Temsirolimus and clofarabine for the treatment of elderly AML patients

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Published: 13 Feb 2011
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Prof Sergio Amadori - Tor Vergata University Hospital, Rome, Italy
Prof Sergio Amadori discusses the results of a trial investigating the use of temsirolimus in combination with low-dose clofarabine as a therapy for older patients with primary refractory or first relapsed acute myeloid leukaemia (AML). The PI3K/AKT signalling pathway is associated with cell proliferation and survival in AML patients. Prof Amadori’s team targeted this pathway with the mTOR inhibitor temsirolimus in order to enhance the sensitivity of leukaemic cells to clofarabine, a second-generation nucleoside analogue. The study demonstrated that a regimen combining temsirolimus with low-dose clofarabine can be safely administered to elderly patients with advanced AML and was associated with encouraging anti-leukaemic activity in this difficult-to-treat patient population.

 

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

 

Interview with Prof Sergio Amadori - Tor Vergata University Hospital, Rome, Italy

Temsirolimus and clofarabine for the treatment of elderly AML patients

 

MO       Moderator

SA        Sergio Amadori

 

 

MO       Well, it's another exciting day here at the American Society of Haematology meeting for e-Cancer Television.  And Sergio Amadori from Rome, you're with me now to tell me about using an mTOR inhibitor in patients with AML, older patients with AML, refractory or relaxed disease.  Now, why were you looking at this particular group of patients?

 

SA        Well, this particular group of patients are very attractive in one sense because for them the therapeutic options are very limited.  The disease is a severe disease, intensive chemotherapy as the standard approach for this disease.  And of course, quite often older patients are unable to undergo intensive treatment with all the associated complications, for example.

 

MO       And what were the indications that Temsirolimus, this mTOR inhibitor, could be used for?

 

SA        Yes.  This agent, or this class of agent, because there are many mTOR inhibitors, are interesting because we have learnt over the last several years that in this disease, this pathway regulated by this protein mTOR is playing a crucial role in regulating some critical cellular activities, like proliferation, differentiation and survival.  This is both in normal cells, as well as in a tumour cell and especially AML cell. 

 

Now, there are data indicating that in AML there is an apparent expiration of this protein.  So this suggests that that could be targeted to be explored for critical intervention.  And since we are in the, let's say, fortunate position to have a drug like... the name of this drug is Rapamysin, which is a specific inhibitor of the mTOR.  This drug is commonly used for preventing rejection in solid organ transplantation.  So it's an old drug, very known to all the transplanters, but is a specific agent, is a specific inhibitor of mTOR. 

 

Now, over the last several years a new derivative of Rapamysin has been developed.  One of these is Temsirolimus, which is injected IVE.  And this drug is able to inhibit specifically this protein.

 

MO       So you've got a molecular label on the AML that you can target and you've set up the Gimama study.  Could you tell me what you did with your patients?  You've got around about 50 patients so far.

 

SA        Yes, so based on this rationale we developed a trial, tried to combine an agent which is recognised as a very active agent in AML - the name is Clofarabine - and to combine this agent with an mTOR inhibitor.  The idea is to see whether the additional mTOR inhibitor could potentiate the effect of chemotherapy.  The aim of the study was to try to get remission in a very difficult-to-treat population of patients, because in this case we selected older patients with events, acute myelogenous leukaemia, which means patients already treated but not responsive to frontline treatment, so first choice treatment, or relapsing after an initial treatment.

 

MO       And for that reason, did you have a control group?

 

SA        No, this study was the... is a phase II trial to test the feasibility of this combination and the activity and the safety.  We know that for these patients, in many countries the treatment choice is just palliation, palliation with supportive care, low-dose chemotherapy, just to keep them alive as much as possible, but we know that, you know, the disease at this point is usually fatal in three, four months.

 

MO       Primarily then you're looking for safety, but because of the effective historical control you can presumably say something about efficacy.  I'd like to ask you about both.  What did you find, first of all, about safety?

 

SA        We found that this combination was feasible.  There was some toxicity related to the myelosuppression induced by Clofarabine, but the duration, the pancytopenia, which is... which means a decline of the white count of platelets, red cell, was in the expected range of approximately 25 to 30 days.  So there were some infections during this phase, which is normal for this category of patients treated with similar approaches, but at the end, this combination was able to induce responses in 21% of the patients with a safety profile which is tolerable and manageable in the vast majority of the patients.

 

MO       So you said induced responses.  You feel there was an anti-leukemic affect then?

 

SA        Yes, 21% enter a complete remission.  And one interesting feature of this trial, what I think is the most important, interesting point from a scientific point of view, is that we found that, overall, 21% responded.  But if you look for those among the 53 patients entering this trial, for those who had evidence of a biological effect of this drug, Temsirolimus, which means inhibition mTOR, so in the patient where the mTOR was effectively inhibited, their CR rate was 62%.  So extremely gratifying, indicating that if the biological effect is taking effect, biological activity of the drug is taking effect, you can induce responses in a substantially higher proportion of patients.

 

MO       There's some thought that mTOR inhibitors could enhance cytotoxic effect too, isn't there?  Did you find any evidence of that?

 

SA        Yes.  In fact, this kind of substantial activity indicated by the 62% of CR rate in patients with evidence of the biological effect is in reality proof of concept that in fact inhibition mTOR could potentiate the effect of chemotherapy, because in the other group of patients where such a biologic effect was not seen, the response rate was 0%, so zero versus 62%.  So a very provocative data, which of course needs to be confirmed in a future trial, but very, very interesting, indicating that if you are able to inhibit the appropriate target you can increase the activity of the anti-leukaemia agent.

 

MO       So provocative, interesting results in a study with just over 50 patients.  What are the clinical implications of this small study?

 

SA        The clinical implication of this study is that we have to continue developing this sort of combination.  And the idea, at this point, is to develop the same programme for, let's say, a subgroup or older patients with AML in better shape.  Better shape means with an earlier disease, so frontline treatment for patients considered to be, in general terms, not eligible for a very intensive chemotherapy, because this is not a very intensive chemotherapy. 

 

MO       Finally, what would you say to busy cancer doctors right now about this sort of approach to acute myeloid leukaemia?

 

SA        Yes.  What I would like to say is that we need to explore new, novel regimens for this disease because the reality, nowadays, is really dismal for this category of patients.  So the hope is that what we are learning on the biology of the disease, the capability to develop target agents able to, you know, target this molecular or genetic or cellular abnormalities could bring hope to really improve the anti-leukemic efficacy of this... of the treatment we have nowadays, because otherwise you are to deal with a disease which is fatal in almost 99% of the patients in three, four months.  That's the reality.

 

MO       So you think specifically molecularly targeted agents...

 

SA        Yes, is the future.

 

MO       ... could work in AML?

 

SA        Yes.  No, no, this is really the future for this disease.  In the last several years, especially in young adults, as opposed to older patients, we are seeing, you know, substantial improvement thanks to the introduction in the therapeutic [unclear] of this new target agent.  And there are plenty of new agents which are being tested now.  Of course, older patients are usually, you know, less frequently included in these experimental studies, in these innovative studies because they tend to tolerate less well, you know, the chemotherapy and many of these target agents.  But this combination, in particular this combination proved to be quite interesting because the tolerance was, generally speaking, acceptable and the efficacy seems to be very promising, especially, as I said, for those who have evidence of biologic effect of this agent.

 

MO       Sergio, thank you very much for joining us on a warm, sunny day here in Orlando, Florida...

 

SA        You're welcome.

 

MO       ... at the American Society of Haematology.