DR RUPARD: So this is a 31-year-old Romanian female who came to our clinic in April of last year, with reasonably mild cytopenias with a white blood cell count of 2.6, hemoglobin 10, platelet 160,000 but the retrospective chart review showed that she had been declining for a couple of years. So my colleague ordered some testing on her and arranged for a follow-up with me. She went for the testing, which was negative for B12, iron, et cetera, but she did not show up for the follow-up. She showed up in November and she was pregnant, and her obstetrician had sent her for evaluation because her cytopenias had worsened somewhat.

So now her CBC was a white blood cell count of 1.5, a hemoglobin of 8.8 and a platelet count of 138,000, which for our lab was low. So after discussion with the patient and her referring doctor, we arranged for a bone marrow biopsy to be done on this pregnant patient. And it showed a hypercellular bone marrow with erythroid hyperplasia and what my hematopathologist described as “marked dyserythropoiesis.” And when she saw it, she called me and said, “Hey, I think this patient is somebody who has CDA, congenital dyserythropoietic anemia,” but she said, “But let’s wait to see what the FISH studies showed.” And strangely enough the FISH studies showed a 20q12 abnormality, hyperdiploidy of chromosome 5 and additional copies of 11q23, and she had 4% blasts on her flow cytometry.

So my question for you gentlemen would be, what does this patient have, and where would you go with her care?

DR LOVE: Could I just ask whether she’s had any exposure to leukemogenic agents?

DR RUPARD: Yes. So we have this population of Eastern European people in my area and most of them were born there. And I asked her this question, and her mother accompanies her to some visits, and they strongly felt that yes, they had been exposed to all sorts of weird things. They couldn’t tell me what — strange smells where they lived. And when I tried to get them to characterize it, the impression I got was the smell of fuel or burning fuel. And that they lived in areas where those kinds of things occurred.

And I’ve seen this from others from this area. I had 1 patient who they had snakes coming up through their plumbing. So her father poured gasoline down the drains to try to kill off the snakes. And so their house smelled like gasoline all the time. So I think that there is some increase in exposure, and this patient and her mother both felt that there had been.

DR LOVE: So first, Harry, what do you think the diagnosis is? And second, what about this exposure history?

DR ERBA: So I think the patient likely does have a myeloid stem cell disorder that is myelodysplastic syndrome. The exposure history I think is important in a young woman with MDS. I would also look for other congenital causes of marrow failure syndromes like Fanconi’s anemia, dyskeratosis congenita, just to name maybe 2 of the more common ones.

Why? Not just academic interest. You probably all remember this from fellowship, but patients with Fanconi’s anemia and dyskeratosis congenita are very susceptible to DNA damage. And so if they do go undergo a bone marrow transplant they have to have a conditioning regimen that takes that into account, otherwise they’ll just have incredible organ toxicity with full doses of therapy.

So not just an academic question. So I would check those.

I’m not really good on Eastern European geography, but if she traveled anywhere around Eastern Europe, the other thing to keep in mind is the Chernobyl accident, too.

DR LOVE: Yes. I was thinking about that. Was she anywhere near that?

DR RUPARD: She was not.

DR ERBA: Yes, just something to keep in mind. Now I’m sure pretty sure Romania’s below — I think I remember that much.

DR RUPARD: If you look at the map, it’s actually not too far from Western Europe. It’s not that far removed. But I think it’s worlds apart in other ways.

DR ERBA: Okay. In terms of the CDA, what she probably saw was a lot of multinuclearity of the erythroid precursors, which is a sign of dysplasia. The 4% blasts are interesting. I’m not sure if that’s by flow or by morphology. But by flow, it actually may overestimate the blast percentage. This is something I’m going to bring because it pertains to all of MDS and AML — when you prepare the bone marrow for flow cytometry, erythroid precursors are preferentially lysed. And so it can make the myeloid blast percentage look a little bit higher. And although it’s still below the 5%, we know from the revised International Prognostic Scoring System that a marrow blast percentage of 4% to 5%, it does impact increased risk. Much more important than if you go from 15% to 20% blasts.

