IFNα therapy has been shown to deplete the MPN HSPC pool through activation and exit from a quiescent state and induction of differentiation. These biological effects seem to be influenced by driver mutation status, JAK2V617F homozygosity, and dosing approach. The clinical implication of the findings from Mosca et al is shown here in the context of other recognized predictors of IFNα outcome. The goal of therapeutic intervention in ET/PV is primarily thrombotic risk reduction, which is believed to be achieved through attainment of a CHR and secondarily disease course modification through a CMR. CHR, complete hematologic remission; CMR, complete molecular remission; VAF, variant allele frequency.
« Whether the molecular observations of Mosca et al can be effectively integrated into routine care of patients with MPN in determining appropriate patient selection and dosing of IFNα based on genotype requires validation in a prospective trial. For example, should patients with essential thrombocythemia (ET) and polycythemia vera (PV) harboring JAK2V617F be treated with a continued upward titration of IFNα to a maximally tolerated dose to optimize the effect on the MPN HSCs and maximize the opportunity to attain a molecular response? Conversely, should ET patients harboring CALR type 1 mutation be maintained on lower doses with a different expectation of molecular response kinetics?
I see the general idea is we should use allele status and goals to a greater extent in selecting treatments. I totally agree, esp now that it is being accepted as an option. Thanks for the reference.
A key note below:
<<these results indicate that progenitor cells harboring
homozygous JAK2V617F were more susceptible to lower doses of IFNα than
heterozygous cells, and CALR type 2 mutant-bearing progenitors were more
effectively targeted than type 1–positive cells>>
The JAK2 result above may follow from Homozy having higher allele burdens than Heterozy, ie there is more allele to reduce from. Homozy seems to relate to more disease burden. In PV Homozy is associated with pruritus.
So maybe Homozy not a great way to wish for better INF effects.
I don't think homozygous status is studied too often, my extensive genetic list didn't have this. But it seems less common than Heterozy and is even more rare in ET.
I think I figured out what Homozy vs heterozy is:
<<People who are heterozygous for the ... gene have one unaffected copy of the gene (from one parent) and one affected copy of the gene (from the other parent). >>
Thanks. It seems research into 'fine tuning' interferon is working at a pace -I haven't heard of any similar research with hydroxy. I wonder if resources are all aligning behind Interferon now as the treatment of choice.
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