Treating Adult Acute Lymphocytic Leukemia in 2016 - Episode 10

Adverse Event Profile of Blinatumomab in ALL

Transcript:Raoul Tibes, MD, PhD: A recent study presented at this ASH from the International Study Group assessed the clinical activity of blinatumomab, which is a bispecific antibody against CD19 and CD3 in the MRD setting in patients with complete remission after chemotherapy. When we talk about it, we come into an age where we’re treating persistent diseases based on highly sensitive molecular assays, comparable to CML where we monitor and check the BCR-ABL transcripts and accordingly adjust our therapies. And it’s exciting these days because now we have the first drug available that can convert MRD-positive disease into MRD-negative disease. In most of the treatment protocols, we do measure MRD at baseline or after cycle number 1, after cycle number 2 to see an appropriate decrease in the MRD levels. There are certain milestones depending on the protocol that tell us how good and how deep the response is.

The recent study that was presented at ASH 2015 now is using blinatumomab in patients that have achieved a CR, but were MRD-positive. Most patients received blinatumomab for one to three cycles and the outcome was measured. In that study, importantly, a large portion of patients were able to convert to MRD-negative disease. In patients who had achieved MRD-negative disease after the first cycle of treatment had an overall survival of 40months or longer. If it took two or three cycles to achieve MRD-positive disease, the outcome and the overall survival was shorter as expected. Important for that study is that the relapse-free survival was in the range of 11 to 24 months or slightly higher. Another important factor to mention is that the majority, three-quarters or more, of the patients actually did go on to receive a hematopoietic stem cell transplantation. That’s important because as of today, an allogeneic stem cell transplantation is the only curative approach for many patients with ALL.

It’s also important to mention that the duration of remission in those patients who had an MRD-negative state after the first cycle was not reached. This tells us that using blinatumomab in patients with MRD-positive disease can convert a large proportion of patients into MRD-negative disease. Those patients that don’t go to a transplant still can have a prolonged disease remission and thereby clearly had a clinical benefit.

Blinatumomab is a bispecific antibody that attracts CD3-positive T-cells to CD19-positive leukemia cells. Once those two cells are physically close to each other, T-cells are activated and essentially start killing leukemia cells. So some of the side effects that can be seen with blinatumomab are allergic reactions, fevers, and an uncommon side effect which we quite don’t understand are neurological side effects or neurological toxicities. In the extreme scenario, there were a few patients that suffered seizures during the initial phase I and phase II trials of blinatumomab. In the large study looking at blinatumomab in MRD-positive disease, for the majority of patients the most frequent side effects were neurological side effects. Up to 30% of the patients had tremors and some other neurological side effects.

Outside of a clinical trial, we have used blinatumomab now several times in the inpatient leukemia service. We had mixed responses and mixed results. So the one question, would I use it in most patients? In appropriate patients, I would use it if they have failed one or two prior therapies or salvage therapies. We usually don’t have an age limit of not treating patients. In the trials, up to 10%-15% of the patients were above the age of 60 or 65, so it is also tolerated in the older patient population. I think age is not necessarily an exclusion against using blinatumomab. We have used it in older patients as well as in younger patients. Blinatumomab is active in Philadelphia-negative ALL but it also has activity in Philadelphia-positive ALL.

So we have used it, I’ve used it off-study. I’ve used it in both patient populations. We had a patient the age of 22 that was refractory to induction therapy and the first salvage we treated her with the blinatumomab. She’s doing well and she went to transplant. Another patient in his early 40s, unfortunately, had a response that was transient for two or three cycles and then relapsed, but this patient probably had a BCR-ABL-negative-like ALL and we were not able to salvage this patient. Another patient above the age of 60 is currently in treatment, and is doing very well. So in my experience, it’s good. Most patients in the hospital or most patients tolerate it well and I have not seen any major side effects so far in the patients we treated. It also depends on the blast or the leukemic burden at baseline of the patient. And now that we use it earlier and earlier on even patients with MRD, the side effects are somewhat lower than in patients with a high blast burden. We’ll see this more in clinical practice. In talking to colleagues in the community, they have used it and their experience is favorable so far. Given the neurological side effects of blinatumomab, including seizures in a few percentage of the patients, I would be careful in patients with prior seizure history or any severe neurological side effects.

Transcript Edited for Clarity