DR RUPARD: This is a 58-year-old Hispanic female who is a Jehovah’s Witness and clearly declined any transfusion throughout the course of her care.

So she presented with profound fatigue that had been worsening over the past year or so. And came into the Emergency Department with this, kind of dragged in by her husband, and she had a white blood cell count of 3.7, hemoglobin of 4.1 and an MCVV of 99 with a platelet count of 258,000. And I will note that the platelet count actually ended up being elevated within a few days of this over 400,000.

So we did the usual work up: iron, B₁₂, folate studies, all within normal limits. And, of course, did a bone marrow biopsy. And I’m going to give you some specifics here, because it’s such an unusual case. So she had a hypercellular marrow with bilineage dysplasia, noted by our — we do have a hematopathologist at our facility who felt that this was concerning for myelodysplastic syndrome, sort of in the clinical setting. There was no increase in blasts. Her karyotype was normal, 46XX, and we did an MDS FISH panel, which was normal. No deletions. No hyperdiploidy, et cetera.

What was interesting is that she did have this background of 5% to 10% of CD138-positive plasma cells with kappa predominance and on flow had a very modest plasma cell population, 0.1% of events, but when we see any in-flow, of course that sets off the radar. And we did a JAK2 as well, and that was negative.

So because things came back essentially negative, we had a Tumor Board about this case and ended up treating her with aggressive erythropoietin. She sought a second opinion at an academic center near us. I think Memorial Sloan Kettering. And their only recommendation was, continue with the EPO and add on some steroids, which seemed reasonable. And we gave her I think 10 mg of dexamethasone daily. And she has had, over the course of a few months, she presented later last year a slow rise in her hemoglobin. I just looked her up here. Her last hemoglobin was 10.6. This was a very slow rise. It was a point every 2 months, really. But she slowly but surely got better.

So really this is a case where this patient got better. And I’m hoping you gentleman can tell me why, because I really don’t understand what her disease was here and what she responded to.

DR LOVE: What is your working diagnosis?

DR RUPARD: It was myelodysplastic syndrome. That’s what our hematopathologist, who’s very good, felt was the primary disorder here. But then whether it was a red herring or not, this plasmacytosis in the background.

DR LOVE: Guillermo.

DR GARCIA-MANERO: Actually, it’s not unusual in some of these MDS cases to see either this kind of nonclonal plasma population. Sometimes you see some lymphoid populations, et cetera. And it goes back to, again, there is this subset of patients with low-risk MDS that has some type of inflammatory component. I’m pretty sure that you ruled out hemolysis and things like this. But if you think about data, there was some data that actually I don’t particularly believe but people have used, where they used things like ATD, cyclosporine for lower-risk MDS. And apparently there are some people, younger, HLA-DR15, maybe with a trisomy 8, that could respond to this type of immune suppressive type of therapy.

So I think that this patient likely has MDS and likely has one of these inflammatory components where this innate immune deregulation or some other pathway that somehow was contained by the steroids. And with the help of the ESA, you were able to restore some degree of hematopoiesis. I think that’s what is happening here.

Sometimes I see extreme cases of this once in a while. And I can tell you my experience is positive. I, sometimes instead of using steroids, and I don’t if this right or wrong, I may use small doses of cyclosporine. And these patients will respond to therapy and they remain stable for quite a bit of time.

DR MORGANSTEIN: I’ve heard that. Would you do it in a hyperplasia? I always thought that was for people who were hypoproliferative MDS, or do you kind of differentiate?

DR GARCIA-MANERO: So this is a very important discussion, and there are 2 schools of thought. So our experience looking at ATG has 2 major parameters. One is hypocellularity of the bone marrow, cyclin H. So in older people, this ATG base — now we're going through a different angle, but ATG likely to be very effective. And most of our activity is in the hypoblastic context. We’ve reviewed that. And actually, Dr Mufti in London at Kings College had exactly the same data. But if you look at the data from the NIH, from Neal Young, they reported a number of studies showing that in the context of hypercellular marrow in younger patients, these are subsets of these patients that respond to the therapy. There’s actually an equation that you can use to predict who may or may not respond to immune suppressive therapy, and it includes younger age, HLA-DR15 positivity.

To be clear, we actually tried to replicate the results, and we were unable. And I’m close with Neal Young, who leads that program. We cannot explain why there is such dramatic differences. Maybe Harry, he can tell us what his experience is. But we only use ATG therapy in patients who look like aplastic anemia. So aplastic anemia or hypoblastic myelodysplastic syndrome is a relatively rare subset of patients with MDS.

But I think it illustrates that there are some patients who we may or may not fully understand who may respond to some type of anti-inflammatory or immunosuppressive type of therapy. That, I think, is what happened here.

DR LOVE: Could I just ask, I know that one of the questions that Erik wanted to address, I’m curious what your thoughts are, Harry, are the special considerations in the management of Jehovah’s Witnesses or other people who won’t accept blood and the potential role for a bloodless transplant. And what about bloodless centers? Do you have one at your place?

DR ERBA: We don’t have a bloodless center. When I was in Michigan, and I’m down in Birmingham, I’ve been sending my patients up to Pennsylvania. There’s a bloodless transplant center there. And you can get patients through reduced-intensity transplant. Clearly, this woman, 58, was able to tolerate a hemoglobin of 4. And you could make the argument with a reduced-intensity transplant, the period of cytopenias is actually quite brief and so be able to get her through that.

