Comparing FLAMSA-Bu and FluBu2 conditioning treatments in patients with R/R AML

Allogeneic hematopoietic stem cell transplant (allo-HSCT) is currently the only curative treatment for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). However, the optimal pretransplant conditioning regimen has not been determined. Phase II trials of sequential fludarabine, amsacrine, and cytarabine (FLAMSA) followed by reduced-intensity conditioning have produced promising results, but comparisons between these regimens and standard conditioning in R/R AML have not been comprehensively studied.

During the 47th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT), Eduardo Rodríguez-Arbolí presented results from a registry analysis performed by the Acute Leukemia Working Party of the EBMT, comparing posttransplant outcomes after FLAMSA with busulfan (FLAMSA-Bu) or fludarabine plus busulfan (FluBu₂) conditioning in patients with active R/R AML.¹ We are pleased to summarize their findings here.

Study design

Eligibility criteria:

• Adults with primary refractory or first/second relapsed AML with active disease at the time of allo-HSCT
• First allo-HSCT performed between 2005 and 2019, from a matched sibling donor or a 10/10 matched unrelated donor
• Received FLAMSA-Bu or FluBu₂ conditioning (busulfan orally at 8 mg/kg or intravenously at 6.4 mg/kg)

Primary endpoint was leukemia-free survival (LFS). Secondary endpoints included overall survival (OS), relapse incidence (RI), non-relapse mortality (NRM), acute/chronic graft-versus-host disease (a/cGvHD), and refined GvHD-free/relapse-free survival (GRFS).

Patients

Overall, 476 patients were included in the analysis, of which 219 received FLAMSA-Bu and 257 FluBu₂ conditioning treatment prior to allo-HSCT. Patient characteristics are shown in Table 1; more patients who received FLAMSA-Bu (95%) were given in vivo T-cell depletion than those who received FluBu₂ (75%; p < 0.001).

Table 1. Patient characterstics¹

Key findings

After a median follow-up of 41 months (interquartile range, 16–71), compared to those treated with FluBu₂, patients who received FLAMSA-Bu showed:

• Lower incidence of relapse after 2 years
• Similar CR and 2-year NRM rates
• Prolonged LFS and OS
• Increased risk of aGvHD, and a trend towards higher risk of cGVHD and longer GRFS

Posttransplant outcomes are detailed in Table 2.

Table 2. Univariate analysis of posttransplant outcomes with FLAMSA-Bu and FluBu₂ conditioning¹

Multivariate analysis with age, year of allo-HSCT, secondary AML, cytogenetic risk, KPS, donor type, in vivo T-cell depletion, patient/donor sex, and cytomegalovirus status as covariates revealed that NRM, OS, GRFS, and cGvHD were similar between FLAMSA-Bu and FluBu₂ treatment groups. However, FLAMSA-Bu treatment was associated with:

• Lower RI (HR, 0.69; 95% CI, 0.48–0.99; p = 0.042)
• LFS benefit (HR, 0.74; 95% CI, 0.55–1.00; p = 0.048)
• Higher risk of Grade II–IV aGvHD (HR, 2.06; 95% CI, 1.24–3.41; p = 0.005)

Subanalysis of patients aged >50 years (76% of the study population) found that the lower risk of relapse and longer LFS with FLAMSA-Bu vs FluBu₂ conditioning remained when univariate analysis was performed (RI: 35.8% vs 46.2%; p = 0.013; LFS: 38.8% vs 31.4%; p = 0.033), although this significance was not retained following multivariate analysis. In this age group, 2-year NRM and OS were comparable between conditioning treatments.

The most common causes of death were disease progression (54.2% vs 58.8%), infection (16.8% vs 16.3%), and GvHD (14.0% vs 13.1%, for FLAMSA-Bu vs FluBu₂).

Conclusion

Conditioning treatment with sequential FLAMSA-Bu resulted in a lower incidence of relapse and a leukemia-free survival benefit compared to FluBu₂ in patients with active R/R AML, although both treatments provided long-term disease control in a substantial proportion of patients. The authors suggested that FLAMSA-Bu may therefore have superior antileukemic activity, although they noted that prospective randomized studies are required to clarify the improvement in transplant outcomes observed.