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How cytogenetic risk impacts the outcome of allogeneic stem cell transplantation

Mar 26, 2021
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Cytogenetic profile is a predictor of outcome in patients with acute myeloid leukemia (AML). It also helps with the choice of the best post-remission therapeutic approach.

However, limited data are available on the impact of cytogenetic risk stratification on the outcome of allogeneic hematopoietic cell transplantation (allo-HCT). Here, we report the results from two studies evaluating the prognostic value of cytogenetic risk stratification in patients undergoing allo-HCT with active disease and in patients with FLT3-mutated, NPM1-negative (FLT3+ NPM1) AML undergoing allo-HCT in remission.

Impact of cytogenetic risk in patients undergoing allo-HCT with active disease1

A retrospective study, investigating the impact of cytogenetic risk on the outcomes of allo-HCT in patients with relapsed/refractory (R/R) AML, included patients aged ≥ 18 years who underwent their first allo-HCT in 2000─2017 with active disease, and who had cytogenetics available at time of diagnosis. Poiani, Battipaglia et al. recently published the results in American Journal of Hematology.1

The primary endpoint of the study was overall survival (OS).

Patient characteristics

The baseline characteristics of the patients according to cytogenetic risk group are reported in Table 1.

Table 1. Patient characteristics according to cytogenetic risk group1

allo-HCT, allogeneic hematopoietic cell transplantation; auto-, autologous; MAC, myeloablative conditioning; PS, performance status; RIC, reduced intensity conditioning; TCD, T-cell depletion.
Values in bold are statistically significant.

 

Characteristic

Favorable
(n = 154)

Intermediate
(n = 1,283)

Adverse
(n = 652)

p value

Median age at allo-HCT, years (range)

46 (19─75)

52 (18─77)

50 (19─78)

< 0.01

Median time from diagnosis to allo-HCT, months (range)

13 (2─132)

6 (1.5─161)

5 (1.5─54)

< 0.01

Disease status at allo-HCT, %
              Primary refractory
              First relapse
              Second relapse


15
64
21


41
48
11


64
32
3

< 0.01

Previous auto-HCT, %

6

6

1

< 0.01

Karnofsky PS at allo-HCT, %
              Good
              Poor
              Missing


78
14
8


78
12
10


78
14
8

0.58

Conditioning regimen, %
              MAC
              RIC
              Missing


54
43
3


51
47
2


51
47
2

0.77

Type of donor, %
              HLA-matched sibling
              Fully matched unrelated donor
              One-antigen mismatched unrelated donor


59
29
12


59
28
13


53
36
11

< 0.01

In vivo TCD, %

52

51

59

0.01

Median follow-up, months (range)

40 (1─167)

51 (1–195)

49 (1─179)

0.90

Results

The main outcomes are shown in Figure 1. The median time to neutrophil engraftment was 15 days for all three cytogenetic groups (p = 0.41) and no difference was observed in the cumulative incidence of engraftment (p = 0.07). In addition, no differences were observed according to cytogenetic risk in non-relapse mortality (NRM) and Grade II─IV acute graft-versus-host disease (aGvHD).

Figure 1. Outcomes according to risk group1


cGvHD, chronic GvHD; CI, confidence interval; d, day; CR, complete remission; GRFS, graft-versus-host disease/relapse-free survival; GvHD, graft-versus-host disease; LFS, leukemia-free survival; OS, overall survival; RI, relapse incidence; y, year.

The multivariate analysis (Table 2) confirmed the univariate results, with patients in the intermediate and adverse groups having worse outcomes compared to patients in the favorable group.

Table 2. Results of multivariate analysis for the main outcomes1

aGvHD, acute GvHD; BM, bone marrow; cGvHD, chronic GvHD; CI, confidence interval; CMV, cytomegalovirus; GRFS, GvHD/relapse-free survival; GvHD, graft-vs-host disease, HLA, human leukocyte antigen; HR, hazard ratio; LFS, leukemia-free survival; NRM, non-relapse mortality; OS, overall survival; PBSC, peripheral blood stem cell; PS, performance status; RI, relapse incidence; TCD, T-cell depletion; UD, unrelated donor.

