Authors' objectives:

The Australian Health Technology Advisory Committee (AHTAC) completed a review of nucleic acid amplification (NAA) technology in 1997. The use of polymerase chain reaction (PCR) was recommended for diagnosis and monitoring of acute lymphoblastic leukaemia (ALL) in that report. MSAC was approached by the Pathology Services Table Committee (PSTC) to review the use of NAA in ALL as well as the other indications considered in the 1997 AHTAC report. MSAC has completed reviews of PCR in the diagnosis and monitoring of acute promyelocytic leukaemia (APL) and acute myeloid leukaemia (AML). The NAA supporting committee developed the following questions for ALL:

- Do appropriately targeted RT-PCR assays increase the proportion of patients who are recognised to have a specific disease entity (BCR-ABL positive ALL) that defines a specific therapeutic strategy? - Does repeated qualitative or quantitative PCR testing post-treatment (chemotherapy or transplant) in ALL for BCR-ABL influence management? - Does repeated qualitative or quantitative PCR testing for BCR-ABL in ALL predict haematological relapse, especially post-transplant?

Detection of other cytogenetic abnormalities has important prognostic and therapeutic implications so PCR testing is a supplementary rather than a replacement test.

Authors' results and conclusions: Diagnostic accuracy in ALL diagnosis: PCR was evaluated for its ability to correctly identify patients with BCR-ABL ALL at presentation. The 27 studies identified and included were all case series thus constituting level IV evidence. The sensitivity of cytogenetic and PCR testing was high for both abnormalities although preparation failure for cytogenetic testing reduced the value of this test. PCR testing detected extra cases not identified by cytogenetic testing. The overall proportion of adults with ALL who were PCR positive, cytogenetic negative was 10.1 per cent (95% CI 8.2, 12.4) and of children was 1.0 per cent (95% CI 0.6, 1.7). PCR was estimated to have a sensitivity of 94.8 per cent (95% CI 92.6, 96.5) and specificity of 97.3 per cent (95% CI 92.4, 99.4). Overall, PCR testing is estimated to detect an additional eight cases per year that are cytogenetically negative. All tests, including cytogenetic testing, are considered to be imperfect reference tests due to their imperfect sensitivity, so the finding of PCR positive and cytogenetic negative cases is not unexpected. For instance, all alternative tests require the presence of a higher proportion of abnormal cells to detect BCR-ABL ALL than PCR. Cryptic molecular rearrangements are also not readily resolved at the cytogenetic level. Therefore, the discrepant proportion probably represents the incremental benefit of adding PCR testing to cytogenetic testing although the benefit may be over estimated due to the low quality of the studies included. Diagnostic accuracy in ALL monitoring: The PCR was evaluated for its ability to predict subsequent cytogenetic and haematological relapse in the monitoring studies. Six studies were eligible for the review of monitoring for BCR-ABL ALL. All were case series constituting level IV evidence. Five of the six studies (85 per cent) used qualitative PCR methods. The pooled diagnostic odds ratio (DOR) from these six selected studies was 4.7 (95% CI 2.2, 10.3). A DOR of 4.7 is consistent with, for example, a sensitivity of 80 per cent and specificity of 54 per cent.

Authors' recommendations: MSAC recommended that there is evidence of safety for PCR testing in the diagnosis and monitoring of BCR-ABL gene rearrangement in patients with acute lymphoblastic leukaemia (ALL). The total number of patients is small; there is limited evidence of effectiveness in diagnosis and monitoring. Additional evidence of cost-effectiveness is unlikely to emerge. MSAC supports public funding in these circumstances.

Authors' methods: Systematic review

Project Status: Completed

URL for project: http://www.msac.gov.au/pdfs/reports/msacref9aiv.pdf

Year Published: 2004

English language abstract: An English language summary is available

Publication Type: Not Assigned

Country: Australia

Organisation Name: Medical Services Advisory Committee

Contact Address: MSAC (MDP 107), GPO Box 9848, Canberra, ACT 2601, Australia. Tel: +61 2 6289 6811; Fax: +61 2 6289 8799.

Contact Name: msac.secretariat@health.gov.au

Contact Email: msac.secretariat@health.gov.au

Copyright: Medicare Services Advisory Committee (MSAC)