Early detection of relapse by prospective reverse transcriptase- polymerase chain reaction analysis of the PML/RARα fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter 'AIDA' trial

Daniela Diverio, Vincenzo Rossi, Giuseppe Avvisati, Silvia De Santis, Alessandra Pistilli, Fabrizio Pane, Giuseppe Saglio, Giovanni Martinelli, Maria Concerta Petti, Alessandra Santoro, Pier Giuseppe Pelicci, Franco Mandelli, Andrea Biondi, Francesco Lo Coco

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Abstract

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/RARα 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/RARα+ 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/RARα, 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 modal, 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/RARα 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.

Original languageEnglish
Pages (from-to)784-789
Number of pages6
JournalBlood
Volume92
Issue number3
Publication statusPublished - Aug 1 1998

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Acute Promyelocytic Leukemia
Gene Fusion
Polymerase chain reaction
RNA-Directed DNA Polymerase
Tretinoin
Reverse Transcriptase Polymerase Chain Reaction
Idarubicin
Consolidation
Multicenter Studies
Fusion reactions
Genes
Recurrence
Polymerase Chain Reaction
Bone
Salvaging
Chemotherapy
Monitoring
Dilution
Assays
Sampling

ASJC Scopus subject areas

  • Hematology

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Early detection of relapse by prospective reverse transcriptase- polymerase chain reaction analysis of the PML/RARα fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter 'AIDA' trial. / Diverio, Daniela; Rossi, Vincenzo; Avvisati, Giuseppe; De Santis, Silvia; Pistilli, Alessandra; Pane, Fabrizio; Saglio, Giuseppe; Martinelli, Giovanni; Petti, Maria Concerta; Santoro, Alessandra; Pelicci, Pier Giuseppe; Mandelli, Franco; Biondi, Andrea; Coco, Francesco Lo.

In: Blood, Vol. 92, No. 3, 01.08.1998, p. 784-789.

Research output: Contribution to journalArticle

Diverio, Daniela ; Rossi, Vincenzo ; Avvisati, Giuseppe ; De Santis, Silvia ; Pistilli, Alessandra ; Pane, Fabrizio ; Saglio, Giuseppe ; Martinelli, Giovanni ; Petti, Maria Concerta ; Santoro, Alessandra ; Pelicci, Pier Giuseppe ; Mandelli, Franco ; Biondi, Andrea ; Coco, Francesco Lo. / Early detection of relapse by prospective reverse transcriptase- polymerase chain reaction analysis of the PML/RARα fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter 'AIDA' trial. In: Blood. 1998 ; Vol. 92, No. 3. pp. 784-789.
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abstract = "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/RARα 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/RARα+ 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/RARα, 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 modal, 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/RARα 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.",
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AU - Avvisati, Giuseppe

AU - De Santis, Silvia

AU - Pistilli, Alessandra

AU - Pane, Fabrizio

AU - Saglio, Giuseppe

AU - Martinelli, Giovanni

AU - Petti, Maria Concerta

AU - Santoro, Alessandra

AU - Pelicci, Pier Giuseppe

AU - Mandelli, Franco

AU - Biondi, Andrea

AU - Coco, Francesco Lo

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N2 - 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/RARα 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/RARα+ 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/RARα, 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 modal, 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/RARα 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.

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