AA-PNH Clone and ATG

[NLJabbari]

Hello All! My son was dx'ed in 2004 w/ SAA. He was stable until 2012 when he was dx'ed with a 20% PNH Clone.
His Hgb and WBC are decent, but his HGB is in the low 8's. He has only had one round of ATG and I thought that perhaps he would benefit from a second round of ATG. His new Hem/Onc Adult Medicine doctor does not think he would benefit and thus is recommending MUD BMT.
Thus far we've only found 2 potential 9/10 matches that are CMV pos. My son is CMV neg.

I'm confused as to why his doctor doesn't think a second round of ATG would be helpful for him.

Anyone have experience with a similar situation or know anything about this?

Thanks

[evansmom]

Hi Norma,

Sorry to read this. To my knowledge, PNH is a result of red cell wall defect which is acquired but not immune mediated. Therefore lowering the immune response with ATG or other immunosuppressants will not work.

You may recall Evan's donor was 9/10 CMV+and he did very well. The doctor had Evan on an IV antiviral starting the day of transplant and kept him on that, switching to oral, for several months post BMT. Also, Evan received weekly IVIG for about a months post BMT, then monthly IVIG until 8 months post. So there are measures they can take, don't spend time worrying about the CMV+. What's most important is where the mismatch is. If it's on A, B, or C, this can have potentially serious implications (GVH or graft failure) but if it's on DRB1 or DQB1 (Evan's was on the allele of DQB1), there is less worry for complications.

While it is a serious decision, I would very much consider a BMT. Yashar has only had one round or ATG, and hopefully has had less than 20 RBC transfusions and few platelet transfusions. He is young and otherwise healthy with this stupid AA hanging over his head and now the PNH. This could be his cure, once and for all. Plus, you have the added benefit of Yashar being old enough to have a say in the decision making, which I would think would help.

Best wishes to Yashar always.

[NLJabbari]

Hi Nicole, Thanks for your reply. I always appreciate your comments as I know you've been down this road and have followed many of the same people that we've been fortunate to have followed along this journey. I value your feedback. It is good to know what markers to be aware of. Thanks for sharing this important information.

I believe you are absolutely right and have pretty much hit the nail on the head as to what "our" thoughts are and how this whole child/adult transition is evolving.

Going from Pediatric Hem/Onc Medicine to Adult, really threw us for a loop as we were transferred during relapse and basically to the "next available doctor!" Very disappointing...very different type of care. In Pedi, the doctors/staff guide you carefully, in Adult Med unfortunately not so much. Fortunately, we switched doctors and are much more comfortable with the "new doc" and the manner in which she's proceeded to treat Yashar.

Currently, we are once again awaiting word on a new appointment to meet with the BMT team at Stanford. We had already met with them last Summer and that unfortunately didn't go well. It seems that with the switching of Dr's, the BMT initial talks/meeting sort of evaporated into thin air or were put in the back burner...very strange.

I'm trying my best not to leave any stone unturned...trying to explore options. I've been keeping up with latest on "Healio/HemOnc Today" and there seems to be a lot on the horizon...the latest med article, "Aryl hydrocarbon receptor may play role in red blood cell development" Very interesting reading sounds promising, but perhaps not for us this late into this whole ordeal...

Overall, Yashar IS very tired of living with the ups and downs of the numbers. Thankfully, he hasn't lost his sense of humor and he LOVES teasing me that the decision will by my call! I know he's just kidding as he tells me that IT will be his decision.

I believe Yashar has received a total of about 25 RBC tx's and a few "Leukocyte Reduced" units of platelets in total. But, I am also concerned about his long-term use of CsA though.

We both are just so tired...

[curlygirl]

I was just talking about this with my son's doctor on Friday's visit. My son had about a 20% PNH clone in May and they drew blood to see if it increased on Friday. I asked if the ATG/Cyclosporine will work given the PNH and our doctor said she thinks it will, because this kind of PNH is secondary to the Aplastic Anemia. It gets confusing because PNH is also an actual primary disease that can also depress the bone marrow. We've had a tussle with insurance where they don't want to pay for the ATG/Cyclosporine (my son's first dose) so his treatment has been delayed, but hopefully we will start shortly. I know it is a tough decision and I will struggle with it, too, if/when it happens. From this article it looks like the medical community has gotten much better at MUD transplants over the years. I'm less scared of it than I was in the beginning but I still don't want my son to have to do it :-(

http://bethematch.org/Physicians/Unr...bling.aspx#SAA

Severe aplastic anemia

Matched related donor hematopoietic cell transplantation is the treatment of choice for pediatric patients with severe aplastic anemia (SAA). A 2006 study of 36 pediatric SAA patients demonstrated no significant difference in four-year overall survival between related and unrelated donors (93% vs. 89%, respectively; p=ns). [19]

Good luck with your decision! I think in your case both decisions would be a right one.

