ESH AL 2018 | Gemtuzumab ozogamicin for AML: challenges and reapproval

This is the first antibody-directed treatment in any cancer and it sets a pathway for targeted treatment in this disease, as it happens the target is the CD33 expression, which happens to be on almost all AML blast cells. There’s been controversy about whether it could ever work because that epitope is not on stem cells leukemic stem cells, therefore they could come back. Now there’s arguments both ways on that point.

It’s had a checkered history, we’ve been investigating, we’ve been involved in the studies, both the sponsored study and investigator study, since the year 2000. The drug originally had approval in the United States and in Japan, but the confirmatory trial done in the States ran into problems with induction – excess induction deaths – although, the induction death rate at 5% is really what you expect, just so happens the study arm, the control arm, had only 1% death, which is just not typical at all, so that was a bit unfortunate, and what was interesting was that that approval was based on an unrandomized trial and the drug was used in a dose of 9 mg/m2, so between the time it got approval and got withdrawn there was quite a lot of investigator initiated trials using it at the 9 mg dose; before transplant, after transplant, with chemotherapy of various types, and it was clear it was too toxic, so it got itself into a bit of trouble, and the toxicity was liver toxicity primarily. It was clear that the academic community made a mistake by jumping in with too high a dose without doing dose finding. Fortunately, we decided to do dose finding and came away with the feeling that in a multicenter basis 3 mg/m2 squared was an acceptable dose with hardly any noticeable toxicity. So, we opened a randomized trial in the UK, just adding it to the first course of chemotherapy, and it didn’t improve remission rates, which in young patients is high in a way, but it definitely significantly reduced the relapse rate. This didn’t convert into overall survival until there was long follow-up on the patients, when eventually it did turn into survival benefit, but in subgroups there was clearly a benefit – in the core binding factor leukemia, it really did very nicely. In the patients with adverse karyotype, it didn’t seem to do anything. So, subsequently there had been another four trials in adults using the same sort of tactics, different doses, more than one dose, and the same thing happens; no improvement in remission rate, significant reduction in relapse risk, not always an improvement in survival, no evidence of benefit in adverse cytogenetics, probably beneficial in favourable risk disease, and if you choose the 3 mg dose perfectly safe.

So, the questions for the drug are the French study, which was probably the influential study in getting it reapproved last year, where they give it three times in a week. Do you need to give it three times? Can you give it once? Can you give it to twice? So, the number of times you have to give it remains to be finally established, and the next issue is whether you need to give it beyond induction – can you give it, do you give it, in consolidation? Two of the trials, the early trials, did have a consolidation option and it didn’t make any difference. The French study that has pretty good results and a significant disease-free survival, although not overall survival benefit, gave it in induction and consolidation, and we don’t know whether you need it in the consolidation, so maybe that’s still a question to us, but in my view if a patient has got a core binding factor leukemia, which is about 15 or 18% of young patients, this drug is helpful. You can add it to a number of chemotherapy schedules, like FLAG-IDA, or MEK, or daunorubicin-Ara-C without undue toxicity, as long as you use 3 mg dose. So, it is now approved and it’s available for use.

I mentioned earlier that it’s always remained approved in Japan, and after we saw our first study in younger patients delivering some benefit and then we did another older patient study, which showed a survival benefit, we were faced with the dilemma of an unlicensed drug out there, clear benefit for the patients, so what do we do in the next trial? Fortunately, we were able to arrange to import the drug from Japan, so every patient in the UK has been getting the drug for 5 or 6 years now. Now that it’s approved of course, they’re going to have to pay for it. So, that’s the story of gemtuzumab ozogamicin – there are still a few studies to be done.