TRANSCRIPTION:

DR STEENSMA: Yes. I was asked some months ago to see a 65-year-old woman in the emergency department who’d been brought there by her family after she developed aphasia and right-sided hemiparesis. And a CT scan of the head showed a left temporal infarct. There was a small area of hemorrhagic transformation and some accompanying edema. Her CBC was quite remarkable. Her hemoglobin was 6 grams per deciliter. Her platelet count was 37,000 per cubic millimeter and her white count unusually high for this disease, 103,000, with 84% circulating atypical promyelocytes and blasts. And some of the blasts just had numerous auer rods. The PTT was prolonged at 39 seconds. The INR was 1.6, and fibrinogen was 140.

DR LOVE: Just before you go on, I just want to ask Doug, if you had been called into the emergency room to see this lady, what would you be thinking?

DR SMITH: I mean, we’re thinking about acute promyelocytic leukemia here. And this is the part of disease we cannot yet get away from, the untoward effects early on of bleeding or clotting.

DR LOVE: And you’re the general oncologist in the emergency room. What do you do?

DR SMITH: This is one of the diseases that, when we suspect it, we initiate treatment with all-trans retinoic acid. And this is a unique case with a very high white count of 103,000. We’re going to have to manage that from the standpoint of she’s got a high-risk disease. And based on the platelets and the white count, that white count needs to be lowered. And ATRA needs to initiated and she needs the full-on support of her coagulopathy. The fibrinogen needs to be managed. The PTP — TT needs to be managed, and the platelets need to be managed to try to give this woman the chance to respond and get through this.

DR KANTARJIAN: And one point that differentiates APL from other acute leukemias, if this was a regular acute leukemia, you would give hydroxyurea or high-dose ara-C. In APL, the best agent that shuts off the DIC more immediately is idarubicin rather than ara-C. So in addition to initiating ATRA, this patient certainly needs an emergent dose of idarubicin, 12 mg/m², to shut off the DIC and to lower the counts.

DR LOVE: So David, what did you do?

DR STEENSMA: So we got ATRA into her as quick as we could. This was a somewhat difficult thing to do just because she was not able to swallow very well, but we managed to get it down. We had the neurosurgeon see her. They didn’t think that there was anything that needed to be done or could be done right at the moment. And she was brought up to the neurologic intensive care unit. She got supportive care for her blood pressure. We did give her hydroxyurea, but unfortunately an echocardiogram showed marked reduction in LVEF. And so we had entertained giving her idarubicin but were somewhat put off by that.

However, she fairly quickly regained her speech that same night, although her right side remained weak.

DR LOVE: What was the thinking about her reduced ejection fraction? What was it from?

DR STEENSMA: She was a diabetic patient. And she had not had very good medical care previously. And so there may have been a myocardial infarction that had occurred previously. It did recover a little bit but not very much. It’s still in the 40% to 45% range.

DR KANTARJIAN: But I don’t think that would be a contraindication. You have to weigh the risk of an anthracycline, which you can give over 6 hours, versus the DIC process. So you could go for gemtuzumab, but you have to get it on a compassionate IND, which takes a few days.

And I think idarubicin, maybe 6 mg/m² given over a longer infusion, could still help her in the long run. The other thing is, the late Dr Zal Arlen, who unfortunately died of a brain tumor, he was at Sloan Kettering, he used to say that he never lost a patient with APL if they kept the platelets over 50,000. And he had a series that he published with twice-daily platelets in APL where the mortality was very low. So in addition to the ATRA, I would advocate for idarubicin, a lot of platelets, certainly, and cryoprecipitate to improve the fibrinogen over 100.

DR LOVE: So before we find out what you actually did, and I want Wendy to respond to this case, can you just describe the rest of the diagnostic information you had prior to making a decision about treatment?

DR STEENSMA: Yes. So we did perform a marrow biopsy, but not surprisingly, it was consistent with APL. The PML ⎯ RAR alpha was present. She did also have FLT3 ITD, which is not surprising — many patients with APL do — and had the typical 15;17 translocation on karyotype without other abnormalities.

I think one thing I would just add, Neil, for this audience is that leukapheresis, which someone might be tempted to do with a very high white count, is really contraindicated in this disease. It does make the coagulopathy worse. And so ATRA and other drugs are better for urgent therapy.

DR LOVE: So at the point that you were ready to treat her, what was her clinical status and her blood work?

DR STEENSMA: So at the point I was ready to treat her, thankfully, with aggressive support, with precipitate platelets, with antiseizure prophylaxis, with corticosteroids because of the brain edema, she had markedly improved. And she still had some right-sided weakness, but her white count had come down to just above the normal range.

DR LOVE: So Wendy, what would you be thinking in terms of treatment for this lady?

DR STEENSMA: The DIC resolved.

DR STOCK: So I think this is a really important discussion. We actually just had a similar patient, much younger but with a very, very aggressive high-white-count APL, who just came to us a couple of weeks ago, with a very similar presentation. And so we did the same thing. I think the most important points are that ATRA must be initiated as quickly as possible, because you want to get those promyelocytes to start to differentiate so that the coagulopathy resolves. I would have added dexamethasone in this patient. She already has a super high white count. And I would try to bring the white count with hydroxyurea.

