Uncommon JAK2 double mutation

[blue_reader]

I was diagnosed with PV (high RBC and platelet counts) back in 2020. I have the JAK2 V617F mutation. My father, in his late 80s now, has been having phlebotomies for the last 20 years for isolated erythrocytosis. He had a JAK2 test done around the time the JAK2 test became available, but it came back negative at the time. As a result, he never had a diagnosis of PV and his threshold for needing a phlebotomy has always been set at a hematocrit of 0.50 or higher. For a number of years now, he's had to have a phlebotomy every 2 months.

We finally had him tested again and it turns out that he has an uncommon JAK2 L611S/V617L double mutation. The VAF for each is 15%.

An article about this double mutation can be found here:

frontiersin.org/journals/on...

My father has elected to continue with phlebotomies using the same threshold. Trying to get down to a hematocrit of 0.45 or lower would be challenging at this point. He also takes an anticoagulant.

Two other members of my father's extended family also had an MPN, so it's helpful to have his own diagnosis finally confirmed for family medical history purposes.

[ainslie]

it may not be as difficult as you think to get Hct down to under 45, it may initially but as the Hct comes down iron deficiency increases (that’s the design) and he may not have a issue.

Alternatively cyto drugs may be a plan to discuss with your Haem.

[blue_reader in reply to ainslie]

Thanks for the reply, ainslie. My dad does already find the phlebotomies every 2 months trying and he is very tired, partially because of these frequent-enough procedures. Unfortunately, cytoreductive drugs aren't a great option since his platelet count is on the low side. Also, he has a history of skin cancers, including a melanoma, so hydroxyurea is essentially off the table. Rusfertide might have been a good option for him, but it's not available yet. At the age of 88, he is comfortable maintaining his current treatment.

[hunter5582]

You and your family are part of the 7-10% of us with a Familial MPN. My daughter and I both have the JAK2v617f mutation. For me it started with ET diagnosed in my 30s which later progressed to PV. My daughter seems to be on the same path. Other member of the family going back several generations have been diagnosed with lymphomas and other blood cancers. Familial MPNs are a real issue that is under active investigation. It is like a multi-factorial issue. One of the known issues is the JAK2 46/1 GGCC predisposing haplotype. This predisposition to acquire the JAK2 mutation can be inherited.

It is a bit surprising that your father would still be on a venesection-only protocol. His would seem to be a case where cytoreduction is indicated. Given his profile, HCT < 50% is likely too high of a target. Venesections alone may not be enough to reach the HCT < 45% target in his case. Options for treating PV have improved greatly. We have moved beyond hydroxyurea and now have Besremi and Jakafi available. Pegasys will soon return to the market as well. As has been demonstrated in recent studies like MAJIC-PV, these newer options can have a superior outcome in terms of survival and quality of life. Moreover, Jakafi and Besremi have been shown to reduce the JAK2 allele burden.

I was refractory to and intolerant of hydroxyurea. I tried venesection-only for a while but the side effects of the venesection-induced iron deficiency were worse than the PV symptoms. I have done much better on the interferons, Pegasys then Besremi. My quality of life has improved significantly and my JAK2 VAF has reduced form 38% to 10%. I feel better now than I did 10 years ago.

I would suggest to your father that he consult with a MPN Specialist familiar with the PV treatment options now available. He may find a treatment plan that would suit him better. here is a link to MPN expert docs. mpnforum.com/tsr-the-list/

Wishing you and your family all the best.

[blue_reader in reply to hunter5582]

Thanks for the reply, Hunter. Interesting information about the JAK2 46/1 GGCC predisposing haplotype given the MPN link in both of our families. As I indicated in my reply to ainslie above, although it would be good to get my dad's HCT under 0.45, he does already find the phlebotomies every 2 months trying. He is very tired, partially because of the fairly frequent phlebotomies. Unfortunately, cytoreductive drugs aren't a great option since his platelet count is on the low side. Also, he has a history of skin cancers, including a melanoma, so hydroxyurea is essentially off the table. Rusfertide might have been a good option for him, but it's not available yet. At the age of 88, he is comfortable maintaining his current treatment.