Targeting SAMHD1 in relapsed/refractory AML: The FLAsH-IV-AML trial

Relapsed/refractory acute myeloid leukemia (R/R AML) is a devastating disease with median survival < 6 months. There is an urgent need to develop more potent salvage therapies.

A new promising alternative is the quadruple combination FAVIDA, where a three-drug backbone of chemotherapy is complemented with the BCL2 inhibitor venetoclax.We previously demonstrated that SAMHD1 is a resistance factor to the important leukemia drug cytarabine, and that inhibition of SAMHD1 by hydroxyurea results in synergistic killing of leukemic cells.

This has been successfully explored in a phase 1-2 trial called HEAT-AML where newly diagnosed AML patients were treated with the standard cytarabine and daunorubicin together with targeted inhibition of SAMHD1 with hydroxyurea.

The response rate has been unexpectedly high, with deep molecular clearance of the disease.Parallel translational studies demonstrate increased levels of active cytarabine in the leukemic cells and synergistic killing of primary AML cells.The current proposal is an novel salvage treatment for R/R AML called FLAsH-IV.

The concept is a placebo-controlled randomized trial where the FAVIDA regimen is complemented with hydroxyurea as a targeted drug to inhibit SAMHD1 and thereby potentiate the cytarabine effect to further enhance the efficacy.If the results are positive, the repurposed and cheap drug hydroxyurea can readily be used essentially worldwide as an add-on in order improve outcome in this severe disease.