Retrospective Analysis of Minimal Residual Disease-Guided Preemptive Treatment in Patients with AML and MDS - the SAL Study Group Experience
2015
Introduction Detection of minimal residual disease (MRD) in
patients with acute myeloid leukemia (AML) and myelodysplastic
syndromes (MDS) in complete hematological remission (CR) offers
a potential therapeutic window allowing early interventions in
order to prevent overt hematological relapse. Due to the
absence of generic markers in AML/MDS, MRD assessment seems to
be a complex procedure. As prospective clinical studies are
sparse, we initiated a retrospective survey within the SAL
(Study Alliance Leukemia) study group and members of the German
Cancer Consortium to evaluate the current clinical use of the
approach and related clinical outcome of treated patients.
Patients Based on questionnaires we analyzed 84 patients from
five clinical centers (pts, m/f=46/38; median age 52 yrs
(19-74)) with either AML (n=77) or MDS (n=7) in CR after
conventional intensive chemotherapy (CTx; n=23) or allogeneic
hematopoietic stem cell transplantation (allo-HSCT; n=61),
undergoing preemptive therapy. Mutations, cytogenetic
aberrations or donor chimerism analysis for transplanted pts
were monitored as MRD markers. Thirty-three pts had a normal
and 14 pts – a complex karyotype; 6 pts carried -7 and/or
inv(3); other aberrations were detected in 29 pts; in 2 pts no
data were available. Among molecular aberrations, NPM1 (n=23)
and FLT3-ITD (n=13) were the most frequent, followed by
CBF/MYH11 (n=8), RUNX1/RUNX1T1 (n=8) and MLL/AF6 (n=3). In 20
pts no mutations were found. For 5 pts data on molecular
diagnostics were not available and MRD was assessed by
chimerism. Results The median time to MRD positivity after
completion of intensive therapy was 12 months (range, 1-97).
Subsequent MRD-guided therapy in pts treated only with CTx
included hypomethylating agents (HMA, 34%), clofarabine (17%),
additional intensive CTx (9%), targeted therapy (gemtuzumab
ozogamycin, 9%), low-dose cytarabine (9%), and allo-HSCT (22%).
Other treatment strategies included interferon alfa and
sorafenib. In transplanted patients the most preferred
treatment for the molecular relapse was donor lymphocyte
infusion (26 pts, 43%; median number of DLI=3, range, 1-6),
alone or in combination (54% with HMA). 32 MRD-based treated
pts (43%) did not experience a hematological relapse and were
either alive (23 pts, median observation time 953 days, range,
30–3660), or died due to another cause (9 pts) with median
survival of 359 days (range, 125-954). In 9 pts without
hematological relapse more than one MRD recurrence was
observed. In the remaining 57% relapsing patients, median time
to hematological relapse was 252 days (range, 24–1161) after
MRD positivity. Interestingly, in some pts the hematological
relapse was observed in the absence of the known mutation,
indicating that the disease probably progressed due to another
subclone. Thus, an accurate initial diagnostic is essential,
ideally a multiple gene approach and comprehensive follow-up.
Conclusions The retrospective analysis demonstrates that
MRD-guided therapies have already entered routine practice in
patients with AML and MDS. The heterogeneous nature of both
cancer entities is reflected by the variety of MRD surveillance
protocols among clinical centers. Therefore, clinical trials
are needed to better define molecular markers and subsets of
patients who might benefit from this approach.
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