SOHO 2023 | The role of PCR and NGS-based MRD in Ph+ ALL
Nicholas Short, MD, The University of Texas MD Anderson Cancer Center, Houston, TX, describes how measurable residual disease (MRD) is measured using PCR and next-generation sequencing (NGS) in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Dr Short compares these two methods and comments on their value for treatment-related decisions. This interview took place at the Eleventh Annual Meeting of the Society of Hematologic Oncology (SOHO 2023) held in Houston, TX.
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Transcript (edited for clarity)
Historically, we really used PCR for BCR-ABL as our main MRD marker in Philadelphia chromosome-positive ALL. There are multiple studies showing that this is very prognostic in this disease, so particularly, patients need to achieve a complete molecular response ideally within three months of therapy to have good outcomes. There have been multiple publications on this, in fact there was one large analysis, it was a combined analysis from multiple institutions looking at patients who achieved a complete molecular response in Ph-positive ALL by about three months into therapy, and asked the question: do they benefit from transplant or not? And there was no benefit to transplant in terms of overall survival, which is of course the most important endpoint...
Historically, we really used PCR for BCR-ABL as our main MRD marker in Philadelphia chromosome-positive ALL. There are multiple studies showing that this is very prognostic in this disease, so particularly, patients need to achieve a complete molecular response ideally within three months of therapy to have good outcomes. There have been multiple publications on this, in fact there was one large analysis, it was a combined analysis from multiple institutions looking at patients who achieved a complete molecular response in Ph-positive ALL by about three months into therapy, and asked the question: do they benefit from transplant or not? And there was no benefit to transplant in terms of overall survival, which is of course the most important endpoint. So the conclusion of that is that we can use this MRD endpoint to identify patients who may not need transplant in first remission, which was historically the standard of care in Ph-positive ALL. Now we use MRD to decide on transplant in Ph-positive ALL. I think the next step now is that we have a better MRD test than the standard PCR for BCR-ABL. What we are using at our institution and in the US, which we have available, is a next-generation sequencing assay for the immunoglobulin or T-cell receptor gene rearrangements, which is sensitive down to 1✕10-6, or one out of a million cells. This looks at a different target than the PCR for BCR-ABL- it’s looking at these gene rearrangements. It suggests that it’s actually more specific for the actual disease than PCR for BCR-ABL. So, for example, there is about 20 to 30% of patients with Ph-positive ALL who still have persistent low-level PCR for BCR-ABL, but who are negative by this highly sensitive next-generation sequencing assay. And there’s now data to suggest that these patients who have low-level PCR but are NGS MRD negative, have just as good outcomes as those patients who are PCR-negative and NGS-negative. Now at our institution, we have actually switched to using both, but we rely primarily on the NGS MRD assay. We still do check PCR for BCR-ABL, but we do not use it as much for treatment-related decisions. I would say the only way the PCR is particularly helpful if we have it alongside an NGS MRD, is that I would be hesitant to stop a TKI in a patient with persistent low-level PCR, even if the patient is NGS MRD negative. But otherwise, we’re really deciding using the NGS MRD assay for our treatment decisions, such as transplant or CAR-T cells, et cetera.
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