DR SMITH: Our group has embraced this, even more so than I was anticipating when I first knew about the data. Sorafenib was added to traditional induction and consolidation therapy for a group of adults, I think up age 60. About 270 some-odd patients were randomized between the 2 treatment arms. And although there’s been a lot of effort with drugs that target FLT3 and drugs that target other markers, plus chemotherapy, this one actually showed a response improvement. It showed a 3-year progression-free survival benefit to the sorafenib arm.

And they gave, interestingly, compared to other studies, they gave the drug, the sorafenib drug, intermittently. So they didn’t give it concurrently with the chemotherapy. They did it for a 10- or 12-day period during induction, and then they did it from consolidation up until 3 days before consolidation. And then they would take a break from it. So our group has been very interested in these data. We were not, even though sorafenib is active in FLT3 leukemias, it was not specific for FLT3 leukemias. And, in fact, the difference in outcomes favoring sorafenib was greater in the non-FLT3-positive patients in that study, small number of FLT3-positive patients. So folks are very interested in this concept at our group and trying to figure out, are there better drugs to do this with? But I think it was, in general, considered a positive step in the right direction study.

DR LOVE: Does that mean, though, that you’re thinking about doing it yourself, outside a trial setting?

DR SMITH: We do use sorafenib outside of the trial setting for our FLT3-positive leukemia patients in an effort to try to get them to transplant. And we actually have a trial for it, but we’ve used it outside of that setting as well. Toxicity has to be accounted for as well with the sorafenib arm. The interesting toxicity that we hadn’t noted before was the bleeding, a slight increased chance of bleeding if you are randomized to the sorafenib arm. In addition, hand-foot syndrome and some other common side effects of the sorafenib. And it should be noted that the sorafenib was a pretty high dose. It was 800 a day or 400 twice a day, so I’m not surprised at all that that group has a slightly more side-effect profile.

DR KANTARJIAN: So I want to make a philosophical comment here as to the mood of the leukemia doctors versus solid tumor doctors. If you had any solid tumor study where the randomized trial showed a difference in median event-free survival of 9 months versus 25 months, more than a double, people with breast cancer, lung cancer, renal cancer will be jumping up and down that this is a major breakthrough. In leukemia, that’s not the case.

Now, it is true that there’s some dampening of the feelings, because there was no survival difference. But if you look at renal cancer, they have 8 drugs FDA approved. Only one prolongs survival, yet the accumulation of those drugs more than doubles the survival of the patients. So I think we leukemia experts have been guilty of being too nihilistic that we’re not advocating for those important treatments.

In myeloma, same thing. They have 10 drugs FDA approved. And I do not recall one of them prolonging survival, but yet the cumulative effect has more than doubled the survival in myeloma.

Sorafenib should be embraced as an important effect. Gemtuzumab ozogamicin should be embraced as an important breakthrough. Azacitidine and decitabine. And then we can work on them in our practice to be able to finally prolong the survival.

I want to make a point about the FLT3 patients. If I have today an FLT3 ITD patient who’s older, say in the seventies, I usually put them on azacitidine and sorafenib, because we’ve done an analysis of all our patients with FLT3 since 2005. This is the time when we started applying FLT3 inhibitors across the board to the young and old patients. And we have a significant improvement in the survival compared to the historical data. So we’re waiting for the randomized trials, but I’m convinced that the FLT3 inhibitors are going to improve the survival in the FLT3 ITD.

In the young patients, we have improved the 5-year survival from 20% to about 40%, which is equivalent to the FLT3 ITD-negative patients. So now we are starting to question whether a pure FLT3 ITD would be an indication for a transplant or whether we treat those patients, include an FLT3 inhibitor and then decide on the transplant based on flow cytometry minimal residual disease.

DR LOVE: Any hypothesis about why you see benefit in FLT3-negative AML?