And she has multiple cytogenetic abnormalities. I’m going to assume that those are in a significant population of the cells. It’d be interesting to see what the karyotype as a whole shows, not just the FISH. But if she does have clonal stem cell abnormalities. I think it rules out the congenital dyserythropoietic anemia, unless she has 2 bad diseases at the same time.

Given her young age, given the complex karyotype, I would consider her for allogeneic transplant, with the caveat that you need to make sure she doesn’t have a congenital fragile DNA or DNA repair syndrome like Fanconi’s anemia.

How far along was she in her pregnancy?

DR RUPARD: In November she was 3 months along.

DR ERBA: So has she delivered?

DR RUPARD: No, she has not. No. She’s in her third trimester now.

DR ERBA: Okay. And Erik, these are her counts now?

DR RUPARD: Her neutrophil count has come up a bit. She’s been placed on steroids. And hemoglobin is in the 8s and her platelet count — this platelet count is in the 140s. So she’s been above 100 most of the time. So really, she’s been asymptomatic other than fatigue, which is multifactorial, clearly.

DR LOVE: Guillermo, could you comment a little bit on the issue of treatment or management of patients who are pregnant? Are there agents that are safe and not safe?

DR GARCIA-MANERO: There’s very little experience. Because, actually by definition, 60 was pediatric. So it is very, very rare that you will encounter a patient like this. So I am not aware actually of any experience in pregnant females with hypomethylating agents. And I’ve never encountered those in my career.

DR LOVE: It kind of sounds like a bad idea.

DR GARCIA-MANERO: Absolutely.

There’s actually data in the pediatric context where those kids tolerate these drugs the same way as adults. But I actually have to say, I don’t think I have encountered like a pregnant situation like this.

I totally agree with Harry. If the pathologist thinks that there is some congenital disorder, for sure you need the family history and to rule out Fanconi, dyskeratosis congenita and so forth, particularly because of what Harry said, that if you’re going to take this patient to transplant, this requires also some degree of expertise in terms of what type of transplant modality you use. But Harry is very observant. He mentioned something very key here. You need to marrow her at some point once she delivers baby and do conventional cytogenetics because some of these FISH probes may give you a little bit of false-positive, et cetera. So you need to make sure that, first of all, that you are not dealing now with a very complex karyotype and you’re pooling the 20/11 just because those are the ones that you look at. And second, that will actually give you 100% certainty of the clonality of this alteration.

So that’s actually I think mandatory. So that will be very important.

And I have to tell you that my prediction will be that once she delivers this baby, counts will probably go up. It will be important to remarrow her. But I think this is a very nice teaching point here that is not 100% related to the case.

First of all, if you look at her by definition, although I agree with Harry that if you look at the end diagnosis of gross MDS, she’s going to transplant, whether it’s today or 6 months or 2 years from now, that’s the path that you’re looking at.

But technically, some people would say low-risk disease but has a very funny karyotype. So — and this is the teaching point — she has 3 good cytogenetic alterations: chromosome 5 is good. Chromosome 20 is good. Actually, chromosome 11 is good. But now you have this interconstination of 3, and when you have 3 with a chromosome 5, Harry’s right. This is kind of trivial, but actually it’s a poor feature if you look at the models.

So I think it’s critical to do conventional cytogenetics. She’s stable. You’re not going to do anything right now. We’ll let the baby deliver and then repeat a full workup. And I will do then the Fanconi, the dyskeratosis congenita and then do next-gen sequencing and conventional cytogenetics.

Some of these people with Fanconi and CDA, actually they may transform into an MDS/AML situation. So it’s kind of like a secondary leukemia. So this FISH doesn’t rule in or out anything. It may be that this person had this type of congenital marrow failure and now is evolved into MDS. By the way, to finish this I asked the world experts at Boston, at NIH once, what is the experience with hypomethylating agents in the context of Fanconi moving into MDS? Zero. This is uncharted territory.

DR LOVE: Erik, any more feedback you want on this case?

DR RUPARD: Yes. So in this we did conventional cytogenetics on her. She had 14 copies of genes with at least 2 of those disorders that I described.

DR GARCIA-MANERO: So it’s real.

DR RUPARD: And 6 copies that were BV.

DR GARCIA-MANERO: Yes, it’s real. Yes.

Important clinical issues in the management of MDS

Case discussions

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