EHA 2016
Older patients with AML benefit greatly from SGN-CD33 and HMA therapy combo
Dr Amir Fathi, Massachusetts General Hospital, Boston, USA
This year we will be providing an update on the ongoing phase I trial investigating the combination of an antibody-drug conjugate called SGN-CD33A, also known as vadastuximab talirine, in combination with hypomethylating agents for patients who are older and have acute myeloid leukaemia.
Could you give us some background on antibody-drug conjugates?
The treatment of acute myeloid leukaemia, or AML, has been traditionally based on intensive chemotherapeutic approaches, combinations of chemotherapies that render the patients aplastic for a long period of time requiring prolonged hospitalisations. Oftentimes toxicities and morbidities related to low blood counts or cytopenias with resultant risk of infections and bleeding that can be lethal. In recent years there has been a development of agents called hypomethylating agents called azacitidine and decitabine. These drugs are gentler, they are easier to give, they are provided in the outpatient setting generally in contrast to traditional chemotherapies. But even though they are gentler and more tolerable their responses tend to be more transient and less robust. Rate of remission is much lower. Nevertheless for the older, less robust patients these have become more the norm for treatment, at least in the United States.
In more recent years, even more recent than hypomethylating therapies, there has been an emergence of antibody based therapies or antibody conjugates. The first such drug that gained some amount of attention and use, both in the States and in Europe and no longer in the States, was Mylotarg which was also an antibody drug conjugate against 33. That drug is no longer in use in the United States for a variety of reasons but that hasn’t stopped the development of other potentially promising antibody drug conjugates across a host of different hematologic malignancies including lymphomas, acute lymphoid leukaemias and now acute myeloid leukaemias. Vadastuximab talirine, which I’m going to be referring to as 33A, is yet another more recent antibody-drug conjugate bound to a fairly potent cytotoxic agent with a stable linker. So it’s the antibody, the linker, the toxin, they’re stable so the toxin doesn’t get released in circulation and cause off-target effects. The antibody circulates, when it reaches the cell, when it recognises CD33 on the surface of leukaemia cells, which the majority of myeloid leukaemia cells have, it incorporates itself into the cell and within the lysosome trafficking environment releases the toxin leading to DNA damage and cell death. So in this sort of targeted payload based cell killing we mainly get on-target cytotoxicity and rare off-target toxicity which is a very important phenomenon.
The drug has been tested as a single agent where it has shown some amount of efficacy in patients who have been heavily pre-treated or in relapsed refractory patients and in this most recent effort we are combining it in the up-front setting at a lower dose in combination with hypomethylating therapy, which is a gentle form of treatment, to help strike a balance between tolerability that has been seen with hypomethylating therapy and now enhanced efficacy, adding the drug and combining the two.
What kind of results are you seeing?
I’m limited in what I can tell you regarding the updates on the results but if you look at what has already been presented a few months ago at ASH the rates of remission are quite high with this combination, significantly higher than what one would have seen with traditional hypomethylating therapies such as Vidaza or Dacogen. Those drugs in older patient populations generally lead to a remission rate of about 18-28%; traditional chemotherapy remission rates hover, depending on who you talk to, between 50-80% depending on the age range of the patient. So, generally speaking, traditional chemotherapy is more potent but also more toxic than hypomethylating therapy. The data we presented at ASH showed that the combination, at least among those earlier patient populations, led to a remission rate in the high 60% range. We’re going to update that data this afternoon.
You mentioned the patient age range there, do you think there could be a way of striking a balance between the hypomethylating agents which help soften the blow for older patients with the more potent 33A effectors depending on age range in that case?
We do. The most important aspect of this and what encourages me is that for the longest time I see an older patient who I’m very hesitant about giving aggressive chemotherapy to, mainly because of his comorbidity, his functional status, his overall robustness. But I also have an appreciation for the aggressiveness, the proliferativeness of his disease. So that hypomethylating therapy, even though they are gentle they’re also gentle in the amount of time they take to work, oftentimes taking 2-3 months before you get a maximal effect. The hope is that if you combine hypomethylating therapy with a more cytotoxic potent compound you may allow yourself the time and space to achieve and accomplish what you need to do. So that this might be again a nice middle ground between traditional chemotherapy and more gentle hypomethylating therapy.
