FLT3-inhibition in infants with acute lymphoblastic leukaemia

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Published: 13 Dec 2019
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Dr Patrick Brown - Johns Hopkins University, Baltimore, USA

Dr Patrick Brown speaks to ecancer at the ASH 2019 meeting in Orlando about follow up results of the addition of lestaurtinib to chemotherapy in infants with acute lymphoblastic leukaemia (ALL).

He explains that, while previous research indicated that the addition of lestaurtinib to chemotherapy did not improve outcomes, they wanted to find markers that may indicate sensitivity to FLT3 inhibition.

Dr Brown reports that two markers were identified in a small proportion of patients who had improved outcomes from the addition of lestaurtinib to chemotherapy.

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FLT3-inhibition in infants with acute lymphoblastic leukaemia

Dr Patrick Brown - Johns Hopkins University, Baltimore, USA

The other abstract deals with a class of drugs called FLT3 inhibitors. FLT3 inhibitors are a type of tyrosine kinase inhibitor. FLT3 is a kinase that is activated and drives leukaemia in many different subtypes of leukaemia but the one we were studying in this abstract is babies, infants with ALL. So we had previously shown that in infant ALL that type of leukaemia really does appear to be driven by overexpression and activation of this kinase called FLT3. Inhibitors of FLT3 had been developed and so we conducted a trial to see whether the addition of a FLT3 inhibitor to standard chemotherapy in these babies would improve their survival.

Unfortunately we found out about 2½ -3 years ago that the study was negative, that when we compared the cure rates of the babies who received the new drug versus didn’t receive the new drug they were the same.

What this abstract did is at the time that we did the study we got a bunch of samples from the patients, both from their bone marrow and from their blood, and we wanted to look for biomarkers that may predict which patients were more or less likely to respond to the FLT3 inhibitor. We’re reporting the results here and what they showed was that there was a small proportion of patients that had excellent FLT3 inhibition pharmacodynamically, which was one of the assays that we did in the lab, and their leukaemia was very sensitive to FLT3 inhibition when we studied it in the laboratory in the culture conditions. For those patients that achieved those two things, that met those two criteria, their outcomes were excellent.

So the lesson that we learned from that is that if we can select patients based on these two markers, the ex vivo sensitivity and we can do intrapatient dose escalation to ensure that all of the patients receiving the drug achieve those good levels of FLT3 inhibition, we anticipate that this approach may be helpful for that subset of patients.

The next steps, this taught us a lot about the role of FLT3 inhibitors for this disease. It will be very difficult for us because of the rarity of this disease to do a whole new study where we tried to translate these lessons we’ve learned into a new clinical trial. Fortunately there are other novel approaches that have come along that are being studied in infant leukaemia and so we’ve moved our attention to those promising studies.

So the real lesson and the impact of this abstract will be to show how important it is to incorporate laboratory assays into our clinical trials so that we can better understand why patients do and don’t respond to our therapies.