Relapse after allogeneic stem cell transplant for acute myeloid leukemia represents, still represents the main cause of transplant failure and post-transplant death. And therefore, many attempts were used to try to prevent a relapse. And there are obvious reasons why we try to prevent relapse, because nobody would like to see a patient relapsing, so for obvious reason, and because treatment for patients who relapse after allo-transplant is still suboptimal for most conditions, and because preventing relapse is, even in term of pharmacoeconomic, much cheaper than treating relapse...
Relapse after allogeneic stem cell transplant for acute myeloid leukemia represents, still represents the main cause of transplant failure and post-transplant death. And therefore, many attempts were used to try to prevent a relapse. And there are obvious reasons why we try to prevent relapse, because nobody would like to see a patient relapsing, so for obvious reason, and because treatment for patients who relapse after allo-transplant is still suboptimal for most conditions, and because preventing relapse is, even in term of pharmacoeconomic, much cheaper than treating relapse.
So, in term of candidate drugs, many types of candidate drugs were tested and the most interesting results are with hypomethylating agents and with tyrosine kinase inhibitors, FLT3 inhibitors specifically. So, in terms of hypomethylating agents, we have mostly data with azacitidine and decitabine. Basically, in term of preclinical studies, we have more and more accumulating evidence that these hypomethylating agents will not be targeting only the leukemic cells, but will also work on the donor immunity and donor adoptive immunotherapy, so shifting the immunological reaction from graft-versus-host disease towards graft-versus-leukemia effect.
Multiple Phase II studies and case series have indicated that low-dose azacitidine, basically 32 milligram per meter square daily for five days, post allo-transplant is feasible, relatively safe and allows a high, I mean allows a prolonged leukemia-free survival after allo-transplant. However, the results are still controversial as some groups are not yet convinced because of the lack of solid Phase III randomized studies for hypomethylating agents.
Conversely, for FLT3 inhibitors, we have now a wealth of data for sorafenib, which is a tyrosine kinase inhibitor targeting FLT3 among other tyrosine kinase. So, you know that internal tandem duplication of FLT3, FLT3-ITD, Is one of the most frequent molecular abnormalities in acute myeloid leukemia, if not the most frequent. In general, this is associated with a high rate of relapse, including early relapse after allo-transplant and a poor outcome, even post allo-transplant.
Multiple, single center, multicenter registry and randomized trials have shown that sorafenib maintenance after allogeneic stem cell transplant in patient with FLT3-ITD AML significantly reduces the relapse rate, is quite safe, and results in a major improvement in leukemia-free survival and overall survival. Basically, the use of sorafenib post allo-transplant has transformed the prognosis of FLT3-ITD AML from a poor prognosis leukemia subtype to a good prognosis leukemia subtype, similar to what happened with the use of tyrosine kinase inhibitors in Philadelphia-positive ALL.
So, currently when we have a 60 year-old patient newly diagnosed with AML, we hope that the patient has a FLT3-ITD because with a global strategy of induction, consolidation, allogeneic transplant, and post-transplant sorafenib maintenance, we can hope for a cure or long-term leukemia-free survival in more than two thirds of these patients.
Based on that, within the EBMT Acute Leukemia Working Party, we recently published consensus guidelines recommending post-transplant sorafenib maintenance in patients with FLT3-ITD AML after allogeneic stem cell class.
