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ALWP/EBMT analysis |FLAMSA-based RIC vs MIC in young patients with R/R AML

Aug 17, 2020

Myeloablative conditioning (MAC) has been used in the eradication of disease and to prolong long-term survival, and is successful in approximately 50% of younger patients with acute myeloid leukemia (AML). However, this treatment modality is associated with a high rate of non-relapse mortality (NRM); therefore, FLAMSA (fludarabine, Ara-C, and amsacrine) chemotherapy (CT) followed by reduced-intensity conditioning (RIC) is being investigated as an effective and safer alternative in this setting.

Rodríguez-Arboli and colleagues 1recently published a comparative reassessment of FLAMSA-based RIC vsMAC in Biology of Blood and Marrow Transplantation. Their aim was to ascertain the best supportive care that contributes to decreasing NRM rates. This was a registry-based analysis by the Acute Leukemia Working Party (ALWP), part of the European Society for Blood and Marrow Transplantation (EBMT).

Methods

Patients eligible for this study were aged 18–50 years, were primary refractory, had relapsed AML at least twice with active disease at the time of transplant, had their first allogeneic hematopoietic stem cell transplant (allo-HSCT) from a matched sibling donor (MSD) or an unrelated donor (UD) between 2005–2018, and had received MAC with cyclophosphamide and total body irradiation (Cy/TBI), busulfan/cyclophosphamide (Bu/Cy), or FLAMSA-RIC (which includes both FLAMSA-CT and FLAMSA-TBI). Patients were excluded if they received oral busulfan and/or  ex-vivo T-cell depleted allografts.

The study endpoints were overall survival (OS), relapse incidence (RI), leukemia-free survival (LFS), non-relapse mortality (NRM), acute graft- versus-host disease (aGvHD), chronic GvHD (cGvHD), and refined GvHD-free, relapse-free survival (GRFS).

Results

This analysis was conducted with 1,018 patients for a median follow-up of 50 months. The patient, disease, and transplant characteristics are shown in Table 1.

Table 1.Patient characteristics 1

AML, acute myeloid leukemia; Ara-C, cytosine arabinoside; A, amsacrine; Bu, busulfan; CsA cyclosporine; CT, chemotherapy; Cy, cyclophosphamide; FLAMSA, fludarabine + Ara-C + amsacrine; GvHD, graft- versus-host disease; IQR, interquartile range; MAC, myeloablative conditioning; MMF, mycophenolate mofetil; MSD, matched sibling donor; MTX, methotrexate; TBI, total body irradiation; UD, unrelated donor

* Bu dosing was 6.4 mg/kg and 12.8 mg/kg in the FLAMSA-CT and MAC groups, respectively.

 

FLAMSA-CT

FLAMSA-TBI

MAC

p

 

(n = 128)

(n = 318)

(n = 572)

 

Median follow-up, months (IQR)

24.5 (15–41)

58.1 (16–94)

65.0 (17–107)

< 0.0001

Median year of transplant

2015

2010

2010

< 0.0001

Median age at transplant, years (range)

41.6 (18.6–50)

39.7 (18.1–50)

37.3 (18.1–49.9)

0.002

AML type, n (%)

0.546

De novo

113 (88.3)

279 (87.7)

515 (90)

Secondary

15 (11.7)

39 (12.3)

57 (10)

Disease status at transplant, n (%)

0.604

Primary refractory

62 (48.4)

170 (53.5)

297 (51.9)

First relapse

57 (44.5)

127 (39.9)

224 (39.2)

Second relapse

9 (7.0)

21 (6.6)

51 (8.9)

Donor type, n (%)

< 0.001

MSD

31 (24.2)

94 (29.6)

223 (39)

UD

97 (75.8)

224 (70.4)

349 (61)

Conditioning scheme, n (%)

Bu/Cy*

68 (53.1)

258 (45.1)

Cy/TBI

314 (54.9)

Bu

18 (14.1)

Melphalan

22 (17.2)

Cy

7 (5.5)

Treosulfan

8 (6.3)

Cy/Treosulfan

5 (3.9)

GvHD prophylaxis, n (%)

CsA/MMF

92 (71.9)

231 (73.3)

45 (8.0)

CsA/MTX

5 (3.9)

8 (2.5)

413 (73.6)

MMF/tacrolimus

15 (11.7)

14 (4.4)

6 (1.1)

CsA

7 (5.5)

17 (5.4)

54 (9.6)

MMF/sirolimus

2 (1.6)

22 (7.0)

