Augmented reduced-intensity allo-HSCT in patients with high-risk AML or MDS: Results of the FIGARO trial

Previously, older patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) were prevented from undergoing potentially curative allogeneic hematopoietic stem cell transplant (allo-HSCT) due to excess toxicity. However, the introduction of reduced-intensity conditioning (RIC) regimens has extended the use of allo-HSCT into this patient population. Despite this, very few randomized clinical studies have investigated RIC regimen choices, with no consensus on the most appropriate treatment.

Registry data have shown favorable allo-HSCT outcomes with sequential fludarabine/amsacrine/cytarabine-busulfan (FLAMSA-Bu), however this has never been fully examined through randomized trials. Here we report the findings from FIGARO, an open label phase II randomized study comparing a FLAMSA-Bu conditioning regimen with conventional fludarabine-based RIC (EudraCT 2012-005538-12), which were published in the Journal of Clinical Oncology by Charles Craddock and colleagues.¹

Study design

Patients were recruited from 20 transplant centers within the UK if they had either of the following diagnoses:

• High-risk AML in first complete remission (CR) with adverse risk cytogenetics or in second CR, or primary refractory AML (failure to achieve a morphological CR after two courses of induction chemotherapy).
• Or high-risk MDS, defined as an International Prognostic Scoring System (IPSS) score of intermediate-1 with >5% blasts, or intermediate-2 or high-risk with <5% blasts.

Further eligibility criteria included:

• Undergoing first allo-HSCT from a matched sibling or unrelated donor.
• Ineligible for myeloablative conditioning due to age or comorbidity.

Patients were assigned 1:1 to a fludarabine-based RIC regimen (investigator’s choice of fludarabine/busulfan/anti-thymocyte globulin [Flu/B₂/ATG], fludarabine/melphalan/alemtuzumab [Flu/Mel/A], or fludarabine/busulfan/alemtuzumab [Flu/B₂/A]) or FLAMSA-Bu (fludarabine + cytarabine 2 g/m² for 4 days + amsacrine 100 mg/m² for 4 days + busulfan; total dose 11.2 mg/mg) plus anti-thymocyte globulin 5 mg/kg over 3 days. Initially, patients aged ≥60 years received a reduced dose of cytarabine (1 g/m² for 4 days) and busulfan (8 mg/kg total); however, following updated safety information this was amended to 1 g/m² cytarabine for 4 days and 6.4 mg/kg total busulfan. All patients also received ciclosporin graft-versus­-host disease prophylaxis.

The primary endpoint was overall survival (OS). Secondary endpoints included:

• Event-free survival
• Cumulative incidence of relapse (CIR)
• Incidence of graft-versus­-host disease
• Transplant-related mortality (TRM)

Patients

In total, 244 patients were eligible for inclusion, with a median age of 59 years (range, 22–75 years). Patient characteristics are shown in Table 1. Overall, 108 patients received allo-HSCT in the control arm, of which 63 received Flu/B₂/ATG, 31 Flu/Mel/A, and 14 Flu/B₂/A. A further 108 patients were treated with FLAMSA-Bu.

Table 1. Patient characteristics in FIGARO*

AML, acute myeloid leukemia; CR, complete remission; FLAMSU-Bu, fludarabine/amsacrine/cytarabine-busulfan; HSCT, hematopoietic stem cell transplant; IPSS, International Prognostic Scoring System; MDS myelodysplastic syndromes; MFC, multiparameter flow cytometric; MRD, measurable residual disease. *Adapted from Craddock et al.1 †Fludarabine-based RIC regimen: investigator’s choice of fludarabine/busulfan/anti-thymocyte globulin, fludarabine/melphalan/alemtuzumab, or fludarabine/busulfan/alemtuzumab.
Characteristic, %	FLAMSU-Bu (n = 122)	Control† (n = 122)
Age, years               ≤60               >60	57 43	58 42
Male	61	58
HSCT comorbidity index               ≤2               ≥3               Unknown	68 15 20	57 28 19
Diagnosis               AML               MDS	67 33	67 33
AML cytogenetic risk               Adverse               Intermediate               Favorable               Unknown	32 63 4 1	29 65 5 1
AML disease status               CR1/CR2               Primary refractory               Unknown	94 5 1	94 6 0
MDS IPSS               ≤2               >2               Unknown	83 5 13	83 0 18
Pretransplant MFC-MRD status               Positive               Negative               Inadequate/no sample	43 29 29	35 38 27

