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ESH ALL 2021 | Myeloid switch of B-cell precursor ALL subtypes

Ester Mejstříková, PhD, and Michaela Nováková, PhD, Second Faculty of Medicine, Charles University, Prague, Czech Republic, discuss a phenomenon, firstly described in 2005, in which a pediatric B-cell precursor acute lymphoblastic leukemia (ALL) subtype switches phenotype towards the monocytic lineage. The investigators observed that the monocytic switch is accompanied by the gradual loss of CD19. A better understanding of the subtypes prone to switch is increasingly important, especially as anti-CD19 therapies are introduced in the treatment protocols and the determination of minimal residual disease (MRD) by flow cytometry (FC) relies on B-cell markers. In a recent study, using exome and RNA sequencing, the monocytic switch correlated positively with three genetic subtypes: rearranged DUX4r, rearranged ZNF384, and PAX5-P80R mutation. Additionally, an important discordance between FC and PCR-determined MRD was found on day 15 in patients with mutated PAX5-P80R. On day 33, the MRD discordance was observed in all three subtypes. This interview took place during the 2021 European School of Hematology (ESH) 2nd Translational Research Conference on Acute Lymphoblastic Leukemia.

Transcript (edited for clarity)

Our project is focused on a very interesting phenomenon previously unexpected that B-cell phenotype is in the B-cell precursor of leukemia is during the chemotherapy in the very early phase, typically, during the corticosteroids pre-phase, change the phenotype to a monocytic lineage. It’s a phenomenon we know approximately since 2005, so it’s a very long story in our life. This phenomenon, especially in pediatric leukemia, is of 8% of all children, and especially in this era, when we have a B-cell targeted treatment, it’s very important to know about the phenomenon because in some patients it might be a cause of failure of this therapy...

Our project is focused on a very interesting phenomenon previously unexpected that B-cell phenotype is in the B-cell precursor of leukemia is during the chemotherapy in the very early phase, typically, during the corticosteroids pre-phase, change the phenotype to a monocytic lineage. It’s a phenomenon we know approximately since 2005, so it’s a very long story in our life. This phenomenon, especially in pediatric leukemia, is of 8% of all children, and especially in this era, when we have a B-cell targeted treatment, it’s very important to know about the phenomenon because in some patients it might be a cause of failure of this therapy.

It’s very interesting that the new subtype of leukemia, which was discovered a few years ago, DUX4 re-arranged, is one of the most frequent subtypes, which is doing this phenomenon of switching two a monocytic lineage.

And the other subsets like ZNF384. It is a much more rare subset and a lot of rearranged cases, it’s something known also from the previous times because it was rarely in the case reports observed previously.

It’s also one of the most practical outputs of this, because the leukemias, they lose the CD19 antigen, which is very important for B-cell monitoring, and we know that especially in the one sub-set PAX5-P80R mutated, the CD19 is lost very quickly, so already at day 15, we don’t see a CD19 on the blast. So, in these subsets, already very early it’s an important discordance between Flow Cytometry MRD and PCR MRD. And in DUX4 rearranged, the CD19, at least in part of the blast, is present on day 15. So on day 15 the correlations still are not too bad, but the discrepancy is most prominent on day 33. And in ZNS384 it is a mixture, we can say that at day 15, still, the correlation is possible, but at day 33, we have also seen the discordant cases between Flow Cytometry MRD and PCR MRD.

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Disclosures

Dr Mejstříková’s lab was involved in MRD assessment for Amgen

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