Allogeneic stem cell transplant for patients in second complete remission

Previous studies investigating the outcome of allogeneic hematopoietic cell transplantation (allo-HCT) in relapsed patients with acute myeloid leukemia (AML), have established that certain factors such as duration of first complete remission (CR1) or age at relapse, could predict the likelihood of CR2. Achieving CR2 has been shown to provide a benefit for subsequent allo-HCT.¹

However, so far there are no available data from large series, which assess the impact of conditioning regimen intensity on the outcomes of HCT in patients with AML in CR2.

Maria H Gilleece, Leeds Teaching Hospitals Trust, Leeds, UK, and colleagues, conducted a study² on behalf of the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Bone Marrow Transplantation (EBMT) to evaluate the difference between reduced intensity conditioning (RIC) and myeloablative conditioning (MAC) in patients with AML who were in CR2, including by age (<50 versus ≥50 years).

Study design and patient characteristics

• Aim: assess patient outcome by conditioning regimen intensity (MAC versus RIC)
• Adult patients with AML in CR2 were identified from the EMBT registry data
• Eligible patients had received a first allo-HCT between 2007-2016 and had cytogenetic profile at diagnosis available
• Donors were either matched family (MFD), volunteer unrelated with a human-leukocyte antigen (HLA) match 10/10 (VUD) or 9/10 (MMVUD), or were haploidentical (Haplo-ID)
• Graft sources: peripheral blood stem cells (PBSC) or bone marrow (BM)
• N= 1879
• MAC: 1010 (54%)
  • Conditioning with treosulfan/fludarabine (TF) and thiotepa/busulfan/fludarabine (TBF) were MAC if busulfan was ≥6mg/kg
• RIC: 869 (46%)
• Median follow-up in surviving patients: 26.16 months (0.49-124.63)
• Baseline characteristics
• Patients receiving RIC (RIC vs MAC):
  • Longer time from diagnosis to transplant: 18.5 months vs 17.7 months, p= 0.017
  • Were older: 57.3 years vs 42.8 years, p< 0.001
  • Had a worse Karnofsky performance status, p< 0.001
  • Higher proportion of adverse or intermediate cytogenetics at diagnosis, p< 10^-3
• Unrelated donors were more common in the RIC group, p< 0.001
• Family donors were more common in the MAC group
• PBSC was the preferred source in both groups
• Primary endpoint: leukemia-free survival (LFS)
• Secondary endpoints: relapse incidence (RI), overall survival (OS), non-relapse mortality (NRM), graft-versus-host disease (GvHD) relapse-free survival (GRFS), acute GvHD (aGvHD) and chronic GvHD (cGvHD)

Results

Two-year survival outcomes are shown in Table 1 (whole cohort) and Table 2 (by conditioning regimen).

Table 1. Two-year outcomes post-allo-HCT in the cohort

 

Percentage (%)

95% CI

LFS

52

49.4-54.5

OS

58.7

56.2-61.2

RI

28.9

26.7-31.2

NRM

19

17.2-21

GFRS

38.7

36.2-41.1

cGvHD

37.2

34.7-39.7

Extensive cGvHD

15.9

14.1-17.8

Table 2. Two-year outcomes of allo-HCT in CR2 by conditioning regimen and age

 

LFS (%)

OS (%)

NRM (%)

GRFS (%)

Patients <50 years old

MAC

54

61

18

38

RIC

54

62

15

42

p value

0.61

0.7

Not reported (NR)

NR

Patients ≥50 years old

MAC

52

58

27

42.4

RIC

49

55

19

36

p value

0.7

0.3

NR

NR

• Two-year OS by cytogenetics (low vs intermediate vs adverse): 67.4% vs 56.8% vs 37.9%

Multivariate analysis

In order to assess the impact of conditioning regimens and other parameters on transplant outcomes, multivariate analysis was conducted (Table 3).

