JAK2V617F allele burden in polycythemia vera: burden of proof

[Manouche]

« The JAK2V617F variant allele frequency (VAF) is a key determinant of outcomes in PV, including thrombosis and myelofibrotic progression. Here, we critically review the dynamic role of JAK2V617F mutation burden in the pathogenesis and natural history of PV, the suitability of JAK2V617F VAF as a diagnostic and prognostic biomarker, and the utility of JAK2V617F VAF reduction in PV treatment »

ashpublications.org/blood/a...

[EPguy]

Good summary of current info. The 1st part is complex stuff. But some observations:

-As quantitative JAK2V617F testing has become sensitive to VAFs of <1%, virtually all patients with a clinical phenotype of PV harbor JAK2V617F (97%) or mutations in exon 12 of JAK2. This means more than 97% so that Jak2 negative PV is even more rare than we saw before.

-15-year myelofibrosis free survival < 50% VAF=100% >50%VAF =40% (old 2010 study but quite an effect)

-JAK2V617F CH vs JAK2V617F MPN. Both can have PV like blood counts. CH is related to the pre MPN CHIP. Some members have high counts but no Dx of MPN, this could be the fit.

-Clinical trials in PV must be carried out over at least a 5-year period to assess outcomes and their relationship to clonal dynamics

-JAK2V617F VAF reductions were more commonly associated with superior complete hematologic responses and spleen responses in both the RESPONSE-1 and PROUD-PV trials Both Rux and IFN have relation of CHR to VAF reductions. The IFN CHR-VAF connection is well covered in prior posts.

-...this interpretation (of VAF reductions on Rux) is confounded by the fact that ruxolitinib trials treated higher-risk (and higher median VAF) patients with PV So Rux may be even more effective for VAF reductions on lower VAF pts.

-in the interferon context, deeper molecular responses associate with longer disease remissions after discontinuation of therapy (I just reviewed a report putting this cutoff at <10%)

-proof is mounting that reduction of VAF is tied to not only blood count control but also thrombosis risk reduction and disease progression reduction

-Taken together, PV treatments that do not address clonal expansion of JAK2V617F and therefore do not reduce JAK2V617F VAF do not optimally address thrombosis or disease progression risk and represent missed opportunities for our patients Implicit by the authors is Plb and HU are not optimum.

[ainslie in reply to EPguy]

great info, and it’s good to see she mentioned (and you highlighted it) that the Rux patients were higher risk than the patients treated with Peg etc. The paper by Clair Harrison and Co presented at ASH 22 showed more than 50% of Rux patients got more than 50% reduction in VAF, I don’t think they were indicated as being high risk, strangely her paper used HU instead oh Peg as BAT for some reason.. This paper shows Peg gives better VAF reduction but as alluded to elsewhere , if they are able to tolerate it in the long term

[Manouche in reply to ainslie]

 «strangely her paper used HU instead oh Peg as BAT for some reason.. »

HU is still officially/scientifically the best available therapy for polycythemia vera.

[EPguy in reply to Manouche]

I think the BAT options in concept are rapidly expanding esp with the new data on Rux and quickly rising use of IFN. But this is really just the last year or even less that these are becoming "normal" practice for many practitioners.

[EPguy in reply to ainslie]

It seems the paper from Dr Harrison is a treasure of new info. Hope we can see it in some way.