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Straight-to-Transplantation Approach Comparable to Remission Induction in Difficult Acute Myeloid Leukemia Cases

July 12, 2024

Mid-July 2024

Thomas R. Collins

Thomas R. Collins is a medical journalist based in West Palm Beach, Florida.

In the first randomized trial to assess whether complete remission (CR) induction or direct-to- transplantation is best for relapsed or poorly responsive acute myeloid leukemia (AML), researchers have found that going right to allogeneic hematopoietic cell transplantation (alloHCT) produced comparable results, but with fewer adverse events (AEs) and less hospital time, despite not reaching the threshold for noninferiority, according to new findings in Lancet Haematology.

Remission induction before HCT has been the standard of care as the result of observational studies suggesting that patients who achieve CR have better outcomes, but researchers in this study, called ASAP, said the new findings may become cause for this practice to come to an end, particularly for certain patients.

“Against the lack of evidence for a benefit with remission induction, the results of the ASAP trial are meaningful and, from our perspective, are sufficient to offer disease control and immediate alloHCT to patients with non-hyperproliferative AML for whom a stem cell donor is readily available,” said Johannes Schetelig, MD, MSc, head of the cell therapy unit at the University Hospital TU Dresden in Germany. “The current standard is not based on evidence from prospective clinical trials. Against this weak standard, we interpret the evidence from the ASAP trial as sufficient to change clinical practice.”

In the trial, 140 patients were randomized to move to alloHCT as soon as possible, and 141 to receive treatment in an effort to induce CR, with high-dose cytarabine and mitoxantrone, before HCT. Patients were 18 to 75 years old, with the average at 61.

For those in the direct-to-transplantation group, the preference was to move to transplant after only watchful waiting. A total of 135 proceeded to alloHCT — 97 after watchful waiting only, and 38 after receiving anti-leukemic therapy. The median time from randomization to transplant was 4.4 weeks. One hundred thirty-four of the patients in the remission induction group completed the treatment, and 68 of those achieved CR. At 16 weeks after randomization, 124 of the 134 patients had received a transplant, with average time to alloHCT at 7.9 weeks.

In the per-protocol group, 84% (n=116) achieved the primary endpoint of CR at day 56 after transplantation, compared to 81% (n=109) in the remission induction group. The estimated difference between the groups was 2.7%, with 95% confidence interval at -6.3 to 11.8. This did not meet the threshold for noninferiority set out at the start of the trial, but it was a result that researchers called “remarkable” nonetheless.

“This degree of error is, from our point of view, acceptable in this specific context,” Dr. Schetelig said.

Fewer patients — 21% versus 61% — in the direct-to-transplant arm had non-hematologic AEs of grade 3 or higher. Researchers found that 16% of patients in this arm had infections, compared to 55% in the induction remission arm, and 24% versus 40% had deterioration on a comorbidity index between randomization and alloHCT. Patients in the direct-to-transplant group also spent a median of 27 fewer days in the hospital until the time of transplant.

Four-year overall survival (OS) was 46% in the direct-to-transplantation group and 40% in the remission induction group.

Dr. Schetelig said the inferiority threshold was not met because all patients in the remission induction arm were moved to transplant whether they achieved CR or not.

“Participating trial sites learned during the conduct of the trial that alloHCT is extremely powerful to induce CR, even in patients with refractory AML,” he said. “The excellence of the control arm ‘killed’ the statistical proof for disease control,” he said, referring to the patients who moved straight to transplant.

A larger trial on the question is not particularly feasible at this point, he said.

“Already, toward the end of the ASAP trial, patients became more and more reluctant to accept remission induction because of the much longer in-hospital stay in this study arm,” Dr. Schetelig said.

More data on HCT for patients with persistent measurable residual disease (MRD) or untreated MRD relapse, he said, “will hopefully convince more physicians that the value of remission induction chemotherapy prior to alloHCT needs to be questioned.”

Any conflicts of interest declared by the authors can be found in the original article.

