There has been a dichotomy between what we have and what we want for patients with B-cell acute lymphoblastic leukaemia (ALL). What we want is a cure for many, but in reality current standard of care chemotherapy regimens only offer a cure for some. Although 80-90% of patients who are newly diagnosed may achieve complete remission (CR), many will have a relapse – with less than half having disease-free survival for ≥3 years.1
For those patients who have relapsed-refractory disease, the chances of CR declines with each salvage therapy – which leaves the vast majority (>70%) not eligible for subsequent allogeneic stem-cell transplantation.1 This is something that has concerned clinicians like Professor David Marks, Professor of Haematology and Stem cell transplantation at the University of Bristol in the UK. The limbic spoke with Prof. Marks about the role emerging therapies like inotuzumab ozogamicin might play.
“Right now, the field is very focussed on exploring options that can get more patients to allogeneic stem cell graft. ALL is one of those diseases where we want to treat curatively, but if a remission can’t be achieved one can only palliate,” explains Prof. Marks.
“You are treating patients aggressively early to get to remission and just hope that they stay there. For those who don’t, it becomes a trade-off of options to get to remission without excessive toxicity in the hope that if they make it to remission, they’ll still be well enough for transplant – and therefore a better shot at a cure.”
This trade-off between achieving CR and acceptable toxicity is a logic that also defines the evaluation of any new regimens in this space. The recent INO-VATE ALL trial – an open-label, two-group, randomised, phase 3 trial in adults with relapsed or refractory ALL is an important trial in this space.1
“It’s an important trial in this space,” explains Prof. Marks, “in that the trial had two primary endpoints: CR and overall survival (OS). The CR endpoint was significantly higher in the inotuzumab ozogamicin group [80.7%] compared with standard intensive chemotherapy [29.4%, p<0.001], however, OS – which is a much debated point – did not,” he explains.
“Most of us understand that was really more a statistical limitation rather than a clinical observation. Because the lines of the Kaplan Meier curve diverge so late it departed from the proportional-hazards assumption. When they corrected for this, the results were more like we expected and suggest a longer OS with inotuzumab than standard regimens.”1
In the trial, the median OS endpoint had a pre-specified two-sided boundary of p=0.0208.1 When the heterogeneity in the curve was observed for standard therapy and an exploratory post-hoc analysis of the restricted mean survival time was performed, it was suggested by the authors that survival benefit occurs at later time points (after 14 months).1
But the real game-changer for Prof. Marks and others within the National Health Service is the ability for the new regimen to provide deep CR, where patients are more likely to benefit from transplant. In the INO-VATE ALL trial, 78.4% of patients who achieved CR had results below minimal residual disease (MRD) compared with only 28.1% on standard therapy (p<0.001) and the duration of remission was 4.6 months with inotuzmab ozogamicin compared with 3.1 months on standard therapy.1
This is a good start. But as Prof Marks explained, “Not only are we looking for CR, we’re really interested in eliminating minimal residual disease as early as we can – and for patients to be coming off the treatment well. In our centre, we were largely able to deliver this treatment without the need for hospitalisation. What we saw in the trial with around 4 out of 10 patients eligible for transplant following therapy compared with around 1 out of 10 on standard care seems to be offering a greater chance of cure for patients.”1
This increase in the number of patients eligible for transplant post therapy is a welcome bridge that patients and clinicians have been looking for in relapsed refractory ALL. But as with all new treatments, there will be adjustments and concessions that need to be made along the way. In the phase 3 trial, veno-occlusive liver disease was the major adverse event associated with treatment (observed in around 1 in 10 patients). Understanding the patients at risk for this adverse event and managing their risk appropriately as the role of prior therapies in the development of the adverse event is still incompletely understood.1
All in all, Prof. Marks says he is optimistic about the future for his patients with ALL. “Now we are entering an age where more and more options will give patients better outcomes compared with standard of care – with side effects that are manageable.1 The introduction of targeted therapies has been a really pleasant development for all of us who manage ALL, and give our patients so many more treatment options than they had even only 5 years ago.”
This article was sponsored by Pfizer, which has no control over editorial content. The content is entirely independent and based on published studies and experts’ opinions, the views expressed are not necessarily those of Pfizer.
- Kantarijan HM et al. N Engl J Med 2016;375:740-753.