Clinical Considerations in the Diagnosis of Patients with MDS

Gail Roboz, MD: Rami, you have the person land with you who has got something wrong with their CBC [complete blood count], because that’s what happens to all of us. There is something wrong with the CBC, they are anemic, they’re leukopenic, something doesn’t work. You talk to them, you’ve gotten their family history, you know their risk factors. And there is something going on with the patient. What’s the work-up? What are you guys doing at your center to make the diagnosis?

Rami Komrokji, MD: Thank you. As Azra mentioned, we are at tertiary centers. Most of the time, the patients have already had the work-up and the bone marrow, but I think we first should look at the blood counts. What is abnormal? For example, leukocytosis, what is the differential? Because leukocytosis really does not mean anything. It could be lymphocytosis and CLL [chronic lymphocytic leukemia], and I would be happy to send it to a separate section from my department completely. But really, what is abnormal? Is it anemia, bicytopenia, pancytopenia? That will be my first step to start thinking of what to do, and as mentioned already, in the context of age and the risk factor and my suspicion. So obviously we always want to get the basics. Although we always say they are the basics, but I cannot emphasize more checking for nutritional deficiencies for example, B12, folate. I recently saw a case, a young kid transferred from another hospital, a bone marrow test from outside found 40% myeloblasts. They ended up to be those giant megaloblastoid changes and severe vitamin B12 deficiency. Although we say those are the basics, I think it’s crucial. So B12, folate, as you mentioned, copper in selected cases. I have also seen somebody on hypomethylating agents for a year, they had copper deficiency. Whenever I see MDS [myelodysplastic syndrome] with ring sideroblasts, bone marrow, and there is no SF3B1 [mutation], I almost get 2 copper levels to make sure it is not copper deficiency before calling it MDS. I will look for nutritional deficiencies, and then it depends on the context. Sometimes if cytopenias are mild, and my suspicion is not high, I am OK observing. But I always tell the fellows there are certain red flags. Pancytopenias worry me more. If I see circulating myeloblasts or immature cells in the peripheral blood, those are absolute indications. Most of the time, obviously, the cytopenia is profound enough for us and there is a concern, we will end up doing a bone marrow aspirate and biopsy, and then we will get cytogenetics.

We do not get a FISH [fluorescence in situ hybridization] test routinely on every patient. I think we published on this as well, that there are only 3% of patients for whom you will catch something on FISH that you do not catch on cytogenetics, unless there is no mitotic activity or something like that. We do the regular cytogenetics, the classical G [Giesma]-banding, FISH selectively, and nowadays, obviously we incorporate next-generation sequencing. Every center has a panel, and there are commercially available ones. I think most of them now, whether they are 20 or 100 genes, capture 90% of the abnormalities that happen in MDS. Every now and then I will look for things that can mimic MDS in selected cases. Sometimes we see somebody having hemolysis and the H [hemolysis index] is high, which you could see sometimes in MDS. But I would think of a…negative, like PNH [paroxysmal nocturnal hemoglobinuria] that can happen. Or less commonly LGL, large granular lymphocytic leukemia, things that can mimic MDS obviously. That is usually my work-up, and it’s as you started the talk, it’s very individualized case by case.

Gail Roboz, MD: I think you have a lot of things to unpack in that. Before we launch into the molecular, there are a couple of things I think are valuable in what you said. The first thing is, all of us, we are getting a prechewed diagnosis, sometimes in a tertiary care center. But I think we probably all, and you guys can nod or not, but I think all of us are going to demand to see the slides, not just the reports. And I think that a lot of the time a repeated bone marrow aspiration and biopsy are performed. Because your point about, how is it that the bone marrow could be misleading, I think it is important to emphasize that first, there are qualities sometimes of both the aspirate and the biopsy that are not great on an initial one. I think, honestly, there is a sensitivity sometimes, more in the commercial laboratories, but I cannot prove it. There is a sensitivity about saying something like “inadequate specimen” because it makes the person feel bad, potentially. But I think sometimes the specimens are not great, and we ask to redo it. So, we even, are not necessarily believing a diagnosis of MDS when it walks through the door. Also, I think it is worth it to say that the cytogenetics absolutely are part of the work-up. It is mandatory to be considering a diagnosis of MDS. Whether a FISH panel is done, I agree, maybe sometimes only in the setting of no mitosis, but also to remind the audience that if you have a dry tap, which can happen sometimes if you have a fibrotic marrow you are trying to figure out, it might still be worth it to send both cytogenetics and FISH from the peripheral blood in case there are some blasts there. I think that was…in your comment. The Venn diagram of PNH, of LGL, all those different things, which are the MDS posers, all of that must get carefully sorted through, and I think the mutational abnormalities can help with that.

Transcript edited for clarity.