Outcome

Variables

HR (95% CI)

p value

RI

Favorable risk (reference)
Intermediate risk
Adverse risk


1.54 (1.12─2.12)
2.12 (1.51─2.97)


< 0.01
< 0.01

Primary refractory (reference)
First relapse
Second relapse


1.35 (1.14─1.59)
1.61 (1.22─2.13)


< 0.01
< 0.01

Patient age (incremental age 10 years)

0.93 (0.88─0.99)

0.02

Year of transplant

0.98 (0.96─1.00)

< 0.02

Karnofsky PS ≥ 90%

0.79 (0.67─0.92)

< 0.01

Center effect

 

< 0.01

NRM

Primary refractory (reference)
Second relapse


1.50 (1.04─2.17)


< 0.04

Patient age (incremental age 10 years)

1.18 (1.07─1.29)

< 0.01

Karnofsky PS ≥ 90%

0.57 (0.45─0.71)

< 0.01

LFS

Favorable risk (reference)
Intermediate risk
Adverse risk


1.34 (1.04─1.74)
1.75 (1.33─2.29)


< 0.01
< 0.01

Primary refractory (reference)
First relapse
Second relapse


1.21 (1.05─1.39)
1.59 (1.27─1.98)


< 0.01
< 0.01

Karnofsky PS ≥ 90%

0.70 (0.62─0.80)

< 0.01

Center effect

 

< 0.02

OS

Favorable risk (reference)
Intermediate risk
Adverse risk


1.38 (1.05─1.8)
1.75 (1.32─2.32)


< 0.02
< 0.01

Primary refractory (reference)
First relapse
Second relapse


1.21 (1.05─1.39)
1.59 (1.26─2.00)


< 0.01
< 0.01

Karnofsky PS ≥ 90%

0.65 (0.57─0.75)

< 0.01

Patient positive CMV serology vs negative

1.16 (1.00─1.34)

< 0.05

GRFS

Favorable risk (reference)
Adverse risk


1.49 (1.16─1.92)


< 0.01

Primary refractory (reference)
Second relapse


1.33 (1.08─1.65)


< 0.01

Karnofsky PS ≥ 90%

0.73 (0.65─0.82)

< 0.01

In vivo TCD: Yes vs No

0.84 (0.73─0.97)

< 0.02

Grade II─IV aGvHD

Patient age (incremental age 10 years)

0.92 (0.85─0.99)

< 0.03

HLA-identical sibling donor (reference)
UD 10/10
UD 9/10

 

 

UD 10/10

1.67 (1.31─2.13)

< 0.01

UD 9/10

1.9 (1.41─2.55)

< 0.01

Female donor to male recipient vs other

1.30 (1.03─1.65)

< 0.03

PBSC vs BM

1.69 (1.08─2.66)

< 0.03

In vivo TCD: Yes vs No

0.64 (0.50─0.82)

< 0.01

Center effect

 

< 0.01

cGvHD

Year of transplant

0.96 (0.94─0.99)

< 0.01

PBSC vs BM

2.21 (1.29─3.77)

< 0.01

In vivo TCD: Yes vs No

0.63 (0.49─0.82)

< 0.01

No significant differences in transplant outcomes were observed according to conditioning intensity but, when analyzed separately the outcomes according to the conditioning intensity, patients in the adverse and intermediate groups and those transplanted with active disease due to relapse had worse outcomes.

Impact of FLT3-ITD status on transplant outcomes

An analysis performed only in patients with FLT3-ITD status available (FLT3-ITD+, n = 301; FLT3-ITD, n = 399) showed worse outcomes in FLT3-ITD+ versus FLT3-ITD patients:

  • Relapse incidence (RI), 59% vs 45%
  • Leukemia-free survival (LFS), 21% vs 32%
  • OS, 24% vs 41%
  • GvHD/relapse-free survival (GRFS), 15% vs 23%

Impact of cytogenetic risk in patients with FLT3+ NPM1 AML undergoing allo-HCT in remission2

In cytogenetically normal patients, FLT3+ NPM1 status predicts poor prognosis and serves as indication for allo-HCT. However, the impact of cytogenetics-based risk stratification in patients with FLT3+ NPM1 AML undergoing allo-HCT is still under investigation. During the 2021 Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, Arnon Nagler presented the results from a retrospective study evaluating the impact of the EBMT cytogenetic risk score stratification in patients with FLT3+ NPM1 AML undergoing allo-HCT in remission.2

Patients included in the study were ≥ 18 years with de novo AML, underwent first allo-HCT from matched siblings, 9-10/10 unrelated, or haplo donors, were in first or second complete remission between 2000─2019, and had both cytogenetics and FLT3 and NPM1 mutation status available.

The primary endpoint of the study was LFS.

