Long-term follow-up of low-intensity chemotherapy with combination therapy for r/r Ph- acute lymphoblastic leukaemia patients

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

I’d like to discuss a bit of a study we reviewed at ASH and this is the study concerning the low dose intensity chemotherapy with mini-CVD in combination with blinatumomab and inotuzumab in the setting of ALL refractory relapse, meaning salvage one and beyond. So this is a study that we published before and now we have the long-term follow-up. We have 96 patients that we treated with the combination of mini-CVD, inotuzumab blinatumomab. What we have reported is that we can achieve a very high complete response rate and very good survival in a population where the disease was invariably fatal. So if you look at the historical data of patients, for adults with acute lymphoblastic leukaemia who relapse, then achieve a complete remission rate of 30-40% with intensive chemotherapy and their median survival is about 6 months and at two years almost nobody is alive, even with the availability of allogeneic transplant.

In this study what we show is that of 64 patients who were in salvage one, the CR rate was 91% and the MRD negativity was 89%. In the setting of salvage two and three, the CR rate was 55-60% and the MRD negativity rate was 63%. When we compared the data of the mini-CVD, ino-blinatumomab, to single agent therapy such as blinatumomab or inotuzumab we have observed that we can improve the estimated four year survival from less than 20% to about 30%. When we look at patients in salvage one, the estimated five year survival was close to 35% which is unheard of. It is a really important breakthrough.

In patients in salvage two and beyond the estimated two year survival rate is close to 20% which is as good as we get with CAR T-cell therapy. Then we reported that patients who achieved MRD negativity do the best and that allogeneic stem cell transplantation is needed.

Now, let’s put this into the context of the total ALL therapy because now we are undergoing a therapeutic revolution in ALL. I hope that five years from now we will not be talking about a cure rate of 50% in adult ALL and the need for three years of intensive chemotherapy. I think the future is going to be the possibility of a potential cure rate, or at least an estimated five-year survival rate, of 70-80%, very close to the cure rates in paediatric ALL. The treatment is going to be with much less chemotherapy and with a shorter duration of treatment that incorporates antibody cocktails including inotuzumab and blinatumomab.

Finally, I’d like to draw attention to an abstract at ASH discussing MRD status. This is abstract 583 and this discusses detection of minimal residual disease at the level of 10-6 and demonstrating that patients who achieve MRD negativity at the level of 10-6 are not relapsing. So in the future perhaps this will be an endpoint of therapy to decide on the duration of the treatment in patients with adult acute lymphoblastic leukaemia and hopefully also in the future this will spill over to paediatric leukaemias where we will need much less of the intensity and the duration of the chemotherapy which will be replaced by antibody cocktails.