aGvHD,   cGvHD

Post-transplant outcomes of patients with therapy-related AML following treatment for prior lymphoid malignancy

Secondary acute myeloid leukemia (sAML) comprises a heterogenous group of diseases. It is most often derived from conditions such as myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPNs), though there is a significant population with therapy-related AML (t-AML) related to prior treatment for a hematological lymphoid malignancy. Patients with t-AML typically have poor outcomes due to the pretreatment received, and/or an older age at diagnosis. Allogeneic hematopoietic stem cell transplant (allo-HSCT) is potentially curative for these patients, though relapse remains an issue. The allo-HSCT outcomes of patients who developed a t-AML after treatment of a B-cell malignancy have not been well studied, and the potential impact of choice of conditioning regimens on post-transplant outcomes has not been discerned.

Katie S. Gatwood, Vanderbilt University Medical Center, Nashville, US, and colleagues conducted a multicenter, retrospective study using the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) registry. They aimed to evaluate the impact of myeloablative (MAC) versus reduced intensity conditioning (RIC) regimen on allo-HSCT outcomes in patients with t-AML following a lymphoid malignancy.

Patient characteristics

The authors analyzed data of adult patients with sAML (n= 549) who had previously been treated for a lymphoid malignancy and had received their first allo-HSCT between 2000–2016. The prior malignancies included acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), lymphoma and plasma cell dyscrasias. Patient characteristics at baseline are shown in Table 1.

Table 1. Baseline characteristics by conditioning regimen

Conditioning regimen

Myeloablative (MAC)

Reduced intensity (RIC)

N

258 (47%)

291 (53%)

Median age at transplant (years)

47.8

55.9

Median time from diagnosis to transplant (months)

4.7

4.7

Previous diagnosis:

·       ALL

·       CLL

·       Lymphoma

·       Multiple myeloma (MM)

 

·       25 (9.7%)

·       29 (11.2%)

·       194 (75.2%)

·       10 (3.9%)

 

·       15 (5.2%)

·       36 (12.4%)

·       219 (75.3%)

·       21 (7.2%)

AML cytogenetics

·       Favorable

·       Intermediate

·       Adverse

·       Missing

 

·       8 (3.1%)

·       73 (28.3%)

·       73 (28.3%)

·       104 (40.3%)

 

·       9 (3.1%)

·       96 (33%)

·       68 (23.4%)

·       118 (40.6%)

Disease status at allo-HSCT

·       Active

·       Complete remission (CR) 1

·       CR2

 

·       80 (31%)

·       161 (62.4%)

·       17 (6.6%)

 

·       92 (31.6%)

·       181 (62.2%)

·       18 (6.2%)

Donor type

·       Matched sibling (MSD)

·       Unrelated (URD)

·       Haploidentical

·       Cord blood transplant

 

·       93 (36%)

·       126 (48.8%)

·       25 (9.7%)

·       14 (5.4%)

 

·       90 (30.9%)

·       174 (59.8%)

·       15 (5.2%)

·       12 (4.1%)

Efficacy

The efficacy results are shown in Table 2, by total cohort, and by conditioning regimen. Patients receiving RIC had a lower risk of non-relapse mortality (NRM), improved leukemia-free survival (LFS), and superior overall survival (OS, Table 3) in multivariate analysis. The choice of conditioning regimen did not significantly impact relapse incidence though.

Table 2. Efficacy results for the total cohort and by conditioning regimen and multivariate analysis

 

Total cohort, %

95% CI

MAC, %

95% CI

RIC, %

95% CI

p value

Two-year LFS

31.7

27.5–35.9

27.9

22–33.8

35.1

29.2–41

0.055

Two-year RI

39.1

34.8–43.4

38.6

32.3–44.9

39.6

33.7–45.5

0.82

Two-year OS

37.4

33–41.8

34.2

27.9–40.5

40.2

34.1–46.3

0.074

Two-year NRM

28.9

25–33

33.3

27.4–39.4

25.3

20.2–30.6

0.04

Two-year graft-versus­-host disease (GvHD)-free relapse-free survival (GRFS)

22.8

19–26.6

19.8

14.5–25.1

25.5

20.1–30.9

0.148

 Table 3. Factors significantly associated with outcomes in multivariate analysis

 