• Intensity of conditioning did not have a significant impact on OS, LFS or RI
• NRM was reduced in patients ≥50 years old receiving RIC
• Other adverse risk factors identified were: increasing age, intermediate or adverse cytogenetics, poor KPS, shorter time between diagnosis to transplant, and transplant from a mismatched donor

Table 3. Factors significantly associated with outcome

Factor

Outcome

Effect

Hazard ratio (HR) and confidence interval

p values 

Conditioning regimen, RIC

NRM

Favored RIC

0.65 (0.5–0.84)

 

0.001

 

Conditioning regimen RIC, and age ≥50 years

NRM

Favored RIC

0.54 (0.38–0.76)

<0.001

Conditioning regimen RIC, and age ≥50 years

cGVHD

Increased

1.38 (1.03–1.85)

0.03

Age <50 years

GRFS

Adverse

1.13 (1.01–1.26)

0.03

Age <50 years

NRM

Increased

1.25 (1.01–1.53)

0.034

Age ≥50 years

NRM

Increased

1.6 (1.21–2.03)

0.001

Karnofsky performance scores (KPS) >80% and age <50 years

NRM

Lowered

0.447 (0.219–0.914)

0.03

KPS >80% and age ≥50 years

NRM

Lowered

0.265 (0.162–0.435)

<10^-5

KPS >80% and age ≥50 years

aGvHD grade II-IV

aGvHD grade III-IV

Lowered

 

 

0.562 (0.322–0.982)

0.338 (0.152–0.748)

0.043

0.007

KPS >80% and age ≥50 years

OS

LFS

GRFS

Improved

0.437 (0.297–0.645)

0.486 (0.331–0.715)

0.363 (0.254–0.518)

<10^-4

<10^-3

0.000

Longer interval from diagnosis to allo-HCT and age <50 years

RI

LFS

OS

GRFS

Improved

 

0.96 (0.948–0.975)

0.982 (0.974–0.99)

0.982 (0.974–0.991)

0.991 (0.985–0.997)

<10^-5

10^-5

<10^-4

0.003

Longer interval from diagnosis to allo-HCT and age ≥50 years

RI

LFS

OS

GRFS

Improved

0.974 (0.963–0.986)

0.987 (0.98–0.995)

0.988 (0.98–0.996)

0.993 (0.986–1)

10^-5

0.001

0.002

0.037

Donor selection: MMVUD or Haplo-ID or donors and age <50 years

NRM

 

 

Increased

MMVUD: 1.986 (1.168–3.377)

Haplo-ID: 2.096 (1.097–4.002)

0.01

0.02

Donor selection: MMVUD or Haplo-ID or donors and age ≥50 years

NRM

 

 

Increased

MMVUD: 2.241 (1.419–3.539)

Haplo-ID: 1.948 (1.069–3.552)

0.001

0.029

Donor selection: MMVUD or Haplo-ID donors and age ≥50 years

aGvHD grade II–IV

Increased 

MMVUD: 2.685 (1.692–4.26)

Haplo-ID: 2.434 (1.341–4.417)

<10^-4

0.003

Donor selection: MMVUD donors and age <50 years

aGvHD grade II–IV

Increased 

2.679 (1.721–4.17)

 

<10^-4

 

Donor selection: female donors and age <50 years

Extensive cGvHD

Increased

1.515 (1.047–2.194)

0.028

Donor source: PBSC and age <50 years

cGvHD

Increased

1.784 (1.253–2.539)

 

0.001

Donor source: PBSC and age ≥50 years

cGvHD

Increased 

 

1.683 (1.08–2.624)

0.021

Allogeneic stem cell transplant for patients in second complete remission

Table 3. Advantages and limitations of study

Advantages

Limitations

Wide range of regimens included

Retrospective

Long follow-up

Only addresses patients in CR2 rather than relapse after CR1

Large sample size

Unknown reasons that allo-HCT was used in CR2

Conclusions

• This study has suggested that MAC and RIC may be similar in terms of RI, OS, GvHD and NRM which should be studied further in prospective studies
• Adverse factors for allo-HCT reported in other studies, such as increasing age, cytogenetics other than good risk, poor performance status, shorter time intervals from initial diagnosis to transplant and mismatched donor allo-HCT, were confirmed

The high relapse rates in patients with AML in CR2 indicate an unmet need for more active therapies.