Data support less aggressive approach before transplant in relapsed/refractory AML
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NEW ORLEANS — Skipping intensive remission-induction chemotherapy prior to allogeneic hematopoietic stem cell transplant did not impact survival outcomes among patients with relapsed/refractory acute myeloid leukemia, according to a study.
Results of the randomized phase 3 ASAP trial, presented at ASH Annual Meeting and Exposition, support watchful waiting and sequential conditioning prior to allogeneic HSCT when a stem cell donor is readily available, and challenge the practice of offering transplant only to patients in complete remission, researchers concluded.
“The benefit of any treatment aiming at better results after allogeneic transplantation by inducing a [complete response] prior to transplantation should be demonstrated in prospective clinical trials,” Johannes Schetelig, MD, MSc, of University Hospital Dresden in Germany, said during a press conference.
Background
Patients who achieve complete remission prior to allogeneic HSCT tend to fare better than those who do not, according to previous research. However, only 35% to 50% of patients with high- or intermediate-risk AML achieve complete remission after standard intensive salvage chemotherapy regimens, Schetelig said.
“As an alternative, so-called sequential conditioning regimens have been developed,” he said. “They combine a meld of chemotherapy with reduced-intensity conditioning and transplantation in a tight scale of less than 2 weeks. Good outcomes with these regimens in a series of prospective trials for patients with active disease prompted us to question the benefit of salvage chemotherapy prior to transplantation.”
Methodology
Schetelig and colleagues enrolled 281 adults who had a poor response after their initial induction therapy (n = 183) or AML relapse (n = 98) and could receive intensive chemotherapy and allogeneic HSCT. The full analysis set included 276 patients (median age, 61 years), 133 of whom had an HLA-compatible unrelated donor with confirmed HLA typing, 104 of whom had ongoing unrelated-donor searches and 39 of whom had a matched sibling donor.
Researchers randomly assigned patients 1:1 to a remission-induction strategy with high-dose cytarabine plus mitoxantrone followed by allogeneic HSCT, or a disease-control group that underwent watchful waiting but could receive low-dose cytarabine and single doses of mitoxantrone to control disease prior to sequential conditioning and HSCT.
Treatment success, defined as complete remission at day 56 after transplant, served as the primary endpoint. Researchers sought to show noninferiority of the disease-control (direct-to-transplant) strategy with a noninferiority margin of 5% and one-sided alpha of 2.5%. Secondary endpoints included OS from randomization and leukemia-free survival from complete response at day 56.
Median follow-up from randomization was 37 months.
Key findings
Most patients in the disease-control group (76%) remained on watchful waiting until they started sequential conditioning. Fewer than half of patients in the remission-induction strategy group (46%) achieved complete remission, and five underwent a second course of intensive chemotherapy. The remainder proceeded with allogeneic HSCT.
Compared with the remission-induction strategy group, the disease-control group had a shorter median time to transplant (4 weeks vs. 8 weeks).
Similar percentages of patients in the disease-control and remission-induction groups had undergone transplant at 24 weeks from randomization (98% vs. 96%) and achieved complete remission at day 56 (84.1% vs. 81.3%; P for noninferiority = 0.047) and 1-year leukemia-free survival from complete remission at day 56 (71.5% vs. 69.9%).
An intent-to-treat analysis showed the disease-control and remission-induction groups had similar rates of 1-year OS (69.1% vs. 71.9%) and 3-year OS (51% vs. 54.2%) from randomization.
The disease-control group had much lower incidence of grade 3 or higher adverse events (23% vs. 64%). “Most notably, before transplantation patients spent on average 23 days less in the hospital in the disease-control arm, yet time to discharge and in-hospital mortality after transplantation did not differ between the two arms,” Schetelig said.
Clinical implications
Proceeding directly to transplant could save patients the additional burden of a weeks-long hospital stay, as well as the cost and toxicity of more treatment, according to researchers. Further analyses will seek to determine whether certain patient subgroups may benefit more from one strategy than the other, Schetelig noted.
Perspective
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Mikkael A. Sekeres, MD, MS
Relapsed or refractory AML tends to be a serious diagnosis and a cancer that grows very, very quickly. It is standard of practice and has been the current philosophy that we need to reduce the tumor burden of acute leukemia before sending patients to transplant. So, we give them more and sometimes quite intensive chemotherapy to try to get their leukemia into remission prior to transplant. In doing so, some patients don’t make it to that transplant. Some die as a result of the chemotherapy alone or develop serious infections that prevent the transplant from being performed.
The investigators embarked on this, I think, fully expecting to demonstrate that giving chemotherapy prior to transplant was beneficial. Instead they showed the opposite — that patients who did not receive intensive chemotherapy prior to transplant did just as well, with similar leukemia-free survival and OS, as patients who received intensive chemotherapy.
I think it is going to be debated within the leukemia and transplant communities whether or not to give chemotherapy prior to transplant, because it is so counter to what we’ve done before and counter to the general consensus that reducing tumor burden improves the outcome of transplant.
Perspective
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Jaime Andres Suarez Londono, MD
The AML treatment landscape has seen great advances in recent years, with approval of multiple agents — many of them oral — that have broadened the arsenal available to achieve remission, newly proposed risk stratification by European LeukemiaNet and initiatives for standardization of markers of minimal residual disease (MRD).
Despite this progress, relapsed/refractory AML remains a clinical challenge. It carries devastating outcomes and adds a significant burden to patients and families — therefore, research in this area is of particular clinical utility.
In this setting, the preponderance of current evidence has positioned allogeneic HSCT as the treatment of choice, by virtue of the graft vs. leukemia effect, for eligible patients who have a stem cell donor.
The need to achieve complete remission before allogeneic HSCT in the relapsed/refractory AML setting is not entirely clear. Stelljes and colleagues bring forth that question in this study.
The results of this abstract validate the use of sequential conditioning followed by allogeneic HSCT without the need for intensive remission induction chemotherapy, possibly limiting toxicity, morbidity and cost to the health care system. This clearly has the potential to influence clinical practice.
In recent years, haploidentical stem cell transplant with post-transplant cyclophosphamide has become widely used, especially in areas of high diversity and among underrepresented minorities in donor registries. The question remains if these results are applicable to such cohorts. Further research should include these diverse and underrepresented minorities.
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Stelljes M, et al. Abstract 4. Presented at: ASH Annual Meeting and Exposition; Dec. 10-13, 2022; New Orleans.
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