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

AML, acute myeloid leukemia; CsA, cyclosporin A; FLAMSA-Bu, sequential fludarabine, amsacrine cytarabine and busulfan; FluBu2, fludarabine and busulfan; GvHD, graft-versus-host disease; IQR, interquartile range; KPS, Karnofsky performance status; MMF, mycophenolate mofetil; MSD, matched sibling donor; MUD, matched unrelated donor.
Characteristic	FLAMSA-Bu (n = 219)	FluBu2 (n = 257)
Median age, years (range)	59 (18–74)	59 (20–76)
Disease status, %               Primary refractory               First relapse               Second relapse	56 39 5	55 37 9
Secondary AML, %	25	28
Cytogenetics, %               Favorable               Intermediate               Adverse	5 58 38	9 66 25
KPS, %               < 90	37	46
Donor type, %               MSD               10/10 MUD	36 64	41 59
In vivo T-cell depletion, %	95	75
GvHD prophylaxis %               CSA + MMF               CSA + methotrexate               CSA               MMF + tacrolimus               MMF + sirolimus               Other	77 3 7 3 8 2	34 28 18 7 0.4 13

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

allo-HSCT, allogeneic hematopoietic stem cell transplant; aGvHD, acute GvHD; CR, complete remission; cGvHD, chronic GvHD; FLAMSA-Bu, sequential fludarabine, amsacrine, cytarabine and busulfan; FluBu2, fludarabine and busulfan; GRFS, GvHD-free/relapse-free survival; GvHD, graft-versus-host disease; LFS, leukemia-free survival; NRM, non-relapse mortality; OS, overall survival; RI, relapse incidence. *Significance is indicated in bold.
Outcome at 2 years (data given as %)	FLAMSA-Bu (n = 219)	FluBu2 (n = 257)	p value*
LFS	41.7	29.3	0.001
CR after allo-HSCT	75	72	0.50
RI	37.7	49.3	0.004
OS	46.9	38.5	0.008
NRM	20.7	21.4	0.76
aGvHD	36.3	19.9	0.001
cGvHD	32.7	26.0	0.09
GRFS	28.3	21.0	0.17

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.