DR MORGANSTEIN: So she’s an 80-year-old, a very sweet couple came in. Came in with her husband every single time. They’re the couple who would come in holding hands every single visit. So she had a history of rheumatoid arthritis and was treated with a biologic by her rheumatologist. He called me up and said that he wanted to see her, because she started to develop a slowly worsening hemoglobin. And when I initially met her, her hemoglobin was 9.1 with some mild other cytopenias. Platelet count was not normal but over 100,000. White count was normal.

I did a bone marrow biopsy, and she had refractory multilineage cytopenias with excess blasts. She had 13% blasts in her marrow.

She’s somebody who started on azacitidine. She received 5 days in a row, every 28 days. I do tell them, based upon some of the other conversations, that you’re going to sick. You’re going to wind up in the hospital. I kind of read them the riot act, and she actually did fairly well.

Became transfusion independent pretty quickly and had a nice remission. After 3 months we did a bone marrow. Her blasts were still there, but they were about 7%, 8%. And we kept her on it. Unfortunately, when she was on maintenance, which I do 5 days in a row every 6 weeks, she developed a gallbladder disease and was actually in the hospital for a long time. Between surgery, infection, recurrence, surgery and then in rehab, she was off her azacitidine for at least 3 months. We repeated her bone marrow, and her blast counts went up. She was over 20% and she was diagnosed with AML.

She’s somebody, even early on, had these conversations regarding palliative care, and I did believe she was palliative. Okay, you could debate that back and forth. And we have an aggressive palliative care team. We talked about how this was going to be, the eventual outcome of this. What her expectations were. She had a very, I won’t say aggressive husband but knowledgeable husband, who shopped her to Boston and New York. And one of the questions early on in her disease was the role of transplantation, of minitransplantations in the elderly.

She was offered it. She declined, okay, but that’s something to talk about. As she progressed to AML, she again went to multiple academic centers. Offered clinical trials. One of them was to try decitabine, okay, which we’ve talked about. So we tried decitabine, and it was not a good idea. She had no response, toxicities and eventually placed on hospice and she passed away.

DR LOVE: So looking back at her case, one question that Neil brought up. Harry, I’m curious what your thoughts are, is there a possible link between the rheumatoid arthritis? What kind of treatments had she gotten?

DR MORGANSTEIN: Yes. She got — I’m trying not to use the brand name — abatacept. I’m killing it. I’m sorry.

DR LOVE: Had she ever gotten any alkylating agents? Cyclophosphamide?

DR MORGANSTEIN: No. No, no. She got these disease-modifying agents, these anti-TNF — and I’ll be honest, I don’t know exactly which classes.

DR LOVE: So Harry, what about, first of all, autoimmune disease and MDS? And second of all, the treatment of RA?

DR ERBA: So let me start with the treatment of RA. I think there’s a little bit more data there. In fact, in the WHO classification of MDS, they now — and AML, they now accept immunomodulating immunosuppressives as a risk factor for the development of these clonal stem cell disorders, which again is interesting in the sense of why would that be? Is it through some genotoxic effect that’s a bystander of the immunomodulatory? Or is it really the alteration in the immune system? But I do think there’s a link there, and I’ve seen a number of patients with RA on these TNF inhibitors come in with AML. So I think there is some risk there.

In terms of the link with autoimmune disease and myelodysplastic syndrome, in terms of pathogenesis, I don’t understand it, but there is an association and I don’t know what else to do with it. Maybe Guillermo has more insight into why that happens, but I don’t.

DR LOVE: Guillermo, any comments about that? And also, anything you want to say about this case and the management?

DR GARCIA-MANERO: Yes. So the French and Moffitt Group actually just published not too long ago 2 papers looking at these types of patients. And it’s becoming, as Harry has said very nicely a number of times, this is becoming a subset of patients who are important. We think, actually, why this may happen, but maybe because of target, and it’s probably through interaction with toll-like receptors and innate immune receptors in the surface of the stem cells. That they have, actually, a physiological reason to exist, but they actually affect stem cell function. So if you look at host responses to bacterial infections, so these are kiac systems that make you basically have a high white count when you get infected. They seem to be altered.

So for instance, there’s very intriguing data. If you look at the North European, like the Swedish Registries, people who have hip replacement or some type of metal in their bodies, that 2 diseases that they get, MDS and MPD. And the concept there is that you may have some type of chronic stimulatory type of pathway through this machinery that may actually lead toward some type of stem cell deregulation.

What I think is the teaching point in this case that I think is very important is that now, in MDS treated with hypomethylating agents, we’re starting to distinguish what we call primary failure versus secondary failure.

Data from the original Phase III trial for rigosertib has not been validated but may suggest, actually, that the natural history of these people are different. So expectations, response, et cetera of a secondary failure, different than a primary failure. And actually, there’s a Phase III trial now with rigosertib only for patients with primary failure. So these are patients who do not respond to the therapy.

So it’s going to be interesting to see if this pans out.

And the second quick teaching point is that, in a patient who progresses through MDS to AML, going back to the next generation, if you were going to do a $1 test, check off FLT3 assay because those patients actually have a tendency to have this mutation. And we just reported the outcome is dismal. Like what happened to this lady. If they transform to AML with an FLT3 mutation, difficult.

I mean, what I’ve seen with people with MDS who transform to AML, they’re difficult. I don’t know if it could be more dismal.

DR GARCIA-MANERO: Yes. And it’s likely because some of them have this kind of FLT3 mutations, et cetera, that in AML are very bad players. So this is correct.

DR ERBA: Yes. I think it’s a combination of things. Not only the biology is different, but the patient is different. Right? Because they’ve been suffering with cytopenias and worsening performance and nutrition status, chronically infected. And then you give them you try your best, saying, “Oh, now it’s 21% blasts. Obviously I need to give 3&7.”

It’s like, I hate doing that. I do it if the patient has a proliferative disease at that point. I do it especially if the patient is thinking about curative options, allogeneic stem cell transplant. In next response, I’m much more likely to recommend off of a study 3&7 or some AML induction therapy. But otherwise, I talk to my patients about this being part of the natural history and just because one day it’s 19% and the next day it’s 21% doesn’t mean I’m going to change my approach to the patient.

I think what you’re seeing here in an 80-year-old who lives in New Jersey is that even traveling up to New York and Boston is too far to go for a clinical trial, which would require her to stay there.

I’m sure they did next-gen sequencing. They sent it to their favorite lab. Maybe they found a target. Maybe they didn’t find a target.

That’s what I would try to do for a patient like this, is hope that she had a target for which I, hopefully, had a clinical trial.

Important clinical issues in the management of MDS

Case discussions

Audio version