Prospective molecular monitoring of BCR/ABL transcript in children with Ph+ acute lymphoblastic leukaemia unravels differences in treatment response
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Published on: March 5, 2018
Giovanni Cazzaniga1, Marina Lanciotti, Vincenzo Rossi
1Centro Ricerca M. Tettamanti, Clinica Pediatrica Università di Milano Bicocca, Monza, Italy.
Insights
Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL) in children is heterogeneous. Monitoring minimal residual disease (MRD) with RT-PCR reveals distinct patient subgroups, aiding treatment response prediction.
Area of Science:
- Pediatric Oncology
- Hematology
- Molecular Biology
Background:
- Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL) in children is a high-risk subgroup with frequent treatment failure.
- Previous studies suggest heterogeneity in treatment response within this group.
Purpose of the Study:
- To prospectively monitor minimal residual disease (MRD) in children with Ph+ ALL using RT-PCR.
- To evaluate the prognostic implications of BCR/ABL fusion transcript clearance during intensive chemotherapy.
Main Methods:
- Prospective RT-PCR monitoring of BCR/ABL fusion transcript in Ph+ ALL children enrolled in the AIEOP-ALL-95 protocol.
- Analysis of 27 patients, categorizing responders based on prednisone/methotrexate pre-phase treatment.
Main Results:
- Poor responders (PPR) consistently showed BCR/ABL positivity and all died of disease progression.
- Good responders (PGR) exhibited heterogeneity, with three subgroups identified based on Ph+ cell clearance within 5 months.
- RT-PCR monitoring demonstrated prognostic value in predicting treatment outcomes.
Conclusions:
- Minimal residual disease monitoring via RT-PCR is crucial for stratifying Ph+ childhood ALL patients.
- Chemotherapy's ability to reduce the leukaemic clone, as assessed by MRD, has significant prognostic implications for treatment strategies.
Abstract:
Children with Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL) represent a subgroup at very high risk for treatment failure, despite intensive chemotherapy. However, recent retrospective studies showed that Ph+ childhood ALL is a heterogeneous disease with regard to treatment response. We have prospectively monitored, by reverse transcription polymerase chain reaction (RT-PCR) during follow-up, the presence of the BCR/ABL fusion transcript in Ph+ ALL children diagnosed in the Italian multicentre Associazione Italiana Ematologia Oncologia Pediatrica ALL-AIEOP-95 therapy protocol. To our knowledge, this is the first report on the evaluation of minimal residual disease (MRD) in childhood Ph+ ALL prospectively enrolled in an intensive, Berlin-Frankfurt-Munster (BFM)-type treatment protocol. Twenty-seven of 36 (75.0%) Ph+ patients consecutively enrolled into the high-risk group of the AIEOP-ALL protocol between May 1995 and October 1999 were successfully analysed. Twenty were good responders to the pre-phase of prednisone/intrathecal methotrexate treatment (PGR) and seven were poor responders (PPR). Within the PPR group, the RT-PCR monitoring constantly showed positivity for the BCR/ABL fusion transcript and all the patients died of disease progression. In contrast, highly sensitive qualitative RT-PCR monitoring revealed heterogeneity within the PGR group of Ph+ childhood ALL patients. Three different subgroups could be defined, according to the clearance of Ph+ cells within the first 5 months of treatment. This provides useful information on the capability of chemotherapy to reduce the leukaemic clone, with prognostic implications.
