Case 4: Treating AML With HMA/Venetoclax


Naval G. Daver, MD:I think even though people say we shouldn’t compare across trials, we always compare across trials, and that’s human nature. You see 2 trials and you see the survival, and that’s where the venetoclax came out looking better. When you do the HMA [hypomethylating agent]/venetoclax, are you admitting these people routinely? Are you starting it outpatient? Are you doing any of the tumor lysis prophylaxis? Dave, what do you do?

David Alan Rizzieri, MD:We’ve done it both ways, depending on the patient’s circumstance, much like what was discussed before. The outpatient still requires a lot of social support and close care. We take advantage of our 7-day access clinic to see these patients. We start them early in the morning and we check [laboratory test results] again in the late afternoon, and if there’s any indication of concern, they are medically admitted. Otherwise, we bring them in the next morning. We’ve done it in both settings in that regard.

Naval G. Daver, MD:And do you use ramp-up?

David Alan Rizzieri, MD:We do.

Naval G. Daver, MD:Are you focusing on the FDA doses or do you have your own different dosing? They said with POSA [posaconazole], 70 [mg], and with VORI [voriconazole], 100 [mg].

David Alan Rizzieri, MD:We’re concerned about these people. As you mentioned, I am concerned about the infections and we do like [posaconazole] as prophylaxis, but I’m not necessarily comfortable in these patients going down so low to 70 to 100 [mg]. If our patients are able to tolerate it, we seem to be at around 200 for the [venetoclax] dose, and patients are tolerating that well, but that’s just empiric. So far, I don’t know what others have tolerated at other sites.

James K. McCloskey II, MD:We do the ramp-up. We rarely admit unless patients have tumor lysis at baseline or they have impaired renal dysfunction, and understanding that the [venetoclax] data that we have currently really did enroll patients who weren’t terribly proliferative. I don’t think those are the patients we’re targeting. I think one of the great things that’s come of this data is that when I want to use [posaconazole], I can more reliably get it. We send in the article, we say, “This is what they used,” and we’re more likely to get that approved because that would be our preferred antifungal, as well.

We’re very fortunate to have a pharmacist that supervises me at all times, but one of the most confusing things around this drug is dosing it with an azole. The standard package insert way of administering that would be 70 mg in combination with [posaconazole]. I think, to be honest, it’s often cumbersome for our patients to take that many tablets. We are going to 100 [mg], and 100 is our goal dose with an understanding that it’s a little higher than the 400, but it was studied all the way to 800, so we feel pretty comfortable with that. We haven’t had a lot of trouble with tumor lysis, but we do monitor patients really closely in the office.

Naval G. Daver, MD:We did that DDI [drug-drug interaction] study, which was with the 12 patients with [posaconazole], and it showed that the levels go up from 8- to 12-fold. As you said, at the same time, the study had actually gone up to 1200 [mg] without major DLT [dose-limiting toxicity]. It wasn’t that we were concerned. We’re usually going at 100 [mg] with [posaconazole] and then with [voriconazole] or with isavuconazole, we’re doing about 200 [mg]. I think one of the important things that we are definitely seeing is that the prolonged, continuous use of venetoclax is not feasible. This is something we’ve discussed with the company and the FDA, but the label doesn’t contain it, and the community doctors and others were maybe not using it frequently.

We routinely will give about 21 days or so in the first cycle, check a bone marrow, and you’ll see almost 80% of these people are either hypocellular, acellular, or in remission. After that, we are going to about a 2-week-on, 2-week-off schedule. There are publications coming out on this, but right now, whenever we go to meetings and people say, “Well, you know, everybody says it’s so good, but I give 3 people venetoclax continuously and in 3 months, they’re all zero ANC [absolute neutrophil count] and have fungal infections.” I think that there is a little bit of art. It’s not like IDH inhibitor orFLT3,where you just give it and you keep giving it. You actually have to allow count recovery in these people. What about somebody who had a higher white count, let’s say a white count of 35,000 or 40,000? He doesn’t have aFLT3, and you think he is a good candidate for AZA/VEN [azacitidine/venetoclax]? Would you give him Hydrea and cytoreduce him? Would you admit this patient and start treatment? What would be your practice for this kind of patient?

David Alan Rizzieri, MD:We cytoreduce first on all of those folks.

Naval G. Daver, MD:Hydrea, Ara-C, or both?

David Alan Rizzieri, MD:I like Hydrea.

Naval G. Daver, MD:Do you have a cutoff, like a protocol, in your institution before starting [venetoclax]?

David Alan Rizzieri, MD:I like to be grading it at under 10, but I’m comfortable under 20.

Naval G. Daver, MD:Yes. What about you, James?

James K. McCloskey II, MD:Similar. I think that it depends on how high the white count is. If I’m really requiring a lot of Hydrea, I might favor the Ara-C to avoid the mucositis that sometimes comes along with high doses of Hydrea. We would cytoreduce those folks, too. We don’t have a specific protocol, but I agree with less than 20.

Naval G. Daver, MD:Yes, we’re pushing for less than 20, as well. Usama, have you seen any of these patients coming to transplant? What do you do for the venetoclax? Are you stopping it a certain number of days before, or right up to transplant conditioning?

Usama Gergis, MD, MBA:Right, 2 points. We stop right before conditioning, so there is no tapering.

Naval G. Daver, MD:No washout.

Usama Gergis, MD, MBA:Or washout. There are really no data that it does anything. The other point with the antifungal is, in the transplant world, we are very comfortable using azoles with calcineurin inhibitors and rapamycin. It increases the rapamycin steady level 9-fold. Again, with a calcineurin inhibitor and rapamycin, you can always test the levels, whereas you do not do that with venetoclax. I think at 100 mg, most people are comfortable with azoles. You cannot just leave them without antifungal prophylaxis with 10% Aspergillus in 60 days or so.

Naval G. Daver, MD:Have you started seeing any, or do you have, trials looking at a post-transplant [azacitidine/venetoclax] approach, maintenance, or are people trying to do that?

Usama Gergis, MD, MBA:The short answer is no, but the [azacitidine] maintenance post-transplant came from your institution, and then it did not pan out that much in a larger trial. For people who are MRD [minimal residual disease] negative, we do not do maintenance other thanFLT3.

Naval G. Daver, MD:OK.FLT3—you’re doing which one, sorafenib or midostaurin?

Usama Gergis, MD, MBA:There is currently an open CTN [Clinical Trials Network] trial with gilteritinib.

Naval G. Daver, MD:So you’re doing with….

Usama Gergis, MD, MBA:We are part of this trial. For people who are not on the trial, we try to get whatever we can get away with. Of course, you have to go through hoops with insurance approvals with these drugs, and they’re $15,000 to $20,000 a month.

Naval G. Daver, MD:That’s going to be a great trial to get the data, because, as you know, they’re doing a lot of sequential MRD, both by flow and PCR [polymerase chain reaction], and then the MORPHO post-transplant trial. One of the things that affected that trial was the data from the SORMAIN study where they showed sorafenib maintenance was superior to none. It had a pretty big difference. I think the trial is still going well, and they expect to complete enrollment at the end of this year. That will be a very nice benchmark study for post-transplant maintenance, so we’ll have to wait and see.

Transcript edited for clarity.

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