Κυριακή, 18 Δεκεμβρίου 2016

PROGRESS IN AML TREATMENT

FLT3 Inhibitors 

FLT3 internal tandem duplications have been associated with poor prognosis in patients with AML. These patients have a much shorter remission duration and poor overall survival. Thus, FLT3 has been found to be an important target for therapy. One year ago at these meetings, a randomized trial[1] looking at standard induction therapy with 7+3 (cytarabine for 7 days and either daunorubicin, idarubicin, or mitoxantrone for 3 days) with or without midostaurin showed that the addition of this FLT3 inhibitor to standard induction significantly improved event-free survival and overall survival for these patients.
Since the development of midostaurin, several second-generation drugs have also produced significant responses without chemotherapy. Quizartinib is currently in phase 3 clinical trials, and at this meeting, interesting studies with gilteritinib and crenolanib were presented. Gilteritinib is a second-generation drug that targets FLT3 internal tandem duplications and tyrosine kinase mutations, domain mutations that have been associated with a mechanism of resistance to earlier drugs. In a phase 1/2 study,[2] patients with relapsed and refractory FLT3-positive AML were given gilteritinib, with an impressive response rate of about 50%. Also of interest, the median overall survival was 31 weeks, far better than what you would expect with standard therapies. This agent is now being taken into phase 3 trials in the relapsed/refractory setting, to compare it with standard salvage chemotherapy.
Crenolanib is another second-generation drug that targets the FLT3 internal tandem duplication and tyrosine kinase domain mutations. This agent has also been shown to produce remissions in about 50% of relapsed and refractory patients. We are now learning how to use these drugs earlier on in the course of patient treatments.
Eunice Wang, MD, from Roswell Park Cancer Institute in Buffalo, New York, presented a study[3] of crenolanib added to 7+3 chemotherapy in patients with newly diagnosed FLT3 mutated AML. This trial showed that crenolanib in combination with standard chemotherapy can produce remissions in nearly 100% of patients. This is quite remarkable. The drug can be given at standard doses without dose reduction, and thus, this is quite encouraging. We can see that FLT3 inhibition is here to stay and an important part of treatment for a subgroup of patients with AML.

Targeting IDH1 

IDH is an interesting mutation that occurs in about 20% of patients with AML. IDH is associated with the accumulation of an oncometabolite called 2-hydroxyglutarate. This in turn causes epigenetic changes that impair cellular differentiation. The IDH2 mutation is known to be an important therapeutic target, and drugs taking aim at IDH2 have now been taken forward into phase 3 studies. At this meeting, IDH1 has also emerged as an important target.
In one study,[4] the IDH1 inhibitor AG120 was given to patients with relapsed and refractory IDH1-mutated AML. In this population, responses were seen in nearly 40% of the patients, with complete responses in nearly 20%. This is quite encouraging. The investigator elegantly showed that these responses correlated well with a disappearance of IDH1 mutations as demonstrated by next-generation sequencing
In a phase 1 study[5] of the IDH1 inhibitor IDH305, 21 patients with relapsed and refractory IDH1-mutated AML were treated with IDH305, and responses were seen in one third of these patients. I believe that these studies validate IDH1 as a therapeutic target in AML and that this will be an important drug [class] for this subset of patients.

CD33-Directed Therapy

The cell surface molecule CD33 is expressed in about 90% of patients with AML. In fact, we know that when gemtuzumab ozogamicin was added to standard chemotherapy,[6] it showed clear benefit in overall survival. This validated CD33 as a therapeutic target. Gemtuzumab ozogamicin was withdrawn from the market for safety concerns, but new approaches to targeting this surface antigen look quite good.
SGN33A is an antibody drug conjugate that consists of an antiCD33 antibody with a pyrrolobenzodiazepine. Initial studies showed clear activity in patients with relapsed and refractory AML. A previous study[7] looked at this drug in combination with hypomethylating agents in older individuals with AML and showed a response rate of 75%. This drug is now being taken forward in phase 3 studies. As with crenolanib, we are learning how to use this drug in combination with chemotherapy.
Harry Erba, MD, PhD, of the University of Alabama in Birmingham, presented a very interesting study[8] in which SGN33A was combined with 7+3 chemotherapy for newly diagnosed younger patients with AML. This combination proved to be safe, with response rates of nearly 80%. This agent may potentially be used as maintenance therapy or monotherapy, and all of these are being investigated.
I have been working on targeting CD33 with a monoclonal antibody known as lintuzumab, using this to deliver a form of radiation directly to leukemia cells. We have been working with an isotope called actinium-225. This combination is unique because it emits an alpha particle that travels a very short distance, essentially delivering focused radiation directly to leukemia cells. We conducted a phase 1 study in older individuals with AML.[9] Of 18 patients treated with low-dose cytarabine in combination with actinium-225 lintuzumab, five patients achieved remission. This outcome is extremely encouraging. All of these remissions were seen after cycle 1, which suggests that the addition of the low-dose cytarabine did very little to contribute to the remission rate. This is being taken forward in a multicenter phase 2 monotherapy study.
Multiple promising approaches are being developed for the treatment of AML. Those that I have described, and many others, were presented at the 2016 ASH meeting. Finally, after 40 years of little progress in the treatment of AML, we are seeing major advances that will lead to improvements in the lives of our patients.

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