Should Patients With R/R AML Be in Complete Response Before Undergoing ASCT?

Roland Walter, MD, PhD

Allogeneic stem cell transplant (ASCT) is an important treatment for relapsed or refractory acute myeloid leukemia (AML). Reviewing the current research, experts are questioning the benefit of giving therapy before or after patients undergo ASCT.

During a debate held at the 11th Annual Meeting of the Society of Hematologic Oncology (SOHO 2023), Roland Walter, MD, PhD, and Johannes Schetelig, MD, discussed the issue. Walter, a professor in the Clinical Research Division and José Carreras/E. Donnall Thomas Endowed Chair for Cancer Research at the Fred Hutch Cancer Center in Seattle, Washington, posited that achieving a best response for ASCT is the preferred approach. In contrast, Schetelig, a professor at the University Hospital Carl Gustav Carus Dresden in Dresden, Germany, argued that therapy is not needed before ASCT, if the patient can proceed to transplantation within a few weeks.

“Patients with AML who achieve a response to induction or salvage chemotherapy have better outcomes, with improved disease-free survival compared with patients who are transplanted with persistent or relapsed disease. The depth of response correlates with posttransplant survival, with the best survival seen among patients who are minimal residual disease [MRD] negative, intermediate survival rates for patients who are MRD positive but in morphological remission, and the worst survival for patients with AML detected by the morphology of the marrow aspirate and visual inspection of the cells,” Walter told the SOHO Daily News in an interview.

Complete Response Is Best Before ASCT

According to Walter, several studies have illustrated the benefit of a patient having a best response prior to undergoing ASCT.

“A variety of observational retrospective studies have shown the importance of disease status with posttransplant survival, including CIBMTR [Center for International Blood and Marrow Transplant Research] data that are published annually as summary survival slides, said Walter.

In terms of prospective research, however, the argument is backed by the BMT-CTN 1506 (MORPHO) study (NCT02997202). In the phase 3 study, the FLT3 inhibitor gilteritinib (Xospata) was administered as post–allogeneic hematopoietic cell transplantation (HCT) therapy to patients with relapsed/refractory FLT3 internal tandem duplication (ITD) mutation-positive AML. This study was among the first to demonstrate the efficacy of MRD-based post-HCT maintenance therapy.¹

“In this study of FLT3-positive AML, all patients were in morphological remission at the time of transplant. Half of the patients had disease measurable by polymerase chain reaction–based MRD testing, and half were MRD negative prior to transplant and immediately following transplant. The 6-year overall survival [rate; OS] among patients who were MRD negative was 82% compared with 69% among patients who were MRD positive. Among patients with MRD-positive disease treated with posttransplant maintenance gilteritinib, 6-year survival was 71% compared with 53% survival among MRD-positive patients treated with a placebo. Notably, patients who were MRD negative did not benefit from maintenance gilteritinib,” explained Walter.

In total, 365 patients were randomized in the MORPHO study and were stratified by pre-HCT MRD of 10-4 or greater, conditioning regimen intensity, and time from HCT to randomization of less than or more than 60 days. Patients received either gilteritinib 120 mg/day or placebo for 24 months.

A relapse-free survival (RFS) benefit was shown in the gilteritinib arm compared with the placebo arm, but the RFS was not statistically significant (HR, 0.679; 95% CI, 0.459-1.005; 2-sided P =.0518). At 2 years, the RFS was 77.2% (95% CI, 70.1%-82.8%) with gilteritinib vs 69.9% (95% CI, 62.4%-76.2%) for placebo. Further, the probability of survival without relapse in the MRD-positive population was slightly longer for those treated with gilteritinib vs placebo (HR, 0.515; 95% CI, 0.316-0.838; P =.0065. In the MRD-negative group, there were 19 RFS events vs 15 RFS events in the gilteritinib vs placebo arms, respectively
(P =.5750).

The overall survival in the gilteritinib arm was similar to that observed with placebo (HR, 0.846; 95% CI, 0.554-1.293; 2-sided P =.4394).

In the gilteritinib arm, 80.3% of patients required dose interruptions compared with 72.9% in the placebo arm. Dose reductions were required in 54.5% of the gilteritinib arm vs 25.4% in the placebo arm. The most common treatment-emergent adverse events (TEAEs) observed in the gilteritinib-treated patients vs those given placebo were neutrophil decrease (42.1% vs 15.8%) and chronic graft-vs-host disease (52.2 v 42.1%). The gilteritinib arm also had more TEAEs leading to treatment withdrawal.

“Based on the MORPHO study, it will become standard practice to treat patients with MRD-positive, FLT3-positive AML with posttransplant gilteritinib,” Walter stated.

