IMPACT OF MRD STATUS PRIOR TO HSCT IN PEDIATRIC AML

Background:

Despite great improvements in treatment protocols, relapse still occurs in 30-40% of all pediatric AML patients, being the leading cause of death with an overall survival (OS) of relapsed AML of only 35%. In an attempt to improve the OS, attention has been focused on the concept of Minimal Residual Disease (MRD), the ability to detect and quantify small trace amount of residual leukemic cells in patients who have otherwise achieved morphologic clinical remission (CR). The hope is that MRD monitoring can guide preemptive interventions and thereby prevent progression from molecular to hematologic relapse and ultimately improve the course and outcome of childhood AML.

Aims:

In this retrospective study we aimed to determine if there is a correlation between the MRD level prior to the allogeneic HSCT and the disease outcome in pediatric AML patients.

Methods:

For the MRD assessment we used quantitative reverse transcriptase polymerase chain reaction (RT-qPCR).

The studied cohort consisted of 38 children with a confirmed AML diagnosis comprising one of the following aberrations: t(8;21), inv(16), t(9;11), FLT3-ITD or NPM1 and who had undergone allogeneic HSCT transplantation. Exclusion criteria were Down syndrome and secondary AML. The median age at initial diagnosis was 9.1 years (range 0 – 18 years) and the female:male ratio  0.93.

Results:

In the study cohort MRD levels directly prior to HSCT were undetectable in a third (32%, n=12) of the patients, five of these patients died, of which four were due to treatment related mortality (TRM). In the remaining 26 patients, MRD was detectable just before the transplantation. Among those, 18 patients (47% of the entire cohort) exhibited high levels, defined as MRD ≥0.01%. The group with high MRD had a death rate of 56% (4 due to TRM) while the group with low MRD had a mortality rate of 50% (4 of 8, 1 caused by TRM). By grouping the non-detectable and low MRD level patients into one group (-/low MRD) and comparing them to the patients from the high group (+ MRD), a trend towards a favourable outcome of the -/low MRD patients in regards to OS was seen, albeit non-significant (P=0.08) (fig. A).

Looking at the time of HSCT during the disease course we saw a clear superior outcome for patients transplanted in first remission (CR1) compared to second remission (CR2) (P=0.01). Likewise for the donor-type, matched sibling (MSD) vs. matched unrelated donors (MUD) showed a preference for MSD with P=0.009.

When testing the timing of the transplantation in combination with the MRD status we again saw that patients transplanted in the first remission had an excellent outcome (fig. B). In cases where HSCT were performed in the second remission the OS considerably worsened, mostly for the patients with high MRD levels prior to HSCT (fig. B).

We did not observe significant differences for overall survival in the favourable- (t(8;21), inv(16), NPM1) and poor-risk- (FLT3-ITD, t(9;11)) groups. This may be explained by the aberrations FLT3-ITD and t(8;21), as the latter exhibited a very poor prognosis with 9 death (4 due to TRM) out of 15 within the first 3 years after HSCT and a good profile for FLT3-ITD positive patients where only 1 out of 7 included in the analysis died.

However, these data should be interpreted with some caution, as the cohort size is relatively small and the study is therefore with low statistic power. In addition, treatment of the patients has not been standardized within the study cohort.

Image / Pictures:

Summary / Conclusion:

In this retrospective multinational study we have examined the impact of Minimal Residual Disease (MRD) levels just prior to hematopoietic stem cell transplantations and found that there seems to be some influence on the outcome when a certain MRD level is present at the time of HSCT. Whether additional therapy to reduce the tumor burden is beneficial before proceeding with HSCTs is still to be tested and verified in future clinical trials.

Keywords: Acute myeloid leukemia, Allogeneic hematopoietic stem cell transplant, Minimal residual

Abstrakta v časopise Haematologica 2013, Suppl1

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