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

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 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/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. © 1998 by The American Society of Hematology.

Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single PML-RARA Fusion Gene

“…As a target for MRD, the ready detection of PML-RARA transcript at the post-consolidation phase by modern PCR-based techniques could improve outcome prediction through the rapid accurate assessment of the response to treatment [143,144]. Several retrospective studies have pointed out that molecular relapse is an independent prognostic factor which precedes the reappearance of APL blasts [84,[145][146][147][148][149][150]. Successive studies established that negative longitudinal PCR assays performed on bone marrow after completing therapy are strongly related with long-term remission.…”

Guidelines on the management of acute myeloid leukaemia in adults

“…For patients with PML – RARA ‐positive APL, a key goal is achievement of PCR negativity in the bone marrow using assays that detect one leukaemic cell in 10 4 cells. Patients with persistent disease or molecular relapse, confirmed in two consecutive assays after completion of consolidation, will invariably relapse unless additional therapy is given (Diverio et al , 1998). The optimal management for such patients is uncertain although a matched donor stem cell transplantation (SCT) can be curative (Lo Coco et al , 2003).…”

Minimal residual disease in chronic lymphocytic leukaemia: is it ready for primetime?

“…The importance of monitoring MRD has been demonstrated in other haematological malignancies, such as acute prolymphocytic leukaemia (APL) and chronic myeloid leukaemia (CML). In patients with APL, the presence of MRD is highly predictive of definite haematological relapse (Diverio et al, 1998). Both prospective and historical comparison studies have shown that patients re-treated at the time of overt haematological relapse have poor survival outcomes compared with patients who are re-treated at the time of molecular relapse (Lo Coco et al, 1999;Breccia et al, 2004).…”