A challenge to this argument is the position that a patient’s AML risk may not be changed, according to Schetelig, and that treatment response prior to transplantation should be regarded as biomarker

“There is an abundance of retrospective data, which demonstrates that those patients who are in CR [complete response] have a more favorable cause after transplantation compared with those who are not in CR. We do not challenge this observation. Also in our trial, patients with chemosensitive AML have a more favorable course after transplantation. However, in our experimental arm, where chemosensitivity was not tested prior to transplantation we identified the same number of patients with more favorable disease based on clinical features," said Walter.

Prior Therapy to induce CR Not Needed Before ASCT

Schetelig does not disagree that it is standard practice to administer treatment in the form of intensive chemotherapy prior to ASCT. But he explained that many patients do not benefit from this treatment.

“It used to be an accepted standard of care to offer intensive salvage chemotherapy, with a goal to achieve a remission prior to transplantation. This standard of care is, I would say, challenged by the data that we presented. But so far, it is a standard. Across all AML risk groups at [most], 50% of the patients benefit from intensive salvage chemotherapy in terms of achieving a complete response. In other words, 50% of the patients fail to achieve this goal; they just have adverse events. Therefore, especially for patients with genetically high-risk AML which is more often treatment refractory intensive salvage chemotherapy is an undesired standard. And this standard has been challenged by the data from the [ETAL3-ASAP] trial [NCT02461537],” said Schetelig, in an interview with the SOHO Daily News.²

ETAL3-ASAP was a randomized, phase 3 trial studying sequential conditioning and immediate ASCT in patients with relapsed/refractory AML. It was the first study to further investigate intensive remission induction chemotherapy and its efficacy in relapsed/refractory AML prior to scheduled transplantation. The study showed that the use of high-dose cytarabine and mitoxantrone as intensive salvage chemotherapy before ASCT did not provide a survival advantage. Patients observed through a watch-and-wait approach before sequential conditioning and ASCT had comparable survival and CR rates.²

Results from the ASAP study evaluated 281 patients with AML, 183 of whom had poor response after first intensive therapy and 98 who had relapsed disease. The full analysis set included 276 patients, due to 5 exclusions. Patients in the study were randomized 1:1 to receive either the remission induction strategy (RIST) consisting of 3 mg/m² cytarabine (1 gm/m² for patients 60 years or older) twice daily on days 1 to 3 plus 10 mg/m² mitoxantrone on days 3 to 5 and subsequent ASCT (RIST) or to disease control (DISC) prior to sequential conditioning and ASCT.

The 1-year OS rate was from randomization was 69.1% (95% CI, 60.6%-76.1%) in the DISC arm vs 71.9% (95% CI, 63.3%-78.9%) in the RIST arm, and the 3-year OS rates were 51.0% (95% CI, 41.8%-59.6%) vs 54.2% (95% CI, 44.4%-62.9%), respectively (log-rank P =.47).

“The ASAP study was a very ambitious study, the first-ever study on this topic, and it shows clearly that there is no net advantage for those patients who receive salvage chemotherapy,” Schetelig said. “However, these data also show that there is a lot of room for improvement. While he sees potential to improve on conditioning regimens, GVHD prophylaxis and donor selection, he considers transplantation as only one step in a complex treatment history. Thorough disease monitoring, optimal timing of transplantation, and pre-emptive or prophylactic therapy after ASCT are of equal importance.”

Schetelig explained the ETAL3-ASAP results are 1 of 3 major pillars his argument was built upon. In addition, he said that no prospective research proves that salvage chemotherapy provides any benefit and, lastly, research from 2022 challenges the notion that achieving MRD negativity changed the prognosis of patients after transplant.³

_REFERENCES

_{1. Levis M. BMT-CTN 1506 (MORPHO): A randomized trial of the FLT3 inhibitor gilteritinib as post-transplant maintenance for FLT3-ITD AML. Presented at: 2023 European Hematology Association Congress; June 8-11, 2023; Frankfurt, Germany. Abstract LB2711.}

_{2. Stelljes M, Middeke JM, Bug G, et al. In patients with relapsed/refractory AML sequential conditioning and immediate allogeneic stem cell transplantation (allo-HCT) results in similar overall and leukemia-free survival compared to intensive remission induction chemotherapy followed by allo-HCT: results from the randomized phase III ASAP trial. Blood. 2022;140(suppl 1):9-11. doi:10.1182/blood-2022-159962}

_{3. Murdock HM, Kim HT, Denlinger K, et al. Impact of diagnostic genetics on remission MRD and transplantation outcomes in older patients with AML. Blood. 2022;139(24):3546-3557. doi:10.1182/blood.2021014520}