So that would be an option. I’m not sure it’s the best option, though, to be quite frank with you. Because she appears to have, if this MDS, a low-risk disease and is not neutropenic as — actually has a thrombocytosis.

So 1 other question I have about this patient. You said you checked JAK2. Was there any marrow fibrosis?

DR RUPARD: There was not. Nope.

DR LOVE: What were you thinking about?

DR ERBA: So there’s 1 special consideration to keep in mind, and that is the situation or the diagnosis of an autoimmune myelofibrosis. Incredibly rare. Okay? How did I learn about autoimmune myelofibrosis? The same way I’m learning about things today. I’m brought in to talk to a group of doctors at a small hospital up in Northern Michigan, and I was the guy with the tie, and all the guys without the ties, they needed to stump me. So they presented this case — I will never forget autoimmune myelofibrosis — and actually made a diagnosis in Birmingham to the benefit of the patient.

So it looks like myelofibrosis. They might not have significant splenomegaly, or they could have some, but it looks like myelofibrosis with low counts, anemia, very, very commonly seen, more commonly seen in women. The atypical megakaryocytes made me wonder about a myelofibrosis where you have the clustering of the megakaryocytes with hyperchromatic nuclei. So that’s 1 consideration where they respond very nicely to immune suppressive therapy.

But the other is, if this is truly MDS, I would consider in her the role of immunosuppressive therapy regardless of the cellularity of the marrow. There is a debate in the literature, maybe it has to do with referral biases. But I have actually seen 1 patient with a hyperplastic marrow respond. Because, although the marrow looks hyperplastic, you have to keep in mind, if the patient is hyperplastic and has erythroid hyperplasia and yet is anemic, something’s keeping those red cells from getting out of the marrow. Okay? So is it a dysplastic process, or is it an immune process where they are just consumed or destroyed before they leave the marrow? And it might not be possible to tell by morphology.

And so I wouldn’t let the hyperplasia lead me astray. I would be interested in an HLA-DR PNH clone that has been known to correlate with response to immunosuppressive therapy. And so in this patient, I think I would be tempted to give her ATG with or without cyclosporine. She’s under 60, so in an age group that might be more likely to respond. She’s a woman, so more likely to have an autoimmune kind of process.

So it may have been the steroids. The only person who benefitted from 40,000 units of an erythropoietic stimulating agent 3 times a week was probably your pharmacist and their children. But, I mean, the real question comes down to, how can we tell that this is myelodysplastic syndrome as opposed to something else, either another myeloid stem cell disorder or a benign condition? And the fact of the matter is, on 1 hand, that’s a very simple question. MDS is defined by morphology. It’s still defined by morphology. Any other test that you use that might show a clonal problem, so next-gen sequencing, FISH panels, array, CGH, comparative genomic hybridization, looking for amplifications and deletions, those may tell you that you have a clonal process, but they don’t tell you that it’s myelodysplastic syndrome.

So you can get those other tests, but I’m not sure that they’re going to really help in this situation. In this patient, I would be very tempted to, as Guillermo said, use an immunosuppressive therapy, and you could just go with some cyclosporine and steroids, too and not give ATG.

DR RUPARD: So the place where she received her second opinion was actually exactly who we refer to, that’s Dr Patricia Ford at the University of Pennsylvania. Does the bloodless transplants. And just a couple of thoughts. The problem here is, the patient presented with a hemoglobin of 4.1. So we couldn’t let her go down significantly further without risking her life. And, of course, ATG or other suppressive therapy would have caused her to go lower, which is why Dr Ford actually was in agreement with EPO. She got the EPO in the hospital before I met her. I actually stopped it. And when I stopped it, her slow increase declined fairly rapidly. And I’m not saying it was the EPO, maybe it was a placebo effect for her doctor. I don’t know. But for whatever reason, we have lowered her dose over time and we’ve attempted to stop it a couple of times and every time we do, her hemoglobin drops. But she was seen and considered for that. And I think that Dr Ford felt, and I certainly understand, that giving her ATG would have probably knocked her hemoglobin down enough that she would have been at risk certainly of the morbidity, if not mortality.

DR GARCIA-MANERO: Because the potential is there. So sometimes the patients have reactions and with a hemoglobin of 4. I would probably have used a low-dose cyclosporine type of approach. That’s what I tend to use. And it’s simple. You use a dose, you start maybe 300 mg orally, 200. I don’t check cyclosporine levels. It’s actually simple. You go by tremor and creatinine/bilirubin and then you adjust, and this is a simple approach that has helped me in some of these cases.

DR RUPARD: So where would you start? What would be your starting dose?

DR GARCIA-MANERO: I would do 300 mg orally a day. And then you look for, I guess, tremor, creatinine, bilirubin and you follow them.

DR ERBA: But now that her hemoglobin is higher, I mean it came up some. You could try other things. And coming back to that, this is a patient where maybe lenalidomide would have a role. I mean, she has a thrombocytosis.

And I agree with your observations. And it might have a benefit in her as some type of immunomodulatory agent. And you might have more room to deal with the cytopenias that may result for it.

Important clinical issues in the management of MDS

Case discussions

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