Ph-Negative ALL: Establishing Blinatumomab's Role in Therapy
Insights From: Max S. Topp, MD, University Hospital of Wuerzburg
Max S. Topp, MD: In ALL [acute lymphoblastic leukemia], we have a situation in which we have initial prognostic factors and dynamic prognostic factors. Of dynamic prognostic factors, the most important 1 is MRD [minimal residual disease] levels. After the standard chemotherapy cocktail and after 3 intense rounds of chemotherapy, if patients are still MRD positive by PCR [polymerase chain reaction]—you still can see the clone in that certified assay—those patients are at a very high risk of relapsing.
And then the level of MRD is absolutely important. So you have patients who are just barely in complete remission, and they still have maybe a tumor load of 1 out of 100 cells being positive by MRD testing, so they’re on the brink of relapsing. And then you have patients who have maybe reached a low level of MRD, like 10-4, 10-5. So that would be somewhere near an MRD response but not of the qualitative level yet.
Nevertheless, all these patients clearly have a clone that is chemotherapy resistant. Level of resistance may differ among patients, but they are resistant. And it has been shown in pediatric cases as well as in adults that the dynamic marker really is the most important prognostic factor making a difference between people being cured or dying of the disease.
So traditionally, we’ve been doing stem cell transplantation in these patients, as the only way of curing a patient who displays this chemotherapy-resistant clone. Obviously transplantation has its merits. It can cure the patient. It comes in with TRM [treatment-related mortality] rate. It decreases based on age, and there’s an age group of about 40 to 45 years old in which well beyond 25% patients die of the procedure. And not every patient will be cured. There still will be patients relapsing. And quality of life for patients who went for a transplant is reduced compared with a patient who hasn’t got that. So that sets the table where we are.
So blinatumomab exploits a completely different mechanism of action. It really allows the immune system to recognize all cells that are CD19 positive and engage T cells, every T cell, to kill off the leukemia. So the first trial was done almost 8 years ago. It was published first showing that in this selective setting, certain patients who are after frontline therapy remain MRD positive or have a relapse on the MRD level. If you give them blinatumomab as a 24-7 infusion over 28 days, there’s an MRD response of 80% of these patients becoming MRD-negative.
And then whether a patient went on to get a transplant or not, these patients can still be cured with this agent. And the first trial showed long-term survival rates of about 60% with this approach. And the recent trial, the last trial that led to registration of blinatumomab in the United States as well as in Europe, now confirmed these results in a much bigger patient set of 100-plus patients. It showed a similar response rate of 80% conversion to MRD negativity and showed that the patients, depending on age as well as their comorbidities, who go to transplant—more the younger patients—had a very favorable outcome. Well beyond 50% are being cured.
And for the elderly patient populations, it may be that they can be cured too. The only problem is with the elderly patient population, because their TRM rate increases with age, you forgo the advantage of the high MRD levels. So it’s an unclear question if you have to take a patient to transplant, particularly if they’re 45 and older. But obviously that is the algorithm that we have now adapted, and it’s been practice changing for us to have blinatumomab in that particular scenario and to identify patients with that really prognostic risk factor.
The data of the trial have been practice changing. Before, if the patient was MRD positive after 3 months of therapy, we would take them to transplant, and we would hope that we still have enough time to conduct a transplant. Perhaps quite often patients would be relapsing.
Now we have a situation in which we can give a drug that controls that situation and prepares the patient well for a transplant, because quite often patients after 3 months of therapy, despite having ALL, have come up with also ID [infectious disease] problems that they have acquired through the therapy. They may have fungal infections. And if they have a situation in which they have 2 months of not receiving chemotherapy, effective therapy for ALL also helps to resolve those ID problems, to put them in a better performance status for getting a transplant. So that is really practice changing for us. Before it was a trigger for the transplant; whatever you can do, fast. Now we have time to actually prepare the patient properly, to do proper work-up, and to put the patient in a better position of going for a transplant.
And for the elderly patient population, I have a couple of patients who I’ve known now for many years who had 3 months of therapy, were MRD positive, and were really suffering from the chemotherapy. They got blinatumomab. And after that, no further therapy, no more chemotherapy, no maintenance, no nothing—and they’re doing great. And so if you would put that in a perspective of quality of life, that’s a huge improvement for those patients. The biggest thing of course is being cured but also really living a good lifestyle.