Addition of blinatumomab to mini-hyper-CVD and inotuzumab improves outcomes in R/R ALL

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Published: 16 Jun 2023
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Dr Nicholas Short - MD Anderson Cancer Center, Houston, USA

Dr Nicholas Short speaks to ecancer at EHA 2023 about a phase II study evaluating the combination of mini-hyper-CDV and inotuzumab followed by blinatumomab consolidation in patients with relapsed/refractory (R/R) acute lymphoblastic leukaemia (ALL).

He reports that over 80% of the 125 patients responded and the best outcomes were seen in patients treated in first salvage.

Dr Short also reports that the addition of blinatumomab induced improvement in relapse-free and overall survival.

I’m presenting updated data from this ongoing study of low-dose chemotherapy with mini-hyper-CVD in combination with inotuzumab and blinatumomab in patients with relapsed/refractory B-cell ALL. Historically, the outcomes of patients with a relapsed/refractory B-cell ALL are very poor, with standard chemotherapy less than half of patients respond, the long-term survival rates are very low. We’ve certainly seen improvements in outcomes with the development of inotuzumab ozogamicin, blinatumomab, and CAR-T cells in the relapsed/refractory setting, and so what we’re trying to do in this study is to evaluate the combination of inotuzumab and blinatumomab and chemotherapy all together, rather than using them all sequentially to see if we can lead to deeper responses, longer, more durability responses, and hopefully actually reducing the need for transplant for even some of these patients with relapsed/refractory disease.

So we enrolled patients with relapsed/refractory B-cell ALL, adult patients. The study has undergone several different iterations. Initially we gave eight cycles of low-dose chemotherapy with mini-hyper-CVD in combination with inotuzumab. Then after about 60 patients were treated we amended the study; now what we’re doing in four cycles of low-dose chemotherapy with inotuzumab, followed by four cycles of blinatumomab, and then maintenance with standard maintenance of POMP alternating with blinatumomab. Then even one more follow up on that, which we’re presenting for the first time, is we’ve now treated fifteen patients with what we call a dose-dense version of this, where actually starting in cycle one, we give chemotherapy, inotuzumab, and blinatumomab, all at the very beginning of treatment, with the goal of inducing deep responses earlier by giving them in combination.

So we treated overall 125 patients. We’ve seen very high rates of response, over 80% of patients respond, and the best outcomes we’ve seen, not surprisingly, are in patients treated in first salvage. So if we look at patients who are refractory to induction therapy, or they’re in their first relapse, when we treat them with the combination by adding blinatumomab, we have a response rate of 98%, with 95% of patients achieving MRD negativity by flow cytometry. We’ve now been able to look back, and we have seen that with the addition of blinatumomab to the initial study design, we’ve also seen improvement in relapse-free and overall survival, suggesting that it’s better to give all of these drugs together rather than sequentially, which is how it’s historically done. 

Another interesting follow-up to that is that we’ve seen that we’ve done a landmark analysis asking the questions: do these patients still benefit from transplant? There was no benefit in terms of overall survival for transplant. That really raises the question, do all patients with relapsed/refractory ALL still need a transplant, which has historically always been standard-of-care, but I think it’s the case that not all patients do benefit from that. 

So with all that said, we’ve seen very encouraging outcomes, particularly in salvage one. Actually, in salvage one we see a three-year survival of over 50%, which is much higher than we see with any of these drugs given as single agent. We’re very encouraged by this, the study continues to accrue. We’re accruing now into the dose-dense version of this trial, where we give all of the drugs at the beginning of cycle one, and we’re hoping we can lead to faster rates of MRD negativity, longer durability of remission, and hopefully identify patients in the future who may not need transplant, even in the relapsed/refractory setting.