SAN FRANCISCO—The first international, multicenter trial in acute lymphoblastic leukemia (ALL) using minimal residual disease (MRD) as a criterion for inclusion has confirmed clinical benefit for patients using a non-chemotherapeutic approach.
In the BLAST trial, blinatumomab, a bispecific T-cell engager antibody that directs cytotoxic T cells to CD19-positive cells, produced a complete MRD response in 80% of patients who were in complete hematologic remission but had quantifiable MRD at the time of treatment.
This echoes results of an earlier phase 2 study, in which blinatumomab produced an 80% MRD response rate in 20 patients with B-precursor ALL and persistent or relapsed MRD.
Nearly all patients with persistent or recurrent MRD relapse despite continued chemotherapy, according to Nicola Gökbuget, MD, PhD, of Goethe University Hospital in Frankfurt, Germany.
“The question,” she said, “is how to treat these patients.”
She presented one effective method, as shown by the BLAST trial, at the 2014 ASH Annual Meeting (abstract 379).
The trial enrolled 116 patients aged 18 or older with B-precursor ALL in complete hematologic remission but with MRD ≥ 10-3.
Patients could be in second or later remission, but they were excluded if they had a prior allogeneic stem cell transplant, circulating blasts or extra medullary ALL involvement, CNS pathology, prior chemotherapy within 2 weeks, or radiotherapy within 4 weeks.
Enrolled patients were a median age of 45 years (range, 18-76), and 34% were 65 or older. Most patients had high baseline MRD levels: 39% were ≥ 10-2 to < 10-1, and 45% were ≥ 10-3 to < 10-2.
Investigators evaluated MRD levels after each cycle. Analysis was performed in a central lab in Kiel, Germany, and was based on amplification of immunoglobulin and/or T-cell receptor gene rearrangements by PCR.
The primary endpoint was the proportion of patients achieving a complete MRD response after 1 cycle of blinatumomab.
Patients received 15 μg/m2 of blinatumomab per day by continuous intravenous infusion for 4 weeks, followed by a treatment-free period of 2 weeks. Responders could receive up to 4 cycles of therapy or receive a transplant any time after the first cycle.
Results
In the efficacy-evaluable population, 80% of 103 patients achieved a complete MRD response after 1 cycle, defined as MRD negative with no amplification in PCR with a minimum sensitivity of 10-4. And 85% achieved an incomplete MRD response of <10-4 with a minimum sensitivity of 10-4.
Results were similar in the full analysis set of 113 patients: 78% achieved complete MRD response after 1 cycle, and 85% achieved an incomplete MRD response.
Dr Gökbuget noted that 2 patients who initially achieved an incomplete response achieved a complete response during continued treatment in cycle 2.
The investigators analyzed the clinical characteristics of the patients and found that no factor—age, treatment interruptions, neurologic events, relapse history, nor gender—correlated with MRD response.
“I think that the good news is that it means that the compound was active in all of the patients,” Dr Gökbuget commented.
Adverse events
All patients experienced at least one adverse event (AE), and 2 were fatal—subdural hemorrhage and treatment-related pneumonitis. Serious treatment-related AEs that occurred in 3% or more of the
patients included tremor (7%), aphasia (5%), and encephalopathy (5%).
Thirty-one percent of patients interrupted their treatment because of AEs, which were primarily due to cytokine-related symptoms like pyrexia and neurologic events, including tremor, aphasia, and dizziness. Seventeen percent of patients permanently discontinued treatment due to an AE.
However, Dr Gökbuget pointed out that most AEs were grade 1 or 2, and the treatment interruption did not correlate with response.
She said the next step for this trial is to investigate whether high MRD response translates into long-term clinical benefit such as continued molecular remission and long-term survival.
“For me personally, this trial is very important because it is an up-to-date trial where we used PCR-based methods to identify patients with a high risk of relapse and treat them before the relapse occurs,” Dr Gökbuget said. “[W]e used a new endpoint, which is also MRD based, and . . . we used a new, non-chemotherapy treatment to eradicate this highly resistant, persistent ALL subclone.”
Blinatumomab received US Food and Drug Administration approval a few days before the start of the ASH Annual Meeting.
The BLAST trial was funded by Amgen Inc., the company developing blinatumomab.