HR

95% CI

p value

LFS

 

 

 

Conditioning regimen (MAC vs RIC)

0.67

0.52–0.85

0.001

Prior autologous HSCT (yes)

1.3

1.01–1.67

0.04

Cytogenetics (adverse vs favorable)

3.15

1.35–7.37

0.008

Active disease at transplant vs CR1

1.68

1.31–2.56

< 0.001

CBT vs MSD

0.9

0.51–1.61

0.04

Donor (female to male)

1.35

1.03–1.77

0.028

OS

 

 

 

Conditioning regimen (MAC vs RIC)

0.69

0.53–0.89

0.004

Cytogenetics (intermediate vs favorable)

3.56

1.01–11.76

0.037

Cytogenetics (adverse vs favorable)

6.61

2–21.85

0.002

Active disease at transplant vs CR1

1.57

1.2–2.04

0.001

RI

 

 

 

Active disease at transplant vs CR1

2.25

1.62–3.13

< 0.001

Karnofsky performance status (KPS, < 80% vs ≥ 80%)

0.46

0.29–0.72

0.001

NRM

 

 

 

Conditioning (MAC vs RIC)

0.58

0.4–0.83

0.003

Cytogenetics (adverse vs favorable)

4.64

1.05–20.54

0.043

KPS (< 80% vs ≥ 80%)

0.4

0.24–0.66

< 0.001

Donor (female to male)

1.521

1.02–2.27

0.04

GFRS

 

 

 

Conditioning regimen (MAC vs RIC)

0.79

0.62–0.99

0.045

Cytogenetics (adverse vs favorable)

2.82

1.29–6.19

0.02

Active disease at transplant vs CR1

1.66

1.3–2.13

< 0.001

KPS (< 80% vs ≥ 80%)

0.47

0.34–0.66

< 0.001

Donor (female to male)

1.32

1.02–1.71

0.037

Rates of GvHD are shown in Table 4. Unrelated donor transplant was associated with higher rate of grade II–IV aGvHD (HR: 1.67, 1.06–2.63, p= 0.027) and a KPS of > 80% was associated with lower rate of grade III–IV aGvHD (HR: 0.45, 0.2–1, p= 0.049).

Table 4. Cumulative incidence of GvHD for total cohort and by conditioning regimen

 

Total cohort, %

95% CI

MAC, %

95% CI

RIC, %

95% CI

p value

Grade II–IV acute GvHD (aGvHD) at day 100 post-transplant

30.6

26.6–34.6

32.7

26.9–38.7

28.6

23.3–34.1

0.2

Grade III–IV aGvHD at day 100 post-transplant

13.7

10.9–16.8

15.37

11.1–20.1

12.3

8.7–16.5

0.26

Chronic GvHD (cGvHD) at two-years

27

23–31.1

23.7

18.3–29.6

30.1

24–36.4

0.16

Extensive cGvHD at two-years

12.8

9.9–16

11.4

7.5–16.1

14

10–18.6

0.38

Other variables associated with poor outcomes in the total cohort were; older age, adverse cytogenetics and active disease at time of transplant.

Deaths

In total, 171 patients receiving MAC and 174 patients receiving RIC died. The main causes (>10% of patients) were:

Given as MAC vs RIC

  • Relapse: 40.8% vs 45.9%
  • Infection: 22.6% vs 19.8%
  • GvHD: 20.1% vs 16.9%
Conclusion

This study has some limitations, including the retrospective nature, potential for selection bias regarding intensity of conditioning, a lack of molecular characterization of AML subtype, a lack of analysis by disease risk, and missing cytogenetic data in around 40% of patients.

In summary, this analysis supports the use of allo-HSCT with RIC for patients with sAML following a prior lymphoid malignancy since patients treated with RIC regimens had a lower risk of NRM and improved LFS, OS and GFRS.

References
  1. Gatwood K.S. et al., Transplant outcomes for patients with therapy-related acute myeloid leukemia with prior lymphoid malignancy: an ALWP of EBMT study. Bone Marrow Trans. 2019 Sep 16. DOI: 10.1038/s41409-019-0673-3
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