Results of venetoclax and azacitidine combination in chemotherapy ineligible untreated patients with AML

Prof Hagop Kantarjian - MD Anderson Cancer Center, Houston, USA

I’d like to discuss abstract 461 at ASH which pertains to the results of azacitidine and venetoclax in patients with newly diagnosed IDH2 mutated acute myeloid leukaemia. In this study azacitidine with or without venetoclax in the randomised VIALE-A study were given either venetoclax with azacitidine or azacitidine alone. This is a subset analysis in the IDH2 mutated patients because now we know that IDH mutated AML is highly sensitive to venetoclax therapy.
What we have shown in the study is that the patients who received the combination of azacitidine and venetoclax compared to azacitidine alone had a significantly higher marrow CR rate of 79% versus 11% with single agent azacitidine but, most importantly, the median survival doubled. So the median survival was 24 months versus 12 months in the patients who received azacitidine alone.

This highlights one of the many examples of the great importance of venetoclax in the context of AML therapy. So venetoclax now is FDA approved in combination with either azacitidine or decitabine or low dose cytarabine in older unfit patients with newly diagnosed acute myeloid leukaemia. But this is not the end of the story. We can improve on the results and increase the potential cure rate in the older patients by moving to triple regimens. So, for example, in patients with FLT3 mutations we can use the combination of azacitidine or decitabine for ten days with a FLT3 inhibitor such as gilteritinib and add venetoclax. But when we do the triple therapy we have to worry about the risk of prolonged myelosuppression so we have to tailor the duration of venetoclax therapy to maybe ten days to two weeks. So these are ongoing studies with very good results.

Also we know, for example, that patients with IDH mutated AML are doing extremely well on the combination of azacitidine venetoclax but the estimated two-year survival is only 50%. So perhaps in these patients we can follow with the triple combination therapy that could be either simultaneous, so azacitidine venetoclax and then an IDH inhibitor or it could be sequenced, so azacitidine venetoclax followed by the IDH inhibitor. Further expanding, we can take the venetoclax for newly diagnosed patients with acute myeloid leukaemia.

At this ASH meeting we reported the results of the intensive chemotherapy with FLAG-Ida venetoclax or CLIA venetoclax in newly diagnosed younger patients with acute myeloid leukaemia. We reported extremely encouraging results with CR rates close to 90%, MRD negativity rates close to 80% and estimated one to three year survival rates of about 80%. So if we can confirm in those pilot trials in 50 or 100 patients that the results continue to be encouraging with the long-term follow-up, this could mean a potential shift from 3 7 therapy as a standard of care to the new combined modalities of more intensified induction therapy with targeted therapies including venetoclax, FLT3 inhibitors and other targeted therapies.

Finally, there are subsets of acute myeloid leukaemia which do very poorly such as TP53 acute myeloid leukaemia. In these settings there were reports of encouraging activity of APR-246 or CD47 antibodies combined with hypomethylating agents in these settings.

The last point I want to make is even though azacitidine venetoclax or decitabine venetoclax are now considered as standards of care in older patients with AML, I think we can do better. We have reported on data with decitabine ten days venetoclax which appears to be better but, more importantly, we are piloting a regimen that I would call a triple nucleoside analogue therapy with venetoclax. So this is a sequence of clofarabine, low dose AraC, venetoclax alternating with azacitidine venetoclax and in the preliminary data of 55 patients that we have treated the marrow CR rate is 90%, the MRD negativity is 84% and the estimated 1½ year survival is 60%. So these are data which could be potentially significantly superior to azacitidine venetoclax that we need to explore further in larger studies and in randomised studies. So I’d like to point your attention to abstract 25 at the ASH meeting that pertains to the triple nucleoside analogue therapy with venetoclax.