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Blood, Vol. 92 No. 3 (August 1), 1998:
pp. 784-789
Early Detection of Relapse by Prospective Reverse
Transcriptase-Polymerase Chain Reaction Analysis of the PML/RAR
Fusion Gene in Patients With Acute Promyelocytic Leukemia Enrolled
in the GIMEMA-AIEOP Multicenter "AIDA" Trial
Daniela Diverio,
Vincenzo Rossi,
Giuseppe Avvisati,
Silvia DeSantis,
Alessandra Pistilli,
Fabrizio Pane,
Giuseppe Saglio,
Giovanni Martinelli,
Maria Concetta Petti,
Alessandra Santoro,
Pier Giuseppe Pelicci,
Franco Mandelli,
Andrea Biondi, and
Francesco Lo Coco for
the GIMEMA and AIEOP Cooperative Groups
From the Dipartimento di Biotecnologie Cellulari ed Ematologia,
Università "La Sapienza", Rome; Clinica Pediatrica,
Ospedale S. Gerardo, Università di Milano, Monza; Istituto L.& A. Seràgnoli, Università di Bologna, Bologna;
CEINGE, Università Federico II, Napoli; Istituto Europeo di
Oncologia, Milano; Clinica Medica, Ospedale Maggiore, Novara; Divisione
di Ematologia, Ospedale V. Cervello, Palermo, Italy.
Although the majority of patients with acute promyelocytic
leukemia (APL) are potentially cured by treatments combining
all-trans retinoic acid (ATRA) and chemotherapy (CHT), a
sizable proportion (around 30%) will relapse during follow-up.
Retrospective molecular monitoring studies using reverse
transcriptase-polymerase chain reaction (RT-PCR) for the specific
PML/RAR fusion gene, have shown that a positive test usually
precedes the occurrence of hematologic relapse. Prospective RT-PCR
analyses were performed since 1993 at diagnosis and at preestablished
time intervals during follow-up in bone marrow (BM) samples of 163 patients with PML/RAR+ APL enrolled in the multicenter
Gruppo Italiano Malattie Ematologiche Maligne dell' Adulto (GIMEMA)
trial AIDA (All-trans retinoic acid plus Idarubicin).
Treatment consisted of ATRA and idarubicin for induction followed by
three polychemotherapy courses as consolidation. The sensitivity level
of the RT-PCR assay for PML/RAR, 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%)
PCR+ conversions were recorded within the first 6 months
postconsolidation. Of 142 who tested persistently PCR in
 2 tests 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 relative 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 during remission is highly
predictive of subsequent hematologic relapse and highlight the
prognostic value of stringent molecular monitoring during the early
postconsolidation phase in APL. As a result of the present study,
salvage treatment in patients enrolled in the GIMEMA trial AIDA is now
anticipated at the time of molecular relapse, defined as the conversion
to PCR positivity in two successive BM samplings during follow-up.
© 1998 by The American Society of Hematology.
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