[NLJabbari]

Thanks Curlygirl! If you don't mind me asking, how old is your son and what was his initial dx'es? Also, where is he being treated?

You're absolutely right in that it is very confusing. We switched Drs in-between the time he relapsed and the 20% PNH clone dx'es via Flow Cytometery blood test. I could have sworn the first Dr. said the BMB pathology report found no evidence of Cytogentic abnormalities? I have to go back and reread this report. To the best of my knowledge, this 20% clone has thankfully not evolved in the last year. I too will have to ask my son's Dr. about this and I will bring it up at the upcoming AAMDS Conference in San Francisco/Santa Clara.

Yes, BMT is a scary thing, but like you said-- they have gotten better and we're hearing a lot of success stories. As it is right now, my son is leaning towards transplant should they find a good willing donor for him.

Thank you so much for your input, it's greatly appreciated.

Please let me know how your son is doing and I pray his Insurance issues will clear up really soon and he can proceed with treatment.

[curlygirl]

NLJabbari, we're in Maryland. We've talked to two hospitals in Maryland and one in DC and they all agree that the PNH clone in association with AA doesn't mean that they ATG/Cyclosporine won't work. I'll let you know when we have a date to start the ATG/Cyclosporine. Hopefully next week. Thanks!

[NLJabbari]

Thanks Curlygirl! Please do keep us posted on your son's progress.
BTW, his particular situation reminds me of a child we met back in 2005 (?) You might want to read her journal as you might see similarities.

http://www.caringbridge.org/visit/an...r/journal/49/0

Take care

[curlygirl]

NLJabbari, The doctors worked it out with insurance, so we go in on Tues. morning for the ATG/Cyclosporine! I'll let you know in a few months how everything looks. Let us know what you and your son decide re: a BMT. Take Care!

[TonyBegg]

I cannot comment about the advisability of ATG/Cyclosporine for AA with PNH but I can clarify what PNH is (mother of my kids K has had it for 23 years and clone size is 35%). PNH is considered a secondary disease responsible for hemolysis (destruction of RBCs via the liver) and thrombophilia (tendency to clotting). Usually there is a primary disease (often AA or MDS) which causes pancytopenia (low counts for all blood components: RBCs, WBCs, and platelets). It is thought that PNH might actually be a response to the primary disease to prolong life. PNH is caused by an acquired mutation of the PIG-A gene of the hematapoietic (sp ?) stem cells of the bone marrow. This causes the blood components to lack (at least) two complement inhibitors (CD55, CD59) which happen to be the two inhibitors the HIV virus mimics to evade lysis by complement (the complement system is the non-specific immune system due to special proteins in the blood). RBCs are mostly affected by complement lysis when the complement system is activated (this can happen with sickness say due to viruses, with stress, allergies, pregnancy and poorly administered blood transfusions - say with washed platelets that are thereby activated as happened with K). Platelets are not lysed as such but can become deformed or activated in some way that makes them prone to clumping (clotting). This could also be a side-effect of the RBC lysis which starves the blood of nitric oxide. Recent research suggests that when the bone marrow is stimulated to counteract the pancytopoenia of the primary disease (AA or MDS) the PNH clone stem cells leave the marrow preferentially because they are slippier. The RBC lysis causes Coca-Cola colored pee, a rise in LDH (Lactate DeHydrogenase) which can be measured by a blood test to show the degree of lysis, and since the RBCs are destroyed by the liver can lead to jaundice (yellow skin, liver pain). So maybe the ATG/Cyclosporine needs to be administered carefully with something to inhibit the complement system from activating. Transfusions are often done with Tylenol and an anti-histamine to suppress complement reactions. There may be other ones the docs can administer.

[curlygirl]

Thank you, Tony, that is interesting to know! My son had dark urine and a high bilirubin level for the week following ATG. They tested his urine at the next visit but his urine was getting normal colored by then. Based on his hemoglobin levels he didn't seem to be having hemolysis, but it definitely could have been him shedding some PNH cells after ATG (which would be hopeful!). He did have significant hemolysis once after a platelet transfusion. At the end he mottled all over - the mottling continued on and off for two days and in the matter of four days his hemoglobin went from the 9s into the 5s (which is a fast loss for him). They thought it was a case of secondary cold agglutinin brought on by his high level of lymphocytes on that visit (90%) which it certainly could have been, but it could have been the PNH, also. Luckily it's been the only time he had a reaction to a blood or platelet product and showed any hemolysis.

Take care and good luck with K's tratment!