹In this study, watchful waiting followed by sequential conditioning prior to aloHCT in patients with relapsed or refractory AML achieved overall survival and leukemia-free survival similar to that achieved with intensive remission induction chemotherapy.

Transplantation is generally considered the only chance of cure in these patients, but transplantation is usually only offered to patients who achieve complete remission. The results of this study therefore contradict current practice. The results suggest that many patients may be able to forego the additional step of salvage chemotherapy and the associated toxicity prior to transplantation.

“We hypothesized that salvage chemotherapy would not provide a net benefit for patients with high-risk AML. Our conclusions are that patients with a poor response after the first induction chemotherapy or the first relapse of AML do not benefit from rescue chemotherapy with high doses of cytarabine plus an anthracycline before transplantation,” said the senior authorJohannes Schetelig, MD, MSc, from the University Hospital TU Dresden, Germany. "Watchful waiting and sequential conditioning prior to allogeneic transplantation result in comparable complete response rates and overall survival rates and may be the preferred option when a stem cell donor is readily available."

The doctor. Schetelig called the 56-day results "amazing" at a press conference during the meeting. The first author of the presentation wasMatthias Stelljes, MD, from the University of Munster, Germany.

Prior to receiving the ASAP study results, it was unclear whether patients with poor response to induction therapy and with relapsed or refractory disease would benefit from intensive salvage therapy. Sequential conditioning with high doses of cytarabine or melphalan followed by reduced-intensity conditioning and aloHCT achieved long-term disease control for this population.

Details and results of the study

To test the hypothesis that high-dose intensive chemotherapy would not improve outcomes in relapsed or refractory AML, the randomized non-inferiority ASAP study enrolled 281 adults with unfavorable-risk AML after the first induction therapy or the first untreated relapse, who were eligible for intensive chemotherapy and aloHCT. About one-third experienced disease relapse and about two-thirds were not in complete remission after cycle 1 of induction therapy. Patients had to have a sibling match donor, an unrelated human leukocyte antigen (HLA) match donor, or an ongoing donor search with two potential unrelated donors and an HLA match probability of at least 90%.

Study participants were randomized 1:1 to either the remission induction strategy arm or the disease control arm. Those in the remission induction strategy arm received rescue chemotherapy with cytarabine at 3 g/m2²(1 g/m²for people over 60 years) twice daily on days 1 to 3 plus mitoxantrone 10 mg/m2²on days 3 to 5 followed by alloHCT. Watchful waiting was recommended in the disease control arm, but a less intensive approach of low-dose cytarabine and single doses of mitoxantrone was approved for disease control; This was followed by sequential conditioning and alloHCT.

The primary endpoint of the study was treatment success, defined as disease-free survival at day 56 after aloHCT. Secondary endpoints were overall survival from randomization and leukemia-free survival from day 65.

The median age in both arms was 61 years. Less than half of the patients were female, and most patients had an Eastern Cooperative Oncology Group performance status of 0 or 1.

In the disease control arm, the median time to transplantation was 4 weeks and, notably, 76% of patients were treated with watchful waiting alone during this period. 16 weeks after randomization, 97% of the intention-to-treat population had undergone transplantation. In the remission induction strategy arm, the median time to transplantation was 8 weeks.

"I would like to point out that the majority of patients who did not achieve a complete response went ahead with transplantation—72% after sequential conditioning," said Dr. shag

The primary endpoint of disease-free survival at day 56 was met by 84.1% of patients in the disease control arm (n=138) and 81.3% of patients in the remission induction arm (n=134), meeting the pre-specified non-inferiority threshold .

"Although this has lost statistical significance, the probability that the true success rate in the study arm is below the non-inferiority limit is only 4.7%," said Dr. shag He acknowledged that disease-free survival at day 56 is not an accepted surrogate endpoint after transplantation. At a median follow-up of 37 months, no differences were observed between the disease-control and remission-induction strategy arms in leukemia-free survival from day 56 or overall survival from the time of randomization (P= 0,61).

[P]Patients with poor response after initial induction chemotherapy or first relapse of AML do not benefit from rescue chemotherapy with high doses of cytarabine plus an anthracycline [to achieve complete remission] prior to transplantation.

— Johannes Schetelig, MD, MSc

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Patients who were in complete remission at day 56 had similar leukemia-free 1-year survival rates: 71.5% in the disease control arm and 69.9% in the remission induction arm. The 3-year overall survival of the analyzed intention-to-treat randomization was approximately 70% in both arms at year 1 and approximately 50% in both arms 3 years after randomization.

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The incidence of Grade 3 or greater adverse events was significantly lower in the disease control arm at 23% and 64%, respectively, than in the remission induction arm (P< 0.001). Importantly, patients randomized to the disease control arm also spent less time in hospital prior to transplantation than patients in the remission induction arm: a median of 19 days versus 42 days (P< 0.001). The mortality rate at day 28 from the time of randomization to the disease control strategy was 3.6% and 1.5% compared to the remission-induction arms, respectively.

In the disease control arm, four patients did not undergo transplantation,compared to six patients in the remission induction strategy arm. Reasons for discontinuing transplantation in the disease control armwere death from sepsis (n = 2), leukemia (n = 1), and patient refusal (n = 1). In the remission induction strategy arm, six patients did not cross over to aloHCT; three patients died, one from intracranial hemorrhage, one fromrefractory AML and one refused transplantation. Time to discharge and in-hospital mortality did not differ between the two arms.

"A more general conclusion and forward-looking statement is that the benefit of any treatment aimed at improving outcomes after allogeneic transplantation by inducing a complete response prior to transplantation should be demonstrated in prospective clinical trials," said Dr. shag

Comment on the study

"This study concludes that patients with relapsed or refractory AML do not receive the added benefit of intensive chemotherapy prior to stem cell transplantation, suggesting that many may proceed directly to transplantation," said the ASH Communications Committee ChairMikkael Sekeres, MD, chief physician of hematology and professor of medicine at the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine. "If true, it completely changes the way we look at relapsing/refractory AML."

Doctor Sekeres continued: “The mortality rate of these patients is very high. Traditionally, we give them high-dose chemotherapy to get them into a transplant. This study completely debunks this and suggests that we no longer need to administer high-dose chemotherapy. All the morbidity of high-dose chemotherapy can actually prevent the transplant from happening. In theory, we can transplant these patients faster. The debate will continue as to whether it is now a good idea to stop giving high-dose chemotherapy before a transplant.”

DISCLOSURE: Dr. shagreceived honoraria from BeiGene, BMS, Janssen, AstraZeneca, and AbbVie; and is employed at DKMS.DR. robberiesserved as a consultant to MSD, Kite, Novartis, Amgen and Pfizer; and has received honoraria or research grants from MSD, Jazz, Kite, Medac, Novartis, and Pfizer.DR. Of courseserved as a consultant or advisor to Celgene and Novartis.

NOTE

1. Stelljes M, Middeke JM, Bug G, et al: Patients with sequential conditioning of relapsed/refractory AML and immediate allogeneic stem cell transplantation (allo-HCT) have similar overall and leukemia-free survival compared to chemotherapy with Intensive remission induction followed by allo-HCT: results of the randomized phase III ASAP study.ASH Annual Meeting and Exhibition 2022. Summary 4. Presented December 11, 2022.