0

 NRM

  • The 2-year NRM estimates for patients receiving Cy/TBI (19%), Bu/Cy (16%), and FLAMSA-TBI (18%) were similar. However, patients undergoing an allo-HSCT following FLAMSA-CT had a significantly lower NRM (7%; p = 0.04)
  • Allo-HSCT recipients from a UD had an increased 2-year NRM in the univariate analysis: 20% in UD recipients vs11% in MSD recipients (p < 0.001)
  • The NRM results were the same for the multivariate analysis: patients who were the recipients of FLAMSA-CT had an HR of 0.40 (95% CI, 0.19–0.82; p = 0.012), and patients who received a UD had an HR of 1.94 (95% CI, 1.31–2.86; p < 0.001)

RI

  • There was no significant difference in the 2-year RI in the univariate analysis between Cy/TBI (51%), Bu/Cy (56%), FLAMSA-TBI (55%), and FLAMSA-CT (53%) recipients (p = 0.86)
  • Patients with AML in second relapse had a higher 2-year RI compared with patients in first relapse: 66% vs55%, respectively, and 51% in primary refractory patients (p = 0.03)
  • This trend was also the same for patients with poor-risk cytogenetics: 64% vs51% vs34% in the poor-, intermediate-, and favorable-risk groups, respectively (p < 0.001)
  • Multivariate analysis demonstrated that secondary relapse (HR, 1.94; 95% CI, 1.38–2.74; p < 0.001) and poor-risk cytogenetics (HR, 2.93; 95% CI, 1.77–4.84; p < 0.001) were predictors of a higher RI

 OS and LFS remission rates

  • Complete remission (CR) following allo-HSCT and MAC was achieved by 69% of patients vs74% of patients obtaining a CR after receiving FLAMSA-TBI, and 76% following FLAMSA-CT (p = 0.36)
  • Patients who were treated with FLAMSA-CT had an increased 2-year OS (34% Cy/TBI vs33% Bu/Cy vs36% FLAMSA-TBI vs50% FLAMSA-CT; p = 0.03); this was confirmed in the multivariate analysis (HR, 0.65; 95% CI, 0.46–0.91; p = 0.01)
  • Patients in second relapse at transplantation had a lower 2-year LFS of 16% vs29% in first relapse vs32% in primary refractory disease (p = 0.003).
  • The LFS results was also the same for patients with poor-risk cytogenetics (25% vs33% vs42% in the poor-, intermediate-, and favorable-risk cytogenetics cohorts, respectively; p = 0.001)
  • The 2-year OS was worse in patients in second relapse (21% vs34% for patients in first relapse vs40% for those with primary refractory disease)
  • The OS results were also the same for patients with poor-risk cytogenetics (33% vs37% vs49% in the poor-, intermediate-, and favorable-risk cytogenetics groups, respectively; p = 0.007)
  • UD transplant recipients had lower OS than MSD recipients (34% vs40%, respectively; p = 0.03)
  • Disease progression was one of the main causes of death: this occurred in 67% of patients after FLAMSA-CT treatment, 59% of patients after FLAMSA-TBI treatment, and 63% of MAC recipients

Engraftment, GRFS, aGvHD, and cGvHD

  • Neutrophil engraftment occurred in 97% of patients who received MAC, FLAMSA-TBI, and FLAMSA-CT (p = 0.93)
  • In both the univariate and multivariate analysis, the type of conditioning regimen had no impact on GRFS and Grades 3–4 aGvHD
  • FLAMSA-CT coupled with Bu/Cy decreased the risk of cGvHD (HR, 0.61; 95% CI, 0.37–0.99; p = 0.043)
  • Similarly, secondary AML increased risk of Grades 3–4 aGvHD (HR, 1.88; 95% CI, 1.17–3.03; p = 0.009)
  • Poor-risk cytogenetics and second relapse at transplantation were significantly associated with a worse GRFS

Conclusion

The authors highlight potential limitations of the study, including the possible introduction of selection bias during the allocation of treatment as it was dependent on center preference.

The team go on to highlight that this study is the largest comparative analysis of clinical outcomes in patients who received MAC or FLAMSA-RIC with active AML. The results show that patients who received FLAMSA-TBI had an NRM rate similar to those treated with MAC. In all analyses, there were no differences in terms of antileukemic activity. These data support the use of FLAMSA-CT as a conditioning regimen in patients with active relapsed or refractory AML due to lower NRM, though the high relapse rates highlight the need for novel therapeutics and warrant further research.

  1. Rodríguez-Arboli E, Labopin M, Tischer J, et al. FLAMSA-based reduced intensity conditioning versus myeloablative conditioning in younger patients with relapsed/refractory acute myeloid leukemia with active disease at the time of allogeneic stem cell transplantation: an ALWP/EBMT analysis.  Biol Blood Marrow Tr. 2020. Online ahead of print.  DOI: 10.1016/j.bbmt.2020.07.020