2010 American Society of Hematology Annual Meeting 3rd - 7th December

Interview with Prof Andre Goy - Hackensack University Medical Center, New Jersey, USA

Inotuzumab ozogamicin therapy for indolent B-cell non-Hodgkin's lymphoma

MO       Moderator

AG       Andre Goy

AG       Well, the field of the treatment of lymphoma has really been revolutionised with the use of monoclonal antibody, so these antibodies bind to a certain molecule on the surface, and we know many of them, and bring onboard the immune system to attack those tumour cells.  So that's the main role of the cold antibodies.  And they have changed the landscape, improved the survival.  But in order to build up on this, because patients develop, over time, chemo resistance to... a resistance to the antibodies, basically try to use these antibodies as vectors to deliver either radiation or chemotherapy.

Here, the case today is to develop... it's an antibody drug conjugate that brings a very potent cytotoxic at the surface of the tumour cell to improve the toxicity profile and improve the efficacy.

MO       So this is a guided-missile approach, and very attractive it is too, but you chose difficult patients because they are indolent non-Hodgkin's lymphoma refractory to Rituximab, refractory to Rituximab with chemotherapy and also refractory to radiotherapy.  That's a difficult combination.

AG       Absolutely.  And on purpose these trials are designed to try to really see where the minine  is so that we can try to develop a compound that actually will benefit those patients.  If a patient has failed Rituximab and there's a lot of treatment with Rituximab and maintenance  Rituximab after chemo immunotherapy now or radio immunotherapy, this is a situation where patients become very often chemo resistant.  So in that population, some of these patients have the median number of  prior therapy... I'm sorry, two-thirds of the patients have more than three prior therapies, three or more prior therapies and up to 14 therapies and the subset of patients have prior fail high dose therapy and stem cells transplants, so this is really a difficult population.

MO       Right, so those are the hoops of fire that you're trying to jump through.  So tell me how you did achieve this, what you did in the study.

AG       So in our centre, and it's a multicentre... it's a multicentre study worldwide, we treated patients, reducing this compound.  And I just want to take one minute to explain that the reason this antibody that was picked, it's an anti-CD22, is when the cold antibody binds the CD22 or the molecule at the surface of the b-cells, it actually, instead of waiting to call the immune system onboard, internalise immediately.  So this is a natural step to take it as a drug shuttle vector antibody dual conjugate. 

So the antibody is linked with the linker to this very potent cytotoxic.  It is given at a dose that was established in the two phase I studies that we have published recently, and once a week for four weeks.  Patients were treated for up to four cycles and then if they responded they could continue up to a maximum of eight cycles.

MO       Now, I believe there is some activity, but I do have to ask you about adverse events.  What did you find?

AG       Well, the adverse event was the toxicity profile was consistent to what had been seen in the phase one - and that was the goal of this study, to verify this - is the main toxicity was actually haematological toxicity with thrombocytopenia.  And thrombocytopenia, in this compound, which is not specific to this compound, it's with every chemotherapy cytotoxic agent because the cells of the bone marrow that divide extensively are sensitive to chemotherapy, so the thrombocytopenia that we're seeing, it actually occurs pretty quickly within the first cycle and usually lingers around 50, 60 and recovers over time. 

The meantime, to recover to what we call a grade one platelet level or thrombocytopenia, was actually in the range of 30 days.  Some patients took a much longer time to recover.  And, as I alluded in the presentation this morning, it might be important in the future, as we move forward this compound, to try to see if we can explore different schedules of dosing to adjust the toxicity profile of thrombocytopenia.

MO       Well, let's move onto efficacy because you've reported that you did have some complete responses.

AG       Correct.

MO       And your overall response rate was something.

AG       The overall response rate was 58% in this very heavily pre-treated population and then one-third of these patients were in complete remission.  So this is really impressive.  And then with the progression for survival in the excess over 11 months in a heavily pre-treated population, this is promising enough to continue to move forward and to use this antibody drug conjugate.  And the next step will obviously be to see on how we're going to integrate this in the paradigmal  treatment of b-cell lymphomas.

MO       Promising it may be, but this is only 43 patients, so we should not get carried away at this stage.  How carefully did you choose those patients?

AG       So these patients are not actually given the number of compounds that are being tested, the number of options available I should say, in a context of follicular lymphoma.  These patients were not picked here and there.  These patients represent the routine population of heavily pre-treated population, difficult patients.  And what we still need to continue, complete the phase II, which we have an additional 20 patients or so to complete this phase II, but we have, in parallel, already started some other studies where we start to integrate in a real lab setting with other cytotoxication or other biological to see if we can improve the response and outcome of these patients.

MO       Clearly, it's not ready for Primetime yet, but what do you think doctors should be thinking about this?

AG       I think it's an exciting opportunity to be able to go beyond the simple monoclonal antibody and to use them to move away from conventional cytotoxic.  Similarly, that we have developed over the last, I would say, five to eight years, we've developed a lot of new biologicals in the field of lymphoma, most of them being targeted therapy, targeted biologicals.  So now we have the opportunity by linking these antibodies through antibody drug conjugate to do targeted chemotherapy.  And targeted chemotherapy might really help us in the future to improve what's called a therapeutic index and reduce the toxicity and improve the efficacy.

MO       And what are your conclusions about the overall outlook for indolent b-cell non-Hodgkin's lymphoma because of these available salvage therapies?

AG       I think it's one more option that we have in a heavily pre-treated population.  We've clearly seen a difficult subset of patients that we have to... promising enough, as I say, to move forward, we still have to evaluate how it will be best to integrate this in a frontline setting or first relapse or early on in the course of the disease.

MO       Andre, it's good to have you here at the American Society of Haematology Annual Meeting.  And thank you for being on e-Cancer TV.

AG       Thank you for having me as well.