I went thru it in detail. It doesn't qualify by my def as easy and fully coherent but plenty of info. Here are my notes:
ashpublications.org/bloodad...
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Daliah trial notes
Key focus is DNMT3A mutation and Uniparental disomy (UPD, “a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent.”)
SUMMARY OF my SUMMARY:
DNMT3A is most associated with non-CHR (Complete Hem Response)
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Prevalence of DMNT3A: This should be laid out clearly for easy reading, but I find it buried and confusing. See qualifier below, but best I can tell:
16% had DMNT3A before therapy, and 7.4% had emergent DMNT3A. Emergent is likely amplification of very small baseline DMNT3A. (I had DNMT3A in my NGS nexgen sequencing, it showed not detected, but how sensitive is our NGS?) .
(see qualifier below) INF leads to 4% probability of having DMNT3A emerging while HU is 1.5% probability
CHR correlates to better AB reductions.
CALR is less responsive to INF AB reductions and HU does not give CHR.
-Are there CALR members here on HU with CHR?
UPD relates to higher AB baseline and better INF AB response. UPD is not found in ET. If your AB is very high, UPD is more likely and we do see members with great AB reductions for example from 80% baselines.
TET mutation alone had odds ratio of 3.03 for prior stroke. TET2, DNMT3A, or ASXL1 + Older Age had this odds ratio of 5.2.
Separately (not discussed in this report) if you search for DNMT3A and supplements NAC and/or Curcumin, there seems to be some positive connection to helping with DNMT3A.
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Details
Misc info:
Homozygous is equivalent to Uniparental disomy (UPD) This study reproduced prior finding that Homozy response is better to INF than Heteorzy. Homozy associates with higher AB.
CALR had lower AB
2-3% of PV is Exon 12.
~10% MPNs are triple neg
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Concomitant (Non-drivers):
are in > 50% of MPNs and increase with progression
TP53 relates to DNA damage response (Unrelated to this study, P53 may benefit from Curcumin and/or NAC.)
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Worse outcomes,
Which ones, how many, and order acquired affect prognosis
<<A subset of patients achieve molecular remissions and normalization of the bone marrow after long-term (INF) treatment>> with some sustained after quitting INF, HU never does this.
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Uniparental disomy (UPD, I believe this is homozygous) is both genes of a pair are from one parent rather than the usual one from each parent. 28% of pts had this type Jak2 and allele burden (AB) was higher with UPD (48 vs 15%) This is not commonly checked in our allele tests but seems relevant to INF effectiveness.
3 most common concomitant mutations are TET2 (24%), DNMT3A (16%), and ASXL1 (10%).
Jak2 UPD relates to higher HCT, Neut, lower PLT.
No ET pts had UPD. I’ve seen this before also.
Triple neg most common in ET and most likely in younger pts. (age 44 vs 64)
ASXL1 is associated with Jak 2 phenotype
TET2, DNMT3A, or ASXL1 associate with older age and major thrombosis and esp prior stroke (odds ratio 5.2) this is very strong correlation when both age and these mutations are present.
TET alone had odds ratio of 3.03 for prior stroke.
Dosing of Pegasys is higher than for PegIntron, typically 45 vs 35 mcg.
Treatment related toxicity and discontinuation were highest with IFNα-2b (PegIntron) , 38% then 30% for IFNα-2a, (Pegasys) and HU was least at 8%. Note re Ropeg below.
As in prior post, IFNα-2a (vs 2b) had the best CHR and 1 month faster CHR (4.9 vs 6 months)
All pts retain some AB. VAF (variant allele frequency or allele burden, AB) decreased in 94% of pts on INF and 75% of HU.
AB decreased 5% in HU, 11% in INF. These are smaller changes than seen with the Ropeg trials. But similar in relative effect (INF better than HU) See other notes on Ropeg study length.
CALR VAF pts had decrease in similar proportions with HU and INF, but reductions were less than for Jak2, CALR -- 2% HU vs 4% INF.
Jak2 UPD had highest start AB and most reduction (49-17%) vs no UPD (15-8%) With HU it was opposite, UPD had less AB reduction (44-30%) than no UPD (22-8%) But HU is less likely to have this durable effect based on other studies.
Treatment emergent mutations in decreasing order DNMT3A, 39%, followed by TET2 11%, ASXL1 8%, PPM1D 8%, and TP53 8%.
VAF of the emergents was 1.5%, and near all in Jak2 pts.
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Data on DMNT3A is confusing and hard to follow.
Table S11shows at baseline 16% pts had DMN3TA. (table S14 matches)
Table S18 shows 10/135 (7.4%) had emergent DMNT3A.
INF vs HU is confusing but seems 61% vs 21% had DNM emergent. These should add to 100% but don’t.
Taking these numbers as is, having DMNT3A before therapy is much more likely than acquiring it during therapy. INF leads to .074 x 0.61= 4% probability of having DMNT3A emerging while HU is 1.5% probability. If this is in the report elsewhere I’d love to know.
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CALR had best CHR, 37% of pts, vs 23% of Jak2.
On HU, CHR strongly correlated to AB reductions. CHR gave AB 25-8%. No CHR gave 30-26%.
Similar results in INF CHR gave AB 29-7%, no CHR gave 27-14%.
CALR had minimal AB reductions for any CHR status. CALR on HU had no CHRs. (any CALR members here on HU with CHR?)
CHR is more likely with INF and without emergent mutations. (INF=51%, HU =22%)
DNMT3A is most associated with non-CHR.
<<we believe it is highly likely that treatment-emergent DNMT3A mutations were preexisting at baseline and selected for with IFNα therapy.>>
<< the majority of DNMT3A mutations found in MPN (and in this study) are heterozygous missense mutations that do not result in complete loss of DNMT3A function>>
Broken DNMT3A leads to more broken Jak2 <<Dnmt3a loss induced aberrant self-renewal of Jak2-mutant hematopoietic stem cells>> .
They note that his study went only to 24 months while ContiPV for Ropeg showed strong allele benefits at 60 months.
Also, Ropeg is better tolerated << Notably, ropeg, which is dosed every 2 weeks, seemed to be well tolerated in the CONTINUATION-PV trial,64 in contrast to our study, in which 34% of the IFNα–treated patients discontinued study medication for toxicity within 24 months, despite a low-dose regimen.>>
They suggest preventative INF therapy to prevent MPN in Jak2+ for pre/non MPN pts who have the mutation but not the disease.
Update on MPN Status and other items
