Inotuzumab ozogamicin and chemotherapy with or without blinatumomab in Philadelphia chromosone-negative ALL
Dr Nicholas Short - MD Anderson Cancer Center, Houston, USA
This is a phase II study, frontline for older patients with newly diagnosed Philadelphia chromosome negative B-cell ALL using a combination of low intensity chemotherapy with a hyper-CVD regimen in combination with inotuzumab ozogamicin which is an anti-CD22 antibody drug conjugate and then with or without the addition of the bispecific T-cell engager blinatumomab.
It’s a phase II study, the primary endpoint was to evaluate the response rate, really co-primary response rate, and overall survival. We’ve enrolled 64 patients so far. Basically it’s a combination of hyper-CVD chemotherapy alternating with low dose methotrexate and cytarabine. So this is a dose reduction of standard hyper-CVAD. The study has undergone several amendments but the current duration of the study we give four cycles of this low-intensity chemotherapy in combination with fractionated inotuzumab ozogamicin. This is then followed by four cycles of blinatumomab and then we do a maintenance regimen of standard POMP chemotherapy alternating with blinatumomab and that’s given for 18 months. So overall we’re decreasing the amount of chemotherapy given and also decreasing the overall duration of therapy, at least compared to standard hyper-CVAD which is commonly given in this population.
The primary endpoint, which is basically looking at the overall response rate, we found that 98% of patients responded so there was actually only one patient who didn’t have a response. Of the responses the responses seemed to be relatively deep with 95% of patients achieving MRD negativity. As far as long-term outcomes, so the three year complete remission duration was 76% and the three year overall survival rate was 55%. This compares very favourably to historical outcomes with standard hyper-CVAD in this population where the five year long-term survival is about 20%.
There has always been a concern about whether or not we can decrease chemotherapy for these patients. We know that these older patients have a lot of toxicity when they’re given intensive chemotherapy. However, when we decrease chemotherapy typically we are concerned that we’re not going to have durable responses. What we’re seeing with this is that if we incorporate these monoclonal antibodies, the very effective ones that have been shown to be effective in the relapsed refractory setting, and move them into the frontline setting we can see that we can improve outcomes with minimising the toxicity of chemotherapy.
The main toxicity, we still see myelosuppression even though we are using lower doses of chemotherapy than with standard hyper-CVAD for example. There are also specific toxicities to the monoclonal antibodies that we’re incorporating. So veno-occlusive disease is a concern with incorporation of inotuzumab ozogamicin and we saw that in 9% of patients. Also blinatumomab can have neurotoxicity but this is very manageable. We saw that in some patients but, again, those were not serious adverse events that led to any long-term negative outcomes.
One interesting thing that we saw is that even though this is for older patients we did stratify the results according to whether patients were 60-69 years or 70 and older. We see definitely a very significant benefit compared to historical results in those patients that are 60-69. While we still see an improvement in the patients who are 70 and older there is a very high rate of death in remission because even though this chemotherapy is reduced these patients are 70 and older, they can still have significant toxicity even with these lower doses of chemo. So the next plan is to do an amendment where we’re actually going to decrease the chemotherapy further for these patients who are 70 and older and then rely more on the inotuzumab and blinatumomab for them, hoping to strike a balance between having effective therapy but also decreasing the toxicity that comes with chemotherapy for these older patients.