ASH 2015

ASH 2015: New targeted therapies for haematological malignancies

Dr Robert Hromas - University of Florida, Gainesville, USA

We’ve just been hearing some pretty big news, some quite remarkable responses in a number of areas including acute myeloid leukaemia, acute lymphoblastic leukaemia, CLL. What do you make of the session we’ve just been at which was all about targeting blood cancer therapies and the fact that they offer now significant improvements in survival if you do target them in some of these new ways?

There are a couple of really important things that we took out of the session. First, our enormous supported investigation into the molecular defects that cause cancer in the first place are now beginning to bear fruit in that we have drugs that target these molecular defects exactly. Why is this important? Because then the toxicities might not overlap, as they target one type of defect in a cancer and we bring another drug that might target another defect in that same cancer they might have two different toxicities and so those non-overlapping toxicities might allow us to combine many of these new drugs up front, especially in myeloma and chronic lymphocytic leukaemia.

Now you had things like midostaurin with Dr Stone talking about acute myeloid leukaemia, also rituximab in ALL from Dr Maury. What do you make of those papers?

Two different, really important studies. The midostaurin study is really interesting because it’s a decade’s worth of effort by an international team of collaborators. They never quit, they believed in this new agent and what they found was that in one specific type of acute myeloid leukaemia, those with the FLT3 mutation for which there were really no other treatments except bone marrow transplant, that this drug was highly effective in. That’s a really important study, so identifying those patients up front, it gives them new hope in a disease that previously was hopeless. The rituximab study, adding rituximab to those acute lymphoblastic leukaemia patients that express CD20 on their surface, was also important but for a different reason. It resolved a long-standing controversy in acute lymphoblastic leukaemia therapy. Previously they thought that CD20 was not expressed enough on the cell surface of an ALL leukaemia cell to allow rituximab to be effective but this study indeed showed that that’s not the case; adding rituximab to acute lymphoblastic leukaemia therapy that expressed CD20 was highly effective.

So we’ve got a new drug and an old drug there.

An old drug in a new situation.

Yes, an old drug in a new situation.

And then a new drug.

And previously a new drug. What did you make of the work on daratumumab, that’s in multiple myeloma, from Dr Plesner?

Daratumumab is the first of many new antibodies targeting multiple myeloma. Rituximab showed the way, it was a monoclonal antibody targeting antigens on the surface of B-cells so for B-cell malignancies it was very effective. Now there’s a whole number of monoclonal antibodies targeting the surface of antigens that are on the surface of other B-cell malignancies like multiple myeloma. Daratumumab is the first example of that and I think there are many more coming. It’s opened the dyke, the dyke will flood out, these will be very effective.

And Dr Moreau had something to say about myeloma as well, didn’t he?

Yes, so multiple myeloma is a disease that requires a long period of treatment and that treatment is often in an infusion suite in a hospital or a cancer centre, often getting multiple drugs through the veins. So it really disrupts patients’ lives. Dr Moreau provided us a way in which we could give very effective therapy entirely by mouth at home.

With a new drug.

With a new drug, ixazomib. So that’s very exciting from the standpoint it’s a highly effective proteasome inhibitor but it’s oral, the first oral proteasome inhibitor. Added to previous therapy like lenalidomide and dexamethasone for myeloma we’re starting to be highly effective.

And some other relatively new players: idelalisib and venetoclax in chronic lymphocytic leukaemia.

So in chronic lymphocytic leukaemia there were three drugs recently approved and then a fourth that was almost certainly to be approved, venetoclax. So it’s an enormously exciting time in CLL as well. Venetoclax was interesting because it’s the first drug that disrupts Bcl2 which signals the CLL cell for survival, so it’s a fundamental signal for the CLL cell to stay alive and divide without stopping. In addition it’s effective against a type of CLL, those patients that have the 17p chromosome deleted, which responded poorly to all other therapy. So that’s why venetoclax is exciting. We think it will also be important moved up front for all CLL patients and indeed maybe follicular lymphoma as well because follicular lymphoma also relies on Bcl2. Idelalisib was approved several years ago for CLL but it targets a completely different pathway, raising the question that perhaps these drugs can be combined up front and we can speak about finally eradicating minimal residual disease in CLL for long-term remissions, perhaps even cure.

And ibrutinib put in a showing at your session here as well, didn’t it?

It did. So the ibrutinib study we talked about at this media session was moving ibrutinib from relapse disease to up front. I think that that’s a principle that we’ll see for many of these myeloma and CLL drugs. They were approved for relapsed disease because we had decent treatments for CLL myeloma already in hand and so to reach FDA approval they tested the drug in the relapse situation. But this study showed that moving ibrutinib up front and comparing it with the types of therapies we already had in hand, ibrutinib was better. So this principle of moving these new molecularly targeted therapies from the relapsed situation to up front therapy will be crucial.

So what do you make of the comment we heard there that there are an incredible number of new drugs being licensed for CLL? Hematologic malignancy seems to be going from strength to strength at the moment.

That’s a wonderful question and a very exciting one. So why so much excitement now? Why so many new drugs approved now and so many great new therapies falling behind us? There’s a whole pipeline of great new therapies flowing towards patients with blood cancers. I think it’s because our generous tax payers have supported the National Institutes of Health research into fundamental defects in cancer for so many years. The National Cancer Institute of the NIH has provided support in understanding what drives a cancer cell to divide without stopping. It’s those defects that the pharmaceutical groups have targeted with their new drugs. I think without that investment we wouldn’t see the tremendous fruit before us now.

So what’s your take-home, if you’re to have a simple one, from this session for cancer doctors?

I think they’re going to have an embarrassment of riches and putting these multiple new drugs together in regimens that can potentially produce long term disease remissions is going to be really a challenge but it’s going to be an enormously exciting challenge. Think of being a blood cancer doctor today when previously, even ten years ago, we would tell our patients, “Well, you have three or four years to live.” Now we can say, “I haven’t lost anybody in three or four years. You could live an enormously long time.” And reaching our patients’ goals with these new therapies is not only a challenge but an enormously exciting challenge.