EARLY DETECTION OF RELAPSE BY PROSPECTIVE REVERSE TRANSCRIPTASE-POLYMERASE CHAIN-REACTION ANALYSIS OF THE PML RAR-ALPHA FUSION GENE IN PATIENTS WITH ACUTE PROMYELOCYTIC LEUKEMIA ENROLLED IN THE GIMEMA-AIEOP MULTICENTER AIDA TRIAL/
D. Diverio et al., EARLY DETECTION OF RELAPSE BY PROSPECTIVE REVERSE TRANSCRIPTASE-POLYMERASE CHAIN-REACTION ANALYSIS OF THE PML RAR-ALPHA FUSION GENE IN PATIENTS WITH ACUTE PROMYELOCYTIC LEUKEMIA ENROLLED IN THE GIMEMA-AIEOP MULTICENTER AIDA TRIAL/, Blood, 92(3), 1998, pp. 784-789
Although the majority of patients with acute promyelocytic leukemia (A
PL) are potentially cured by treatments combining all-trans retinoic a
cid (ATRA) and chemotherapy (CHT), a sizable proportion (around 30%) w
ill relapse during follow-up. Retrospective molecular monitoring studi
es using reverse transcriptase-polymerase chain reaction (RT-PCR) for
the specific PML/RAR alpha fusion gene, have shown that a positive tes
t usually precedes the occurrence of hematologic relapse. Prospective
WT-PCR analyses were performed since 1993 at diagnosis and at preestab
lished time intervals during follow-up in bone marrow (BM) samples of
163 patients with PML/RAR alpha(+) APL enrolled in the multicenter Gru
ppo Italiano Malattie Ematologiche Maligne dell' Adulto (GIMEMA) trial
AIDA (All-trans retinoic acid plus Idarubicin). Treatment consisted o
f ATRA and idarubicin for induction followed by three polychemotherapy
courses as consolidation. The sensitivity level of the RT-PCR assay f
or PML/RAR alpha, as assessed by serial dilution experiments, was 10(-
4). All patients were in hematologic remission and tested PCR- at the
end of consolidation. of 21 who converted to PCR-positive thereafter,
20 underwent hematologic relapse at a median time of 3 months (range,
1 to 14) from the first PCR+ result. seventeen of these 21 (81%) PCRconversions were recorded within the first 6 months postconsolidation.
Of 142 who tested persistently PCR- in greater than or equal to 2 tes
ts after consolidation, 8 had hematologic relapse and 134 remained in
complete remission (CR) after a median follow-up of 18 months (range,
6 to 38) postconsolidation. Using a time-dependent Cox model, the rela
tive risk of hematologic relapse of patients who converted to PCR+ was
31.8 (confidence limits 95%, 12.9 to 78.3). our results indicate that
conversion to PCR positivity for PML/RAR alpha during remission is hi
ghly predictive of subsequent hematologic relapse and highlight the pr
ognostic value of stringent molecular monitoring during the early post
consolidation phase in APL. As a result of the present study salvage t
reatment in patients enrolled in the GIMEMA trial AIDA is now anticipa
ted at the time of molecular relapse, defined as the conversion to PCR
positivity in two successive BM samplings during follow-up. (C) 1998
by The American Society of Hematology.