DR KANTARJIAN: No. That was the very surprising finding, which tells us that we really don’t now as much as we think we do about the biology of the disease and the mechanisms of drugs. So this is a very happy surprise, and it suggests that perhaps better FLT3 inhibitors such as quizartinib or the third generation, when added to the chemotherapy, could improve the outcome not only of the FLT3 ITD patients but also across the board.

DR LOVE: Just to clarify, though, are you using sorafenib right now in FLT3-negative AML?

DR KANTARJIAN: The data just came out. We need to discuss this in our leukemia meeting and decide. Today we do it as a routine practice in all patients who are FLT3 ITD. So when we screen the patients, if they are FLT3-positive, the protocols incorporate the addition of sorafenib if the patients are not eligible for other studies.

We have not decided to do the sorafenib yet in the FLT3-negative patients, but this study brings up a discussion that should consider very seriously that possibility.

DR STOCK: I just wanted to emphasize that I think it’s fascinating. We’re always so focused on getting the best targeted agent to treat a disease. And here, I think the idea was that we were going to improve the outcome of the FLT3-mutated patients, but sorafenib is a multitargeted kinase inhibitor. And I think that likely we know that there are many other kinases that are activated in AML. And perhaps the reason for the benefit, as Doug pointed out, it was more even in the non-FLT3-mutated patients. It’s because of its nonspecific, multitargeted kinase effect. And I think that that is a very interesting point.

And sometimes when we design our trials, we’re so focused on one particular group, but we should be more inclusive because sometimes, like you see here, there’s a pleasant surprise that occurs that isn’t really what we necessarily had hypothesized to begin with. And when we have a multitargeted kinase inhibitor, it could just be that that’s the better drug for all of AML than just for a particular subset.

DR SCHIFFER: Yes. That’s certainly one explanation. But let’s assume that the mechanism is its effect on FLT3 alone. Most AMLs overexpress FLT3. So that is conceivably a driver in the absence of a mutated FLT3. And, in fact, when the discussions were held about the 7 + 3 plus or minus midostaurin, most of us really wanted essentially 2 studies in one — FLT3-negative and FLT3 mutated — in order to address this question. The company, I think mistakenly, did not want to do it.

With respect to sorafenib, a lot of this started with anecdotal dramatic responses in FLT3-mutated people who relapsed after transplant, where essentially you have very, very little to do. And some fairly dramatic responses were seen, not universal by any means. But they were more dramatic than the activity of sorafenib against FLT3 might have predicted, because it’s not the strongest FLT3 inhibitor, also suggesting that there may have been some immunologic manipulation that may have occurred. Because I think that’s really where a lot of this started, was post allo relapse.

DR LOVE: Hagop, sorafenib is not the easiest drug to give even in the younger population. We’ve seen that in solid tumors. What about in the AML population, in terms of real-world impact? How easy or difficult is it to give?

DR KANTARJIAN: We use it at 400 mg twice a day, and we do see, commonly, fatigue and skin rashes and diarrhea. We haven’t seen much beyond this. And when we have problems, we go down to 200 twice a day or even 200 mg daily. So it’s manageable, but I would say that, similar to all targeted therapies, you have to use it on a daily basis, continuously rather than interrupted dose schedules.

DR SMITH: Yes. Charlie makes a good point in the non-FLT3 patients. Any chemotherapy will upregulate FLT ligand throughout, so you can get super sky-high levels. And one of the reasons that one of the FLT3 inhibitors may not have worked so well is that it can’t overcome that much. That may not be so important in a non-FLT3 leukemia, yet the ligand is still elevated. And sorafenib, a lot of different impact, may be able to help overcome some of those stimulatory effects as well.

So one of the most exciting parts about the paper presented is that I think it reopened our eyes to thinking, “Hey, adding these targeted therapies, be they specific or be they broad and dirty targets, can have an impact on our disease, a meaningful impact, I think, for a lot of people, doubling of their effect.” So I think we’re opening the door again to some of these.

Chronic Lymphocytic Leukemia (CLL)

Chronic Myeloid Leukemia (CML)

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

Myelodysplastic Syndromes (MDS)

Acute Lymphocytic Leukemia (ALL)