DR TIBES: My laboratory actually reported almost 6 or 7 years ago at the ASH meeting — we published it subsequently — of a potent sensitizing effect of venetoclax, formerly known as ABT-199, to azacitidine.

So we were one of the first labs to report activity of this drug in AML as well. And based on our input, a study was designed. And there have been now the first data in AML. So venetoclax is a Bcl-2 inhibitor, Bcl-2 proteins that prevent apoptosis. Apoptosis is cell death. So cancer cells or leukemia cells, including CLL cells but also AML cells, have found a way to increase Bcl-2. That prevents cell death. So now venetoclax is essentially — it’s not directly a Bcl-2 inhibitor, but actually it’s a BH3 mimetic.

Without going into detail, it’s essentially inhibiting or blocking to Bcl-2 and freeing up the potential of cells to die again. So it is a Bcl-2 inhibitor in that sense. So there were single-agent data in AML. There were responses seen, but those responses were short lived. And now there were several trials in combination as a lower-intensity approach. So earlier we talked about induction chemotherapy, consolidation, as well as transplant if it’s appropriate.

There are many patients — AML is a disease of the elderly, so the average age or the median age is around 70, 69 to 72, depending which study you read. So it’s a disease of the older patients. And many older patients do not want to receive intensive therapy or are not candidates for an allogeneic stem cell transplantation. And that’s a real community world — real-life setting in the community.

So what do we have available? We have azacitidine available. We have decitabine available to use as a lower-intensity therapy. So venetoclax, or the Bcl-2 inhibitor venetoclax, has been tested in the first Phase I/II studies early on together with azacitidine. And the results have been reported in abstract form. And there were very good remission rates in the range of 75% and upwards. And at this recent ASCO meeting there was also a report with low-dose ara-C, so subcutaneous low-dose ara-C given for 10 days with venetoclax, which is an oral medication. And the response rates were also in the 65% to 70%, the CR and CRI rates. And close to 70% of the patients actually — it’s a small study there, like 26 patients. But 70% of the patients were alive at 1 year. And those are quite some encouraging numbers.

DR LOVE: I’ve got to ask you — I keep getting out on tangents, but it’s interesting. The fact that you work with venetoclax — I’m sure — thought about it a lot. I’m just kind of curious, because I’ve been fascinated by the tumor lysis syndrome that’s been seen with it. And I was just curious since you work with it so much, do you think it’s just really a straightforward issue of it just kills a lot of cancer cells, or do you think it’s something more sophisticated than that, more complicated?

DR TIBES: No, it just kills a lot of cancer cells. And it’s a direct mechanism, so you essentially take this Bcl-2 away. And the apoptotic escape — so the cell death escape — is just opened up. So you see cell deaths and tumor lysis.

DR LOVE: Do you think there’s something biologically also about tumor lysis in CLL and venetoclax, specifically, there’s some — I’m just curious why you see it so often.

DR TIBES: I think it’s just a very potent drug. It’s a very potent drug that has a direct on-target effect of taking the brake away, essentially. You take the brake away to cell death, and it just opens up the floodgate.

DR LOVE: That's fascinating. Fascinating.

DR TIBES: And that’s why this drug is given often at lower dosages the first couple of days a week. And then the dosage is increased. In the trials, you actually do observe the patients the first few days in the hospital for tumor lysis. So that’s very important. You have to monitor, because it’s a potent drug.

And we’ve seen tumor lysis with other drugs, as well. There’s the drug flavopiridol, which is not approved, or a CDK, so cyclin-dependent kinase inhibitors. We also have seen tumor lysis in CLL and other diseases. So it’s just being aware of managing them. And then we can prevent it, essentially.

Non-Hodgkin lymphoma (NHL), Hodgkin lymphoma and chronic lymphocytic leukemia (CLL)

Acute and chronic leukemias and myeloproliferative neoplasms

Multiple myeloma (MM)