I agree with Dr Kantarjian about the anthracycline, although in my experience what we’ve tried to do is start the ATRA first to get the DIC to resolve a bit and then add the idarubicin, which, in the case of our patient, we did around day 4, day 5, day six, because by then some of the DIC was beginning to resolve, although the white count was still very, very high and we were worried about that.

So I think once that part has been done, there are studies now that show that the addition of arsenic trioxide to front-line therapy improves outcome. And in this case, we would have also continued the ATRA, given the idarubicin and initiated arsenic trioxide.

DR LOVE: So Doug, agree or disagree?

DR SMITH: Agree. And I left off the steroid part, but absolutely, steroid early on — this person — patients at very high risk for the complications of ATRA and as far as differentiation syndrome or ATRA syndrome. So we would go ahead and treat with steroids right at the onset of therapy.

DR SCHIFFER: It’s interesting. I submitted a similar case without the drama of a bleed in the head of a person with a high white count, because with lower-risk APL, I think most of us would not use chemotherapy. But I don’t think there is a standard for what you do with people with higher white counts. Obviously start the ATRA. Transfusion support is critical in keeping the platelet count high with 2, 3, sometimes 4 transfusions, which sometimes you don’t need cryo because you’re giving fibrinogen with the plasma, but sometimes you do need cryo. But I guess the question I would ask, and I don’t really know the answer, is, I think you need chemotherapy to drop the white count. Our instinct is to give it early. Do we need arsenic as part of induction? Or can we use it as consolidation?

DR KANTARJIAN: No. I don’t think so. So there is data that shows that idarubicin prevents the transit of promyelocytes into the cycle, which is very different from how ara-C works. If you give ara-C to a patient like this, you exacerbate the DIC.

But if you give the anthracyclines, you shut off the DIC within hours. ATRA takes about 2 to 4 days to reduce the DIC process. So I would reverse the order of the treatments. I would give ATRA, but I would certainly give idarubicin immediately, because that’s the one drug that shuts off the DIC process within hours. And the low ejection fraction is a relative contraindication, but as I said, you can get around it with a tiny dose of the idarubicin.

DR KANTARJIAN: So the FLT3 is interesting, because it’s a proliferation marker. And in patients with APL, there is a significantly higher median white cell count in the patients who are FLT3 ITD —

DR SCHIFFER: With FLT3 process.

DR KANTARJIAN: — versus the others.

DR LOVE: Let’s hear about the follow-up, because it’s kind of interesting in view of what you all are saying.

DR STEENSMA: Thankfully, she had a very good outcome. The DIC very rapidly corrected. And given that and the low EF, and I hear what has been said here, we ended up not giving her an anthracycline and, instead, once the diagnosis was confirmed, we started her on arsenic. And she had a very nice response. She became molecularly negative already after induction. We took her through the whole Lo-Coco et al regimen, with several more cycles of arsenic and ATRA as an outpatient. Other than some mild headache, she had no adverse effects. And the headache was only the week she was taking the ATRA.

She went through a physical therapy program and regained some function in her right arm. And she’s now completed all the consolidation therapy, has a normal looking marrow, molecularly negative and seems to have had a good outcome.

DR SCHIFFER: And you got the white count down with hydroxyurea?

DR STEENSMA: With hydroxyurea.

DR SCHIFFER: And then started the arsenic?

DR STEENSMA: And then started the arsenic, correct.

DR LOVE: How do you like that one, Charlie?

DR SCHIFFER: I think they were fortunate in that the hydroxyurea will get the white count down but not necessarily to the lowest levels. And this is like old-fashioned APL, where your concern was the exacerbation of hemorrhage when you kill the leukemia cells. And you had to be incredibly aggressive with supportive care and have a little bit of luck.

DR KANTARJIAN: One issue about CNS prophylaxis: So people don’t pay attention to it, but there are studies that show that there’s a slight, tiny incidence of CNS leukemia. And that usually happens in patients who have an initial bleed, a high white cell count. We found that all 6 patients that developed CNS leukemia in APL in our whole group had an LDH over 1,000. So in this patient, I would certainly consider some form of CNS prophylaxis, because we lost a handful of patients with APL who had multiple relapses and ended up with resistant CNS leukemia.

And she has the 2 factors that, in other studies, predicted for higher CNS disease — the high white cell count and the bleed. So I probably would give some CNS prophylaxis.

DR SCHIFFER: After CR.

DR KANTARJIAN: Yes.

DR STEENSMA: We did do that, actually. I should have mentioned that. We gave her triple intrathecal therapy. I can’t remember if it was 3 or 4 times.

DR KANTARJIAN: Usually 2 to 4 intrathecals in CR.

DR LOVE: Doug, what about maintenance therapy in this situation?

DR SMITH: Yes, that’s a question for our group, because I do think this is a high-risk patient. And it appears that in earlier studies, pre-arsenic-based studies, maintenance did seem to be an important part, the thought that arsenic, as either part of induction or consolidation, could lower the need or eliminate the need for maintenance therapy has come forward. And this patient certainly makes me anxious because of the high white count, the CNS bleed and the risk of CNS disease and the fact that she did not receive traditional chemotherapy, which is what we’ve based everything on in the past. So I think that it’s worth considering maintenance.

Chronic Lymphocytic Leukemia (CLL)

Chronic Myeloid Leukemia (CML)

Acute Myeloid Leukemia (AML) and Acute Promyelocytic Leukemia (APL)

Myelodysplastic Syndromes (MDS)

Acute Lymphocytic Leukemia (ALL)