Translational AML trial improves clinical outcome and identifies novel drugs for future treatment

The LD-VenEx trial exemplifies the vast potential of clinical trials integrating translational research programs, says research group leader Kim Theilgaard-Mönch.

In a large investigator-initiated trial, clinicians form 18 Nordic AML centers collaborate with researchers from BRIC, Helsinki, Karolinska, And Oslo University to test the effect of a new combination treatment for AML patients. The trial includes extensive OMICs mapping as well as high throughput drug screening with the purpose to predict the clinical response to the treatment and to identify new potential treatments.  According to research group leader Kim Theilgaard-Mönch, the trial is an excellent example of the potential of translational research in haematology.

Can dose reduction reduce side effects and improve quality-of-life?
The Danish standard treatment of AML consist of intensive combination chemotherapy. The treatment is effective and aims at full remission or partial remission to enable bone marrow transplantation. Unfortunately, some patients do not tolerate the treatment or experience relapse. In the new trial clinicians test a combination therapy of the chemotherapy drug azacitidin and the small molecule inhibitor drug venetoclax, which enhances the effect of many chemotherapeutics. The combination treatment was recently approved by the Danish Medicine Council as first line treatment for AML patients who do not tolerate intensive chemotherapy. The combination treatment with 1 week of azacytidine & 4 weeks of venetoclax has shown significant better clinical response and survival compared with standard azacytidine monotherapy. However, the combination treatment also has more side effects in form of low blood cell count leading to more serious infections and need for transfusions. In the new trial, the duration of venetoclax treatment is shortened from 4 weeks to 1 week in combination with 1-week azacytidine treatment for each 4-week treatment cycle to reduce the side effects and hospitalizations, and ultimately improve quality-of-life for AML patients.

So far, the LD-VenEx trial has recruited 6 AML patients and is expected to complete the recruitment of 120 AML within the next year. 

Read interview with AML patient and trial participant Vivian Christensen on the Danish Cancer Society Website (in Danish) 

Patient cancer cells reveal new potential treatments
As part of the LD-VenEx trial bone marrow samples from patients are collected and analyzed at the High throughput drug screening Lab, where research group leader Krister Wennerberg and his team will test novel drugs and drug combinations that effectively kill the cancer stem cells of each individual patient. More specifically the ex vivo drug response of AML patient cells toward azacitidine/venetoclax treatment will be tested to identify those patients exhibiting clinical response to the combination therapy. Moreover, ex vivo response of patient cells toward 30-40 new drugs and drug combinations will be teste to identify new effective treatments modalities for AML patients, who do not respond to azacitidine/venetoclax treatment or eventually exhibit disease progression or relapse.

Even though the cancer seems to be gone, a patient can still have few residual cancer stem cells in the bone marrow, which can eventually flair up. We want to see if we can find drug combinations that can kill these cancer stem cells, says Krister Wennerberg.

About the trial
The so-called LD-VenEX trial was initiated by the Nordic AML group and will recruit patients at 18 Nordic AML centers in Denmark, Norway, Sweden, and Finland. The trial was initially supported by the Novo Nordisk Foundation’s Program for Translational Hematology and has obtained funding by The Regions of Denmark and the Danish Cancer Society’s “Knæk Cancer” initiative. The LD-VenEx trial is sponsored by the clinical trial unit at Dept. of Hematology Rigshospitalet and the Danish Research Center for Precision Medicine in Blood Cancer, which was established in 2018 on the basis on a 20 Mio DKK grant from Knæk Cancer at the Biotech Research and Innovation Centre (BRIC), UCPH, and all Danish AML centers.

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