Patient characteristics

The baseline characteristics of the patients according to cytogenetic risk group are reported in Table 3.

Table 3. Patient characteristics according to cytogenetic risk group2

CR, complete remission; CR1, first CR; CR2, second CR; HCT, hematopoietic cell transplantation; IQR, interquartile range; MAC, myeloablative conditioning; MSD, matched sibling donor; RIC, reduced intensity conditioning; UD, unrelated donor.
Values in bold are statistically significant.

Characteristic

Good
(n = 112)

Intermediate
(n = 1,313)

Adverse
(n = 206)

p value

Median age, years (range)

39.9 (19─68.6)

49.6 (18─76.8)

48.2 (18.1─71.1)

< 0.0001

Type of donor

MSD/syngeneic, %
UD, %
              10/10, n
              9/10, n
              HLA unknown, n
Other relative, %

38.4
51.8
33
11
14
9.8

38.2
51.9
397
110
175
9.8

33.5
60.7
60
23
42
5.8

0.15

Status at HCT, %

CR1
CR2

66.1
33.9

91.1
8.9

90.3
9.7

< 0.0001

Karnofsky score, %

< 90
90

23.2
76.8

20.2
79.8

23.3
76.7

0.48

Conditioning regimen

MAC, %
RIC, %
Missing, n

63.4
36.6
0

56.4
43.6
3

60.4
39.6
4

0.23

Median follow-up, months (IQR)

29.9 (15.5─61.5)

38.4 (15.7─75.0)

28.6 (12.5─58.4)

0.005

Results

No differences were observed according to cytogenetic risk in graft failure and engraftment, or in the incidence of Grade II─IV and Grade III─IV aGvHD, chronic (c)GvHD, and NRM. The incidence of extensive cGvHD was higher in patients in the good vs intermediate vs poor risk groups (27% vs 15.7% vs 20.3; p = 0.041), but this was not confirmed in the multivariate analysis.

Significant differences were observed according to cytogenetic risk in RI, LFS, and OS (Table 4).

Table 4. Outcomes according to cytogenetic risk group2

CI, confidence interval; HR, hazard ratio; LFS, leukemia-free survival; OS, overall survival; RI, relapse incidence.
Values in bold are statistically significant.

Cytogenetics

RI

LFS

OS

HR
(95% CI)

p value

HR
(95% CI)

p value

HR
(95% CI)

p value

Intermediate vs good

1.82
(1.19─2.77)

0.005

1.48
(1.06─2.06)

0.02

1.43
(1─2.05)

0.052

Adverse vs good

1.83
(1.13─2.94)

0.013

1.65
(1.13─2.4)

0.009

1.74
(1.16─2.61)

0.008

These results were confirmed in the multivariate analysis. In addition, the multivariate analysis found that significant differences in GRFS were observed in the adverse vs good risk group (HR, 1.41; 95% CI, 1.03─1.93; p = 0.032).

The main causes of death in the good vs intermediate vs adverse risk groups were:

  • Original disease: 42.4% vs 52.6% vs 51.2%
  • GvHD: 21.2% vs 18.9 vs 17.9
  • Infections: 21.2% vs 15.4% vs 17.9%

Conclusion

  • Results from these studies demonstrated that cytogenetic risk is a valid predictor of transplant outcome in both the R/R setting and in patients with FLT3+ NPM1 AML undergoing allo-HCT, and it should be considered in the setting of allo-HCT for risk stratification
  • Adverse risk cytogenetics were associated with the worst outcomes
  • Regardless of cytogenetic risk, patients transplanted with active disease due to relapse had worse outcomes than those transplanted with active disease due to refractoriness to chemotherapy

  1. Poiani M, Labopin M, Battipaglia G, et al. The impact of cytogenetic risk on the outcomes of allogeneic hematopoietic cell transplantation in patients with relapsed/refractory acute myeloid leukemia: On behalf of the acute leukemia working party (ALWP) of the European group for blood and marrow transplantation (EBMT). Am J Hematol. 2021;96(1):40-50. DOI: 1002/ajh.26000
  2. Nagler A, Labopin M, Craddock C, et al. The role of cytogenetic risk stratification in FLT3 mutated NPM1 negative AML patients undergoing allogeneic stem cell transplantation (alloSCT) in remission: A study on behalf of the ALWP of the EBMT. Abstract #50. 2021 TCT Meetings of ASTCT and CIBMTR; Feb 10, 2021; Virtual.

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