Rituximab for AA/PNH?

[TonyBegg]

Karin has had PNH (39% clone) for 23 years. July 5th this year she desperately needed RBC and platelet transfusions for the first time (was yellow from bilirubin a break-down product of hemoglobin). We are trying Papaya Leaf extract to stabilize the thrombocytopenia (early days yet but platelets stable at 17000 this week and last week). LDH is 630, neutrophils 0.75 x 10^9 / Liter, normal marrow cellularity. Have seen two case studies in which Rituximab dramatically reduced/eliminated the PNH clone, one was AA/PNH and the other was non-Hodgkin's Lymphoma/PNH (where Rituximab was used with heavy chemo). Dr Brodksy at Johns Hopkins did an in vitro study of Rituximab and PNH B-cells - cytotoxicity of Rituximab is higher for PNH B-cells because of absence of GPI-anchor, but he does not see it as a treatment for PNH. T-cell suppression tends to favor the PNH clone but the AA/PNH case study author suggests the opposite is the case for B-cells. Another paper suggests that persistent B-cells can trigger the T-cells that cause autoimmune diseases like AA. There has been a Phase II trial for Rituximab and moderate AA (NCT 00229619) although I cannot find results for it. Would be great if treating the AA with this not-so-toxic regimen (Rituximab) also put the PNH into remission. Q. Does anyone out there know anything about this treatment for AA/PNH?? I am aware of Eculizumab but that does not treat the thrombocytopenia and can lead to an increase in the PNH clone because it stops lysis of PNH cells, and is a lifetime commitment whereas Rituximab involves short courses with gaps in-between - only 2 in the AA/PNH case study. Of course if thrombosis is occurring you had better be on it!

[curlygirl]

Tony,
This is very interesting. My son has SAA with a 19% PNH clone. He had ATG in July and is on Cyclosporine, we are waiting to see if it works. I have always had in the back of my head that his SAA may be B rather than T cell related. I.e. rather than his T cells being the problem that his T cells are reacting to a problem being caused by his B cells. The reason I say this is that two years ago my son had a common childhood B cell autoimmune response to some unnammed virus, he had Henoch–Schönlein purpura (HSP). He got the purpura and the swelling that goes along with it, but recovered from it fine in less than a month with no lasting complications. Then last summer he had a very sight relapse - had a few spots on his legs but not the swelling or arthritis. Recovered nicely in a couple of days. Then he got sick in April (looking back probably started in March) with a nasty upper respiratory virus (he tested positive for Rhino-virus or enterovirus, the test didn't distinguish which it was) and came down with Aplastic Anemia. He began to recover on his own in May but then went downhill again, and when he did his viral symptoms from April came back. My suspicion is that his body has a B-cell overreaction to viruses. We went to three hospitals for consultations and each hematologist I talked to doesn't know of a connection between the two (HSP or AA) or why that would happen. Of course HSP is much more common than AA. I actually asked once why different auto-immune diseases caused by many of the same factors are treated with different drugs, e.g. Rituximab, Intravenous immunoglobulin (IVIG), etc. I would have liked to have tried Rituximab. At the same time I realize that our doctors are hematologists, not immunonogists, and luckily all of the doctors I've talked to are very good at treating AA patients, and really my son needed to be treated ASAP. But I probably need to talk to an immunologist at a large university, mainly for my own curiosity at this point since we already did the ATG.

[marmab]

Even though I am a hypo MDS/AA overlap case, both my regular doctors and second-opinion doctors feel that I am more in the SAA camp and are treating me as such. They all recommend BMT soon (I am really on the fence about it), but that is another story.

I am one of those people in whom ATG/CsA triggered hemolysis. Discontinuation of CsA, and administration of rituximab and prednisone stopped the hemolysis, and my hemoglobin rose to the mid-10s (highest # in years!) and has held there since 10/12. I have had four-week rounds of rituximab four times total in the past year, to try to "rein in" my immune system (B cell activity plays a role here?) when I have had autoimmune "episodes" (we think) out of the blue that make my plts plummet. The rituximab enables me to go a bit longer between plt tx, from every three days, for instance, to 8-11 days, which is particularly helpful as I need HLA-matched plts. That said, when I receive rituximab, I also usually get prednisone, so it's hard to say exactly what is going on biochemically, but I can't help but think that B cell activity does play a role in this disease. Basically the rituximab seems to work, but unfortunately not for long -- a month or two after each round my plts tend to bottom out quickly again. I am aware that many doctors feel that rituximab is not efficacious in the treatment of AA.

[TonyBegg]

Marmab. Have you tried Papaya Leaf Extract to help maintain your platelet levels. Karin is trying it (Herbal Papaya is the company although Iowa Select Herbs makes them too, capsules 600mg of Papaya Leaf Extract (not just papain), 2 in morning and 2 at night) and over three weeks the platelets have been 17000, 17000, 16000, 15000, in CBCs taken once a week, so not maintaining but not plummeting as they were prior to taking the Papaya Leaf Extract. It is disappointing that you are having to take Rituximab so often, but the side effects are not too bad I suppose compared to other immuno-suppression regimes. If you look up immunological memory (to say a "bone marrow injury" in this case) it seems to be mainly carried by the B-cells which then present anti-gens to the T-cells and keep them active. There is some T-cell memory too but the papers focus on B-cells.

[curlygirl]

While reading again, I found these articles. They discuss cases where Hairy Cell Leukemia (HCL) mimics Aplastic Anemia. I thought it was interesting in reference to this post for three reasons: 1) HCL is often easily put into remission with one round of chemo, so is easier to treat than most cancers. Aplastic Anemia often also responds to one round of immunosuppression; 2) HCL sometimes presents first as Aplastic Anemia; & 3) refractory cases of HCL are treated with Rituximab, and sometimes Alemtuzumab (Campath) and some people on the board had success with the NIH Campath trial for refractory Aplastic Anemia:

Aplastic anemia terminating in hairy cell leukemia. A report of two cases. http://www.ncbi.nlm.nih.gov/pubmed/6697293

Persistent remission after immunosuppressive therapy of hairy cell leukemia mimicking aplastic anemia: two case reports. http://www.ncbi.nlm.nih.gov/pubmed/12774930

In particular, I thought you would find the last sentence of the second citation interesting:

"Sustained improvement of hematopoiesis in such B-cell malignancies after ATG/ ALG therapy suggests that the mechanisms underlying successful immunosuppressive therapy for aplastic anemia may involve B-cell suppression, inhibiting hematopoietic stem cells."