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Treating MRD after allogeneic transplant in patients with AML – a real-world analysis

Nov 2, 2020
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The presence of measurable residual disease (MRD) after allogeneic hematopoietic stem cell transplant (allo-HSCT) is associated with increased risk of relapse and inferior prognosis for patients with acute myeloid leukemia (AML; visit the AML Hub for an overview). However, the value of MRD-directed therapy after allo-HSCT has not yet been standardized. Results from the phase II RELAZA2 trial (NCT01462578) indicate that MRD-guided treatment after transplant may be an effective strategy to delay relapse in patients with AML.

Here, we are pleased to summarize a study by Elizabeth Krakow and colleagues,1 presented at the Virtual 46th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT). This study sought to determine and compare in a real-world setting the impact of MRD treatment versus treatment for morphologic relapse after allo-HSCT in patients with AML.

Study design

A total of 333 patients with AML who had persistent or relapsed disease following their first allo-HSCT were included in this retrospective, observational analysis.

Endpoints included:

  • Overall survival (OS), measured from first disease detection post allo-HSCT (t0).
  • Failure-free survival, defined as survival without progression to either morphologic disease (for t0 MRD-positive patients), or morphologic disease at post-treatment restaging (for t0 morphologic patients).
  • Complete remission (CR), defined as morphologic remission without MRD, regardless of blood count recovery.
  • MRD, defined as < 5% bone marrow blasts with malignancy confirmed by flow cytometry, cytogenetics, or molecular testing.

The following assessments were made:

  1. Impact of timing of treatment on outcomes for patients with MRD positivity at first detection after allo-HSCT.
  2. Impact of type of first treatment on outcomes for all patients.

Key findings

Selected patient characteristics at first detection of AML after allo-HSCT (t0) are shown in Table 1. The most common first treatments used after allo-HSCT were chemotherapy (CT) and hypomethylating agents (HMAs); other treatments included donor leukocyte infusion, and second allo-HSCT. The HMA cohort was generally older, started treatment earlier after allo-HSCT, and had a higher proportion of patients treated for MRD (59% vs 3%), compared with the CT cohort. Treatment comparisons were adjusted for these factors.

Table 1. Selected characteristics for patients at first detection of AML after allo-HSCT1

allo-HSCT, allogeneic hematopoietic stem cell transplant; BM, bone marrow; CT, chemotherapy; ELN, European LeukemiaNet; HMA, hypomethylating agent; MRD, measurable residual disease; PB, peripheral blood; t0, time of first disease detection post allo-HSCT.

Characteristic at t0

All
(n = 333)

CT
(n = 123)

HMA
(n = 112)

Median age, years (range)

52.2 (2.3–81.1)

46.8 (2.3–76.4)

57.2 (3.4–81.1)

Time from allo-HSCT to t0, days (range)

84 (14–3898)

223 (14–3898)

73 (14–3106)

Disease presentation, %
  BM/PB
  Extramedullary
  MRD only

 
47
9
43

 
66
18
16

 
27
1
72

ELN adverse risk, %

54

54

50


At first detection of persistent or recurrent AML after allo-HSCT, patients with MRD positivity (n = 144) had superior OS initially, compared with patients with morphologic disease relapse (n = 188; median OS, 208 days vs 135 days; HR, 0.53; 95% CI, 0.40–0.69; p < 0.0001). However, long-term survival was similar between the two groups of patients.

The impact of treatment on hazard of death, for patients whose first disease detection after allo-HSCT was MRD, is shown in Table 2.

Table 2. Overall survival (modelling treatment as time-dependent covariate) for patients with t0 MRD positivity1

AML, acute myeloid leukemia; CI, confidence interval; HR, hazard ratio; MRD, minimal residual disease; OS, overall survival; t0, time of first disease detection post allo-HSCT.

State

Adjusted HR for OS

95% CI

p value

No treatment (n = 62)

Reference

Treatment for MRD (n = 72)

0.96

0.55–1.67

0.88

Treatment for morphological AML (n = 40)

Reference

Treatment for MRD (n = 72)

0.21

0.21–0.22

< 0.0001


The HR for OS for patients treated for MRD was similar to that for patients who were untreated. However, patients treated for MRD had a significantly lower HR, compared with those treated for morphological disease (HR = 0.21; p < 0.0001).

It is noteworthy that, of the 62 patients with t0 MRD-positive AML who were not immediately treated, 14 (23%) had MRD-negative CR on subsequent testing.

There was no significant difference in OS between patients treated with CT or HMA (HR = 1.33; p = 0.18). Failure-free survival was similar between the two treatment groups, and both treatments were equally likely to induce MRD-negative CR (43% vs 42%).

Conclusions

This observational study supports the notion that delaying treatment for MRD after allo-HSCT until detection of morphologic disease has a negative impact on OS. Here, the investigators observed a significantly increased hazard of death for patients treated for morphologic AML, compared with those treated for MRD. It was noted, however, that 23% of MRD-positive patients who were completely untreated subsequently became MRD negative, albeit temporarily.

The investigators acknowledge the limitations of the analyses, which include confounding by indication (more aggressive AML may be treated more aggressively), and unmeasured confounding (i.e., the effect of immunosuppression is not considered). Additionally, survival estimates associated with first treatment may have been influenced by subsequent lines of therapy.

  1. Krakow EF, Baker TA, Gooley JM, et al. Real-world utility of treating minimal residual disease after allogeneic hematopoietic cell transplantation for acute myeloid leukemia. Poster #B257. 46th Annual Meeting of the EBMT; Aug 29, 2020; Virtual.

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