Results

Median follow-up was 35 months. Key findings, summarized in Table 2, were:

• Overall and event-free survival at 2 years were similar between patients who received fludarabine-based RIC or FLAMSA-Bu regimens.
• Within the FLAMSA-Bu arm, there was no difference in survival
  • between patients diagnosed with AML or MDS;
  • between cytogenic risk categories in patients with AML; or
  • between patients <60 years vs patients >60 years.
• At 1-year, there was no significant difference in TRM between treatment arms.
• Incidences of acute and chronic GvHD were also comparable.
• Stratification according to treatment regimen, diagnosis, or age did not reveal any significant differences in 2‑year CIR.

Table 2. Clinical outcomes in patients who received FLAMSU-Bu or control reduced-intensity conditioning regimens in FIGARO*

aGvHD, acute graft-versus-host disease; cGvHD, chronic graft-versus-host disease; CIR, cumulative incidence of relapse; EFS, event-free survival; FLAMSU-Bu, fludarabine/amsacrine/cytarabine-busulfan; OS, overall survival; TRM, treatment-related mortality. *Data from Craddock et al.1 †Fludarabine-based RIC regimen: investigator’s choice of fludarabine/busulfan/anti-thymocyte globulin, fludarabine/melphalan/alemtuzumab, or fludarabine/busulfan/alemtuzumab.
Outcome, %	FLAMSU-Bu (n = 122)	Control† (n = 122)	p value
2‑year OS	60.9	58.8	0.81
2‑year EFS	54.2	48.7	0.82
1‑year TRM	20.5	16.8	0.53
Cumulative incidence of aGvHD at Day 100               Grade II–IV               Grade III–IV	8.3 5.8	10.1 1.7	0.93 0.23
Cumulative incidence of cGvHD at 1 year	19.2	25.2	0.53
2-year CIR	26.7	29.5	0.81

In patients with available pretransplant measurable residual disease (MRD) data, MRD at any level was detected by conventional flow cytometry in 29 patients receiving FLAMSA-Bu (n = 77) and 38 control patients (n = 79). Patients with MRD positivity showed the following:

• A higher 2-year CIR at 2 years (41.0%) vs MRD-negative patients (20.0%; hazard ratio, 1.97; 95% confidence interval [CI], 1.18–3.28; p = 0.01).
• A shorter 2-year OS (51.4%) vs MRD-negative patients (70.1%; p = 0.05).
• A similar 2-year TRM (12.1%) to MRD-negative patients (21.6%; hazard ratio, 0.60; 95% CI, 0.29–1.27; p = 0.18).

Furthermore, there was no difference in MRD clearance between FLAMSA-Bu and conventional RIC treatment at Day 42.

Following use of an unsupervised computational approach to analyze flow cytometric sample files, alongside stringent criteria to select patients with the most extensive immunophenotypic blast aberrancies (quantifiable, unsupervised multiparameter flow cytometric-MRD in at least two different antibody combinations), 2-year CIR after allo-HSCT was 50.5% for MRD-positive patients compared with 20.6% for those with a negative or equivocal test (p < 0.001). Relapse prediction accuracy was 73%.

Acquisition of full donor T cell chimerism (FDTCC) was similar between the FLAMSA-Bu and control arms and it was unaffected by pretransplant MRD status. Interestingly, acquisition of FDTCC 3 months after allo-HSCT was associated with lower 2-year CIR (13.1%; 95% CI, 7.3–20.5) when compared with patients who did not have FDTCC at 3 months (44.8%; 95% CI, 30.0–58.3; p < 0.001). Relapse and OS rates were similar between patients with and without pre-transplant MRD positivity.

Conclusion

Use of the intensified RIC regimen FLAMSA-Bu did not improve allo-HSCT outcomes in patients with high‑risk AML or MDS, regardless of pretransplant flow cytometric MRD status. However, pretransplant MRD status was correlated with an increased risk of relapse by both conventional and unsupervised analyses. The authors also proposed that acquisition of FDTCC may alleviate the adverse prognosis given by pretransplant MRD positivity and has potential as an approach to improve outcomes in patients transplanted with an RIC regimen.