General AML

Conditioning regimens for patients with relapsed/refractory acute myeloid leukemia undergoing stem cell transplantation: FT versus TBF versus FLAMSA

Patients with primary refractory, or relapsed, acute myeloid leukemia (AML) undergoing a potentially curative allogeneic stem cell transplant (SCT) require an effective conditioning regimen to optimize their outcomes. Numerous conditioning regimens have been developed in the past decade, however, limited data currently exists which compares these regimens. Therefore, there are little data to guide physicians in determining the ideal conditioning treatment for their patients.

Francesco Saraceni, ASUR Marche, Ancona, IT, and colleagues, conducted a registry-based retrospective study on behalf of the Acute Leukemia Working Party (ALWP) of the European Society of Blood and Marrow Transplantation (EBMT), designed to compare three currently available conditioning regimens for patients with relapsed/refractory (R/R) AML undergoing SCT.

The study compared the conditioning regimens; fludarabine-treosulfan (FT), thiotepa-busulfan-fludarabine (TBF) and sequential fludarabine, intermediate dose cytarabine (Ara-C), amsacrine, total body irradiation (TBI)/busulfan and cyclophosphamide (FLAMSA), based on various measures of outcome (complete remission [CR] rates, overall survival [OS] rates, non-relapse mortality [NRM], leukemia-free survival [LFS] and graft-versus-host disease [GvHD]-free relapse-free survival [GRFS]).

Study design and patient characteristics

Given as FT vs TBF vs FLAMSA unless otherwise stated.

  • Adult patients with active AML disease receiving a matched sibling donor (MSD) or unrelated donor (UD) transplant who received FT, TBF or FLAMSA as conditioning regimen
    • Also included patients with primary refractory AML and those in first or second relapse
  • N = 856, split into subgroups based on conditioning regimen; 113 vs 112 vs 631
    • MSD vs UD: 42% vs 58%
    • FLAMSA protocol (busulfan- vs TBI- based): 32% vs 68%
    • Median age: 58 vs 52 vs 52 (P < 0.001)
    • Karnofsky performance at SCT (<80%): 13% vs 11% vs 10%
    • ATG use: 88% vs 58% vs 39%
Results

Table 1 below shows the key patient outcomes by the conditioning regimen used. It also includes factors associated with each outcome, determined by multivariate analysis. Table 2 shows the engraftment analysis, as well as main causes of death by subgroup.

Table 1: Patient outcomes by conditioning regimen

Factor

Global population

FT

TBF

FLAMSA

P value

Multivariate analysis

CR at day 100

Not available (NA)

92%

80%

88%

0.13

NA

OS at 2-years

34%

37%

24%

34%

0.10

Inferior OS:

Karnofsky performance < 80% (P = 0.01)

Patient CMV positive (P = 0.02)

NRM at 2-years

22%

26%

24%

20%

0.24

Increased risk of NRM:

Older age (per 10 years; P = 0.002)

Transplant from mismatched UD ( HLA- 9/10, P = 0.03)

Death within 100 days

7%

5%

13%

6%

NA

NA

LFS at 2-years

27%

29%

22%

27%

0.28

Inferior LFS:

Patient CMV positive (P = 0.005)

GRFS at 2-years

20%

23%

13%

20%

NA

Inferior GRFS:

Patient CMV positive (P = 0.05)

Karnofsky performance < 80% (P = 0.01)

Incidence of relapse at 2-years

52%

46%

54%

53%

0.33

Increased risk relapse:

Age at transplant (P = 0.005)

Relapsed vs primary refractory AML (P = 0.01)

Patient CMV positive (P = 0.03)

Grade III–IV acute GvHD (aGvHD)

NA

10%

12%

11%

0.9

Increased risk aGvHD:

Transplant from mismatched UD (HLA 9/10; P < 0.001)

Transplant from opposite gender (P = 0.045)

Severe chronic GvHD (cGvHD)

NA

13%

19%

11%

0.5

Increased risk of cGvHD:

Donor CMV positive (P = 0.05)

The use of anti-thymocyte globulin (ATG) reduced the risk of aGvHD grade III–I (P = 0.018) and severe cGvHD (P = 0.005) but did not influence the relapse incidence

Table 2: Engraftment analysis and most common causes of death

 

FT

TBF

FLAMSA

P value

Engraftment rate (%)

98

91

95

0.1

Median time to engraftment (days)

16

15

14

0.02

Graft failure (n)

1

1

4

Not available (NA)

Secondary graft rejection (n)

0

0

6

NA

Total deaths (n)

75

67

410

NA

Cause of death:

 

 

 

 

Original disease (%)

59

40

63

NA

Infection (%)

16

27

19

NA

GvHD (%)

10

10

8

NA

Conclusion
  • In this cohort of patients with R/R AML, all three conditioning regimens gave similar outcomes, with long term OS in the range of 24–37% (global population 34%)
  • In multivariate analysis, the following patient characteristics were found to have significant associations with outcomes:
    • Negative influence on survival:
      • Karnofsky performance <80%
      • Patient positive CMV serology
    • Higher risk of disease recurrence:
      • Disease status of relapsed AML
    • Higher risk of grade III–IV aGvHD and NRM:
      • Transplant from mismatched UD
    • Lower risk of aGvHD and cGvHD:
      • The use of ATG
  • Of note, age at transplant did not influence survival, despite a maximum age of 76
    • The authors suggest age should not be a criteria to withholding transplant
  • The use of ATG had no influence on relapse rates indicating that the effect on GvHD did not negatively impact the graft-versus-leukemia effect
  • Limitations of the study:
    • Retrospective analysis
    • Lack of information of why each regimen was selected for each patient
    • Lack of data on other important factors, such as minimal residual disease status, post-transplant
  • Relapse, as shown in this study, continues to be a major cause of death and transplant failure, therefore novel strategies to improve relapse rates are required
References
  1. Saraceni F. et al. Fludarabine-treosulfan compared to thiotepa-busulfan-fludarabine or FLAMSA as conditioning regimen for patients with primary refractory or relapsed acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT). J Hemtol. & Onc. 2019 Apr 25. DOI: 10.1186/s13045-019-0727-4
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