Reference

Stelljes M, Middeke JM, Bug G, et al. Remission induction versus immediate allogeneic haematopoietic stem cell transplantation for patients with relapsed or poor responsive acute myeloid leukaemia (ASAP): a randomised, open-label, phase 3, non-inferiority trial. Lancet Haematol. 2024;11(5):e324-e335.

Perspectives: The Age-Old Dilemma of AML

Patients with AML who relapse after achieving a CR or who fail induction chemotherapy have a poor prognosis and rarely survive without an alloHCT. Clinicians are reluctant to take these patients directly to an alloHCT because of the high risk of relapse post-transplant and delays related to lack of a readily available donor and insurance approval. Concern with taking patients directly to alloHCT has also been heightened by the recognition that MRD defined by flow cytometry or molecular techniques can be associated with a risk of relapse equivalent to that seen with transplant in patients with active disease.1 Reinduction chemotherapy is often attempted but is not always successful in inducing a second remission and can lead to additional morbidity, thus compromising the ability to proceed to transplant.

More than 30 years ago, the Seattle group published the results of alloHCT in 126 patients who were taken to transplant in untreated first relapse and showed that patients receiving an intense myeloablative regimen of cyclophosphamide and total body irradiation had a relapse-free survival of 38% at three years.2 More recent studies have taken a similar approach.3 However, no randomized trials have been conducted to determine the best strategy in this setting. The Study Alliance Leukemia and the German Cooperative Transplant Study Group are to be applauded for carrying out such a logistically challenging randomized trial.4 Of the 141 patients in the remission induction therapy group, 134 (95%) received the per-protocol salvage high-dose cytarabine and mitoxantrone chemotherapy, and 68 (51%) achieved CR. Of the 128 patients who proceeded to alloHCT, 65 (51%) were in CR, and 63 (49%) were not. Patients not in remission received sequential conditioning consisting of intensive chemotherapy followed by reduced-intensity conditioning.

The authors concluded that “watchful waiting and immediate transplantation could be an alternative for fit patients with poor response or relapsed AML who have a stem cell donor available.” The trial results are somewhat surprising in that the patients taken to immediate transplant with overt disease had a four-year OS of 46%, which is better than one might expect and may reflect patient selection and more indolent disease.

The authors acknowledge the multiple limitations of their study but are to be congratulated for carrying it out. Importantly, it may not have broad applicability given the need to have a donor readily available and for the patient to have sufficiently indolent disease to allow “watchful waiting.” Additionally, the availability of a wider donor pool including haploidentical family donors and mismatched unrelated donors as well as newer effective therapies like venetoclax and molecularly targeted agents with less morbidity may be used in place of cytotoxic chemotherapy and could alter the approach to management.

The ASAP trial certainly adds a new perspective to the management of relapsed and refractory AML but may not have entirely resolved this age-old dilemma of AML.

Mark R. Litzow, MD
Professor of Medicine, Division of Hematology
Mayo Clinic, Rochester, Minnesota

References 

  1. Araki D, Wood BL, Othus M, et al. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia: time to move toward a minimal residual disease-based definition of complete remission? J Clin Oncol. 2016;34(4):329-336.  
  2. Clift RA, Buckner CD, Appelbaum FR, et al. Allogeneic marrow transplantation during untreated first relapse of acute myeloid leukemia. J Clin Oncol 1992;10(11):1723-1729. 
  3. Steckel NK, Groth C, Mikesch JH, et al. High-dose melphalan-based sequential conditioning chemotherapy followed by allogeneic haematopoietic stem cell transplantation in adult patients with relapsed or refractory acute myeloid leukaemia. Br J Haematol. 2018;180(6):840-853.  
  4. Stelljes M, Middeke JM, Bug G, et al. Remission induction versus immediate allogeneic haematopoietic stem cell transplantation for patients with relapsed or poor responsive acute myeloid leukaemia (ASAP): a randomised, open-label, phase 3, non-inferiority trial. Lancet Haematol. 2024;11(5):e324-e335. 

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